U.S. patent application number 11/683917 was filed with the patent office on 2007-07-05 for substituted heterocyclic compounds.
Invention is credited to Venkata Palle, Jeff Zablocki.
Application Number | 20070155728 11/683917 |
Document ID | / |
Family ID | 32713240 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070155728 |
Kind Code |
A1 |
Palle; Venkata ; et
al. |
July 5, 2007 |
Substituted Heterocyclic Compounds
Abstract
Disclosed are novel heterocyclic compounds having the structure
##STR1## which are useful for the treatment of various disease
states, in particular cardiovascular diseases such as atrial and
ventricular arrhythmias, intermittent claudication, Prinzmetal's
(variant) angina, stable and unstable angina, exercise induced
angina, congestive heart disease, and myocardial infarction. The
compounds are also useful in the treatment of diabetes.
Inventors: |
Palle; Venkata; (Gurgaon,
IN) ; Zablocki; Jeff; (Mountain View, CA) |
Correspondence
Address: |
CV THERAPEUTICS, INC.
3172 PORTER DRIVE
PALO ALTO
CA
94304
US
|
Family ID: |
32713240 |
Appl. No.: |
11/683917 |
Filed: |
March 8, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10745224 |
Dec 19, 2003 |
7205303 |
|
|
11683917 |
Mar 8, 2007 |
|
|
|
60437860 |
Jan 3, 2003 |
|
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|
Current U.S.
Class: |
514/218 ;
514/252.12; 514/252.13; 540/575; 544/359; 544/399 |
Current CPC
Class: |
A61P 21/00 20180101;
A61P 9/10 20180101; A61P 3/10 20180101; A61P 9/00 20180101; C07D
401/04 20130101; C07D 231/56 20130101; A61P 9/04 20180101; A61P
17/02 20180101; A61P 19/00 20180101; A61P 9/06 20180101; C07D
277/62 20130101; C07D 277/82 20130101; C07D 295/15 20130101 |
Class at
Publication: |
514/218 ;
514/252.12; 540/575; 514/252.13; 544/359; 544/399 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/496 20060101 A61K031/496; A61K 31/495 20060101
A61K031/495; C07D 403/02 20060101 C07D403/02 |
Claims
1. A compound of the formula: ##STR25## wherein: R.sup.1 and
R.sup.2 are independently optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted aryl, or optionally
substituted heteroaryl; A is --(CR.sup.9R.sup.10).sub.m--; in which
m is 1 or 2; and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, and R.sup.10, are independently hydrogen,
optionally substituted lower alkyl, or --C(O)R; in which R is
--OR.sup.11 or --NR.sup.11R.sup.12, where R.sup.11 and R.sup.12 are
hydrogen or optionally substituted lower alkyl; or R.sup.3 and
R.sup.4, R.sup.5 and R.sup.6, R.sup.7 and R.sup.8, R.sup.9 and
R.sup.10, when taken together with the carbon to which they are
attached, represent carbonyl; or R.sup.3 and R.sup.7, or R.sup.3
and R.sup.9, or R.sup.3 and R.sup.11, or R.sup.5 and R.sup.7, when
taken together form a bridging group --(CR.sup.13R.sup.14).sub.n--,
in which n is 1, 2 or 3, and R.sup.13 and R.sup.14 are
independently hydrogen or optionally substituted lower alkyl; with
the proviso that the maximum number of carbonyl groups is 1; the
maximum number of --C(O)NR.sup.11R.sup.12 groups is 1; and the
maximum number of bridging groups is 1; T is oxygen or sulfur; X is
a covalent bond or --(CR.sup.15R.sup.16).sub.p--, in which R.sup.15
and R.sup.16 are hydrogen, optionally substituted lower alkyl, or
--C(O)OR.sup.17 and p is 1, 2 or 3, in which R.sup.17 is hydrogen,
optionally substituted lower alkyl, or optionally substituted
phenyl; Y.sup.1 and Y.sup.2 are independently
--(CR.sup.18R.sup.19).sub.q--, in which q is 1, 2 or 3 and R.sup.18
and R.sup.19 are independently hydrogen, hydroxy, or optionally
substituted lower alkyl; with the proviso that R.sup.18 and
R.sup.19 are not hydroxy when q is 1; and Z is a covalent bond,
--C(O)NR.sup.20--, or --NR.sup.20C(O)--, where R.sup.20 is hydrogen
or optionally substituted lower alkyl; or Y.sup.2 and Z taken
together are a covalent bond; with the proviso, that when R.sup.1
and R.sup.2 are optionally substituted phenyl and X is a covalent
bond, Z is not a covalent bond.
