U.S. patent application number 10/398636 was filed with the patent office on 2004-02-12 for heteroaryl alkyl piperazine derivatives as fatty acid oxidation inhibitors.
Invention is credited to Elzein, Elfatih, Ibrahim, Prabha N, Palle, Venkata P, Shunk, Kevin, Zablocki, Jeff A.
Application Number | 20040029889 10/398636 |
Document ID | / |
Family ID | 24787627 |
Filed Date | 2004-02-12 |
United States Patent
Application |
20040029889 |
Kind Code |
A1 |
Zablocki, Jeff A ; et
al. |
February 12, 2004 |
Heteroaryl alkyl piperazine derivatives as fatty acid oxidation
inhibitors
Abstract
Novel compounds of the general formula (I): and pharmaceutically
acceptable acid addition salts thereof, wherein the compounds are
useful in therapy to protect skeletal muscles against damage
resulting from trauma or to protect skeletal muscles subsequent to
muscle or systemic diseases such as intermittent claudication, to
treat shock conditions, to preserve donor tissue and organs used in
transplants, in the treatment of cardiovascular diseases including
atrial and ventricular arrhythmias, Prinzmetal's (variant) angina,
stable angina, and exercise induced angina, congestive heart
disease, and myocardial infarction. 1
Inventors: |
Zablocki, Jeff A; (Mountain
View, CA) ; Ibrahim, Prabha N; (Mountain View,
CA) ; Shunk, Kevin; (Palo Alto, CA) ; Elzein,
Elfatih; (Fremont, CA) ; Palle, Venkata P;
(Gurgaon, IN) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF
300 SOUTH WACKER DRIVE
SUITE 3200
CHICAGO
IL
60606
US
|
Family ID: |
24787627 |
Appl. No.: |
10/398636 |
Filed: |
July 14, 2003 |
PCT Filed: |
October 19, 2001 |
PCT NO: |
PCT/US01/51032 |
Current U.S.
Class: |
514/252.12 ;
514/252.13; 544/359 |
Current CPC
Class: |
C07D 209/42 20130101;
C07D 277/82 20130101; A61P 37/06 20180101; A61K 31/496 20130101;
A61P 9/10 20180101; A61P 39/00 20180101; C07D 417/12 20130101; C07D
215/38 20130101; A61P 43/00 20180101; C07D 277/68 20130101; A61P
21/00 20180101; C07D 215/233 20130101; C07D 213/65 20130101; C07D
241/44 20130101; A61P 9/08 20180101; C07D 277/62 20130101; A61P
19/00 20180101; C07D 295/15 20130101; C07D 277/66 20130101; C07D
263/58 20130101; A61P 9/00 20180101; A61P 19/04 20180101; C07D
263/57 20130101; C07D 277/64 20130101; C07D 215/20 20130101; C07D
487/08 20130101; A61P 9/06 20180101; C07D 217/02 20130101; A61P
7/00 20180101; A61P 9/04 20180101 |
Class at
Publication: |
514/252.12 ;
514/252.13; 544/359 |
International
Class: |
A61K 031/496; C07D
43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 23, 2000 |
US |
09694155 |
Claims
We claim:
1. A substituted piperazine compound having the following formula:
86wherein m=1, 2, or 3; q=NH, O, or S; R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are each independently selected from the group
consisting of hydrogen, halo, NO.sub.2, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22, SO.sub.2R.sup.22,
SO.sub.2N(R.sup.20).sub.2, NR.sup.20CO.sub.2R.sup.22,
NR.sup.20CON(R.sup.20).sub.2, COR.sup.20, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 all,
C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, heterocyclyl, aryl, and
heteroaryl, wherein the alkyl and aryl substituent are optionally
substituted with 1 substituent selected from the group consisting
of halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, and SO.sub.2R.sup.22 and wherein
R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4
or R.sup.4 and R.sup.5 when taken together with the carbons to
which they are attached may form a 6-membered aromatic ring that is
optionally substituted by alkyl, trifluoroalkyl, alkoxy, or
halogen; R.sup.6, R.sup.7 and R.sup.8 each independently selected
from the group consisting of hydrogen or C.sub.1-3 alkyl; R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and
R.sup.16 are each independently selected from the group consisting
of hydrogen, CO.sub.2R.sup.20, CON(R.sup.20).sub.2, C.sub.1-4
alkyl, or aryl wherein the alkyl and aryl substituents are
optionally substituted with 1 substituent selected from the group
consisting of halo, CF.sub.3, CN, OR.sup.20, N(R.sup.20).sub.2,
CO.sub.2R.sup.20, CON(R.sup.20).sub.2 or aryl, wherein R.sup.9 and
R.sup.10 may together form a carbonyl, or R.sup.11 and R.sup.12 may
together form a carbonyl, or R.sup.13 and R.sup.14 may together
form a carbonyl, or R.sup.15 and R.sup.16 may together form a
carbonyl with the proviso that R.sup.11 and R.sup.13 or R.sup.9 and
R.sup.15 or R.sup.9 and R.sup.11 or R.sup.11 and R.sup.15 or
R.sup.9 and R.sup.13 may join together to form a ring including
from 1 to 3 carbon atoms; R.sup.17 is heteroaryl that is optionally
substituted with from 1 to 3 substituents selected from the group
consisting of hydrogen, halo, NO.sub.2, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22, SO.sub.2R.sup.22,
SO.sub.2N(R.sup.20).sub.2, NR.sup.20CO.sub.2R.sup.22,
NR.sup.20CON(R.sup.20).sub.2, COR.sup.20, CO.sub.2R.sup.20,
CON(R.sub.20).sub.2, NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl,
C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, heterocyclyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.20; R.sup.20 is
selected from the group consisting of H, C.sub.1-15 alkyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo, alkyl, mono- or dialkylamino, alkyl, CN, --O--C.sub.1-6
alkyl, or CF.sub.3; and R.sup.22 is selected from the group
consisting of C.sub.1-15 alkyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo, alkyl,
monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl
amide, CN, O--C.sub.1-6 alkyl, CF.sub.3, or heteroaryl.
2. The compound of claim 1 wherein q=NH or O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, SO.sub.2N(R.sup.20).sub.2,
CO.sub.2R.sup.20, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, heterocyclyl, aryl, or heteroaryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, or SO.sub.2R.sup.22; R.sup.6, R.sup.7 and R.sup.8
each independently selected from the group consisting of hydrogen
or C.sub.1-3 alkyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each independently
selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, C.sub.1-4 alkyl, or wherein R.sup.9 and
R.sup.10 may together form a carbonyl, or R.sup.11 and R.sup.12 may
together form a carbonyl, or R.sup.13 and R.sup.14 may together
form a carbonyl, or R.sup.15 and R.sup.16 may together form a
carbonyl; R.sup.17 is heteroaryl that is optionally substituted
with from 1 to 3 substituents selected from the group consisting of
hydrogen, halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, SO.sub.2R.sup.22,
SO.sub.2N(R.sub.20).sub.2, NR.sub.20CO.sub.2R.sup.22,
NR.sup.20CON(R.sup.20).sub.2, CO.sub.2R.sup.20, CON(R.sup.20)
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo, NO.sub.2,
CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, or SO.sub.2 R.sup.2; and R.sup.20 is selected from
the group consisting of H, C.sub.1-15 alkyl, aryl, or heteroaryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
alkyl, monoalkylamino, dialkylamino, alkylcyano, --O--C.sub.1-6
alkyl, or CF.sub.3.
3. The compound of claim 1 wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are each independently selected from the group
consisting of hydrogen, halo, CF.sub.3, OR.sup.20, C.sub.1-5 alkyl,
C.sub.2-5 alkenyl, or C.sub.2-5 alkynyl, wherein the allyl
substituent is optionally substituted with CF.sub.3; R.sup.6,
R.sup.7 and R.sup.8 are each independently selected from the group
consisting of hydrogen or C.sub.1-3 alkyl; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are
each independently selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, or C.sub.1-4 alkyl wherein R.sup.9 and
R.sup.10 may together form a carbonyl, or R.sup.11 and R.sup.12 may
together form a carbonyl, or R.sup.13 and R.sup.14 may together
form a carbonyl, or R.sup.15 and R.sup.16 may together form a
carbonyl; R.sup.17 is heteroaryl that is optionally substituted
with from 1 to 2 substituents selected from the group consisting of
hydrogen, halo, CF.sub.3, OR.sup.20, N(R.sup.20).sub.2,
CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, aryl, or heteroaryl, wherein the alkyl and aryl
substituents are optionally substituted with 1 substituent selected
from the group consisting of halo, CF.sub.3, OR.sup.20, or
N(R.sup.20).sub.2; and R.sup.20 is selected from the group
consisting of H, C.sub.1-8 alkyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo,
--O-C.sub.1-3 alkyl, or CF.sub.3.
4. The composition of claim 1 wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are each independently selected from the group
consisting of hydrogen, halo, CF.sub.3, OR.sup.20, C.sub.1-3 alkyl,
C.sub.2-3 alkenyl, or C.sub.2-3 alkynyl, wherein the alkyl is
optionally substituted with CF.sub.3; R.sup.6, R.sup.7 and R.sup.8
each independently selected from the group consisting of hydrogen
or methyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15 and R.sup.16 are each independently selected
from the group consisting of hydrogen or C.sub.1-2 alkyl, wherein
R.sup.9 and R.sup.10 may together form a carbonyl, or R.sup.11 and
R.sup.12 may together form a carbonyl, or R.sup.13 and R.sup.14 may
together form a carbonyl, or R.sup.15 and R.sup.16 may together
form a carbonyl; R.sup.17 is a heteroaryl that is optionally
substituted with from 1 to 2 substituents selected from the group
consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-5 alkyl, C.sub.2-3
alkenyl, C.sub.2-3 alkynyl, aryl, or heteroaryl, wherein the alkyl
and aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, CF.sub.3, OR.sup.20, or
N(R.sup.20).sub.2; and R.sup.20 is selected from the group
consisting of H, C.sub.1-5 alkyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo, --OMe, or
CF.sub.3.
5. The composition of claim 1 wherein m=1; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20, or
C.sub.1-3 alkyl wherein the alkyl substituent is optionally
substituted with CF.sub.3; R.sup.6, R.sup.7 and R.sup.8 each
independently selected from the group consisting of hydrogen or
methyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15 and R.sup.16 are each independently selected from the
group consisting of hydrogen, or methyl, wherein R.sup.9 and
R.sup.10 may together form a carbonyl, or R.sup.11 and R.sup.12 may
together form a carbonyl, or R.sup.13 and R.sup.14 may together
form a carbonyl, or R.sup.15 and R.sup.16 may together form a
carbonyl; R.sup.17 is a heteroaryl that is optionally substituted
with from 1 to 2 substituents selected from the group consisting of
hydrogen, halo, CF.sub.3, OR.sup.20, N(R.sup.20).sub.2,
CON(R.sup.20).sub.2, C.sub.1-3 alkyl, aryl, or heteroaryl, wherein
the alkyl and aryl substituents are optionally substituted with 1
substituent independently selected from the group consisting of
halo, CF.sub.3, OR.sup.20, or N(R.sup.20).sub.2; and R.sup.20 is
selected from the group consisting of H, C.sub.1-3 alkyl, or aryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent individually selected from the group consisting
of halo, --OMe, and CF.sub.3.
6. The compound of claim 1 wherein R.sup.17 is a heteroaryl that is
a fused 6,5 membered ring system containing from 1 to 5 heteroatoms
each selected from the group consisting of N, O, or S that is
optionally substituted with from 1 to 3 substituents selected from
the group consisting of hydrogen, halo, NO.sub.2, CF.sub.3, CN,
OR.sup.20, SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22,
SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.2R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
COR.sup.20, CO.sub.2R.sup.20, CON(R.sup.20).sub.2,
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 allyl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent independently selected from the group consisting of
halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22.
7. The composition of claim 6 wherein q=NH, O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, SO.sub.2N(R.sup.20).sub.2,
CO.sub.2R.sup.20, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, heterocyclyl, aryl, or, heteroaryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22 or SO.sub.2R.sup.22; R.sup.6, R.sup.7 and R.sup.8 each
independently selected from the group consisting of hydrogen or Cl
.sub.3 alkyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15 and R.sup.16 are each independently selected
from the group consisting of hydrogen, CON(R.sup.20).sub.2,
C.sub.1-4 alkyl, or aryl wherein the alkyl and aryl substituents
are each optionally substituted with 1 substituent selected from
the group consisting of halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2 or aryl wherein R.sup.9 and
R.sup.10 may together form a carbonyl, or R.sup.11 and R.sup.12 may
together form a carbonyl, or R.sup.13 and R.sup.14 may together
form a carbonyl, or R.sup.15 and R.sup.16 may together form a
carbonyl with the proviso that R.sup.11 and R.sup.13 or R.sup.9 and
R.sup.15 or R.sup.9 and R.sup.11 or R.sup.11 and R.sup.15 or
R.sup.9 and R.sup.13 may join together to form a ring; R.sup.17 is
a heteroaryl that is a fused 6,5 membered ring system containing
from 1 to 4 heteroatoms each selected from the group consisting of
N, O, and S that is optionally substituted with 1-3 substituents
selected from the following hydrogen, halo, NO.sub.2, CF.sub.3, CN,
OR.sup.20, SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22,
SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.2R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
CO.sub.2R.sup.20, CON(R.sup.20).sub.2, NR.sup.20SO.sub.2R.sup.22,
C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl,
heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl
substituents are optionally substituted with 1 substituent selected
from the group consisting of halo, NO.sub.2, CF.sub.3, CN,
OR.sup.20, SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22, or
SO.sub.2R.sup.22; and R.sup.20 is selected from the group
consisting of H, C.sub.1-15 alkyl, aryl, or heteroaryl, wherein the
allyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo, alkyl,
monoalkylamino, dialkylamino, alkyl-CN, --O--C.sub.1-6 alkyl, or
CF.sub.3.
8. The composition of claim 6 wherein q=NH or O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
C.sub.1-5 alkyl, C.sub.2-5 alkenyl, or C.sub.2-5 alkynyl, wherein
the alkyl substituent is optionally substituted with CF.sub.3 or
wherein R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 or R.sup.3 and
R.sup.4 or R.sup.4 and R.sup.5 when taken together with the carbons
to which they are attached may form a 6-membered aromatic ring that
is optionally substituted by alkyl, trifluoroalkyl, alkoxy, or
halogen; R.sup.6, R.sup.7 and R.sup.8 each independently selected
from the group consisting of hydrogen or C.sub.1-3 alkyl; R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and
R.sup.16 are each independently selected from the group consisting
of hydrogen, CON(R.sup.20).sub.2, C.sub.1-3 alkyl, or aryl wherein
the alyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo,
N(R.sup.20).sub.2, and aryl or wherein R.sup.9 and R.sup.10 may
together form a carbonyl, or R.sup.11 and R.sup.12 may together
form a carbonyl with the proviso that R.sup.11 and R.sup.13 or
R.sup.9 and R.sup.15 or R.sup.9 and R.sup.11 or R.sup.11 and
R.sup.15 or R.sup.9 and R.sup.13 may join together to form a ring;
R.sup.17 is a heteroaryl that is a fused 6,5 membered ring system
containing from 1 to 3 heteroatoms selected from the group
consisting of N, O, or S that is optionally substituted with from 1
to 2 substituents selected from the group consisting of hydrogen,
halo, CF.sub.3, OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent independently selected from the
group consisting of halo, CF.sub.3, OR.sup.20, or
N(R.sup.20).sub.2; and R.sup.20 is selected from the group
consisting of H, C.sub.1-8 alkyl, aryl, or heteroaryl wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo,
--O--C.sub.1-3 alkyl, or CF.sub.3.
