U.S. patent application number 09/792167 was filed with the patent office on 2001-11-29 for substituted alkyl piperazine derivatives.
Invention is credited to Blackburn, Brent K., Elzein, Elfatih, Palle, Venkata P., Varkhedkar, Vaibhav, Zablocki, Jeff.
Application Number | 20010047001 09/792167 |
Document ID | / |
Family ID | 27391813 |
Filed Date | 2001-11-29 |
United States Patent
Application |
20010047001 |
Kind Code |
A1 |
Varkhedkar, Vaibhav ; et
al. |
November 29, 2001 |
Substituted alkyl piperazine derivatives
Abstract
Novel compounds of the general formula: 1 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.
Inventors: |
Varkhedkar, Vaibhav;
(Sunnyvale, CA) ; Palle, Venkata P.; (Mountain
View, CA) ; Zablocki, Jeff; (Mountain View, CA)
; Elzein, Elfatih; (Fremont, CA) ; Blackburn,
Brent K.; (Los Altos, CA) |
Correspondence
Address: |
A. Blair Hughes
McDonnell Boehnen Hulbert & Berghoff
32nd Floor
300 S. Wacker Drive
Chicago
IL
60606
US
|
Family ID: |
27391813 |
Appl. No.: |
09/792167 |
Filed: |
February 22, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60209262 |
Jun 5, 2000 |
|
|
|
60184306 |
Feb 22, 2000 |
|
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Current U.S.
Class: |
514/252.12 ;
514/255.03; 544/400 |
Current CPC
Class: |
C07D 317/58 20130101;
C07D 241/08 20130101; C07D 241/42 20130101; C07D 317/54 20130101;
C07D 241/04 20130101; C07D 295/15 20130101 |
Class at
Publication: |
514/252.12 ;
544/400; 514/255.03 |
International
Class: |
A61K 031/495; C07D
241/04 |
Claims
We claim:
1. A substituted piperazine compound having the following formula:
27R.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; 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
selected from the group consisting of alkyl, cycloalkyl, and fused
phenylcycloalkyl wherein the point of attachment is on the
cycloalkyl wherein the alkyl, cycloalkyl, and fused
phenylcycloalkyl are optionally substituted with from 1 to three
substituents selected from the group consisting of halo, CF.sub.3,
CN, OR.sup.20, SR.sup.20, 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, C.sub.1-2
alkyl, and aryl wherein the optional aryl substituent is optionally
substituted with from 1 to 3 substituents selected from the group
consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20, and C.sub.1-6
alkyl; 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 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.2).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.2-4 alkenyl, C.sub.2-4
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; 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.2-3 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 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 selected from the group consisting of alkyl,
cycloalkyl, and fused phenylcycloalkyl wherein the point of
attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and
fused phenylcycloalkyl are optionally substituted with from 1 to
two substituents selected from the group consisting of halo,
CF.sub.3, CN, OR.sup.20, SR.sup.20, S(O)R.sup.22, SO.sub.2R.sup.22,
C.sub.1-2 alkyl, and aryl wherein the optional aryl substituent is
optionally substituted with from 1 to 3 substituents selected from
the group consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20, and
C.sub.1-6 alkyl; 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 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.1-3 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 selected from the group consisting of
alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of
attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and
fused phenylcycloalkyl are optionally substituted with from 1 to
two substituents selected from the group consisting of halo,
CF.sub.3, OR.sup.20, S(O)R.sup.22, C.sub.1-2 alkyl, and aryl
wherein the optional aryl substituent is optionally substituted
with from 1 to 3 substituents selected from the group consisting of
halo, phenyl, CF.sub.3, CN, OR.sup.20, and C.sub.1-6 alkyl; 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 compound of claim 1 wherein m=1 or 2; 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.22 and
C.sub.1-4 alkyl and wherein R.sup.22 is a C.sub.1-3 alkyl; R.sup.6,
R.sup.7 and R.sup.8 each independently selected from the group
consisting of hydrogen and 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.2).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 selected from the group consisting of alkyl,
cycloalkyl, and fused phenylcycloalkyl wherein the point of
attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and
fused phenylcycloalkyl are optionally substituted with from 1 to
two substituents selected from the group consisting of halo,
CF.sub.3, OR.sup.20, and aryl wherein the optional aryl substituent
is optionally substituted with from 1 to 3 substituents selected
from the group consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20,
and C.sub.1-6 alkyl; 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 5 wherein 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 and
C.sub.1-4 alkyl, or R.sup.9 and R.sup.10 together form a carbonyl,
or R.sup.11 and R.sup.12 together form a carbonyl, or R.sup.13 and
R.sup.14 together form a carbonyl, or R.sup.15 and R.sup.16
together form a carbonyl, R.sup.10 and R.sup.11 together form
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.