2. The compound of claim 1, wherein R.sup.1 is optionally
substituted aryl and R.sup.2 is optionally substituted aryl or
optionally substituted cycloalkyl.
3. The compound of claim 2, wherein X is a covalent bond and T is
oxygen.
4. The compound of claim 3, wherein Y.sup.1 and Y.sup.2 are lower
alkylene.
5. The compound of claim 4. wherein Y.sup.1 is methylene or
ethylene and Y.sup.2 is methylene.
6. The compound of claim 5, wherein R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.10 are hydrogen and A
is methylene.
7. The compound of claim 6, wherein Z is a covalent bond.
8. The compound of claim 7, wherein R.sup.1 is optionally
substituted phenyl and R.sup.2 is optionally substituted
cyclohexyl.
9. The compound of claim 8, wherein R.sup.1 is 2,6-dimethylphenyl,
R.sup.2 is cyclohexyl, and Y.sup.1 is methylene, namely
N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]ace-
tamide.
10. The compound of claim 7, wherein R.sup.1 and R.sup.2 are both
optionally substituted phenyl.
11. The compound of claim 10, wherein R.sup.1 is
2,6-dimethylphenyl.
12. The compound of claim 11, wherein R.sup.2 is 4-methoxyphenyl
and Y.sup.1 is ethylene, namely
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-
-1-yl}acetamide.
13. The compound of claim 11, wherein R.sup.2 is 2-methoxyphenyl
and Y.sup.1 is ethylene, namely
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-
yl}acetamide.
14. The compound of claim 6, wherein Z is --C(O)NR.sup.20--, in
which R.sup.20 is hydrogen.
15. The compound of claim 14, wherein R.sup.1 and R.sup.2 are both
optionally substituted phenyl.
16. The compound of claim 15, wherein R.sup.1 is
2,6-dimethylphenyl, R.sup.2 is 2-fluorophenyl, and Y.sup.1 is
methylene, namely
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-
-fluorophenyl)butanamide.
17. The compound of claim 6, wherein Z is --NR.sup.20C(O)--, in
which R.sup.20 is hydrogen.
18. The compound of claim 17, wherein R.sup.1 and R.sup.2 are both
optionally substituted phenyl.
19. The compound of claim 18, wherein R.sup.1 is
2,6-dimethylphenyl, R.sup.2 is 2-fluorophenyl, and Y.sup.1 is
methylene, namely
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}piperazinyl)acetamide.
20. A method of treating a disease state chosen from diabetes,
damage to skeletal muscles resulting from trauma or shock and a
cardiovascular disease in a mammal by administration of a
therapeutically effective dose of a compound of claim 1.
21. The method of claim 20, wherein the cardiovascular disease is
atrial arrhythmia, intermittent claudication, ventricular
arrhythmia, Prinzmetal's (variant) angina, stable angina, unstable
angina, congestive heart disease, or myocardial infarction.
22. The method of claim 21, wherein the disease state is
diabetes.