9. The compound of claim 6 wherein q=NH or O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
C.sub.1-3 alkyl, C.sub.2-3 alkenyl, or C.sub.2-3 alkynyl, wherein
the alkyl substituent is optionally substituted with CF.sub.3;
R.sup.6, R.sup.7 and R.sup.8 each independently selected from the
group consisting of hydrogen or methyl; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are
each independently selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, C.sub.1-3 alkyl, or aryl wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, N(R.sup.20).sub.2, or
aryl wherein R.sup.9 and R.sup.10 may together form a carbonyl with
the proviso that R.sup.11 and R.sup.13 or R.sup.9 and R.sup.15 or
R.sup.9 and R.sup.11 or R.sup.11 and R.sup.15 or R.sup.9 and
R.sup.13 may join together to form a ring; R.sup.17 is a heteroaryl
that is a fused 6,5 membered ring system containing from 1 to 2
heteroatoms selected from the group consisting of N, O, or S that
is optionally substituted with from 1 to 2 substituents selected
from the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-4 alkyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo, CF.sub.3, or OR.sup.20; and R.sup.20 is selected from the
group consisting of H, C.sub.1-5 alkyl, aryl, or heteroaryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
--OMe, or CF.sub.3.
10. The compound of claim 6 wherein q=NH or O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20, or
C.sub.1-3 alkyl wherein the alkyl substituent is optionally
substituted with CF.sub.3 and wherein R.sup.2 and R.sup.3 when
taken together with the carbons to which they are attached may form
a 6-membered aromatic ring that is optionally substituted by alkyl,
trifluoroalkyl, alkoxy, or halogen; R.sup.6, R.sup.7 and R.sup.8
each independently selected from the group consisting of hydrogen
or methyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15 and R.sup.16 are each independently selected
from the group consisting of hydrogen, or C.sub.1-2 alkyl, wherein
the alkyl substituent is optionally substituted with 1 substituent
selected from the group consisting of N(R.sup.20).sub.2, or aryl or
wherein R.sup.9 and R.sup.10 may together form a carbonyl; R.sup.17
is a heteroaryl that is a fused 6,5 membered ring system containing
from 1 to 2 heteroatoms selected from the group consisting of N, O,
or S that is optionally substituted with from 1 to 2 substituents
selected from the group consisting of hydrogen, halo, CF.sub.3,
OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl,
aryl, or heteroaryl, wherein the alkyl and aryl substituents are
optionally substituted with 1 substituent selected from the group
consisting of halo, CF.sub.3, or OR.sup.20; and R.sup.20 is
selected from the group consisting of H, C.sub.1-3 alkyl, or aryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
--OMe, or CF.sub.3.
11. The composition of claim 10 wherein q=O; and R.sup.17 is a
heteroaryl that is a fused 6,5 membered ring system selected from
the group consisting of indole, benzothiazole, and benzoxazole that
is optionally substituted with from 1 to 2 substituents selected
from the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo, CF.sub.3, or OR.sup.20.
12. The composition of claim 10 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, CF.sub.3, OR.sup.20, or C.sub.1-2
alkyl and wherein R.sup.2 and R.sup.3 when taken together with the
carbons to which they are attached may form a 6-membered aromatic
ring that is optionally substituted by alkyl, trifluoroalkyl,
alkoxy, or halogen; R.sup.6, R.sup.7 and R.sup.8 are each hydrogen;
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15
and R.sup.16 are each independently selected from the group
consisting of hydrogen or C.sub.1-2 alkyl, or wherein R.sup.9 and
R.sup.10 may together form a carbonyl; R.sup.17 is a heteroaryl
that is a fused 6,5 membered ring system selected from the group
consisting of indole, benzothiazole, and benzoxazole that is
optionally substituted with 1 substituent selected from the group
consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl, or aryl,
wherein the allyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo or
CF.sub.3; and R.sup.20 is selected from the group consisting of H
or C.sub.1-3 alkyl.
13. The compound of claim 12 wherein R.sup.17 is benzothiazole that
is optionally substituted with 1 substituent selected from the
group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl, or aryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo or
CF.sub.3.
14. The compound of claim 12 wherein R.sup.17 is benzothiazole that
is optionally substituted at the 2-position with 1 substituent
selected from the group consisting of hydrogen, methyl or
phenyl.
15. The compound of claim 12 wherein R.sup.17 is 5-substituted
benzothiazole that is optionally substituted with 1 substituent
selected from the group consisting of hydrogen, halo, CF.sub.3,
OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.2).sub.2, C.sub.1-3 alkyl,
or aryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo or CF.sub.3. R.sup.20 is selected from the group consisting
of H or methyl.
16. A compound of claim 12 wherein R.sup.17 is 5-substituted
benzothiazole that is optionally substituted at the 2-position with
1 substituent selected from the group consisting of hydrogen,
methyl or phenyl; and R.sup.20 is selected from the group
consisting of H or methyl.
17. A compound of claim 12 wherein q=O; R.sup.1, R.sup.1, R.sup.3,
R.sup.4 and R.sup.5 are each independently selected from the group
consisting of hydrogen, OR.sup.20, or methyl; R.sup.6, R.sup.7 and
R.sup.8 are each hydrogen; R.sup.11 and R.sup.15 are each selected
from the group consisting of hydrogen or methyl, R.sup.9, R.sup.10,
R.sup.12, R.sup.13, R.sup.14 and R.sup.16 are each hydrogen and
R.sup.9 and R.sup.10 may together form a carbonyl; R.sup.17 is
5-substituted benzothiazole that is substituted at the 2-position
with methyl; and R.sup.20 is H.
18. A compound of claim 12 wherein q=O; R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are each independently selected from the group
consisting of hydrogen, OR.sup.20, or methyl; R.sup.6, R.sup.7 and
R.sup.8 are each hydrogen; R.sup.11 and R.sup.15 are each selected
from the group consisting of hydrogen or methyl, R.sup.9, R.sup.10,
R.sup.12, R.sup.13, R.sup.14 and R.sup.16 are each hydrogen and
R.sup.9 and R.sup.10 may together form a carbonyl; R.sup.17 is
5-substituted benzothiazole that is substituted at the 2-position
with phenyl; and R.sup.20 is H.
19. A compound of claim 12 wherein q=O; R.sup.1, R.sup.4 and
R.sup.5 are each independently selected from the group consisting
of hydrogen, OR.sup.20, or methyl and wherein R.sup.2 and R.sup.3
when taken together with the carbons to which they are attached may
form a 6-membered aromatic ring that is optionally substituted by
alkyl, trifluoroalkyl, alkoxy, or halogen; R.sup.6, R.sup.7 and kg
are each hydrogen; R.sup.11 and R.sup.15 are each selected from the
group consisting of hydrogen or methyl, R.sup.9, R.sup.10,
R.sup.12, R.sup.13, R.sup.14 and R.sup.16 are each hydrogen and
R.sup.9 and R.sup.10 may together form a carbonyl; R.sup.17 is
5-substituted benzothiazole that is substituted at the 2-position
with methyl; and R.sup.20 is H.
20. A compound of claim 6 or 7 or 8 or 9 or 10 or 11 or claim 12 or
13, or 14 or 15 or 16 wherein R.sup.17 is 5-substituted
benzothiazole that is substituted at the 2-position with
methyl.
21. A compound of claim 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or
14 or 15, or 16 wherein R.sup.17 is 5-substituted benzothiazole
that is substituted at the 2-position with phenyl.
22. The compound of claim 1 wherein R.sup.17 is a heteroaryl that
is a fused 6, 6 membered ring system containing from 1 to 4
nitrogen atoms that is optionally substituted with from 1 to 3
substituents selected from the group consisting of hydrogen, halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.3R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
COR.sup.20, CO.sub.2R.sup.20, CON(R.sup.20).sub.2,
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent independently selected from the group consisting of
halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22.
23. The compound of claim 22 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, SO.sub.2N(R.sup.20).sub.2,
CO.sub.2R.sup.20, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, heterocyclyl, aryl, or heteroaryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, or SO.sub.2R.sup.22; R.sup.6, R.sup.7 and R.sup.8
each independently selected from the group consisting of hydrogen
or C.sub.1-3 alkyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each independently
selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, C.sub.1-4 alkyl, or aryl wherein the alkyl and
aryl substituents are each optionally substituted with 1
substituent selected from the group consisting of halo, CF.sub.3,
OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2 or aryl wherein
R.sup.9 and R.sup.10 may together form a carbonyl, or R.sup.11 and
R.sup.12 may together form a carbonyl, or R.sup.13 and R.sup.14 may
together form a carbonyl, or R.sup.15 and R.sup.16 may together
form a carbonyl with the proviso that R.sup.11 and R.sup.13 or
R.sup.9 and R.sup.15 or R.sup.9 and R.sup.11 or R.sup.11 and
R.sup.15 or R.sup.9 and R.sup.13 may join together to form a ring;
R.sup.20 is selected from the group consisting of H, C.sub.1-15
alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents
are optionally substituted with 1 substituent selected from the
group consisting of halo, alkyl, monoalkylamino, dialkylamino,
alkyl-CN, --O--C.sub.1-6 alkyl, or CF.sub.3; and
24. The compound of claim 22 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20, Cl
alkyl, C.sub.2-5 alkenyl, or C.sub.2-5 alkynyl, wherein the alkyl
substituent is optionally substituted with CF.sub.3; R.sup.6,
R.sup.7 and R.sup.5 each independently selected from the group
consisting of hydrogen or C.sub.1-3 alkyl; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are
each independently selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, C.sub.1-3 alkyl, or aryl wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, N(R.sup.20).sub.2, and
aryl or wherein R.sup.9 and R.sup.10 may together form a carbonyl,
or R.sup.11 and R.sup.12 may together form a carbonyl with the
proviso that R.sup.11 and R.sup.13 or R.sup.9 and R.sup.15 or
R.sup.9 and R.sup.11 or R.sup.11 and R.sup.15 or R.sup.9 and
R.sup.13 may join together to form a ring; R.sup.17 is a heteroaryl
that is a fused 6, 6 membered ring system containing from 1 to 3
nitrogen atoms that is optionally substituted with from 1 to 2
substituents selected from the group consisting of hydrogen, halo,
CF.sub.3, OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent independently selected from the
group consisting of halo, CF.sub.3, OR.sup.20, or
N(R.sup.20).sub.2; and R.sup.20 is selected from the group
consisting of H, C.sub.1-8 alkyl, aryl, or heteroaryl wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo,
--O--C.sub.1-3 alkyl, or CF.sub.3.
25. The compound of claim 22 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydro-gen, OR.sup.20, or methyl; R.sup.6,
R.sup.7 and R.sup.8 each hydrogen; R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each
independently selected from the group consisting of hydrogen,
C.sub.1-2 alkyl, or R.sup.9 and R.sup.10 may together form a
carbonyl; R.sup.17 is a heteroaryl that is a fused 6, 6 membered
ring system containing from 1 to 2 nitrogen atoms that is
optionally substituted with methyl; and R.sup.20 is H.
26. The compound of claim 22 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen or methyl; R.sup.6, R.sup.7 and
R.sup.8 each hydrogen; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each hydrogen; and
R.sup.17 is a heteroaryl that is a fused 6,6-membered ring system
containing from 1 to 2 nitrogen atoms that is optionally
substituted with methyl.
27. The compound of claim 1 wherein R.sup.17 is a 5 or 6-membered
ring containing from 1 to 3 heteroatoms selected from the group
consisting of N, S, or O that is optionally substituted with from 1
to 3 substituents selected from the group consisting of hydrogen,
halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, SO.sub.2R.sup.22,
SO.sub.2N(R.sup.20).sub.2, NR.sup.20CO.sub.2R.sup.22,
NR.sup.20CON(R.sup.20).sub.2, COR.sup.20, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl,
C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, heterocyclyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent independently selected from the
group consisting of halo, NO.sub.2, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22, or
SO.sub.2R.sup.22.
28. The compound of claim 27 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, SO.sub.2N(R.sup.20).sub.2,
CO.sub.2R.sup.20, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, heterocyclyl, aryl, or heteroaryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, or SO.sub.2R.sup.22; R.sup.6, R.sup.7 and R.sup.8
each independently selected from the group consisting of hydrogen
or C.sub.1-3 alkyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each independently
selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, C.sub.1-4 allyl, or aryl wherein the alkyl and
aryl substituents are each optionally substituted with 1
substituent selected from the group consisting of halo, CF.sub.3,
OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2 or aryl wherein
R.sup.9 and R.sup.10 may together form a carbonyl, or R.sup.11 and
R.sup.12 may together form a carbonyl, or R.sup.13 and R.sup.14 may
together form a carbonyl, or R.sup.15 and R.sup.16 may together
form a carbonyl with the proviso that R.sup.11 and R.sup.13 or
R.sup.9 and R.sup.15 or R.sup.9 and R.sup.11 or R.sup.11 and
R.sup.15 or R.sup.9 and R.sup.13 may join together to form a ring;
R.sup.17 is a 5 or 6-membered ring containing from 1 to 3
heteroatoms selected from the group consisting of N, S, or O that
is optionally substituted with from 1 to 3 substituents selected
from the group consisting of hydrogen, halo, NO.sub.2, CF.sub.3,
CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2, S(O)R,
SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.2R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
COR.sup.20, CO.sub.2R.sup.20, CON(R.sup.20).sub.2,
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent independently selected from the group consisting of
halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22. R.sup.20 is
selected from the group consisting of H, C.sub.1-15 alkyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo, alkyl, monoalkylamino, dialkylamino, alkyl-CN,
--O--C.sub.1-6 alkyl, or CF.sub.3; and R.sup.22 is selected from
the group consisting of C.sub.1-15 alkyl, aryl, or heteroaryl
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide,
heteroaryl amide, CN, O--C.sub.1-6 alkyl, CF.sub.3, or
heteroaryl.
29. The compound of claim 27 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
C.sub.1-5 alkyl, C.sub.2-5 alkenyl, or C.sub.2-5 alkynyl, wherein
the alkyl substituent is optionally substituted with CF.sub.3;
R.sup.6, R.sup.7 and R.sup.8 each independently selected from the
group consisting of hydrogen or C.sub.1-3 alkyl; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are
each independently selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, C.sub.1-3 alkyl, or aryl wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, N(R.sup.20).sub.2, and
aryl or wherein R.sup.9 and R.sup.10 may together form a carbonyl,
or R.sup.11 and R.sup.12 may together form a carbonyl with the
proviso that R.sup.11 and R.sup.13 or R.sup.9 and R.sup.15 or
R.sup.9 and R.sup.11 or R.sup.11 and R.sup.15 or R.sup.9 and
R.sup.13 may join together to form a ring; R.sup.17 is a 5 or 6
membered ring including from 1 to 3 heteroatoms selected from N, S,
or O nitrogen atoms that is optionally substituted with from 1 to 2
substituents selected from the group consisting of hydrogen, halo,
CF.sub.3, OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent independently selected from the
group consisting of halo, CF.sub.3, OR.sup.20, or
N(R.sup.20).sub.2; and R.sup.20 is selected from the group
consisting of H, C.sub.1-8 alkyl, aryl, or heteroaryl wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo,
--O--C.sub.1-3 alkyl, or CF.sub.3.
30. The compound of claim 29 wherein R.sup.17 is a 6 membered ring
including from 1 to 2 nitrogen atoms that is optionally substituted
with from 1 to 2 substituents selected from the group consisting of
hydrogen, halo, CF.sub.3, OR.sup.20, N(R.sup.20).sub.2,
CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, aryl, or heteroaryl, wherein the alkyl and aryl
substituents are optionally substituted with 1 substituent
independently selected from the group consisting of halo, CF.sub.3,
OR.sup.20, or N(R.sup.20).sub.2.
31. The compound of claim 30 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, OR.sup.20, or methyl; R.sup.6,
R.sup.7 and R.sup.8 are each hydrogen; R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each
independently selected from the group consisting of hydrogen,
C.sub.1-2 alkyl, or R.sup.9 and R.sup.10 may together form a
carbonyl; R.sup.17 is a 6 membered ring containing from 1 to 2
nitrogen atoms that is optionally substituted with methyl; and
R.sup.20 is H.
32. The compound of claim 30 wherein q=O; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen or methyl; R.sup.6, R.sup.7 and
R.sup.8 are each hydrogen; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each hydrogen; and
R.sup.17 is a 6 membered ring containing 1 nitrogen atom that is
optionally substituted with methyl.