7. The compound of claim 5 wherein 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.
8. The compound of claim 5 wherein 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.
9. 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, or C.sub.1-3
alkyl wherein the alkyl substituent is optionally substituted with
CF.sub.3.
10. The compound of claim 1 wherein R.sup.6, R.sup.7 and R.sup.8
each independently selected from the group consisting of hydrogen
or methyl.
11. The compound 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, 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 selected from the group consisting of
alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of
attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and
fused phenylcycloalkyl are optionally substituted with from 1 to
two substituents selected from the group consisting of halo,
CF.sub.3, OR.sup.20, and aryl wherein the optional aryl substituent
is optionally substituted with from 1 to 2 substituents selected
from the group consisting of halo, phenyl, CF.sub.3, OR.sup.20, and
C.sub.1-4 alkyl; and R.sup.20 is selected from the group consisting
of H or C.sub.1-3 alkyl.
12. The compound of claim 11 wherein R.sup.17 is selected from the
group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl
wherein the point of attachment is on the cycloalkyl wherein the
alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally
substituted with 1 substituent selected from the group consisting
of halo, CF.sub.3, OR.sup.20, and aryl wherein the optional aryl
substituent is optionally substituted with from 1 to 2 substituents
selected from the group consisting of halo, phenyl, CF.sub.3,
OR.sup.20, and C.sub.1-4 alkyl.
13. The compound of claim 1 wherein R.sup.17 is selected from the
group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl
wherein the point of attachment is on the cycloalkyl wherein the
alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally
substituted with 1 substituent selected from the group consisting
of halo, CF.sub.3, OR.sup.20, and aryl wherein the optional aryl
substituent is optionally substituted with from 1 to 2 substituents
selected from the group consisting of halo, phenyl, CF.sub.3,
OR.sup.20, and C.sub.1-4 alkyl.
14. The compound of claim 11 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, OCH.sub.3, or methyl.
15. The compound of claim 11 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, or methyl.
16. The compound of claim 11 wherein 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.
17. A compound 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, 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
selected from the group consisting of alkyl, cycloalkyl, and fused
phenylcycloalkyl wherein the point of attachment is on the
cycloalkyl wherein the alkyl, cycloalkyl, and fused
phenylcycloalkyl are optionally substituted with 1 substituent
selected from the group consisting of halo, CF.sub.3, OR.sup.20,
and aryl wherein the optional aryl substituent is optionally
substituted with from 1 to 2 substituents selected from the group
consisting of halo, phenyl, CF.sub.3, OR.sup.20, and C.sub.1-4
alkyl; and R.sup.20 is methyl or H.
18. The compound of claim 17 wherein R.sup.17 is alkyl having from
1 to 6 carbon atoms and cycloalkyl.
19. The compound of claim 17 wherein R.sup.17 is a fused
phenylcycloalkyl that is optionally substituted with from 1 to 2
substituents selected from the group consisting of halo, CF.sub.3,
OR.sup.20, C.sub.1-2 alkyl, and aryl.
20. The compound of claim 17 wherein R.sup.17 is phenylmethyl that
is optionally substituted with from 1 to 2 substituents selected
from the group consisting of halo, CF.sub.3, OR.sup.20, C.sub.1-4
alkyl, and aryl.