23. A pharmaceutical composition comprising at least one
pharmaceutically acceptable excipient and a therapeutically
effective amount of a compound of claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/745,224, filed Dec. 5, 2003, which issued ______, as
U.S. Pat. No. ______, which claims priority to U.S. Provisional
Patent Application Ser. No. 60/437,860, filed Jan. 3, 2003, the
complete disclosure of which is hereby incorporated by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel heterocyclic
derivatives, and to their use in the treatment of various disease
states, in particular cardiovascular diseases such as atrial and
ventricular arrhythmias, intermittent claudication, Prinzmetal's
(variant) angina, stable and unstable angina, exercise induced
angina, congestive heart disease, ischemia, reperfusion injury,
diabetes, and myocardial infarction. The invention also relates to
methods for their preparation, and to pharmaceutical compositions
containing such compounds.
SUMMARY OF THE INVENTION
[0003] Certain classes of piperazine compounds are known to be
useful for the treatment of cardiovascular diseases, including
arrhythmias, angina, myocardial infarction, and related diseases
such as intermittent claudication. For example, U.S. Pat. No.
4,567,264 discloses a class of substituted piperazine compounds
that includes a compound known as ranolazine,
(.+-.)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propy1]-1-
-piperazineacetamide, and its pharmaceutically acceptable salts,
and their use in the above disease states.
[0004] Despite the desirable properties demonstrated by ranolazine,
which is a very effective cardiac therapeutic agent, believed to
function as a fatty acid oxidation inhibitor, there remains a need
for compounds that have similar therapeutic properties to
ranolazine, but are more potent and have a longer half-life.
SUMMARY OF THE INVENTION
[0005] It is an object of this invention to provide novel
substituted heterocyclic compounds that are fatty acid oxidation
inhibitors with good therapeutic half-lives. Accordingly, in a
first aspect, the invention relates to compounds of Formula I:
##STR2## wherein: [0006] R.sup.1 and R.sup.2 are independently
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted cycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl;
[0007] A is --(CR.sup.9R.sup.10).sub.m--; in which m is 1 or 2; and
[0008] R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, and R.sup.10, are independently hydrogen, optionally
substituted lower alkyl, or --C(O)R; [0009] in which R is
--OR.sup.11 or --NR.sup.11R.sup.12, where R.sup.11 and R.sup.12 are
hydrogen or optionally substituted lower alkyl; or [0010] R.sup.3
and R.sup.4, R.sup.5 and R.sup.6, R.sup.7 and R.sup.8, R.sup.9 and
R.sup.10, when taken together with the carbon to which they are
attached, represent carbonyl; or [0011] R.sup.3 and R.sup.7, or
R.sup.3 and R.sup.9, or R.sup.3 and R.sup.11, or R.sup.5 and
R.sup.7, when taken together form a bridging group
--(CR.sup.13R.sup.14).sub.n--, in which n is 1, 2 or 3, and
R.sup.13 and R.sup.14 are independently hydrogen or optionally
substituted lower alkyl; [0012] with the proviso that the maximum
number of carbonyl groups is 1; [0013] the maximum number of
--C(O)NR.sup.11R.sup.12 groups is 1; and [0014] the maximum number
of bridging groups is 1; [0015] T is oxygen or sulfur; [0016] X is
a covalent bond or --(CR.sup.15R.sup.16).sub.p--, in which R.sup.15
and R.sup.16 are hydrogen, optionally substituted lower alkyl, or
--C(O)OR.sup.17 and p is 1, 2 or 3, in which R.sup.17 is hydrogen,
optionally substituted lower alkyl, or optionally substituted
phenyl; [0017] Y.sup.1 and Y.sup.2 are independently
--(CR.sup.18R.sup.19).sub.q--, in which q is 1, 2 or 3 and R.sup.18
and R.sup.19 are independently hydrogen, hydroxy, or optionally
substituted lower alkyl; with the proviso that R.sup.18 and
R.sup.19 are not hydroxy when q is 1; and [0018] Z is a covalent
bond, --C(O)NR.sup.20--, or --NR.sup.20C(O)--, where R.sup.20 is
hydrogen or optionally substituted lower alkyl; or [0019] Y.sup.2
and Z taken together are a covalent bond; [0020] with the proviso,
that when R.sup.1 and R.sup.2 are optionally substituted phenyl and
X is a covalent bond, Z is not a covalent bond.