33. The composition of claim 10 wherein q=NH; and R.sup.17 is a
heteroaryl that is a fused 6,5 system containing from 1 to 2
heteroatoms selected from the group consisting of N, O, or S that
is optionally substituted with from 1 to 2 substituents selected
from the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo, CF.sub.3, OR.sup.20, or N(R.sup.20).sub.2;
34. The composition of claim 10 wherein q=NH; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen, CF.sub.3, OR.sup.20, or C.sub.1-2
alkyl; R.sup.6, R.sup.7 and R.sup.8 are each hydrogen; R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and
R.sup.16 are each independently selected from the group consisting
of hydrogen or C.sub.1-2 alkyl, or wherein R.sup.9 and R.sup.10 may
together form a carbonyl; R.sup.17 is a heteroaryl that is a fused
6,5 membered ring system selected from the group consisting of
benzothiazole, and benzoxazole that is optionally substituted with
1 substituent selected from the group consisting of hydrogen,
CF.sub.3, OR.sup.20, C.sub.1-3 alkyl, or aryl, wherein the alkyl
and aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo or CF.sub.3; and
R.sup.20 is selected from the group consisting of H or C.sub.1-3
alkyl.
35. The composition of claim 10 wherein q=NH; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each independently selected from
the group consisting of hydrogen or methyl; R.sup.6, R.sup.7 and
R.sup.8 are each hydrogen; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each hydrogen; and
R.sup.17 is a heteroaryl that is a fused 6,5 membered ring system
selected from the group consisting of benzothiazole, and
benzoxazole that is optionally substituted with methyl.
36. A compound selected from the group consisting of
N-(2,6-dimethyl-phenyl)-2-(4-{2-hydroxy-3-[2-(3-trifluoromethylphenyl)-be-
nzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide,
2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxy-propyl]-piperazin-1-yl}-N-(2,6-d-
imethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methy-
lbenzothiazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,4-(3-{4-[(2,6-dime-
thylphenylcarbamoyl)-methyl]-piperazin-1-yl}-2-hydroxy-propoxy)-1H-indole--
2-carboxylic acid amide,
2-{4-[3-(benzothiazol-6-yloxy)2-hydroxy-propyl]-p-
iperazin-1-yl}-N-(2,6-dimethyl-phenyl)-acetamide,
N-(2,6-dimethylphenyl)-2-
-{4-[2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)-propyl]-piperazin-1-yl}ace-
amide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-y-
loxy)-propyl]-3,5-dimethyl-piperazine-1-yl}acetamide,
2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}-
-N-(4-hydroxyphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-
-phenyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-phenyl-benzoxazol-5-yloxy)-pr-
opyl)-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)2-{4-[2-hydroxy-3-(2-
-phenyl-benzothiazol-7-yloxy)-propyl]-piperazin-1-ylacetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)--
propyl]-2-oxo-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hyd-
roxy-3-(2-methyl-benzoxazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[2-(4-trifluoromethyl-phenyl)-be-
nzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinoxalin-2-yloxy)-propyl]-pip-
erazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(pyridin-3-
-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-h-
ydroxy-3-(quinolin-4-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(isoquinolin-5-yloxy)-propyl]-pi-
perazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinolin-
-6-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-
-hydroxy-3-(2-methyl-quinolin-7-yloxy)-propyl]-piperazin-1-yl}acetamide,
2-{4-[3-(benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinyl}-N-(2,6-dime-
thylphenyl)acetamide,
2-{4-[3-(benzoxazol-2-ylamino)-2-hydroxypropyl]piper-
azinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylb-
enzothiazol-5-yloxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6-dimethylphenyl-
)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-
,6-dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethyl-
piperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3--
(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethyl-
phenyl)acetamide,
2-{(2R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-ylox-
y)propyl]-2-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpipe-
razinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methyl-
benzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazinyl}-N-(2,6-dimethylpheny-
l)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]--
2-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-diazaper-
hydroepinyl)}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methyl-
benzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-hydroxyphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethyl-
piperazinyl}-N-(4-carboxamidophenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3-
-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethy-
lphenyl)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-me-
thylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2,6-dimethyl-4-hydroxyphen-
yl)acetamide,
2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-
-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
N-(4-sulfamoyphenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenylbenzox-
azol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-nap-
hthylacetamide,
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{4-[2-hydroxy-3-(-
2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-phe-
nylacetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piper-
azinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(4-methoxyph-
enyl)propyl]piperazinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-N-(2-c-
hloro-4-methylphenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-
-yloxy)propyl]piperazinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(3,-
5-dichlorophenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-ylo-
xy)propyl]piperazinyl}-N-(3,4-dichlorophenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[3--
methoxy-5-(trifluoromethyl)phenyl]acetamide,
2-{4-[2-hydroxy-3-(2-phenylbe-
nzothiazol-5-yloxy)propyl]piperazinyl}-N-[3,-5-dichloro)phenyl]acetamide,
and
2-{4-[2-hydroxy-3-(2-((1E)buta-1,3-dienyl)benzothiazol-5-yloxy)propyl-
]piperazinyl}-N-[4-chloro-2-methoxy-5-methylphenyl]acetamide.
37. A method of treatment comprising administering a
therapeutically effective amount of a compound of claim 1 to a
mammal in need of a treatment selected from the group consisting of
protecting skeletal muscles against damage resulting from trauma,
protecting skeletal muscles subsequent to muscle or systemic
diseases, treating shock conditions, preserving donor tissue and
organs used in transplants, or treating cardiovascular
diseases.
38. The method of claim 37 wherein the cardiovascular disease is
selected from the group consisting of atrial and ventricular
arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise
induced angina, congestive heart disease, or myocardial
infarction.
39. The method of claim 37 or 38 wherein the therapeutically
effective amount ranges from about 0.01 to about 100 mg/kg weight
of the mammal.
40. The method of claim 37 or 38 wherein the mammal is a human.
41. A pharmaceutical composition of matter comprising the
composition of claim 1 and one or more pharmaceutical
excipients.
42. The pharmaceutical composition of matter of claim 41 wherein
the pharmaceutical composition is in the form of a solution.
43. The pharmaceutical composition of matter of claim 41 wherein
the pharmaceutical composition is in a form selected from the group
consisting of a tablet or a capsule.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is concerned with piperazine
derivatives, therapeutic dosage forms including one or more of the
derivatives, and methods for treating diseases in mammals, and in
particular, in a human in a therapy selected from the group
including protecting skeletal muscles against damage resulting from
trauma, protecting skeletal muscles subsequent to muscle or
systemic diseases such as intermittent claudication, to treat shock
conditions, to preserve donor tissue and organs used in
transplants, and to treat cardiovascular diseases including atrial
and ventricular arrhythmias, Prinzmetal's (variant) angina, stable
angina, and exercise induced angina, congestive heart disease, and
myocardial infarction.
[0003] 2. Description of the Art
[0004] U.S. Pat. No. 4,567,264, the specification of which is
incorporated herein by reference, discloses a class of substituted
piperazine compounds that includes a compound known as ranolazine,
(.+-.)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-
-piperazineacetamide, and its pharmaceutically acceptable salts,
and their use in the treatment of cardiovascular diseases,
including arrhythmias, variant and exercise-induced angina, and
myocardial infarction.
[0005] U.S. Pat. No. 5,506,229, which is incorporated herein by
reference, discloses the use of ranolazine and its pharmaceutically
acceptable salts and esters for the treatment of tissues
experiencing a physical or chemical insult, including cardioplegia,
hypoxic or reperfusion injury to cardiac or skeletal muscle or
brain tissue, and for use in transplants. In particular, ranolazine
is particularly useful for treating arrhythmias, variant and
exercise-induced angina, and myocardial infarction by partially
inhibiting cardiac fatty acid oxidation. Conventional oral and
parenteral ranolazine formulations are disclosed, including
controlled release formulations. In particular, Example 7D of U.S.
Pat. No. 5,506,229 describes a controlled release formulation in
capsule form comprising microspheres of ranolazine and
microcrystalline cellulose coated with release controlling
polymers.
[0006] Despite the important discovery that ranolazine is a very
useful cardiac therapeutic agent, there remains a need for
compounds that are partial fatty acid oxidation inhibitors that
have a half-life greater than ranolazine and that have activities
as least similar to ranolazine.
SUMMARY OF THE INVENTION
[0007] This invention includes novel heteroaryl alkyl piperazine
derivatives that are partial fatty acid oxidation inhibitors with
good therapeutic half-lives.
[0008] This invention also includes novel substituted piperazine
compounds that can be administered to a mammal to protect skeletal
muscles against damage resulting from trauma, to protecting
skeletal muscles subsequent to muscle or systemic diseases such as
intermittent claudication, to treat shock conditions, to preserve
donor tissue and organs used in transplants, and to treat
cardiovascular diseases including atrial and ventricular
arrhythmias, Prinzmetal's (variant) angina, stable angina, and
exercise induced angina, congestive heart disease, and myocardial
infarction.
[0009] This invention includes a class of substituted piperazine
compounds having the formula: 2
[0010] wherein
[0011] m=1, 2, or 3;
[0012] q=NH, O, or S;
[0013] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each
independently selected from the group consisting of hydrogen, halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.2R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
COR.sup.20, CO.sub.2R.sup.20, CON(R.sup.20).sub.2,
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the
alkyl and aryl substituent are optionally substituted with 1
substituent selected from the group consisting of halo, NO.sub.2,
CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, and SO.sub.2R.sup.22 and wherein R.sup.1 and R.sup.2
or R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 or R.sup.4 and
R.sup.5 when taken together with the carbons to which they are
attached may form a 6-membered aromatic ring that is optionally
substituted by alkyl, trifluoroalkyl, alkoxy, or halogen;
[0014] R.sup.6, R.sup.7 and R.sup.8 each independently selected
from the group consisting of hydrogen or C.sub.1-3 alkcyl;
[0015] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15 and R.sup.16 are each independently selected from the
group consisting of hydrogen, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, C.sub.1-4 alkyl, or aryl wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, CF.sub.3, CN,
OR.sup.20, N(R.sup.20).sub.2, CO.sub.2R.sup.20, CON(R.sup.20).sub.2
or aryl, wherein R.sup.9 and R.sup.10 may together form a carbonyl,
or R.sup.11 and R.sup.12 may together form a carbonyl, or R.sup.13
and R.sup.14 may together form a carbonyl, or R.sup.15 and R.sup.16
may together form a carbonyl or R.sup.11 and R.sup.13 or R.sup.9
and R.sup.15 or R.sup.9 and R.sup.11 or R.sup.11 and R.sup.15 or
R.sup.9 and R.sup.13 may join together to form a ring including
from 1 to 3 carbon atoms;
[0016] R.sup.17 is heteroaryl that is optionally substituted with
from 1 to 3 substituents selected from the group consisting of
hydrogen, halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, SO.sub.2R.sup.22,
SO.sub.2N(R.sup.20).sub.2, NR.sup.20CO.sub.2R.sup.22,
NR.sup.20CON(R.sup.20).sub.2, COR.sup.20, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 is
alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, heterocyclyl, aryl,
or heteroaryl, wherein the alkyl and aryl substituents are
optionally substituted with 1 substituent selected from the group
consisting of halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22;
[0017] R.sup.20 is selected from the group consisting of H,
C.sub.1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl
substituents are optionally substituted with 1 substituent selected
from the group consisting of halo, alkyl, mono- or dialkylamino,
alkyl, CN, --O--C.sub.1-6 alkyl, or CF.sub.3; and
[0018] R.sup.22 is selected from the group consisting of C.sub.1-15
alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents
are optionally substituted with 1 substituent selected from the
group consisting of halo, alkyl, monoalkylamino, dialkylamino,
alkyl amide, aryl amide, heteroaryl amide, CN, O--C.sub.1-6 alkyl,
CF.sub.3, or heteroaryl.
[0019] In another embodiment, this invention is a substituted
piperazine compound selected from the group consisting of
N-(2,6-dimethyl-phenyl)-2--
(4-{2-hydroxy-3-[2-(3-trifluoromethylphenyl)-benzoxazol-5-yloxy]-propyl}-p-
iperazin-1-yl)acetamide,
2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxy-propyl]--
piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2--
{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}ace-
tamide,4-(3-{4-[(2,6-dimethylphenylcarbamoyl)-methyl]-piperazin-1-yl}-2-hy-
droxy-propoxy)-1H-indole-2-carboxylic acid amide,
2-{4-[3-(benzothiazol-6--
yloxy)2-hydroxy-propyl]-piperazin-1-yl}-N-(2,6-dimethyl-phenyl)-acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-6-yloxy)--
propyl]-piperazin-1-yl} aceamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-
-(2-methyl-benzothiazol-5-yloxy)-propyl]-3,5-dimethyl-piperazine-1-yl}acet-
amide,
2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-piperazin-
-1-yl}-N-(4-hydroxy-phenyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydro-
xy-3-(2-phenyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-phenyl-benzoxazol-5-yloxy)-pr-
opyl)-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)2-{4-[2-hydroxy-3-(2-
-phenyl-benzothiazol-7-yloxy)-propyl]-piperazin-1-ylacetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-p-
ropyl]-2-oxo-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydr-
oxy-3-(2-methyl-benzoxazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[2-(4-trifluoromethyl-phenyl)-be-
nzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinoxalin-2-yloxy)-propyl]-pip-
erazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(pyridin-3-
-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-h-
ydroxy-3-(quinolin-4-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(isoquinolin-5-yloxy)-propyl]-pi-
perazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinolin-
-6-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-
-hydroxy-3-(2-methyl-quinolin-7-yloxy)-propyl]-piperazin-1-yl}acetamide,
2-{4-[3-(benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinyl}-N-(2,6-dime-
thylphenyl)acetamide,
2-{4-[3-(benzoxazol-2-ylamino)-2-hydroxypropyl]piper-
azinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylb-
enzothiazol-5-yloxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6-dimethylphenyl-
)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-
,6-dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethyl-
piperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3--
(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethyl-
phenyl)acetamide, 2-{(2R)-4-[(2S)-2-hy
oxy-3-(2-methylbenzothiazol-5-yloxy-
)propyl]-2-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpipe-
razinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methyl-
benzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazinyl}-N-(2,6-dimethylpheny-
l)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]--
2-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-diazaper-
hydroepinyl)}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methyl-
benzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-hydroxyphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethyl-
piperazinyl}-N-(4-carboxamidophenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3-
-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethy-
lphenyl)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-me-
thylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2,6-dimethyl-4-hydroxyphen-
yl)acetamide,
2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-
-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
N-(4-sulfamoyphenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenylbenzox-
azol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-nap-
hthylacetamide,
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{4-[2-hydroxy-3-(-
2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-phe-
nylacetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piper-
azinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(4-methoxyph-
enyl)propyl]piperazinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-N-(2-c-
hloro-4-methylphenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-
-yloxy)propyl]piperazinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(3,-
5-dichlorophenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-ylo-
xy)propyl]piperazinyl}-N-(3,4-dichlorophenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[3--
methoxy-5-(trifluoromethyl)phenyl]acetamide,
2-{4-[2-hydroxy-3-(2-phenylbe-
nzothiazol-5-yloxy)propyl]piperazinyl}-N-[3,-5-dichloro)phenyl]acetamide,
and
2-{4-[2-hydroxy-3-(2-((1E)buta-1,3-dienyl)benzothiazol-5-yloxy)propyl-
]piperazinyl}-N-[4-chloro-2-methoxy-5-methylphenyl]acetamide.
[0020] In yet another embodiment, this invention is a method for
administering one or more composition of this invention to a mammal
in a treatment selected from the group consisting of protecting
skeletal muscles against damage resulting from trauma, protecting
skeletal muscles subsequent to muscle or systemic diseases such as
intermittent claudication, to treat shock conditions, to preserve
donor tissue and organs used in transplants, and to treat
cardiovascular diseases including atrial and ventricular
arrhythmias, Prinzmetal's (variant) angina, stable angina, and
exercise induced angina, congestive heart disease, and myocardial
infarction.