21. The compound of claim 17 wherein R.sup.2, R.sup.3, and R.sup.4
are each hydrogen and R.sup.1 and R.sup.5 are each methyl.
22. The compound 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 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
selected from the group consisting of alkyl having from 1 to 6
carbon atoms, cycloalkyl having from 4 to 6 carbon atoms, fused
phenylcycloalkyl with a phenyl that is optionally substituted with
from 1 to 2 substituents selected from the group consisting of
halo, CF.sub.3, OH, methyl, and aryl, and aryl that is optionally
substituted with from 1 to 2 substituents selected from the group
consisting of halo, CF.sub.3, OH, C.sub.1-2 alkyl, and aryl.
23. The compound of claim 1 selected from the group consisting of
substituted piperazine compound selected from the group consisting
of
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylpheny-
l)acetamide;
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)-
piperazinyl]acetamide;
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmet-
hoxy)propyl]piperazinyl}acetamide,
2-({2-[4-(3-cyclopentyloxy-2-hydroxypro-
pyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide,
2-({2-[4-(3-cyclohexylo-
xy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide,
2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2-
,6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophen-
yl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide,
2-(4-{3-[(2,4-difluorop-
henyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamid-
e,
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]me-
thoxy}propyl)piperazinyl]acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-
-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide,
2-(4-{3-[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,-
6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-m-
ethoxyphenyl)methoxy]propyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)--
2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}-
piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenyl-
phenyl)methoxy]propyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{-
3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydoxy-3-(2-naphthylmethoxy)propyl]piperaz-
inyl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydro-
xypropyl]piperazinyl}acetamide, and
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-flu-
orophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide.
24. 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.
25. The method of claim 24 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.
26. The method of claim 24 wherein the therapeutically effective
amount ranges from about 0.01 to about 100 mg/kg weight of the
mammal.
27. The method of claim 24 wherein the mammal is a human.
28. A pharmaceutical composition of matter comprising the
composition of claim 1 and one or more pharmaceutical
excipients.
29. The pharmaceutical composition of matter of claim 28 wherein
the pharmaceutical composition is in the form of a solution.
30. The pharmaceutical composition of matter of claim 28 wherein
the pharmaceutical composition is in a form selected from the group
consisting of a tablet or a capsule.
Description
[0001] This application claims priority of U.S. Patent Application
60/184306 filed on Feb. 22, 2000, and to U.S. Patent Application
60/209262 filed on Jun. 5, 2000, the specifications of each of
which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is concerned with substituted
piperazine compounds, therapeutic dosage forms including one or
more of the compounds, 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.
[0004] 2. Description of the Art
[0005] 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.
[0006] 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.
[0007] 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
[0008] This invention includes novel substituted piperazine
compounds that are partial fatty acid oxidation inhibitors with
good therapeutic half-lives.
[0009] 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.
[0010] This invention includes a class of substituted piperazine
compounds having the following formula: 2
[0011] wherein
[0012] m=1, 2, or 3;
[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;
[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 alkyl;
[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 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;
[0016] R.sup.17 is selected from the group consisting of alkyl,
cycloalkyl, and fused phenylcycloalkyl wherein the point of
attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and
fused phenylcycloalkyl are optionally substituted with from 1 to
three substituents selected from the group consisting of halo,
CF.sub.3, CN, OR.sup.20, SR.sup.20, 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, C.sub.1-2
alkyl, and aryl wherein the optional aryl substituent is optionally
substituted with from 1 to 3 substituents selected from the group
consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20, and C.sub.1-6
alkyl;
[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 still another embodiment, this invention is a substituted
piperazine compound selected from the group consisting of
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylpheny-
l)acetamide;
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)-
piperazinyl]acetamide;
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmet-
hoxy)propyl]piperazinyl}acetamide,
2-({2-[4-(3-cyclopentyloxy-2-hydroxypro-
pyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide,
2-({2-[4-(3-cyclohexylo-
xy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide,
2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2-
,6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophen-
yl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide,
2-(4-{3-[(2,4-difluorop-
henyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamid-
e,
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]me-
thoxy}propyl)piperazinyl]acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-
-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide,
2-(4-{3-[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,-
6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-m-
ethoxyphenyl)methoxy]propyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)--
2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}-
piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenyl-
phenyl)methoxy]propyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{-
3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-hydoxy-3-(2-naphthylmethoxy)propyl]piperaz-
inyl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydro-
xypropyl]piperazinyl}acetamide, and
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-flu-
orophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)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] This invention concerns substituted piperazine compounds
having the following formula: 3
[0022] 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;
[0023] 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;
[0024] 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;
[0025] R.sup.17 is selected from the group consisting of alkyl,
cycloalkyl, and fused phenylcycloalkyl wherein the point of
attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and
fused phenylcycloalkyl are optionally substituted with from 1 to
three substituents selected from the group consisting of halo,
CF.sub.3, CN, OR.sup.20, SR.sup.20, 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, C.sub.1-2
alkyl, and aryl wherein the optional aryl substituent is optionally
substituted with from 1 to 3 substituents selected from the group
consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20, and C.sub.1-6
alkyl;
[0026] 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
[0027] 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.