[0021] A second aspect of this invention relates to pharmaceutical
formulations, comprising a therapeutically effective amount of a
compound of Formula I and at least one pharmaceutically acceptable
excipient.
[0022] A third aspect of this invention relates to a method of
using the compounds of Formula I in the treatment of a disease or
condition in a mammal that is amenable to treatment by a fatty acid
oxidation inhibitor. Such diseases include, but are not limited to,
protection of skeletal muscles against damage resulting from
trauma, intermittent claudication, shock, and cardiovascular
diseases including atrial and ventricular arrhythmias, Prinzmetal's
(variant) angina, stable angina, unstable angina, congestive heart
disease, diabetes, and myocardial infarction. The compounds of
Formula I can also be used to preserve donor tissue and organs used
in transplants.
[0023] A fourth aspect of this invention relates to methods of
preparing the compounds of Formula I.
[0024] Of the compounds of Formula I, one preferred class includes
those compounds in which A is methylene, particularly those
compounds in which R.sup.3, R.sup.4, R.sup.5, R.sup.7, and R.sup.8
are hydrogen. A preferred group within this class includes those
compounds in which R.sup.1 is optionally substituted aryl and
R.sup.2 is optionally substituted aryl or optionally substituted
cycloalkyl, especially where X is a covalent bond and T is oxygen,
and Y.sup.1 and Y.sup.2 are both lower alkylene. A preferred
subgroup includes those compounds in which Y.sup.1 is methylene or
ethylene, Y.sup.2 is methylene, and Z is a covalent bond,
particularly where R.sup.1 is optionally substituted phenyl and
R.sup.2 is optionally substituted cycloalkyl. Another preferred
subgroup includes those compounds in which Y.sup.1 is methylene or
ethylene, Y.sup.2 is methylene, and Z is --C(O)NR.sup.20-- or
--NR.sup.20C(O)--, especially where R.sup.20 is hydrogen, and
R.sup.1 and R.sup.2 are both optionally substituted phenyl.
[0025] In another aspect, the invention includes the compounds:
[0026]
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}-piperazinyl)acetamide; [0027]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]-
-propyl}piperazinyl)acetamide; [0028]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)-carbon-
ylamino]propyl}piperazinyl)acetamide; [0029]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-
yl}acetamide; [0030]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-
-1-yl}acetamide; [0031]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazi-
n-1-yl}acetamide;
N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazin-1-yl]aceta-
mide; [0032]
2-{4-[4-(4-tert-butylphenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimeth-
ylphenyl)acetamide; [0033]
2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylph-
enyl)acetamide. [0034]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[3-
-methoxy-5-(trifluoromethyl)phenyl]acetamide; [0035]
N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]ace-
tamide; [0036]
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-methoxyphenyl)carbonylamino]-2-hydroxy-
propyl}piperazinyl)acetamide; [0037]
N-[(2,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2--
hydroxypropyl}piperazinyl)acetamide; [0038]
N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazinyl]acetamid-
e; [0039]
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-{3-[(2-fluorophenyl)carbonyla-
mino]-2-hydroxypropyl}piperazinyl)acetamide; [0040]
2-(4-{4-[4-(tert-butyl)phenyl]-4-hydroxybutyl}piperazinyl)-N-(2,6-dimethy-
lphenyl)acetamide; [0041]
N-(3,4-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}-piperazinyl)acetamide; [0042]
N-(2,6-dimethylphenyl)-2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperaziny-
l}acetamide; [0043]
N-(3,5-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}piperazinyl)acetamide; [0044]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-
yl}acetamide; [0045]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[5-
-methoxy-3-(trifluoromethyl)phenyl]acetamide; [0046]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-
yl}acetamide; [0047]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-na-
phthylacetamide; [0048]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazi-
nyl}acetamide; [0049]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-in-
dan-5-ylacetamide; [0050]
N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]pipe-
razinyl}-acetamide; [0051]
N-(2-chloro-4-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hyd-
roxypropyl}piperazinyl)acetamide; [0052]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-
-fluorophenyl)butanamide; [0053]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}-piperazinyl)-3-hydroxy-N-(-