DETAILED DESCRIPTION OF THE INVENTION
[0021] A class of substituted piperazine compounds having the
following formula: 3
[0022] wherein
[0023] m=1, 2, or 3;
[0024] q=NH, O, or S;
[0025] R.sup.1, R.sup.2, R, R.sup.4 and R.sup.5 are each
independently selected from the group consisting of hydrogen, halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.2R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
COR.sup.20, CO.sub.2R.sup.20, CON(R.sup.20).sub.2,
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 yl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the
alkyl and aryl substituent are optionally substituted with 1
substituent selected from the group consisting of halo, NO.sub.2,
CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, and SO.sub.2R.sup.22, and wherein R.sup.2 and R.sup.3
or R.sup.3 and R.sup.4 or R.sup.4 and R.sup.5 when taken together
with the carbons to which they are attached may form a 6-membered
aromatic ring that is optionally substituted by alkyl,
trifluoroalkyl, alkoxy, or halogen;
[0026] R.sup.6, R.sup.7 and R.sup.8 each independently selected
from the group consisting of hydrogen or C.sub.1-3 alkyl;
[0027] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15 and R.sup.16 are each independently selected from the
group consisting of hydrogen, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, C.sub.1-4 alkyl, or aryl wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, CF.sub.3, CN,
OR.sup.20, N(R.sup.20).sub.2, CO.sub.2R.sup.20, CON(R.sup.20).sub.2
or aryl, wherein R.sup.9 and R.sup.10 may together form a carbonyl,
or R.sup.11 and R.sup.12 may together form a carbonyl, or R.sup.13
and R.sup.14 may together form a carbonyl, or R.sup.15 and R.sup.16
may together form a carbonyl or R.sup.11 and R.sup.13 or R.sup.9
and R.sup.15 or R.sup.9 and R.sup.11 or R.sup.11 and R.sup.15 or
R.sup.9 and R.sup.13 may join together to form a ring including
from 1 to 3 carbon atoms;
[0028] R.sup.17 is heteroaryl that is optionally substituted with
from 1 to 3 substituents selected from the group consisting of
hydrogen, halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, SO.sub.2R.sup.22,
SO.sub.2N(R.sup.20).sub.2, NR.sup.20CO.sub.2R.sup.22,
NR.sup.20CON(R.sup.20).sub.2, COR.sup.20, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl,
C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, heterocyclyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22;
[0029] R.sup.20 is selected from the group consisting of H,
C.sub.1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl
substituents are optionally substituted with 1 substituent selected
from the group consisting of halo, alkyl, mono- or dialkylamino,
alkyl, CN, --O--C.sub.1-6 alkyl, or CF.sub.3; and
[0030] R.sup.22 is selected from the group consisting of C.sub.1-15
alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents
are optionally substituted with 1 substituent selected from the
group consisting of halo, alkyl, monoalkylamino, dialkylamino,
alkyl amide, aryl amide, heteroaryl amide, CN, O--C.sub.1-6 alkyl,
CF.sub.3, or heteroaryl.
[0031] In a preferred embodiment, q=NH or O.
[0032] In a preferred embodiment, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are each independently selected from the group
consisting of hydrogen, halo, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, SO.sub.2N(R.sup.20).sub.2, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, NO.sub.2, CF.sub.3, CN,
OR.sup.20, SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22, or
SO.sub.2R.sup.22. In another preferred embodiment, R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each independently
selected from the group consisting of hydrogen, halo, CF.sub.3,
OR.sup.20, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, or C.sub.2-5
alkynyl, wherein the alkyl substituent is optionally substituted
with CF.sub.3. In yet another preferred embodiment, R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each independently
selected from the group consisting of hydrogen, halo, CF.sub.3,
OR.sup.20, or C.sub.1-3 alkyl wherein the alkyl substituent is
optionally substituted with CF.sub.3. More preferably R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each independently
selected from the group consisting of hydrogen, CF.sub.3,
OR.sup.20, or C.sub.1-2 alkyl, with hydrogen, OR.sup.20, or methyl
being more preferred and hydrogen or methyl being most
preferred.
[0033] In an alternative preferred embodiment, any one of R.sup.1
and R.sup.2 or R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 or
R.sup.4 and R.sup.5 when taken together with the carbons to which
they are attached may form a 6-membered aromatic ring that is
optionally substituted by alkyl, trifluoroalkyl, alkoxy, or halogen
with the remaining substituents defined as set forth in the
paragraph above. In this embodiment, it is most preferred that
R.sup.2 and R.sup.3 when taken together with the carbons to which
they are attached form a 6-membered aromatic ring.
[0034] In a preferred embodiment, R.sup.6, R.sup.7 and R.sup.8 each
independently selected from the group consisting of hydrogen or
C.sub.1-3 alkyl and most preferably hydrogen or methyl.
[0035] In a preferred embodiment, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each
independently selected from the group consisting of hydrogen,
CON(R.sup.20).sub.2, C.sub.1-4 alkyl, or wherein R.sup.9 and
R.sup.10 may together form a carbonyl, or R.sup.11 and R.sup.12 may
together form a carbonyl, or R.sup.13 and R.sup.14 may together
form a carbonyl, or R.sup.15 and R.sup.16 may together form a
carbonyl. In yet another embodiment, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each
independently selected from the group consisting of hydrogen or
C.sub.1-2 alkyl, wherein R.sup.9 and R.sup.10 may together form a
carbonyl, or R.sup.11 and R.sup.12 may together form a carbonyl, or
R.sup.13 and R.sup.14 may together form a carbonyl, or R.sup.15 and
R.sup.16 may together form a carbonyl. In a more preferred
embodiment, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15 and R.sup.16 are each independently selected
from the group consisting of hydrogen, or methyl, wherein R.sup.9
and R.sup.10 may together form a carbonyl, or R.sup.11 and R.sup.12
may together form a carbonyl, or R.sup.13 and R.sup.14 may together
form a carbonyl, or R.sup.15 and R.sup.16 may together form a
carbonyl. In another embodiment, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each
independently selected from the group consisting of hydrogen, or
C.sub.1-2 alkyl, wherein the alkyl substituent is optionally
substituted with 1 substituent selected from the group consisting
of N(R.sup.20).sub.2, or aryl or wherein R.sup.9 and R.sup.10 may
together form a carbonyl. In another preferred embodiment, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and
R.sup.16 are each independently selected from the group consisting
of hydrogen or C.sub.1-2, alkyl, or wherein R.sup.9 and R.sup.10
may together form a carbonyl. In still another preferred
embodiment, R.sup.11 and R.sup.15 are each selected from the group
consisting of hydrogen or methyl, R.sup.9, R.sup.10, R.sup.12,
R.sup.13, R.sup.14 and R.sup.16 are each hydrogen and R.sup.9 and
R.sup.10 may together form a carbonyl. In another preferred
embodiment, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15 and R.sup.16 are each hydrogen.
[0036] In one preferred embodiment, R.sup.17 is a heteroaryl that
is optionally substituted with from 1 to 2 substituents selected
from the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent independently selected from the
group consisting of halo, CF.sub.3, OR.sup.20, or
N(R.sup.20).sub.2. In another embodiment, R.sup.17 is a heteroaryl
that is a fused 6,5 membered ring system containing from 1 to 5
heteroatoms each selected from the group consisting of N, O, or S
that is optionally substituted with from 1 to 3 substituents
selected from the group consisting of hydrogen, halo, NO.sub.2,
CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.2R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
COR.sup.20, CO.sub.2R.sup.20, CON(R.sup.20).sub.2,
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent independently selected from the group consisting of
halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22. In this
embodiment, R.sup.17 is preferably a heteroaryl that is a fused 6,5
membered ring system containing from 1 to 3 heteroatoms selected
from the group consisting of N, O, or S that is optionally
substituted with from 1 to 2 substituents selected from the group
consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, or heteroaryl, wherein the alkyl
and aryl substituents are optionally substituted with 1 substituent
independently selected from the group consisting of halo, CF.sub.3,
OR.sup.20, or N(R.sup.20).sub.2. More preferably R.sup.17 is a
heteroaryl that is a fused 6,5 membered ring system containing from
1 to 2 heteroatoms selected from the group consisting of N, O, or S
that is optionally substituted with from 1 to 2 substituents
selected from the group consisting of hydrogen, halo, CF.sub.3,
OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl,
aryl, or heteroaryl, wherein the alkyl and aryl substituents are
optionally substituted with 1 substituent selected from the group
consisting of halo, CF.sub.3, or OR.sup.20. Even more preferably in
this embodiment, R.sup.17 is a heteroaryl that is a fused 6,5
membered ring system selected from the group consisting of indole,
benzothiazole, and benzoxazole that is optionally substituted with
from 1 to 2 substituents selected from the group consisting of
hydrogen, halo, CF.sub.3, OR.sup.20, N(R.sup.20).sub.2,
CON(R.sup.20).sub.2, C.sub.1-3 alkyl, aryl, or heteroaryl, wherein
the alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo, CF.sub.3,
or OR.sup.20. In this preferred embodiment, R.sup.17 is preferably
benzothiazole that is optionally substituted with 1 substituent
selected from the group consisting of hydrogen, halo, CF.sub.3,
OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl,
or aryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo or CF.sub.3. More preferably R.sup.17 is benzothiazole that
is optionally substituted at the 2-position with 1 substituent
selected from the group consisting of hydrogen, methyl or phenyl.
In an alternative preferred embodiment, R.sup.17 is 5-substituted
benzothiazole that is optionally substituted with 1 substituent
selected from the group consisting of hydrogen, halo, CF.sub.3,
OR.sup.20, N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-3 alkyl,
or aryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo or CF.sub.3. The 5-substituted benzothiazole is preferably
substituted at the 2-position with 1 substituent selected from the
group consisting of hydrogen, methyl or phenyl.
[0037] In another preferred embodiment, R.sup.17 is a heteroaryl
that is a fused 6, 6 membered ring system containing from 1 to 4
nitrogen atoms that is optionally substituted with from 1 to 3
substituents selected from the group consisting of hydrogen, halo,
NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20, N(R.sup.20).sub.2,
S(O)R.sup.22, SO.sub.2R.sup.22, SO.sub.2N(R.sup.20).sub.2,
NR.sup.20CO.sub.2R.sup.22, NR.sup.20CON(R.sup.20).sub.2,
COR.sup.20, CO.sub.2R.sup.20, CON(R.sup.20).sub.2,
NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl, C.sub.2-15 alkenyl,
C.sub.2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the
alkyl and aryl substituents are optionally substituted with 1
substituent independently selected from the group consisting of
halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22. More
preferably, R.sup.17 is a heteroaryl that is a fused 6, 6 membered
ring system containing from 1 to 3 nitrogen atoms that is
optionally substituted with from 1 to 2 substituents selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, or heteroaryl, wherein the alkyl
and aryl substituents are optionally substituted with 1 substituent
independently selected from the group consisting of halo, CF.sub.3,
OR.sup.20, or N(R.sup.20).sub.2. Most preferably, R.sup.17 is a
heteroaryl that is a fused 6, 6 membered ring system containing
from 1 to 2 nitrogen atoms that is optionally substituted with
methyl;
[0038] In yet another preferred embodiment, R.sup.17 is a 5 or
6-membered ring containing from 1 to 3 heteroatoms selected from
the group consisting of N, S, or O that is optionally substituted
with from 1 to 3 substituents selected from the group consisting of
hydrogen, halo, NO.sub.2, CF.sub.3, CN, OR.sup.20, SR.sup.20,
N(R.sup.20).sub.2, S(O)R.sup.22, SO.sub.2R.sup.22,
SO.sub.2N(R.sup.20).sub.2, NR.sup.20CO.sub.2R.sup.22,
NR.sup.20CON(R.sup.20).sub.2, COR.sup.20, CO.sub.2R.sup.20,
CON(R.sup.20).sub.2, NR.sup.20SO.sub.2R.sup.22, C.sub.1-15 alkyl,
C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, heterocyclyl, aryl, or
heteroaryl, wherein the alkyl and aryl substituents are optionally
substituted with 1 substituent independently selected from the
group consisting of halo, NO.sub.2, CF.sub.3, CN, OR.sup.20,
SR.sup.20, N(R.sup.20).sub.2, S(O)R.sup.22, or SO.sub.2R.sup.22.
More preferably, R.sup.17 is a 5 or 6 membered ring including from
1 to 3 heteroatoms selected from N, S, or O nitrogen atoms that is
optionally substituted with from 1 to 2 substituents selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, or heteroaryl, wherein the alkyl
and aryl substituents are optionally substituted with 1 substituent
independently selected from the group consisting of halo, CF.sub.3,
OR.sup.20, or N(R.sup.20).sub.2. Even more preferably, R.sup.17 is
a 6 membered ring including from 1 to 2 nitrogen atoms that is
optionally substituted with from 1 to 2 substituents selected from
the group consisting of hydrogen, halo, CF.sub.3, OR.sup.20,
N(R.sup.20).sub.2, CON(R.sup.20).sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, or heteroaryl, wherein the alkyl
and aryl substituents are optionally substituted with 1 substituent
independently selected from the group consisting of halo, CF.sub.3,
OR.sup.20, or N(R.sup.20).sub.2. Most preferably in this
embodiment, R.sup.17 is a 6 membered ring containing from 1 to 2
nitrogen atoms that is optionally substituted with methyl.
[0039] In yet still another preferred embodiment, R.sup.17 is a
heteroaryl that is a fused 6,5 membered ring system selected from
the group consisting of benzothiazole, and benzoxazole that is
optionally substituted with 1 substituent selected from the group
consisting of hydrogen, CF.sub.3, OR.sup.20, C.sub.1-3 alkyl, or
aryl, wherein the allyl and aryl substituents are optionally
substituted with 1 substituent selected from the group consisting
of halo or CF.sub.3 and preferably optionally substituted with
methyl.
[0040] In a preferred embodiment, R.sup.20 is selected from the
group consisting of H, C.sub.1-15 alkyl, aryl, or heteroaryl,
wherein the alkyl and aryl substituents are optionally substituted
with 1 substituent selected from the group consisting of halo,
alkyl, monoalkylamino, dialkylamino, alkylcyano, --O--C.sub.1-6
alkyl, or CF.sub.3. R.sup.20 is selected from the group consisting
of H, C.sub.1-5 alkyl, aryl, or heteroaryl, wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
selected from the group consisting of halo, --OMe, or CF.sub.3. In
a more preferred embodiment, R.sup.20 is selected from the group
consisting of H, C.sub.1-3 alkyl, or aryl, wherein the alkyl and
aryl substituents are optionally substituted with 1 substituent
individually selected from the group consisting of halo, --OMe, and
CF.sub.3. Most preferably, R.sup.20 is selected from the group
consisting of H or C.sub.1-3 alkyl and most preferably H or
methyl.
[0041] In a preferred embodiment, R.sup.22 is selected from the
group consisting of C.sub.1-15 alkyl, aryl, or heteroaryl wherein
the alkyl and aryl substituents are optionally substituted with 1
substituent selected from the group consisting of halo, alkyl,
monoalkylamino, dialkylaminio, alkyl amide, aryl amide, heteroaryl
amide, CN, O--C.sub.1-6 alkyl, CF.sub.3, or heteroaryl.