[0028] It is preferred that m=1 or 2 and most preferred when
m=1.
[0029] In preferred compositions of this invention, 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.22 and C.sub.1-4 alkyl and wherein R.sup.22 is a C.sub.1-3
alkyl. In other preferred compositions, 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.
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,
or methyl with R.sup.2, R.sup.3, and R.sup.4 as hydrogen and
R.sup.1 and R.sup.5 as methyl being preferred.
[0030] In other preferred compositions of this invention, R.sup.6,
R.sup.7 and R.sup.8 each independently selected from the group
consisting of hydrogen and C.sub.1-3 alkyl with hydrogen or methyl
being preferred and hydrogen being most preferred.
[0031] In yet other preferred compositions of this invention,
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. In alternative preferred
compositions, 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 and C.sub.1-4 alkyl, or
R.sup.9 and R.sup.10 together form a carbonyl, or R.sup.11 and
R.sup.12 together form a carbonyl, or R.sup.13 and R.sup.14
together form a carbonyl, or R.sup.15 and R.sup.16 together form a
carbonyl, R.sup.10 and R.sup.11 together form
--CH.sub.2CH.sub.2CH.sub.2C- H.sub.2--. 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. More preferably,
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 another 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, or, 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 may each be
hydrogen.
[0032] In compounds of this invention, R.sup.17 may be selected
from the group consisting of alkyl, cycloalkyl, and fused
phenylcycloalkyl wherein the point of attachment is on the
cycloalkyl wherein the alkyl, cycloalkyl, and fused
phenylcycloalkyl are optionally substituted with from 1 to three
substituents selected from the group consisting of halo, CF.sub.3,
CN, OR.sup.20, SR.sup.20, 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, C.sub.1-2
alkyl, and aryl wherein the optional aryl substituent is optionally
substituted with from 1 to 3 substituents selected from the group
consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20, and C.sub.1-6
alkyl. In certain preferred compounds of this invention, R.sup.17
is selected from the group consisting of alkyl, cycloalkyl, and
fused phenylcycloalkyl wherein the point of attachment is on the
cycloalkyl wherein the alkyl, cycloalkyl, and fused
phenylcycloalkyl are optionally substituted with from 1 to two
substituents selected from the group consisting of halo, CF.sub.3,
CN, OR.sup.20, SR.sup.20, S(O)R.sup.22, SO.sub.2R.sup.22, C.sub.1-2
alkyl, and aryl wherein the optional aryl substituent is optionally
substituted with from 1 to 3 substituents selected from the group
consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20, and C.sub.1-6
alkyl. In other preferred compounds of this invention, R.sup.17 is
selected from the group consisting of alkyl, cycloalkyl, and fused
phenylcycloalkyl wherein the point of attachment is on the
cycloalkyl wherein the alkyl, cycloalkyl, and fused
phenylcycloalkyl are optionally substituted with from 1 to two
substituents selected from the group consisting of halo, CF.sub.3,
OR.sup.20, and aryl wherein the optional aryl substituent is
optionally substituted with from 1 to 3 substituents selected from
the group consisting of halo, phenyl, CF.sub.3, CN, OR.sup.20, and
C.sub.1-6 alkyl. Is other preferred compounds of this invention,
R.sup.17 is selected from the group consisting of alkyl having from
1 to 6 carbon atoms, cycloalkyl having from 4 to 6 carbon atoms,
fused phenylcycloalkyl with a phenyl that is optionally substituted
with from 1 to 2 substituents selected from the group consisting of
halo, CF.sub.3, OH, methyl, and aryl, and aryl that is optionally
substituted with from 1 to 2 substituents selected from the group
consisting of halo, CF.sub.3, OH, C.sub.1-2 alkyl, and aryl. In
still other preferred compounds of this invention, R.sup.17 is
alkyl having from 1 to 6 carbon atoms and cycloalkyl or R.sup.17 is
a fused phenylcycloalkyl that is optionally substituted with from 1
to 2 substituents selected from the group consisting of halo,
CF.sub.3, OR.sup.20, C.sub.1-2 alkyl, and aryl or R.sup.17 is
phenylmethyl that is optionally substituted with from 1 to 2