4-methoxyphenyl)butanamide; [0054]
N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-
piperazinyl}-acetamide; [0055]
N-(2,6-dimethylphenyl)-2-(4-{3-[(3,4,5-trimethoxyphenyl)carbonylamino]-2--
hydroxypropyl}piperazinyl)acetamide; [0056]
N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-
-piperazinyl}acetamide; [0057]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-be-
nzylacetamide; [0058]
N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl-
}acetamide; [0059]
N-cyclohexyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}-pip-
erazinyl)acetamide; [0060]
N-benzothiazol-2-yl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl-
}acetamide; [0061]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-ph-
enylacetamide; [0062]
2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-N-benzylacetamide;
[0063]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazi-
nyl)-N-(3,4,5-trichlorophenyl)acetamide; [0064]
N-cyclohexyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetam-
ide; [0065]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(2-
-phenylethyl)acetamide; [0066]
N-cyclopentyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}aceta-
mide; [0067]
N-[2-(2,4-dichlorophenyl)ethyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-
-hydroxypropyl}piperazinyl)acetamide; [0068]
N-[(3,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-
acetamide; [0069]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[4-
-(trifluoromethyl)phenyl]acetamide; [0070]
N-[(2,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-
acetamide; [0071]
4-[4-({N-[(3,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-f-
luorophenyl)-3-hydroxybutanamide; [0072]
N-[(4-chlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acet-
amide; [0073]
4-[4-({N-[(2,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-f-
luorophenyl)-3-hydroxybutanamide; [0074]
N-(1H-indazol-5-yl)-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;
[0075]
4-(4-{[N-(3,5-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-f-
luorophenyl)-3-hydroxybutanamide; [0076]
N-benzothiazol-2-yl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;
[0077]
4-(4-{[N-(3,4-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-f-
luorophenyl)-3-hydroxybutanamide; [0078]
2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-N-benzylacetamide;
[0079]
4-(4-{[N-(4-chloro-2-methoxy-5-methylphenyl)carbamoyl]methyl}piperazinyl)-
-N-(2-fluorophenyl)-3-hydroxybutanamide; [0080]
N-cyclohexyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;
[0081]
N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[3-methoxy-5-(trifluoromethyl)phen-
yl]carbamoyl}-methyl)piperazinyl]butanamide; [0082]
N-cyclopentyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;
[0083]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-naphthylcarbamoyl)methyl]pi-
perazinyl}butanamide; [0084]
2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-N-(2-phenylethyl)acetamide;
[0085]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-indan-5-ylcarbamoyl)methyl]-
piperazinyl}butanamide; [0086]
N-[2-(2,4-dichlorophenyl)ethyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl-
]acetamide; [0087]
4-(4-{[N-(2-chloro-4-methylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluo-
rophenyl)-3-hydroxybutanamide; [0088]
2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-N-(2-phenylethyl)a-
cetamide; [0089]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophe-
nyl)-3-hydroxybutanamide; [0090]
N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl-
]-piperazinyl}acetamide; [0091]
N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-benzylcarbamoyl]methyl}piperazinyl)-
butanamide; [0092]
N-benzothiazol-2-yl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-
acetamide; [0093]
N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piper-
azinyl}acetamide; [0094]
4-{4-[(N-cyclohexylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hyd-
roxybutanamide; [0095]
N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]--
piperazinyl}acetamide; [0096]
4-{4-[(N-cyclopentylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hy-
droxybutanamide; [0097]
N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]--
piperazinyl}acetamide; [0098]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-phenylcarbamoyl)methyl]piperazinyl}-
butanamide; [0099]
N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-
acetamide; [0100]
N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(3,4,5-trichlorophenyl)carbamoyl]me-
thyl}-piperazinyl)butanamide; [0101]
N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(2-phenylethyl)carbamoyl]methyl}-pi-
perazinyl)butanamide; [0102]
2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-benzylacetamide;
[0103]