[0042] In a most preferred embodiment, this invention is a
substituted piperazine compound selected from the group consisting
of
N-(2,6-dimethyl-phenyl)-2-(4-{2-hydroxy-3-[2-(3-trifluoromethylphenyl)-be-
nzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide,
2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxy-propyl]-piperazin-1-yl}-N-(2,6-d-
imethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methy-
l-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,4-(3-{4-[(2,6-dim-
ethylphenylcarbamoyl)-methyl]-piperazin-1-yl}-2-hydroxy-propoxy)-1H-indole-
-2-carboxylic acid amide,
2-{4-[3-(benzothiazol-6-yloxy)2-hydroxy-propyl]--
piperazin-1-yl}-N-(2,6-dimethyl-phenyl)-acetamide,
N-(2,6-dimethylphenyl)--
2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-6-yloxy)-propyl]-piperazin-1-yl}a-
ceamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-
-yloxy)-propyl]-3,5-dimethyl-piperazine-1-yl}acetamide,
2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}-
-N-(4-hydroxy-phenyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(-
2-phenyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-phenyl-benzoxazol-5-yloxy)-pr-
opyl)-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)2-{4-[2-hydroxy-3-(2-
-phenyl-benzothiazol-7-yloxy)-propyl]-piperazin-1-ylacetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-p-
ropyl]-2-oxo-piperazin-1-yl} acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hyd-
roxy-3-(2-methyl-benzoxazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[2-(4-trifluoromethyl-phenyl)-be-
nzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinoxalin-2-yloxy)-propyl]-pip-
erazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(pyridin-3-
-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-h-
ydroxy-3-(quinolin-4-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(isoquinolin-5-yloxy)-propyl]-pi-
perazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinolin-
-6-yloxy)-propyl]-piperazin-1-yl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-
-hydroxy-3-(2-methyl-quinolin-7-yloxy)-propyl]-piperazin
1-yl}acetamide,
2-{4-[3-(benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinyl}-N-(2,6-dime-
thylphenyl)acetamide,
2-{4-[3-(benzoxazol-2-ylamino)-2-hydroxypropyl]piper-
azinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylb-
enzothiazol-5-yloxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6-dimethylphenyl-
)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-
,6-dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethyl-
piperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3--
(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethyl-
phenyl)acetamide,
2-{(2R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-ylox-
y)propyl]-2-methylpiperazinyl]-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpipe-
razinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methyl-
benzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazinyl}-N-(2,6-dimethylpheny-
l)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]--
2-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-diazaper-
hydroepinyl)}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methyl-
benzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-hydroxyphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethyl-
piperazinyl}-N-(4-carboxamidophenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3-
-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethy-
lphenyl)acetamide,
2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-me-
thylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2,6-dimethyl-4-hydroxyphen-
yl)acetamide,
2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-
-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl)piperazinyl}--
N-(4-sulfamoyphenyl)acetamide,
2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenylbenzox-
azol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-nap-
hthylacetamide,
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{4-[2-hydroxy-3-(-
2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-phe-
nylacetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piper-
azinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(4-methoxyph-
enyl)propyl]piperazinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-N-(2-c-
hloro-4-methylphenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-
-yloxy)propyl]piperazinyl}-N-(3,4,5-trichlorophenyl)acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(3,-
5-dichlorophenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-ylo-
xy)propyl]piperazinyl}-N-(3,4-dichlorophenyl)-acetamide,
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[3--
methoxy-5-(trifluoromethyl)phenyl]acetamide,
2-{4-[2-hydroxy-3-(2-phenylbe-
nzothiazol-5-yloxy)propyl]piperazinyl}-N-[3,-5-dichloro)phenyl]acetamide,
and
2-{4-[2-hydroxy-3-(2-((1E)buta-1,3-dienyl)benzothiazol-5-yloxy)propyl-
]piperazinyl}-N-[4-chloro-2-methoxy-5-methylphenyl]acetamide.
[0043] The following definitions apply to terms as used herein.
[0044] "Halo" or "Halogen"--alone or in combination means all
halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo
(I).
[0045] "Hydroxyl" refers to the group --OH.
[0046] "Thiol" or "mercapto" refers to the group --SH.
[0047] "Alkyl"--alone or in combination means an alkane-derived
radical containing from 1 to 20, preferably 1 to 15, carbon atoms
(unless specifically defined). It is a straight chain alkyl,
branched alkyl or cycloalkyl. Preferably, straight or branched
alkyl groups containing from 1-15, more preferably 1 to 8, even
more preferably 1-6, yet more preferably 1-4 and most preferably
1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
t-butyl and the like. The term "lower alkyl" is used herein to
describe the straight chain alkyl groups described immediately
above. Preferably, cycloalkyl groups are monocyclic, bicyclic or
tricyclic ring systems of 3-8, more preferably 3-6, ring members
per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
adamantyl and the like. Alkyl also includes a straight chain or
branched alkyl group that contains or is interrupted by a
cycloalkyl portion. The straight chain or branched alkyl group is
attached at any available point to produce a stable compound.
Examples of this include, but are not limited to,
4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl. A
substituted alkyl is a straight chain alkyl, branched alkyl, or
cycloalkyl group defined previously, independently substituted with
1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy,
amino optionally mono- or di-substituted with alkyl, aryl or
heteroaryl groups, amidino, urea optionally substituted with alkyl,
aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally
N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl
groups, alkylsulfonylamino, arylsulfonylamino,
heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,
heteroarylcarbonylamino, or the like.
[0048] "Alkenyl"--alone or in combination means a straight,
branched, or cyclic hydrocarbon containing 2-20, preferably 2-17,
more preferably 2-10, even more preferably 2-8, most preferably 2
to 4 carbon atoms with at least one, preferably 1-3, more
preferably 1-2, and most preferably one, carbon to carbon double
bond. In the case of a cycloalkyl group, conjugation of more than
one carbon to carbon double bond is not such as to confer
aromaticity to the ring. Carbon to carbon double bonds may be
either contained within a cycloalkyl portion, with the exception of
cyclopropyl, or within a straight chain or branched portion.
Examples of alkenyl groups include ethenyl, propenyl, isopropenyl,
butenyl, cyclohexenyl, cyclohexenylalkyl and the like. A
substituted alkenyl is the straight chain alkenyl, branched alkenyl
or cycloalkenyl group defined previously, independently substituted
with 1 to 3 groups or substituents of halo, hydroxy, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy,
heteroaryloxy, amino optionally mono- or di-substituted with alkyl,
aryl or heteroaryl groups, amidino, urea optionally substituted
with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl
optionally N-mono- or N,N-di-substituted with alkyl, aryl or
heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,
heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,
heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl, or the like attached at any available point
to produce a stable compound.
[0049] "Alkynyl"--alone or in combination means a straight or
branched hydrocarbon containing 2-20, preferably 2-17, more
preferably 2-10, even more preferably 2-8, most preferably 2-4,
carbon atoms containing at least one, preferably one, carbon to
carbon triple bond. Examples of alkynyl groups include ethynyl,
propynyl, butynyl and the like. A substituted alkynyl refers to the
straight chain alkynyl or branched alkynyl defined previously,
independently substituted with 1 to 3 groups or substituents of
halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or
di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea
optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl
groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with
alkyl, aryl or heteroaryl groups, alkylsulfonylamino,
arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino,
arylcarbonylamino, heteroarylcarbonylamino, or the like attached at
any available point to produce a stable compound.
[0050] "Alkyl alkenyl" refers to a group --R--CR'.dbd.CR'"R"",
where R is lower alkyl, or substituted lower alkyl, R', R'", R""
may independently be hydrogen, halogen, lower alkyl, substituted
lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted
hetaryl as defined below.
[0051] "Alkyl alkynyl" refers to a groups --RC.ident.CR' where R is
lower alkyl or substituted lower alkyl, R' is hydrogen, lower
alkyl, substituted lower alkyl, acyl, aryl, substituted aryl,
hetaryl, or substituted hetaryl as defined below.
[0052] "Alkoxy" denotes the group --OR, where R is lower alkyl,
substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl,
substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, or substituted
cycloheteroalkyl as defined.
[0053] "Alkylthio" denotes the group --SR, --S(O).sub.n=1-2--R,
where R is lower alkyl, substituted lower alkyl, aryl, substituted
aryl, aralkyl or substituted aralkyl as defined herein.
[0054] "Acyl" denotes groups --C(O)R, where R is hydrogen, lower
alkyl substituted lower alkyl, aryl, substituted aryl and the like
as defined herein.
[0055] "Aryloxy" denotes groups --OAr, where Ar is an aryl,
substituted aryl, heteroaryl, or substituted heteroaryl group as
defined herein.
[0056] "Amino" denotes the group NRR', where R and R' may
independently by hydrogen, lower alkyl, substituted lower alkyl,
aryl, substituted aryl, hetaryl, or substituted hetaryl as defined
herein or acyl.
[0057] "Amido" denotes the group --C(O)NRR', where R and R' may
independently by hydrogen, lower alkyl, substituted lower alkyl,
aryl, substituted aryl, hetaryl, substituted hetaryl as defined
herein.
[0058] "Carboxyl" denotes the group --C(O)OR, where R is hydrogen,
lower alkyl, substituted lower alkyl, aryl, substituted aryl,
hetaryl, and substituted hetaryl as defined herein.
[0059] "Aryl"--alone or in combination means phenyl or naphthyl
optionally carbocyclic fused with a cycloalkyl of preferably 5-7,
more preferably 5-6, ring members and/or optionally substituted
with 1 to 3 groups or substituents of halo, hydroxy, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy,
heteroaryloxy, amino optionally mono- or di-substituted with alkyl,
aryl or heteroaryl groups, amidino, urea optionally substituted
with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl
optionally N-mono- or N,N-di-substituted with alkyl, aryl or
heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,
heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,
heteroarylcarbonylamino, or the like.
[0060] "Substituted aryl" refers to aryl optionally substituted
with one or more functional groups, e.g., halogen, lower alkyl,
lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,
hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl,
nitro, cyano, thiol, sulfamido and the like.
[0061] "Heterocycle" refers to a saturated, unsaturated, or
aromatic carbocyclic group having a single ring (e.g., morpholino,
pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl,
quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having
at least one hetero atom, such as N, O or S, within the ring, which
can optionally be unsubstituted or substituted with, e.g., halogen,
lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido,
carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl,
substituted hetaryl, nitro, cyano, thiol, sulfamido and the
like.
[0062] "Heteroaryl"--alone or in combination means a monocyclic
aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic
aromatic group having 8 to 10 atoms, containing one or more,
preferably 1-4, more preferably 1-3, even more preferably 1-2,
heteroatoms independently selected from the group O, S, and N, and
optionally substituted with 1 to 3 groups or substituents of halo,
hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy,
aryloxy, heteroaryloxy, amino optionally mono- or di-substituted
with alkyl, aryl or heteroaryl groups, amidino, urea optionally
substituted with alkyl, aryl, heteroaryl or heterocyclyl groups,
aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl,
aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,
heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,
heteroarylcarbonylamino, or the like. Heteroaryl is also intended
to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide
of a tertiary ring nitrogen. A carbon or nitrogen atom is the point
of attachment of the heteroaryl ring structure such that a stable
aromatic ring is retained. Examples of heteroaryl groups are
pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl,
quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl,
thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,
tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl,
benzothiazolyl, benzoxazolyl, and the like. A substituted
heteroaryl contains a substituent attached at an available carbon
or nitrogen to produce a stable compound.
[0063] "Heterocyclyl"--alone or in combination means a non-aromatic
cycloalkyl group having from 5 to 10 atoms in which from 1 to 3
carbon atoms in the ring are replaced by heteroatoms of O, S or N,
and are optionally benzo fused or fused heteroaryl of 5-6 ring
members and/or are optionally substituted as in the case of
cycloalkyl. Heterocycyl is also intended to include oxidized S or
N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring
nitrogen. The point of attachment is at a carbon or nitrogen atom.
Examples of heterocyclyl groups are tetrahydrofuranyl,
dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl,
dihydrobenzofuryl, dihydroindolyl, and the like. A substituted
hetercyclyl contains a substituent nitrogen attached at an
available carbon or nitrogen to produce a stable compound.
[0064] "Substituted heteroaryl" refers to a heterocycle optionally
mono or poly substituted with one or more functional groups, e.g.,
halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino,
amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted
heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,
sulfamido and the like.
[0065] "Aralkyl" refers to the group --R--Ar where Ar is an aryl
group and R is lower alkyl or substituted lower allyl group. Aryl
groups can optionally be unsubstituted or substituted with, e.g.,
halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido,
carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted
heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,
sulfamido and the like.
[0066] "Heteroalkyl" refers to the group --R-Het where Het is a
heterocycle group and R is a lower alkyl group. Heteroalkyl groups
can optionally be unsubstituted or substituted with e.g., halogen,
lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido,
carboxyl, aryl, aryloxy, heterocycle, substituted heterocycle,
hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and
the like.
[0067] "Heteroarylalkyl" refers to the group --R-HetAr where HetAr
is an heteroaryl group and R lower alkyl or substituted lower
alkyl. Heteroarylalkyl groups can optionally be unsubstituted or
substituted with, e.g., halogen, lower alkyl, substituted lower
alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle,
substituted heterocycle, hetaryl, substituted hetaryl, nitro,
cyano, thiol, sulfamido and the like.
[0068] "Cycloalkyl" refers to a divalent cyclic or polycyclic alkyl
group containing 3 to 15 carbon atoms.
[0069] "Substituted cycloalkyl" refers to a cycloalkyl group
comprising one or more substituents with, e.g., halogen, lower
alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl,
aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted
hetaryl, nitro, cyano, thiol, sulfamido and the like.
[0070] "Cycloheteroalkyl" refers to a cycloalkyl group wherein one
or more of the ring carbon atoms is replaced with a heteroatom
(e.g., N, O, S or P).
[0071] "Substituted cycloheteroalkyl" refers to a cycloheteroalkyl
group as herein defined which contains one or more substituents,
such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene,
amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle,
substituted heterocycle, hetaryl, substituted hetaryl, nitro,
cyano, thiol, sulfamido and the like.
[0072] "Alkyl cycloalkyl" denotes the group --R-cycloalkyl where
cycloalkyl is a cycloalkyl group and R is a lower alkyl or
substituted lower alkyl. Cycloalkyl groups can optionally be
unsubstituted or substituted with e.g. halogen, lower alkyl, lower
alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl,
aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,
substituted hetaryl, nitro, cyano, thiol, sulfamido and the
like.
[0073] "Alkyl cycloheteroalkyl" denotes the group
--R-cycloheteroalkyl where R is a lower alkyl or substituted lower
alkyl. Cycloheteroalkyl groups can optionally be unsubstituted or
substituted with e.g. halogen, lower alkyl, lower alkoxy,
alkylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl,
aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted
hetaryl, nitro, cyano, thio, sulfamido and the like.
[0074] "Optional" and "optionally" mean that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where the event or circumstance
occurs and instances in which it does not. For example, "optional
pharmaceutical excipients" indicates that a formulation so
described may or may not include pharmaceutical excipients other
than those, specifically stated to be present, and that the
formulation so described includes instances in which the optional
excipients are present and instances in which they are not.
[0075] "Treating" and "treatment" refer to any treatment of a
disease in a mammal, particularly a human, and include:
[0076] (i) preventing the disease from occurring in a subject which
may be predisposed to the disease but has not yet been diagnosed as
having it;
[0077] (ii) inhibiting the disease, i.e., arresting its
development; or
[0078] (iii) relieving the disease, i.e., causing regression of the
disease.
[0079] All of the aforementioned embodiments include the
pharmaceutically acceptable acid addition salts thereof,
particularly the mono- and dihydrochlorides, and mixtures
thereof.
[0080] The compounds having the general formula Ia (q=O) or Ic
(q=S) can be prepared as outlined in Schemes 1-5. A general
synthesis of the compounds of this invention is outlined in Scheme
1. Compound IV can be prepared by N-acylation of substituted
aniline II with 2-substituted chloroacetylchloride III. Compound II
is available commercially or readily prepared through reduction of
the corresponding nitrobenzene derivative (acid/SnCl.sub.2 or
catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J.
March, (1992) A. Wiley-Interscience). Some examples of commercially
available substituted anilines corresponding to general structure
II include 2,6-dimethylaniline, 2,3-dimethylaniline,
2-methylaniline, 4-methylaniline, 4-methylaniline,
2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline,
2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline,
2,6-difluoroaniline, 2,5-difluoroaniline, 3,4-difluoroaniline,
2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline,
2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline,
4-acetoxyaniline. 4
[0081] Compound VI can be obtained by reacting compound IV with
N-protected substituted piperazine V through warming in an
appropriate solvent (e.g. DMF, EtOH). Protection of the nitrogen of
compound V is only required when it is useful to control the
regiochemistry of the addition of Compound V with compound IV. In
some cases, compound V can be obtained from commercial resources.