substituents selected from the group consisting of halo, CF.sub.3,
OR.sup.20, C.sub.1-4 alkyl, and aryl.
[0033] In the compounds of this invention, 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. More preferably, R.sup.20 is selected
from the group consisting of H or C.sub.1-3 alkyl and most
preferably, R.sup.20 is methyl or H.
[0034] Most preferably, the substituted piperazine compounds of
this invention are selected from the group consisting of
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylpheny-
l)acetamide;
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)-
piperazinyl]acetamide;
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmet-
hoxy)propyl]piperazinyl}acetamide,
2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-
-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}-
piperazinyl)acetamide,
2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxyprop-
yl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2--
[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]ace-
tamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)methoxy-
]propyl}piperazinyl)acetamide,
2-(4-{3-[(2,4-dimethoxyphenyl)methoxy]-2-hy-
droxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)methoxy]propyl-
}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)me-
thoxy]-2-hydroxypropyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4--
{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}-
piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)meth-
oxy]-2-hydroxypropyl}piperazinyl)acetamide,
N-(2,6-dimethylphenyl)-2-{4-[2-
-hydoxy-3-(2-naphthylmethoxy)propyl]piperazinyl}acetamide,
N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]pipera-
zinyl}acetamide, and
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)metho-
xy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide.
[0035] The following definitions apply to terms as used herein.
[0036] "Halo" or "Halogen"--alone or in combination means all
halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo
(I).
[0037] "Hydroxyl" refers to the group --OH.
[0038] "Thiol" or "mercapto" refers to the group --SH.
[0039] "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.
[0040] "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.
[0041] "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.
[0042] "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.
[0043] "Alkyl alkynyl" refers to a groups --RC?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.
[0044] "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.
[0045] "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.
[0046] "Acyl" denotes groups --C(O)R, where R is hydrogen, lower
alkyl substituted lower alkyl, aryl, substituted aryl and the like
as defined herein.
[0047] "Aryloxy" denotes groups --OAr, where Ar is an aryl,
substituted aryl, heteroaryl, or substituted heteroaryl group as
defined herein.
[0048] "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.
[0049] "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.
[0050] "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.
[0051] "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.
[0052] "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.
[0053] "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.
[0054] "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.
[0055] "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.
[0056] "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.
[0057] "Aralkyl" refers to the group --R--Ar where Ar is an aryl
group and R is lower alkyl or substituted lower alkyl 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.
[0058] "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.
[0059] "Cycloalkyl" refers to a divalent cyclic or polycyclic alkyl
group containing 3 to 15 carbon atoms.
[0060] "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.
[0061] "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.
[0062] "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.
[0063] "Treating" and "treatment" refer to any treatment of a
disease in a mammal, particularly a human, and include:
[0064] (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;
[0065] (ii) inhibiting the disease, i.e., arresting its
development; or
[0066] (iii) relieving the disease, i.e., causing regression of the
disease.