4-[4-({N-[2-(2,4-dichlorophenyl)ethyl]carbamoyl}methyl)piperaziny-
l]-N-(2-fluorophenyl)-3-hydroxybutanamide; [0104]
N-cyclohexyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetami-
de; [0105]
N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[4-(trifluoromethyl)phenyl]carbamoy-
l}methyl)-piperazinyl]butanamide; [0106]
N-cyclopentyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetam-
ide; [0107]
4-[4-({N-[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}methyl)piperazinyl-
]-N-(2-fluorophenyl)-3-hydroxybutanamide; [0108]
N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-
-piperazinyl}acetamide; [0109]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-(1H-indazol-5-yl)carbamoyl)methyl]--
piperazinyl}butanamide; [0110]
2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-(2-phenylethyl)ac-
etamide; [0111]
N-(4-chloro-2-methoxy-5-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylam-
ino]-2-hydroxypropyl}piperazinyl)acetamide; [0112]
2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-{2-[4-(trifluorom-
ethyl)phenyl]ethyl}acetamide; [0113]
N-cyclopentyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}pip-
erazinyl)-acetamide; [0114]
2-(4-{3-[(2,4-difluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)--
N-(2,6-dimethylphenyl)acetamide; [0115]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)carbony-
lamino]-propyl}piperazinyl)acetamide; [0116]
2-{4-[3-(benzothiazol-5-ylcarbonylamino)-2-hydroxypropyl]piperazinyl}-N-(-
2,6-dimethylphenyl)acetamide; [0117]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]-
propyl}-piperazinyl)acetamide; [0118]
N-[(4-chlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydr-
oxypropyl}piperazinyl)acetamide; [0119]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophe-
nyl)-3-hydroxybutanamide; [0120]
N-[(3,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2--
hydroxypropyl}piperazinyl)acetamide; [0121]
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}piperazinyl)acetamide; [0122]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-hydroxyphenyl)carbonylamino]-
propyl}-piperazinyl)acetamide; and [0123]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)carbonylamino]-
propyl}-piperazinyl)acetamide. Definitions and General
Parameters
[0124] As used in the present specification, the following words
and phrases are generally intended to have the meanings as set
forth below, except to the extent that the context in which they
are used indicates otherwise.
[0125] The term "alkyl" refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 20 carbon
atoms. This term is exemplified by groups such as methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl,
n-decyl, tetradecyl, and the like.
[0126] The term "substituted alkyl" refers to:
[0127] 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5
substituents, preferably 1 to 3 substituents, selected from the
group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl,
cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,
thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,
heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,
aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
[0128] 2) an alkyl group as defined above that is interrupted by
1-10 atoms independently chosen from oxygen, sulfur and NR.sub.a--,
where R.sub.a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All
substituents may be optionally further substituted by alkyl,
alkoxy, halogen, CF.sub.3, amino, substituted amino, cyano, or
--S(O).sub.nR, in which R is alkyl, aryl, or heteroaryl and n is 0,
1 or 2; or
3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5
substituents as defined above and is also interrupted by 1-10 atoms
as defined above.
[0129] The term "lower alkyl" refers to a monoradical branched or
unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6
carbon atoms. This term is exemplified by groups such as methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl,
and the like.
[0130] The term "substituted lower alkyl" refers to lower alkyl as
defined above having 1 to 5 substituents, preferably 1, 2, or 3
substituents, as defined for substituted alkyl, or a lower alkyl
group as defined above that is interrupted by 1, 2, 3, 4, or 5
atoms as defined for substituted alkyl, or a lower alkyl group as
defined above that has both 1, 2, 3, 4 or 5 substituents as defined
above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined
above.
[0131] The term "alkylene" refers to a diradical of a branched or
unbranched saturated hydrocarbon chain, preferably having from 1 to
20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1,
2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--),
the propylene isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--) and the like.