Examples of commercially available compounds corresponding to
general structure V include 2-methylpiperazine,
2,5-dimethylpiprazine, 2,6-dimethylpiperazine,
2,3,5,6-tetramethylpiperazine, piperazine-2-carboxylic acid,
perhydroquinoxaline, 2-aminomethyl-6-methylpiperazine,
2-aminomethylpiperazine, 2-(o-chlorophenyl)piperazine, and
2-(m-chlorophenyl)piperazine. Deprotection of compound VI can be
accomplished using the standard conditions (e.g. for Boc group use
TEA, for CBZ and benzyl use hydrogenation). Compound Ia or Ic can
be prepared by reacting compound VII with epoxide VIII through
warming in an appropriate solvent (ethanol, DMF, CHCl.sub.2, THF)
or by stirring at room temperature in the presence of a lanthamide
(III) Lewis acid (Chini, M et al., Tetrahedron Lett., 35: 433-36
(1994). 5
[0082] Epoxide VIII (where m=1, 2, or 3) can be prepared as
outlined in Scheme 2. Heating substituted phenol, or thiophenol IX
with epichlorohydrin, epibromohydrin, or 4-bromo-1,2-epoxybutane
and potassium carbonate in acetone or sodium hydride in DMF can
afford epoxide VIII. Compound IX can be obtained from commercial
resources. Examples of commercially available compounds
corresponding to structure XI include
2-methyl-5-hydroxybenzothiazole, 2-hydroxybenzothiazole,
8-hydroxyquinolidine, 6-hydroxyquinoline, 4-hydroxyquinoline,
5-hydroxyisoquinoline, 3-hydroxypyridine, 2-quinoxalinol, and
4-(imidazol-1-yl)phenol. In some cases compound VIII can be
obtained from commercial sources. Examples of commercially
available compounds corresponding to general structure VIII include
4-glycidyloxy-2-indolecar- boxamide.
[0083] Compound IX can in turn be prepared by the deprotection of
the corresponding methyl or benzyl ethers (x) using Lewis acids as
shown in Scheme 3 (BBr.sub.3, BF.sub.3, etc.--see Advanced Organic
Chemistry, Ed. J. March (1992) A. Wiley Intersciences, p 434).
Benzyl ethers can also be deprotected by refluxing with palladium
hydroxide in ethanol/cyclohexene (see Catalytic hydrogenation over
platinum metals, P. N. Rylander, Academic Press, New York, N.Y.,
(1976) p 464). Commercially available methyl ethers include
6-methoxy-2-methyl-benzothiazole. 6
[0084] Compound IX can also be prepared by the diazotization of the
corresponding amino compounds (XI) as shown in Scheme 4 (Boggust,
W. A and Cocker, W. J. Chem. Soc. 1949, 355). Commercially
available amines include 6-amino-benzothiazole. 7
[0085] The 6, 5 fused ring system of compound X can be prepared by
the cyclization of commercially available ethers of 2-aminophenols,
2-aminothiophenols, or 2-aminoanilines (XII) with orthoesters
(XIII) (Musser, J. H. et al., J. Med. Chem. 1985, 28, 1255-1259) or
imidates (XIV) (Gregory, G. I. Et al., J. Chem. Soc. Perkin Trans.
1, 1973, 47-51) as shown in Scheme 5 and 6 respectively.
Commercially available, ethers of aminophenols include
4-methoxy-2-aminophenol, orthoesters include trimethyl orthoformate
and trimethyl orthoacetate, imidates include ethyl acetimidate
hydrochloride, and ethyl benzimidate hydrochloride. 8 9
[0086] The thiophenol analog of compound XII can be prepared from
the commercially available compound XV by reacting with sodium
disulfide hydrate followed by reduction using tin and hydrochloric
acid (Dannley, R. L. and Zazaris, D. A; Can. J. Chem. 1965, 43,
2610-2612) as shown in Scheme 7. Commercially available nitro
compounds include 3-nitro-4-chloroanisole. 10
[0087] Imidate XIV can be prepared by bubbling HCl gas through an
alcoholic solution of the commercially available nitrites XVI as
shown in Scheme 8. Commercially available nitrites include,
benzonitrile, 4-trifluoromethylbenzonitrile and
3-trifluoromethylbenzonitrile. 11
[0088] Sulfur containing 6,5 fused ring system of compound X can
also be prepared from the commercially available ethers of anilines
XVII (Stevens, M. F. G. et al, J. Med. Chem. 1994, 37, 1689-1695)
as shown in Scheme 9. Thioamide XX can be obtained by the reaction
of Lawesson's reagent with amide XIX which in turn can be prepared
by the reaction of compound XVII with compound XVIII. Cyclization
of XX with potassium ferrocyanide under basic conditions can afford
compound XXI. Commercially available ethers of anilines include
benzyloxyanilines and anisidines. 12
[0089] A general synthesis of the compound XXV of this invention is
outlined in Scheme 10. Compound XXV can be prepared by the
deprotection of compound XXIII using the standard conditions (e.g.
for BOC group use TFA, for CBZ and benzyl use hydrogenation).
Compound XXIII in turn can be prepared by the reaction of the
commercially available protected monoketopiperazine analog compound
XXII with compound IV and sodium hydride in an appropriate solvent
(DMF, THF). An example of the commercially available
monoketopiperazines include 4-benzyloxycarbonylpiperazine-2-one.
13
[0090] A general synthesis of the compound Ib (q=NH) of this
invention is outlined in Schemes 11 and 12. Compound XXVII can be
prepared by refluxing compound VII with the epoxide XXVI in a
suitable solvent (ethanol, THF). Deprotection of compound XXVII can
be accomplished by using standard conditions (e.g. for BOC group
use TFA; for CBZ use hydrogenation or Pd(OH).sub.2). Compound Ib
can be prepared by refluxing compound XXVIII with compound XXIX in
a suitable solvent (ethanol, THF). Commercially available compound
XXIX includes 2-chlorobenzothiazole, 2-chlorobenzoxazole,
2-chloropyridine, 2-chloropyrimidine,
2-chloro-4-(trifluoromethyl)pyrimidine, and chloropyrazine. 14
[0091] Epoxide XXVI in turn can be prepared as shown in Scheme 12.
Commercially available compound XXX can be protected using the
standard conditions (for BOC protection use BOC anhydride; for CBZ
protection use CBZ-Cl). Compound XXV can be prepared by the
reaction of compound XXXI using m-chloroperbenzoic acid in a
suitable solvent (e.g. dichloromethane). An example of a
commercially available compound XXX includes by is not limited to
alkylamine. 15
[0092] Compound V can be prepared as described in Scheme 13.
Alkylation of compound XXXII with alkyl halides using t-BuLi as
base can afford compound XXXIII as described by Pohlman et. al. (J.
Org. Chem, 1997, 62, 1016-1022). Reduction of XXXIV using diborane
can afford the N-benzyl protected version of compound V after N-Boc
deprotection with trifluoroacetic acid (TFA) [for the diborane
reduction see Jacobson et. al, J. Med. Chem, 1999, 42,1123-1144].
16
[0093] Compound V can also be prepared through standard coupling
(eg. EDC or PyBroP) of D or L amino acids and standard deprotection
as outlined in Scheme 14 (Cledera, P. et al. Tetrahedron, 1998 p.
12349-12360; Smith, R. A. et al Bioorg. Med. Chem. Lett. 1998, p.
2369-2374). Reduction of the diketopiperazine XXXVII with diborane
can afford the N-benzyl protected version of compound V. 17
[0094] Compound V can also be prepared as described in Scheme 15.
Bromination of aldehydes XXXVIII followed by the reaction with
ethylene diamine can afford the imine XLI. Catalytic hydrogenation
of compound XLI can afford compound V (Bogeso, K. P., et al, J.
Med. Chem. 1995, 38, p 4380-4392). Commercially available aldehydes
include isobutyraldehyde. 18
[0095] Compound V also includes the bicyclic homologs of piperazine
(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83,
3,8-diazabicyclo[3.2.1] octane 84, and 2,5-diazabicyclo[2.2.2]
octane 85. 19
[0096] Commercially available bicyclic analogs include
(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83. Compounds 84, 85,
and the (1R,4R) isomer of 83 can be prepared by published
procedures (for 84 and 85--see Sturm, P. A. et al, J. Med. Chem.
1974, 17, 481-487; for 83 see--Barish, T. F. and Fox, D. E. J. Org.
Chem., 1990, 55, 1684-1687).
[0097] Specific examples of the preparation of compounds
corresponding to the general schemes described above are disclosed
in Scheme 16-29 of the Examples which further illustrate
alternative methods for preparing compounds of this invention. In
particular, 2,6-methylaniline was acylated with 2-chloroacetyl
chloride 2 using saturated bicarbonate and ether (1:1) as base and
co-solvent, respectively to afford the chloroacetamide derivative
3. Further reaction of compound 3 with piperazine afforded compound
5 through warming in ethanol. Reaction of compound 5 with epoxide 6
by warming both components in ethanol at reflux afforded piperazine
derivative 7 as illustrated in Scheme 16. Compound 6 was prepared
by warming epichlorohydrin with the phenol 8 in acetone in the
presence of K.sub.2CO.sub.3 as described in Scheme 17. 20 21
[0098] The benzoxazole derivative 8 was prepared by the
deprotection of compound 13 as shown in Scheme 18. Compound 10 was
prepared by condensation of 2-amino-4-methoxyphenol 12. Compound 12
was obtained by the catalytic hydrogenation of the commercially
available 4-methoxy-2-nitrophenol 11, and the benzimidate
derivative 13 as shown in Scheme 19. Compound 13 was obtained from
3-trifluoromethylbenzonitrile 14 using a Pinner reaction
(ethanol/anhydrous HCl). 22 23 24
[0099] Synthesis of the key intermediates that were used in the
preparation of the compounds described in this invention are shown
in Scheme 21-25. Compound 16 was prepared by the diazotization of
the commercially available 6-aminobenzothiazole as shown in scheme
21. 25
[0100] Compound 19 was prepared by condensation of compound 12 with
trimethyl orthoacetate 18 as shown in Scheme 22. 26
[0101] Compound 22 can be prepared by the reduction of compound 21
with tin and hydrochloric acid as shown in Scheme 23. Compound 21
was synthesized by reacting compound 20 with sodium disulfide
hydrate. 27
[0102] Compound 26 was prepared by the reaction of compound 25 with
Lawesson's reagent as shown in Scheme 24. Compound 25 was prepared
by the reaction of the aniline 23 with benzoyl chloride 24.
Cyclization of the thioamide 26 with potassium ferrocyanide in
aqueous sodium hydroxide gave a mixture of compounds 27 and 28.
Compounds 27 and 28 were separated by column chromatography. 28
[0103] Debenzylation of compound 27 was carried out as shown in
Scheme 25 by transfer hydrogenolysis using Pearlmann's catalyst in
ethanol/cyclohexene. 29
[0104] Synthesis of compound 34 of this invention is described in
Scheme 26. The amide 3 was prepared as described in Scheme 16.
Reaction of 3 with the manion of the anion of the
monoketopiperazine 30 formed through treatment with sodium hydride
in DMF gave compound 31. Compound 34 was obtained through warming
compound 32 with the epoxide 33 in ethanol. Compound 32 was
prepared by the deprotection of compound 31 by catalytic
dehydrogenation. Epoxide 33 was prepared in the same manner as
compound 6 described in Scheme 17. 30
[0105] Synthesis of a specific compound 39 of this invention is
described in Scheme 27. The synthesis of compound 5 was described
previously (Scheme 16). Warming compound 5 to reflux with the
epoxide 35 in ethanol gave compound 36. Deprotection of 36 by
treatment with palladium hydroxide in ethanol/cyclohexene under
reflux conditions gave the amine 37. The final compound 39 was
prepared by reacting 37 with 2-chlorobenzothiazole in ethanol and
triethylamine. 31
[0106] Epoxide 35 was synthesized as described in Scheme 28.
Allylamine 40 was reacted with benzyl chloroformate in
dichloromethane to afford compound 42. Reaction of
m-chloroperbenzoic acid with 42 gave the epoxide 35. 32
[0107] The acid addition salts of the compounds of this invention
may be converted to the corresponding free base by treating with a
suitable base, such as potassium carbonate or sodium hydroxide,
typically in the presence of aqueous solvent, and at a temperature
of between about 0 degrees C. and 100 degrees C. The free base form
is isolated by conventional means, such as extraction with an
organic solvent.
[0108] Salts of the compounds of this invention may be interchanged
by taking advantage of differential solubilities and volatilities,
or by treating with the appropriately loaded ion exchange resin.
This conversion is carried out at a temperature between about
0.degree. C. and the boiling point of the solvent being used as the
medium for the procedure. Administration of the active compounds
and salts described herein can be via any of the accepted modes of
administration for therapeutic agents. These methods include oral,
parenteral, transdermal, subcutaneous and other systemic modes. The
preferred method of administration is oral, except in those cases
where the subject is unable to ingest, by himself, any medication.
In those instances it may be necessary to administer the
composition parentarally.
[0109] Depending on the intended mode, the compositions may be in
the form of solid, semi-solid or liquid dosage forms, such as, for
example, tablets, suppositories, pills, capsules, powders, liquids,
suspensions, or the like, preferably in unit dosage forms suitable
for single administration of precise dosages. The compositions may
include one or more conventional pharmaceutical excipients and at
least one active compound of this invention or the pharmaceutically
acceptable salts thereof and, in addition, may include other
medicinal agents, pharmaceutical agents, carriers, adjuvants,
diluents, etc.
[0110] The amount of active compound administered will, of course,
be dependent on the subject being treated, the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician. However, an effective
dosage is in the range of 0.1-30 mg/kg/day, preferably 0.5-20
mg/kg/day. For an average 70 kg human, this would amount to 7-2100
mg per day, or preferably 35-1400 mg/day. Since many of the effects
of the compounds herein (protect skeletal muscles against damage
resulting from trauma; protect skeletal muscles subsequent to
muscle or systemic diseases such as intermittent claudication;
treat shock conditions; preserve donor tissue and organs used in
transplants; and treat cardiovascular diseases including atrial and
ventricular arrhythmias, Prinzmetal's (variant) angina, stable
angina, exercise induced angina, congestive heart disease, and
myocardial infarction) are achieved through a similar mechanism
partial fatty acid oxidation inhibition) dosages (and forms of
administration) are all generally within the same general and
preferred ranges for all these utilities.
[0111] For solid compositions, conventional non-toxic solid
include, for example, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, sodium saccharin, talcum, cellulose,
glucose, sucrose, magnesium carbonate, and the like may be used.
The active compound as defined above may be formulated as
suppositories using, for example, polyalkylene glycols, for
example, propylene glycol, as the carrier. Liquid pharmaceutically
administrable compositions can, for example, be prepared by
dissolving, dispersing, etc. an active compound as defined above
and optional pharmaceutical adjuvants in a excipient, such as, for
example, water, saline, aqueous dextrose, glycerol, ethanol, and
the like, to thereby form a solution or suspension. If desired, the
pharmaceutical composition to be administered may also contain
minor amounts of nontoxic auxiliary substances such as wetting or
emulsifying agents, pH buffering agents and the like, for example,
sodium acetate, sorbitan monolaurate, triethanolamine sodium
acetate, triethanolamine oleate, etc. Actual methods of preparing
such dosage forms are known, or will be apparent, to those skilled
in this art; for example, see Remington's Pharmaceutical Sciences,
Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The
composition or formulation to be administered will, in any event,
contain a quantity of the active compound(s), a therapeutically
effective amount, i.e. in an amount effective to alleviate the
symptoms of the subject being treated. For oral administration, a
pharmaceutically acceptable non-toxic composition is formed by the
incorporation of any of the normally employed excipients, such as,
for example pharmaceutical grades of mannitol, lactose, starch,
magnesium stearate, sodium saccharin, talcum, cellulose, glucose,
sucrose, magnesium, carbonate, and the like. Such compositions take
the form of solutions, suspensions, tablets, pills, capsules,
powders, sustained release formulations and the like. Such
compositions may contain 10%-95% active ingredient, preferably
1-70%.
[0112] Parenteral administration is generally characterized by
injection, either subcutaneously, intramuscularly or intravenously.
Injectables can be prepared in conventional forms, either as liquid
solutions or suspensions, solid forms suitable for solution or
suspension in liquid prior to injection, or as emulsions. Suitable
excipients are, for example, water, saline, dextrose, glycerol,
ethanol or the like. In addition, if desired, the pharmaceutical
compositions to be administered may also contain minor amounts of
non-toxic auxiliary substances such as wetting or emulsifying
agents, pH buffering agents and the like, such as for example,
sodium acetate, sorbitan monolaurate, triethanolamine oleate,
etc.
[0113] A more recently devised approach for parenteral
administration employs the implantation of a slow-release or
sustained-release system, such that a constant level of dosage is
maintained. See, e.g., U.S. Pat. No. 3,710,795, which is
incorporated herein by reference. In another recent approach, the
compositions of this invention can be administered orally in a
sustained release dosage form using the compositions and/or methods
disclosed in U.S. patent application Ser. No. 09/321,522, filed on
May 27, 1999, the specification of which is incorporated herein by
reference.