[0067] The compositions of this invention are useful for treating
mammals in a therapy 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. The treatment is accomplished using a
therapeutically effective amount of at least one compound of this
invention and/or a pharmaceutically acceptable acid addition salt
thereof in admixture with a pharmaceutically acceptable
excipient.
[0068] Compounds falling within the scope of this invention include
the optical isomers (+) and (-) and R- and S- isomers of the
above-identified compounds and mixtures thereof. This invention
includes the individual isomers and all possible mixtures thereof.
All of the aforementioned embodiments include the pharmaceutically
acceptable acid addition salts thereof, particularly the mono- and
dihydrochlorides, and mixtures thereof.
[0069] The compounds having the general formula I can be prepared
as outlined in Schemes 1-6. A general synthesis of the compounds of
this invention is outlined in Scheme 1. 4
[0070] 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 aniline 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.
[0071] 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 sources.
Examples of commercially available compound corresponding to the
general structure V include 2-methyl piperazine, 2,5-dimethyl
piperazine, 2,6-dimethyl piperazine and
4-benzyloxycarbonylpiperazin-2-one. Deprotection of compound VI can
be accomplished using the standard conditions (e.g. for Boc group
use TFA, for CBZ and benzyl use hydrogenation). Compound I can be
prepared by reacting compound VII with epoxide VIII through warming
in an appropriate solvent (ethanol, DMF). 5
[0072] Epoxide VIII can be prepared as outlined in Scheme 2.
Heating alkyl alcohol IX with epichlorohydrin or epibromohydrin and
sodium hydride in DMF can afford epoxide VIII. In some cases
compound VIII can be obtained from commercial resources. Examples
of commercially available compounds of general structure VIII
include glycidyl isopropyl ether, N butyl glycidyl ether, T butyl
glycidyl ether and iso-butyl glycidyl ether.
[0073] Compound V can be prepared as described in Scheme 3.
Alkylation of compound XII with alkyl halides using t-BuLi as base
can afford compound XIII as described by Pohlman et. al. (J. Org.
Chem, (1997), 62, 1016-1022). Reduction of XIV using diborane can
afford 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). 6
[0074] Compound V can also be prepared through standard coupling
(eg. EDC or PyBroP) of D or L amino acids as outlined in Scheme 4
[For preparations of diketopiperazines see--P. Cledera et al.
Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg.
Med. Chem. Lett. (1998) p. 2369-2374]. Reduction of the
diketopiperazine with diborane can afford the N-benzyl protected
version of compound V. 7
[0075] A specific example of the preparation of a compound from
this invention is disclosed in Schemes 5 and 6 to further
illustrate how to prepare the compounds of this invention. 8
[0076] In particular, 2,6-dichloroaniline was acylated with
2-chloroacetyl chloride 2 using saturated bicarbonate and ether
(1:1) as base and co-solvent, receptively 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. Compound 6 in turn was
prepared by warming epibromohydrin with 2-indanol in DMF in
presence of NaH as described in Scheme 6. 9
[0077] 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] 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%.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] The following Examples are representative of the invention,
but are not to be construed as limiting the scope of the
claims.
EXAMPLE 1
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]a-
cetamide (7)
Part A
Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3)
[0086] 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 diluted with 100 mL ether and the
organic layer was dried over MgSO.sub.4, filtered and concentrated
to afford compound 3 as a white solid.
Part B
Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5)
[0087] To a solution of compound 3 in 100 mL EtOH (5 g, 25.2 mmol)
was added compound 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.
Part C
Synthesis of 2-(oxiran-2-ylmethoxy)indane (6)
[0088] To a solution of 60% NaH (0.18 g, 4.5 mmol) in DMF (10 ml)
cooled to 0 degrees was added 2-indanol (0.5 g, 3,73 mmol) in DMF
(2 ml) dropwise. After stirring for 30 minutes epibromohydrin (1.11
g, 8.18 mmol) in DMF (1 ml) was added dropwise. The reaction was
allowed to warm to room temperature and stirred for 48 h. The
solvent was removed in vacuo and the residue was purified using
Prep TLC (30:1, DCM:MeOH) to afford compound 6.