[0132] The term "lower alkylene" refers to a diradical of a
branched or unbranched saturated hydrocarbon chain, preferably
having from 1, 2, 3, 4, 5, or 6 carbon atoms.
[0133] The term "substituted alkylene" refers to:
[0134] (1) an alkylene group as defined above having 1, 2, 3, 4, or
5 substituents selected from the group consisting of alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
[0135] (2) an alkylene group as defined above that is interrupted
by 1-20 atoms independently chosen from oxygen, sulfur and
NR.sub.a--, where R.sub.a is chosen from hydrogen, optionally
substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and
heterocycyl, or groups selected from carbonyl, carboxyester,
carboxyamide and sulfonyl; or
[0136] (3) an alkylene group as defined above that has both 1, 2,
3, 4 or 5 substituents as defined above and is also interrupted by
1-20 atoms as defined above. Examples of substituted alkylenes are
chloromethylene (--CH(Cl)--), aminoethylene
(--CH(NH.sub.2)CH.sub.2--), methylaminoethylene
(--CH(NHMe)CH.sub.2--), 2-carboxypropylene isomers
(--CH.sub.2CH(CO.sub.2H)CH.sub.2--), ethoxyethyl
(--CH.sub.2CH.sub.2O--CH.sub.2CH.sub.2--), ethylmethylaminoethyl
(--CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2--),
1-ethoxy-2-(2-ethoxy-ethoxy)ethane
(--CH.sub.2CH.sub.2O--CH.sub.2CH.sub.2--OCH.sub.2CH.sub.2--OCH.sub.2CH.su-
b.2--), and the like.
[0137] The term "aralkyl" refers to an aryl group covalently linked
to an alkylene group, where aryl and alkylene are defined herein.
"Optionally substituted aralkyl" refers to an optionally
substituted aryl group covalently linked to an optionally
substituted alkylene group. Such aralkyl groups are exemplified by
benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
[0138] The term "alkoxy" refers to the group R--O--, where R is
optionally substituted alkyl or optionally substituted cycloalkyl,
or R is a group --Y-Z, in which Y is optionally substituted
alkylene and Z is optionally substituted alkenyl, optionally
substituted alkynyl; or optionally substituted cycloalkenyl, where
alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined
herein. Preferred alkoxy groups are alkyl-O-- and include, by way
of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy,
and the like.
[0139] The term "alkylthio" refers to the group R--S--, where R is
as defined for alkoxy.
[0140] The term "alkenyl" refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group preferably having from 2
to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even
more preferably 2 to 6 carbon atoms and having 1-6, preferably 1,
double bond (vinyl). Preferred alkenyl groups include ethenyl or
vinyl (--CH.dbd.CH.sub.2), 1-propylene or allyl
(--CH.sub.2CH.dbd.CH.sub.2), isopropylene
(--C(CH.sub.3).dbd.CH.sub.2), bicyclo[2.2.1]heptene, and the like.
In the event that alkenyl is attached to nitrogen, the double bond
cannot be alpha to the nitrogen.
[0141] The term "lower alkenyl" refers to alkenyl as defined above
having from 2 to 6 carbon atoms.
[0142] The term "substituted alkenyl" refers to an alkenyl group as
defined above having 1, 2, 3, 4 or 5 substituents, and preferably
1, 2, or 3 substituents, selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0143] The term "alkynyl" refers to a monoradical of an unsaturated
hydrocarbon, preferably having from 2 to 20 carbon atoms, more
preferably 2 to 10 carbon atoms and even more preferably 2 to 6
carbon atoms and having at least 1 and preferably from 1-6 sites of
acetylene (triple bond) unsaturation. Preferred alkynyl groups
include ethynyl, (--C.ident.CH), propargyl (or propynyl,
--C.ident.CCH.sub.3), and the like. In the event that alkynyl is
attached to nitrogen, the triple bond cannot be alpha to the
nitrogen.