[0114] It is within the scope of this invention to administer one
or more compounds of this invention to a mammal, and preferably to
a human by other known routes of pharmaceutical dosage form
administration including, but not limited to by bolus,
intravenously, transdermally, through inhalation, sub-cutaneously,
or any other therapeutic agent administration method or route know
to one skilled in the art.
[0115] The following Examples are representative of the invention,
but are not to be construed as limiting the scope of the
claims.
EXAMPLE 1
[0116]
N-(2,6-dimethyl-phenyl)-2-(4-{2-hydroxy-3-[2-(3-trifluoromethylphen-
yl) benzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide (7):
33
[0117] Part A.
[0118] Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide
(3):
[0119] 2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in
ether (100 mL) and saturated aqueous NaHCO.sub.3 (100 mL) and the
reaction mixture was cooled in an ice/water bath. To the cold
solution was added chloroacetyl chloride 2 (9.17 g, 81.2 mmol)
dropwise over a period of 2 h. The mixture was allowed to warm to
RT over 14 h. The mixture was extracted with ethyl acetate
(3.times.50). The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated. The residue was triturated
in ether and filtered to afford compound 3 as a white solid.
[0120] Part B.
[0121] Synthesis of N-(2,6-dimethylphenyl)-piperazin-1-yl-acetamide
(5):
[0122] To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100
mL) was added piperazine 4 (2.1 g, 25.0 mmol) and
N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture
was refluxed for 24 h. The mixture was concentrated in vacuo and
the residue was purified by column chromatography (10:1 DCM: MeOH)
to afford compound 5.
[0123] Part C.
[0124] Synthesis of
5-(oxiran-2-yl-methoxy)-2-[(3-trifluoromethyl)phenyl]b- enzoxazole
(6):
[0125] 1. Synthesis of 2-amino-4-methoxyphenol (12):
[0126] A solution of 4-methoxy-2-nitrophenol 11 (10 g, 59.1 mmol)
and Pd/C (1.0 g) in methanol (100 ml) was placed on a Parr shaker
under H.sub.2 (50 psi) for 60 minutes. The reaction mixture was
filtered through Celite 521 and the filter cake washed with MeOH.
The filtrate was evaporated (in vacuo), to yield compound 12 as a
tan solid.
[0127] 2. Synthesis of 3-trifluoromethyl-benzimidic Acid Ethyl
Ester Hydrochloride (13):
[0128] To a solution of
.alpha.,.alpha.,.alpha.-trifluoromethyl-m-tolunitr- ile 14 (1 g,
5.84 mmol) in EtOH (10 mL, anhydrous) was bubbled HCl (gas,
anhydrous) for 10 minutes and the solution was stirred overnight.
The solvent was evaporated to yield compound 13 as a white solid.
The resulting solid was used in the next step without
purification.
[0129] 3. Synthesis of
5-methoxy-2-(3-trifluoromethylphenyl)-benzoxazole (10):
[0130] A solution of compound 13 and compound 12 (850 mg, 6.13
mmol) in THF (10 mL) was heated to reflux and allowed to stir
overnight. The reaction mixture was allowed to cool and the THF
evaporated (in vacuo). The residue was dissolved in ethyl acetate
and washed with water. The organic layer was dried over MgSO.sub.4
and treated with activated carbon Norit A. The mixture was filtered
through Celite 521, and evaporated (in vacuo) and the residue was
purified using column chromatography (20% Ethyl acetate/hexanes) to
afford compound 10 as a light yellow solid.
[0131] 4. Synthesis of 2-[(3-trifluoromethyl)phenyl]benzoxazol-5-ol
(8):
[0132] To a solution of compound 10 (200 mg, 0.68 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was added BBr.sub.3 (1M in
CH.sub.2Cl.sub.2, 1 mL, 1 mmol) dropwise. The resulting solution
was allowed to stir for 48 h. The solvent was removed by
evaporation (in vacuo) and the residue was dissolved in ethyl
acetate and washed with saturated NaHCO.sub.3. The organic layer
was dried over MgSO.sub.4 and evaporated (in vacuo). The residue
was purified using column chromatography (30% ethyl
acetate/hexanes) to yield compound 8 as a white solid.
[0133] 5. Synthesis of
5-(oxiran-2-yl-methoxy)-2-[(3-trifluoromethyl)pheny- l]benzoxazole
(6):
[0134] To a suspension of NaH (7 mg, 60% dispersion in oil, 0.18
mmol) in DMF (2 mL, anhydrous) was added a solution of compound 8
(54 mg, 0.19 mmol) in DMF (2 mL, anhydrous) dropwise. The solution
was allowed to stir for 15 minutes. To the above solution
epichlorohydrin (50 .mu.L, 0.63 mmol) was added and the resulting
solution was allowed to stir overnight. The solvent was evaporated
(in vacuo) and the residue dissolved in water and extracted with
ethyl acetate. The organic layers were combined, dried over
MgSO.sub.4 and evaporated to yield compound 6 as a clear oil.
[0135] Part D.
[0136] Synthesis
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[2-(3-trifluorom-
ethylphenyl)-benzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide
(7):
[0137] A solution of compound 5 (183 mg, 0.73 mmol) and compound 6
in EtOH (2 mL) and triethylamine (0.2 mL) was heated to 90.degree.
C. and allowed to stir overnight. The reaction mixture was allowed
to cool and the solvent evaporated (in vacuo) to yield an oil. The
oil was purified by prep TLC (5/0.5/94.5
MeOH/NH.sub.4OH/CH.sub.2Cl.sub.2) to yield compound 7 as a white
Solid: Mass Spectrum (MH.sup.+)=583.4
EXAMPLE 2
[0138]
2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxy-propyl]-piperazin-1-yl}-N--
(2,6-dimethylphenyl)acetamide (43): 34
[0139] Synthesis of 2-(oxiran-2-ylmethoxy)benzothiazole (44):
35
[0140] Compound 44 was prepared in the manner of compound 6
substituting 2-hydroxybenzothiazole for compound 8 in partC-5 of
Example 1.
[0141] Compound 43 was prepared in the manner of compound 7
substituting compound 44 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=455.3.
EXAMPLE 3
[0142]
N-(2,6-dimethylphenyl)-2-}4-[2-hydroxy-3-(2-methyl-benzothiazol-5-y-
loxy)-propyl]-piperazin-1-yl]acetamide (45): 36
[0143] Synthesis of 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole
(33): 37
[0144] Compound 33 was prepared in the manner of compound 6
substituting 2-methylbenzothiazol-5-ol for compound 8 in partC-5 of
Example 1.
[0145] Compound 45 was prepared in the manner of compound 7
substituting compound 33 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=469.3
EXAMPLE 4
[0146]
4-(3-}4-[(2,6-dimethylphenylcarbamoyl)-methyl]-piperazin-1-yl}-2-hy-
droxy-propoxy)-1H-indole-2-carboxylic Acid Amide (46): 38
[0147] Compound 19 was prepared in the manner of compound 7
substituting the commercially available
4-glycidyloxy-2-indolecarboxamide for compound 6 in part D of
compound 7: Mass Spectrum (MH.sup.+)=480.4.
EXAMPLE 5
[0148]
2-{4-[3-(benzothiazol-6-yloxy)2-hydroxy-propyl]-piperazin-1-yl}-N-(-
2,6-dimethylphenyl)-acetamide (47): 39
[0149] Synthesis of Benzothiazol-6-ol (16): 40
[0150] To a solution of 6-aminobenzothiazole (1.0 g, 6.66 mmol) in
water (22 mL) and H.sub.2SO.sub.4 (16 mL) at 5.degree. C. was added
a solution of sodium nitrite (460 mg, 6.72 mmol) in water (13 mL)
keeping the temperature below 5.degree. C. The resulting solution
was allowed to stir for 15 minutes. The reaction mixture was heated
to 160.degree. C. and a solution of H.sub.2SO.sub.4 (50 mL) and
water (38 mL) was slowly added. The resulting mixture was allowed
to stir for 1 h. The mixture was allowed to cool and an aqueous
solution of 50% sodium hydroxide was added until the pH=7. The
mixture was extracted with ethyl acetate and washed with brine. The
combined organic was dried over MgSO.sub.4 and evaporated to yield
a semi-solid. The semi-solid was purified by column chromatography
(40% ethyl acetate/hexanes) to yield benzothiazo-6-ol 16 as an
off-white solid.
[0151] Synthesis of 6-(oxiran-2-ylmethoxy)benzothiazole (48):
41
[0152] Compound 48 was prepared in the manner of compound 6
substituting compound 16 for compound 8 in partC-5 of Example
1.
[0153] Compound 47 was prepared in the manner of compound 7
substituting compound 48 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=455.3.
EXAMPLE 6
[0154]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-6-y-
loxy)-propyl]-piperazin-1-yl}aceamide (49): 42
[0155] Synthesis of 2-methylbenzothiazol-6-ol (50): 43
[0156] Compound 50 was prepared from the commercially available
6-methoxy-2-methyl-benzothiazole as described in partC-4 of Example
1.
[0157] Synthesis of 2-methyl-6-(oxiran-2-ylmethoxy)benzothiazole
(51): 44
[0158] Compound 51 was prepared in the manner of compound 6
substituting compound 50 for compound 8 in partC-5 of Example
1.
[0159] Compound 49 was prepared in the manner of compound 7
substituting compound 51 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+) 469.3.
EXAMPLE 7
[0160]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-y-
loxy)-propyl]-3,5-dimethyl-piperazine-1-yl}acetamide (52): 45
[0161] Synthesis of
N-(2,6-dimethylphenyl)-2-C3,5-dimethylpiperazin-1-yl)a- cetamide
(53): 46
[0162] Compound 53 was prepared in the manner of compound 3
substituting 2,6-dimethylpiperazine for piperazine in part A of
Example 1.
[0163] Compound 52 was prepared in the manner of compound 7
substituting compound 33 for compound 6 and compound 53 for
compound 5 in part D of compound 7: Mass Spectrum
(MH.sup.+)=497.4.
EXAMPLE 8
[0164]
2-{14-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-piperazi-
n-1-yl}-N-(4-hydroxy-phenyl)acetamide (54): 47
[0165] Synthesis of 4-aminophenyl Acetate (55): 48
[0166] Compound 55 was prepared in the manner of compound 12
substituting 4-nitrophenyl acetate for compound 11 in part C-1 of
Example 1.
[0167] Synthesis of 4-(2-chloroacetylamino)phenyl Acetate (56):
49
[0168] Compound 56 was prepared in the manner of compound 3
substituting compound 55 for compound 1 in part A of Example 1.
[0169] Synthesis of 4-(2-piperazinylacetylamino)phenyl Acetate
(57): 50
[0170] Compound 57 was prepared as described in part B of Example 1
substituting compound 56 for compound 3.
[0171] Compound 54 was prepared in the manner of compound 7
substituting compound 33 for compound 6 and compound 57 for
compound 5 in part D of compound 7: Mass Spectrum
(MH.sup.+)=457.5.
EXAMPLE 9
[0172]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-phenyl-benzothiazol-5-y-
loxy)-propyl]-piperazin-1-yl}acetamide (58): 51
[0173] Synthesis of phenyl-N-[3-(phenylmethoxy)phenyl]carboxamide
(25): 52
[0174] To a solution of 3-benzyloxyaniline 23 (1.0 g, 5.0 mmol) and
TEA (0.74 mL, 5.3 mmol) in CH.sub.2Cl.sub.2 was added benzoyl
chloride (0.61 mL, 5.26 mmol) dropwise and the mixture was allowed
to stir overnight. The reaction mixture was diluted with water and
the resulting solid was collected by vacuum filtration. The solid
was allowed to air dry, to yield compound 25 as a white solid.
[0175] Synthesis of
phenyl{[(3-phenylmethoxy)phenyl]amino}methane-1-thione (26): 53
[0176] A solution of compound 25 (455 mg, 1.5 mmol) and Lawesson's
reagent (0.6 mol equiv) in chlorobenzene (15 mL) was heated to
120.degree. C. and allowed to stir for 1.5 h. The reaction was
allowed to cool and the solvent was evaporated (in vacuo). The
residue was purified by column chromatography (ethyl acetate/hexane
1:9) to yield compound 26 as a yellow solid.
[0177] Synthesis of 2-phenyl-5-(phenylmethoxy)benzothiazole (27):
54
[0178] To a solution of compound 26 (960 mg, 3 mmol) in ethanol (5
mL) was added an aqueous sodium hydroxide solution (30%, 8 mol
equiv). The mixture was diluted with water (6 mL) to give a final
solution of 10% aqueous sodium hydroxide. The resulting solution
was added to a stirred solution of potassium ferricyanide (4 mol
equiv) in water at 90.degree. C. in aliquots (1 mL) and the
resulting mixture was heated for 30 min. The reaction mixture was
allowed to cool and the product was extracted with ethyl acetate.
The organic layer was dried and evaporated. The residue, a mixture
of 27 and 28, was column purified (ethyl acetate/hexane--1:99) to
provide compound 27 as a white solid.
[0179] Synthesis of 2-phenylbenzothiazol-5-ol (29): 55
[0180] Palladium hydroxide (100 mg) was added to a solution of 27
(260 mg, 0.8 mmol) of ethanol/cyclohexene (5 mL/2 mL) followed by
warming for reflux for 16 h. The reaction mixture was cooled and
the catalyst was removed by filtration (through Celite). The
solvent was evaporated to provide compound 29 as a white solid.
[0181] Synthesis of 5-(oxiran-2-ylmethoxy)-2-phenylbenzothiazole
(59): 56
[0182] Compound 59 was prepared in the manner of compound 6
substituting compound 29 for compound 8 in partC-5 of Example
1.
[0183] Compound 58 was prepared in the manner of compound 7
substituting compound 59 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=531.6
EXAMPLE 10
[0184]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-phenyl-benzoxazol-5-ylo-
xy)-propyl)-piperazin-1-yl}acetamide (60): 57
[0185] Synthesis of 5-(oxiran-2-ylmethoxy)-2-phenylbenzoxazole
(61): 58
[0186] Compound 61 was prepared in the manner of compound 6
substituting ethyl benzimidate hydrochloride for compound 13 in
partC1-5 of Example 1.
[0187] Compound 60 was prepared in the manner of compound 7
substituting compound 61 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=515.3.
EXAMPLE 11
[0188]
N-(2,6-dimethylphenyl)2-{4-[2-hydroxy-3-(2-phenyl-benzothiazol-7-yl-
oxy)-propyl]-piperazin-1-ylacetamide (62): 59
[0189] Synthesis of 7-(oxiran-2-ylmethoxy)-2-phenylbenzothiazole
(63): 60
[0190] Compound 63 was prepared in the manner of compound 59
substituting deprotected compound 28 for compound 29 in example
9.
[0191] Compound 62 was prepared in the manner of compound 7
substituting compound 63 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=531.3.
EXAMPLE 12
[0192]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-y-
loxy)-propyl]-2-oxo-piperazin-1-yl}acetamide (64): 61
[0193] Synthesis of Phenylmethyl
4-{[N-(2,6-dimethylphenyl)carbamoyl]methy-
l}-3-oxopiperazinecarboxylate (31): 62
[0194] To a solution of compound 30 (252 mg, 1.3 mmol) in THF (13
mL) and NaH (62 mg, 1.6 mmol) was added Compound 3 (300 mg, 1.3
mmol). The solution was allowed to stir under nitrogen overnight.
The reaction was quenched with water (0.1 mL) and dried over
Na.sub.2SO.sub.4. The solution was concentrated and purified using
column chromatography conditions to yield compound 31 as a
solid.
[0195] Synthesis of
N-(2,6-dimethylphenyl)-2-(2-oxopiperazinyl)-acetamide (32): 63
[0196] To a solution of compound 31 in methanol (10 mL) 10%
palladium on carbon was added. The reaction vessel was charged with
hydrogen (40 p.s.i) and agitated for 4 h. The catalyst was removed
by filtration and the filtrate was concentrated and purified using
column chromatography (1:15 MeOH:DCM) to yield compound 32 as a
semi solid.