Part D
Synthesis of
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)-
piperazinyl]acetamide (7)
[0089] To a solution of 6 (0.43 g, 2.3 mmol) in ethanol(4 ml) was
added 5 (0.405 g, 1.64 mmol). The solution was heated to reflux and
stirred for 24 h. Upon completion the solution was concentrated in
vacuo and purified using Prep TLC (10:1, DCM:MeOH) to yield 7. Mass
Spectrum (M+1)=438.36. 10
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl-
)acetamide (10)
[0090] Compound 10 was prepared in a similar manner to compound 7,
substituting the commercially available glycidyl isopropyl ether
for 2-(oxiran-2-ylmethoxy)indane in part D to afford 10: Mass
spectrum MS (MH+)=364.37. 11
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3
(phenylmethoxy)propyl]piperazinyl- }acetamide (11)
[0091] Compound 11 was prepared in a similar manner to compound 7,
substituting the commercially available benzyl glycidyl ether for
2-(oxiran-2-ylmethoxy)indane in part D to afford 11. Mass Spectrum
(M+1)=412.36. 12
2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylph-
enyl)acetamide (12)
[0092] Compound 12 was prepared in a similar manner to compound 7,
substituting the commercially available cyclopentanol for 2-indanol
in part C to afford 12: Mass spectrum MS (MH+)=390.
2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphe-
nyl)acetamide (13)
[0093] Compound 13 was prepared in a similar manner to compound 7,
substituting the commercially available cyclohexanol for 2-indanol
in part C to afford 13: Mass spectrum MS (MH+)=404. 13
2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,-
6-dimethylphenyl)acetamide (14)
[0094] Compound 14 was prepared in a similar manner to compound 7,
substituting the commercially available 4-t-bu-benzylalcohol for
2-propanol in part C. MS (M+1)=468.44 14
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}p-
iperazinyl)acetamide(15)
[0095] Compound 15 was prepared in a similar manner to compound 7,
substituting the commercially available 2-fluorobenzylalcohol for
2-propanol in part C. MS (M+1)=430.39 15
2-4-{-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-di-
methylphenyl)acetamide(16)
[0096] Compound 16 was prepared in a similar manner to compound 7,
substituting the commercially available 2,4-difluorobenzylalcohol
for 2-propanol in part C. MS (M+1)=448.38 16
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]metho-
xy}propyl)piperazinyl]acetamide (17)
[0097] Compound 17 was prepared in a similar manner to compound 7,
substituting the commercially available
4-trifluoromethyl-benzylalcohol for 2-propanol in part C. MS
(M+1)=480.37 17
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl}-
piperazinyl)acetamide (18)
[0098] Compound 18 was prepared in a similar manner to compound 7,
substituting the commercially available 2-methoxy-benzylalcohol for
2-propanol in part C. MS (M+1)=442.41 18
2-(4-{3-[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-
-dimethylphenyl)acetamide (19)
[0099] Compound 19 was prepared in a similar manner to compound 7,
substituting the commercially available 2,4-dimethoxy-benzylalcohol
for 2-propanol in part C. MS (M+1)=472.42 19
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)methoxy]propyl}-
piperazinyl)acetamide(20)
[0100] Compound 14 was prepared in a similar manner to compound 7,
substituting the commercially available 4-methoxy-benzylalcohol for
2-propanol in part C. MS (M+1)=442.42 20
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}p-
iperazinyl)acetamide (21)
[0101] Compound 21 was prepared in a similar manner to compound 7,
substituting the commercially available 4-fluoro-benzylalcohol for
2-propanol in part C. MS (M+1)=430.40 21
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}p-
iperazinyl)acetamide (22)
[0102] Compound 22 was prepared in a similar manner to compound 7,
substituting the commercially available 4-methyl-benzylalcohol for
2-propanol in part C. MS (M+1)=426.41 22
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}p-
iperazinyl)acetamide (23)