[0197] Compound 64 was prepared in the manner of compound 7
substituting compound 33 for compound 6 and compound 32 for
compound 5 in part D of compound 7: Mass Spectrum
(MH.sup.+)=483.3
EXAMPLE 13
[0198]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzoxazol-5-ylo-
xy)-propyl]-piperazin-1-yl}acetamide (65): 64
[0199] Synthesis of 5-methoxy-2-methyl-benzoxazole (19): 65
[0200] A solution of 2-amino-4-methoxyphenol 17 (8 g, 57.4 mmol) in
trimethyl orthoacetate 18 (50 mL) was heated to reflux and allowed
to stir for 24 h. The reaction was allowed to cool and the excess
18 was evaporated (in vacuo). The residue was dissolved in ethyl
acetate and washed with water. The organic layer was dried over
MgSO.sub.4 and treated with activated carbon Norit A. The resulting
solution was filtered through Celite 521 and evaporated to yield an
oil. The oil was chromatographed on silica gel (20% ethyl
acetate/hexanes) to yield compound 19 as a light yellow solid.
[0201] Synthesis of 2-methyl-5-oxiran-2-ylmethoxybenzoxazole (67):
66
[0202] Compound 67 was prepared in the manner of compound 6
substituting 6-hydroxy-2-methyl-benzoxazole 66 for compound 8 in
part C-5 of Example 1.
[0203] Compound 66 in turn was obtained by the deprotection of
compound 19 as described in partC-4 of Example 1.
[0204] Compound 65 was prepared in the manner of compound 7
substituting compound 67 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=543.4
EXAMPLE 14
[0205]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[2-(4-trifluoromethyl-phen-
yl)-benzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide (68):
67
[0206] Synthesis of
5-(oxiran-2-ylmethoxy)-2-(4-trifluoromethyl-phenyl)ben- zoxazole
(69): 68
[0207] Compound 69 was prepared in the manner of compound 6
substituting 4-trifluoromethylbenzimidic acid ethyl ester
hydrochloride for compound 13 in partC1-5 of Example 1.
[0208] Compound 68 was prepared in the manner of compound 7
substituting compound 69 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=583.4
EXAMPLE 15
[0209]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinoxalin-2-yloxy)-propy-
l]-piperazin-1-yl}acetamide (70): 69
[0210] Synthesis of 2-(oxiran-2-ylmethoxy)quinoxaline (71): 70
[0211] Compound 71 was prepared in the manner of compound 6
substituting quinoxaline-2-ol for compound 8 in part C-5 of Example
1.
[0212] Compound 70 was prepared in the manner of compound 7
substituting compound 71 for compound 6 in part D of compound 7:
Mass Spectrum (MH)=450.9.
EXAMPLE 16
[0213]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(pyridin-3-yloxy)-propyl]--
piperazin-1-yl}acetamide (72): 71
[0214] Synthesis of 3-(oxiran-2-ylmethoxy)pyridine (73): 72
[0215] Compound 73 was prepared in the manner of compound 6
substituting 3-hydroxypyridine for compound 8 in part C-5 of
Example 1.
[0216] Compound 72 was prepared in the manner of compound 7
substituting compound 73 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=399.4.
EXAMPLE 17
[0217]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinolin-4-yloxy)-propyl]-
-piperazin-1-yl}acetamide (74): 73
[0218] Synthesis of 4-(oxiran-2-ylmethoxy)quinoline (75): 74
[0219] Compound 75 was prepared in the manner of compound 6
substituting 4-hydroxyquinoline for compound 8 in part C-5 of
Example 1.
[0220] Compound 74 was prepared in the manner of compound 7
substituting compound 75 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=449.4.
EXAMPLE 18
[0221]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(isoquinolin-5-yloxy)-prop-
yl]-piperazin-1-yl}acetamide (76): 75
[0222] Synthesis of 5-(oxiran-2-ylmethoxy)isoquinoline (77):
[0223] Compound 77 was prepared in the manner of compound 6
substituting 5-hydroxyisoquinoline for compound 8 in part C--S of
Example 1.
[0224] Compound 76 was prepared in the manner of compound 7
substituting compound 77 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)==449.4.
EXAMPLE 19
[0225]
N-(2,6-dimethylphenyl)-2-{4-12-hydroxy-3-(quinolin-6-yloxy)-propyl]-
-piperazin-1-yl}acetamide (78): 76
[0226] Synthesis of 6-(oxiran-2-ylmethoxy)quinoline (79): 77
[0227] Compound 79 was prepared in the manner of compound 6
substituting 6-hydroxyquinoline for compound 8 in part C-5 of
Example 1.
[0228] Compound 78 was prepared in the manner of compound 7
substituting compound 79 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=449.4
EXAMPLE 20
[0229]
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-quinolin-7-yloxy-
)-propyl]-piperazin-1-yl}acetamide (80): 78
[0230] Synthesis of 2-methyl-7-(oxiran-2-ylmethoxy)quinoline (81):
79
[0231] Compound 81 was prepared in the manner of compound 6
substituting 7-hydroxy-2-methyl-quinoline for compound 8 in part
C-5 of Example 1.
[0232] Compound 80 was prepared in the manner of compound 7
substituting compound 81 for compound 6 in part D of compound 7:
Mass Spectrum (MH.sup.+)=463.5.
EXAMPLE 21
[0233]
2-{4-[3-(benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinyl}-N-(2,-
6-dimethylphenyl)acetamide (39): 80
[0234] Synthesis of (phenylmethoxy)-N-prop-2-enylcarboxamide (42):
81
[0235] To a solution of allylamine (3.34 g, 5.85 mmol) in
dichloromethane (100 mL) and triethylamine (16 mL) benzyl
chloroformate (8.25 mL, 5.78 mmol) was added at 0.degree. C. The
mixture was stirred at 0.degree. C. for 2 hours and additional 90
minutes at RT. The solvent was removed by evaporation and the
residue was purified by flash column chromatography (30%
EtOAc/Hexanes) to yield compound 42 as a clear oil.
[0236] Synthesis of
N-(oxiran-2-ylmethoxy)(phenylmethoxy)carboxamide (35): 82
[0237] Compound 42 (5.0 g, 2.61 mmol) was treated with
m-chloroperbenzoic acid (11.71 g, 9.1 mmol) in dichloromethane (110
mL) at room temperature for 18 h. Dichloromethane was evaporated to
afford a viscous oil which was then purified by flash column
chromatography (30% EtOAc/Hexanes) to give compound 35 as a clear
oil.
[0238] Synthesis of
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[phenylmethox-
y]carbonylamino]propyl}piperazinyl)acetamide (36): 83
[0239] A solution of compound 42 (2.5 g, 1.2 mmol) and compound 5
(5.94 g, 2.4 mmol) in ethanol (100 mL) and triethylamine (3.34 mL)
was refluxed for 18 h. Solvents were removed and the residue was
purified by flash column chromatography (ethyl acetate) to afford
compound 36 as a white solid.
[0240] Synthesis of
2-[4-(3-amino-2-hydroxypropyl)piperazinyl]-N-(2,6-dime-
thylphenyl)acetamide (37): 84
[0241] A solution of compound 36 (3.0 g, 0.66 mmol) in methanol (70
mL) in presence of 10% Palladium on Carbon (0.337 g) was stirred
under hydrogen atmosphere for 16 h. Filtration of catalyst followed
by concentration afforded compound 37 as a sticky solid.
[0242] To a solution of compound 37 (75 mg) in ethanol (2 mL) was
added triethylamine (0.13 mL) and 2-chlorobenzthiazole (87 mg)
followed by warming to reflux for 16 h. The reaction mixture was
concentrated and purified by preparative TLC (5%
MeOH/Dichloromethane) to give Compound 39 as a white solid. Mass
Spectrum (MH.sup.+)=454.4.
EXAMPLE 22
[0243]
2-{4-[3-(benzoxazol-2-ylamino)-2-hydroxypropyl]piperazinyl}-N-(2,6--
dimethylphenyl)acetamide (82): 85
[0244] Compound 82 was prepared in the manner of compound 39 by
substituting 2-chlorobenzoxazole for 2-chloro-benzothiazole as in
example 21. Mass Spectrum (MH.sup.+)=438.4. The following compounds
were made in the same manner as shown in Examples 1-21. The
compounds all provided satisfactory mass spectrum data
(MH.sup.+).
[0245]
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-di-
methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0246]
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-di-
methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0247]
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-di-
methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0248]
2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-
-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0249]
2-{(2R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-
-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0250]
2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-meth-
ylpiperazinyl)-N-(2,6-dimethylphenyl)acetamide
[0251]
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-di-
methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0252]
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-meth-
ylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0253]
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-di-
azaperhydroepinyl)}-N-(2,6-dimethylphenyl)acetamide
[0254]
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-(4-hydroxyphenyl)acetamide
[0255]
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-di-
methylpiperazinyl}-N-(4-carboxamidophenyl)acetamide
[0256]
2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-
-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0257]
2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}-N-(2,6-dimethylphenyl)acetamide
[0258]
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-(2,6-dimethyl-4-hydroxyphenyl)acetamide
[0259]
2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-di-
azabicyclo[2.2.1]hept-2-yl}-N-(2,6-dimethylphenyl)acetamide
[0260]
2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}-N-(4-sulfamoyphenyl)acetamide,
[0261]
2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]-3-m-
ethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide
[0262]
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-naphthylacetamide
[0263]
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-}4-[2-hydroxy-3-(2-methylb-
enzothiazol-5-yloxy)propyl]piperazinyl}acetamide
[0264]
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-phenylacetamide
[0265]
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-(3,4,5-trichlorophenyl)acetamide
[0266]
2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-N-(3,4,5-tri-
chlorophenyl)acetamide
[0267]
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl--
N-(2-chloro-4-methylphenyl)-acetamide
[0268]
2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-(3,4,5-trichlorophenyl)acetamide
[0269]
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-(3,5-dichlorophenyl)-acetamide
[0270]
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-(3,4-dichlorophenyl)-acetamide
[0271]
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-[3-methoxy-5-(trifluoromethyl)phenyl]acetamide
[0272]
2-{4-[2-hydroxy-3-(2-phenylbenzothiazol-5-yloxy)propyl]piperazinyl}-
-N-[3,-5-dichloro)phenyl]acetamide
[0273]
2-{4-[2-hydroxy-3-(2-((1E)buta-1,3-dienyl)benzothiazol-5-yloxy)prop-
yl]piperazinyl}-N-[4-chloro-2-methoxy-5-methylphenyl]acetamide
EXAMPLE 23
[0274] Mitochondrial Assays
[0275] Rat heart mitochondria were isolated by the method of
Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).
[0276] Palmitoyl CoA oxidation--The Palmityl CoA oxidation was
carried out in a total volume of 100 micro liters containing the
following agents: 110 mM KCl, 33 mM Tris buffer at pH 8, 2 mM KPi,
2 MM MgCl.sub.2, 0.1 MM EDTA, 14.7 microM defatted BSA, 0.5 mM
malic acid, 13 mM carnitine, 1 mM ADP, 52 micrograms of
mitochondrial protein, and 16 microM 1-C14 palmitoyl CoA (Sp.
Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters per
assay). The compounds of this invention were added in a DMSO
solution at the following concentrations: 100 microM, and 50
microM. In each assay, a DMSO control was used. After 15 min at
30.degree. C., the enzymatic reaction was centrifuged (20,000 g for
1 min), and 70 microliters of the supernatant was added to an
activated reverse phase silicic acid column (approximately 0.5 ml
of silicic acid). The column was eluted with 2 ml of water, and 0.5
ml of the eluent was used for scintillation counting to determine
the amount of C.sup.14 trapped as C.sup.14 bicarbonate ion.
1TABLE 1 Inhibition of mitochondrial fatty acid oxidation using
palmitoyl CoA as substrate - % of Control at 2 concentrations and
IC.sub.50. Compound # 100 .mu.m (%) 50 .mu.m (%) IC.sub.50 (.mu.m)
7 -- 77 -- 39 27 -- -- 43 21 -- -- 45 87 -- .about.20 46 61 --
.about.125 47 70 -- .about.125 49 3 -- -- 52 95 -- .about.1 54 81
-- .about.8 60 -- 61 -- 62 -- 62 -- 64 41 -- -- 68 -- 68 -- 70 12
-- -- 72 8 -- -- 74 12 -- -- 76 26 -- -- 78 42 -- -- 80 22 -- -- 82
22 -- --
EXAMPLE 25
[0277] Metabolic Stability: As a measure of metabolic stability the
compounds of this invention were incubated with human liver S-9
microsomal fractions. After, 30 minutes at 37 C, the amount of
parent drug remaining was determined using LC-mass spec. The
response factors for each compound was determined by establishing a
standard curve and using an internal standard during the analysis
of the samples. An average of five experiments for percentage of
ranolazine remaining at the 30 minute time point is 57%. The
compounds of this invention were assayed as described in the
protocol below and the percentage of parent remaining was divided
by the average % of ranolazine remaining (57%) affording a
metabolic stability factor. A compound with a stability number
greater than 1.2 has a better stability than ranolazine in the
liver S-9 assay. A compound with a stability number between 1.2 and
0.8 has an equivalent stability in the liver S-9 assay. A compound
with a stability number less than 0.8 is less stable than
ranolazine in the liver S-9 assay.
[0278] The purpose of this experiment is to compare the percentages
remaining for compounds of this invention with the percentage
remaining for ranolazine after 30 minutes of incubation with human
liver S9 fractions.
[0279] Reagents:
[0280] The following reagents were used; Potassium phosphate, 0.5M
pH 7.4 (incubation buffer), kept at room temperature; 0.05M
MgCl.sub.2 kept at 4.degree. C.; .beta.-Nicotinamide adenine
dinucleotide phosphate, tetrasodium salt, reduced form (NADPH),
0.02M solution in water (.about.16.6 mg/mL) from Sigma Lot #
79H7044 prepared on day of use. 1 mM of ranolazine or Compounds 43,
45, 47, 52, 70, 74, 76, 78, and 80 in ACN further diluted to obtain
100 .mu.M in 10% ACN; Human S9 stock: 20 mg/mL from Gentest.
[0281] Procedure:
[0282] Incubation mixtures were prepared as follows:
2 TABLE 2 Volume per 0.25 mL of Final Component Incubation Mixture
concentration 10 .mu.M CVT 25 .mu.L 10 .mu.M compounds MgCl.sub.2
25 .mu.L 0.005 M NADPH 25 .mu.L 0.002 M S9 25 .mu.L 2 mg/mL
Incubation Buffer 25 .mu.L 0.05 M Water 125 .mu.L -- *1% organic
solvent (acetonitrile) was used in incubation mixture. Generally,
30 incubates were prepared at a time by pre-mixing 0.75 mL of
MgCl.sub.2, 0.75 mL of incubation buffer, 0.75 mL of NADPH, 3.75 mL
of water. Then pipette 200 .mu.L/incubate, add 25 .mu.L of compound
being tested, mix, and initiate reaction by addition of S-9.
[0283] Combine all components with incubation buffer and re-pipette
200 .mu.L/tube+25 .mu.L of the compound being tested along with 25
.mu.L of S-9.
[0284] After 5 min of pre-incubation at 37.degree. C., at 0 and 30
min after starting the reaction, a 50 .mu.l aliquot of the
incubation mixture was removed and added to 100 .mu.L of 9:1
acetonitrile: methanol containing the internal standard.
[0285] The mixture was centrifuged and a 100 .mu.L aliquot of the
supernatant was diluted in 1 mL of solvent C (0.1% Formic Acid in
water). Then samples were analyzed for change between the ratio of
compound to internal standard at time zero and 30 minutes by LC/MS
(injected 10 .mu.L).
[0286] Analytical and Data Calculations:
[0287] Samples were analyzed for the starting compounds and
potential metabolite/s by LC/MS using an internal standard and an
ODS-C18 column with a flow rate of 0.25 ml/min. Following the above
procedure resulted in the following relative stability factors as
compared to ranolazine for the compounds of this invention as
illustrated in Table 3.
3 TABLE 3 Compound # Liver S9 Stability Factor 43 0.6 45 0.8 46 1.1
47 1.5 52 0.5 70 0.1 74 1.0 76 0.8 78 0.6 80 0.5
* * * * *