[0103] Compound 23 was prepared in a similar manner to compound 7,
substituting the commercially available 4-phenylbenzylalcohol for
2-propanol in part C. MS (M+1)=488.42 23
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}pi-
perazinyl)acetamide (24)
[0104] Compound 24 was prepared in a similar manner to compound 7,
substituting the commercially available 4-n-bu-benzylalcohol for
2-propanol in part C. MS (M+1)=468.45 24
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-naphthylmethoxy)propyl]piperaz-
inyl}acetamide (25)
[0105] Compound 25 was prepared in a similar manner to compound 7,
substituting the commercially available 2-naphthylmethanol for
2-propanol in part C. MS (M+1)=462.41 25
N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperaz-
inylacetamide (26)
[0106] Compound 26 was prepared in a similar manner to compound 7,
substituting the commercially available cyclohexylmethanol for
2-propanol in part C. MS (M+1)=418.55 26
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}--
3,3-dimethylpiperazinyl)acetamide (27)
[0107] Compound 26 was prepared in a similar manner to compound 7,
substituting the commercially available 4-fluorobenzylalcohol for
2-propanol in part C and 2,2-dimethylpiperazine for compound 4 part
B. MS (M+1)=458.5
EXAMPLE 2
Mitochondrial Assays
[0108] Rat heart mitochodria were isolated by the method of
Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).
[0109] Palmitoyl CoA oxidation--The Palmityl CoA oxidation was
carried out in a total volume of 100 microliters 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, 30 microM,
and 3 microM. In each assay, a DMSO control was used. After 15 min
at 30 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 3 concentrations.
Compound # 100 .mu.M 30 .mu.M 3 .mu.M Ranolazine 75% 90% -- 10 100%
97% -- 7 68% -- -- 11 79% -- -- 12 41% -- -- 13 30% -- -- 14 21% --
-- 15 100% -- -- 16 97% -- -- 17 35% -- -- 18 96% -- -- 19 97% --
-- 20 100% -- -- 21 87% -- -- 22 45% -- -- 23 12% -- -- 24 15% --
-- 25 38% -- -- 26 70% -- -- 27 73% -- --
EXAMPLE 3
Palmitoyl Carnitine Oxidation
[0110] The Palmitoyl carnitine oxidation was carried out in a total
volume of 100 microliters 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, 0.1 mg/ml of defatted BSA, 0.5 mM malic acid, 3 mM ADP, 52
micrograms of mitochondrial protein, and 43 microM 1-C14 palmitoyl
carnitine (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, 30
microM, and 3 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. The data are presented as % activity of
control.
2TABLE 2 Inhibition of mitochondrial fatty acid oxidation using
palmitoyl carnitine as substrate - % of Control At 3
concentrations. Compound # 100 .mu.M 30 .mu.M 3 .mu.M Ranolazine
63% 98% -- 10 80% -- -- 7 -- -- -- 11 -- -- -- 12 -- -- -- 13 -- --
--
EXAMPLE 4
Metabolic Stability
[0111] 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.
[0112] 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.
Reagents
[0113] The following reagents were used; Potassium phosphate, 0.5M
pH 74. (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 7, 9, and
10-13 in ACN further diluted to obtain 100 .mu.M in 10% ACN; Human
S9 stock: 20 mg/mL from Gentest Lot 3.
Procedure
[0114] Incubation mixtures were prepared as follows:
3TABLE 3 Volume per 0.25 mL of Incubation Final Component Mixture
concentration 100 .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.
[0115] 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.
[0116] 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.
[0117] 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).
Analytical and Data Calculations
[0118] Samples were analyzed for the starting compounds and
potential metabolite/s by LC/MS using an internal standard on a
Micromass platform mass spec with a Keystone Inc. BDS 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 4.
4 TABLE 4 Compound # Liver S-9 stability factor Ranolazine 1.0 10
-- 7 0.37 11 -- 12 1.48 13 1.20 15 -- 16 -- 17 1.0 18 -- 19 -- 20
-- 21 -- 22 0.61 23 0.05 24 0.02 25 0.01 26 -- 27 --
* * * * *