[0144] The term "substituted alkynyl" refers to an alkynyl group as
defined above having 1, 2, 3, 4 or 5 substituents, and preferably
1, 2, or 3 substituents, selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0145] The term "aminocarbonyl" refers to the group --C(O)NRR where
each R is independently hydrogen, alkyl, cycloaklyl, aryl,
heteroaryl, heterocyclyl or where both R groups are joined to form
a heterocyclic group (e.g., morpholino). Unless otherwise
constrained by the definition, all substituents may optionally be
further substituted by 1, 2, or 3 substituents chosen from alkyl,
carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,
CF.sub.3, amino, substituted amino, cyano, and --S(O).sub.nR, where
R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0146] The term "ester" or "carboxyester" refers to the group
--C(O)OR, where R is alkyl, cycloalkyl, aryl, heteroaryl, or
heterocyclyl, which may be optionally further substituted by alkyl,
alkoxy, halogen, CF.sub.3, amino, substituted amino, cyano, or
--S(O).sub.nR.sub.a, in which R.sub.a is alkyl, aryl, or heteroaryl
and n is 0, 1 or 2.
[0147] The term "acylamino" refers to the group --NRC(O)R where
each R is independently hydrogen, alkyl, aryl, heteroaryl, or
heterocyclyl. All substituents may be optionally further
substituted by alkyl, alkoxy, halogen, CF.sub.3, amino, substituted
amino, cyano, or --S(O).sub.nR, in which R is alkyl, aryl, or
heteroaryl and n is 0, 1 or 2.
[0148] The term "acyloxy" refers to the groups --O(O)C-alkyl,
--O(O)C-cycloalkyl, --O(O)C-aryl, --O(O)C-heteroaryl, and
--O(O)C-heterocyclyl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0149] The term "aryl" refers to an aromatic carbocyclic group of 6
to 20 carbon atoms having a single ring (e.g., phenyl) or multiple
rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g.,
naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and
the like.
[0150] Unless otherwise constrained by the definition for the aryl
substituent, such aryl groups can optionally be substituted with 1,
2, 3, 4 or 5 substituents, preferably 1, 2, or 3 substituents,
selected from the group consisting of alkyl, alkenyl, alkynyl,
alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,
aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,
keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,
heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,
heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,
heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
--SO-alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless otherwise
constrained by the definition, all substituents may optionally be
further substituted by 1, 2, or 3 substituents chosen from alkyl,
carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,
CF.sub.3, amino, substituted amino, cyano, and --S(O).sub.nR, where
R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0151] The term "aryloxy" refers to the group aryl-O-- wherein the
aryl group is as defined above, and includes optionally substituted
aryl groups as also defined above. The term "arylthio" refers to
the group R--S--, where R is as defined for aryl.
[0152] The term "amino" refers to the group --NH.sub.2.
[0153] The term "substituted amino" refers to the group --NRR where
each R is independently selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl
provided that both R groups are not hydrogen, or a group --Y-Z, in
which Y is optionally substituted alkylene and Z is alkenyl,
cycloalkenyl, or alkynyl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0154] The term "carboxyalkyl" refers to the groups --C(O)O-alkyl,
--C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined
herein, and may be optionally further substituted by alkyl,
alkenyl, alkynyl, alkoxy, halogen, CF.sub.3, amino, substituted
amino, cyano, or --S(O).sub.nR, in which R is alkyl, aryl, or
heteroaryl and n is 0, 1 or 2.
[0155] The term "cycloalkyl" refers to cyclic alkyl groups of from
3 to 20 carbon atoms having a single cyclic ring or multiple
condensed rings. Such cycloalkyl groups include, by way of example,
single ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclooctyl, and the like, or multiple ring structures
such as adamantanyl, and bicyclo[2.2.1]heptane, or cyclic alkyl
groups to which is fused an aryl group, for example indan, and the
like.
[0156] The term "substituted cycloalkyl" refers to cycloalkyl
groups having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or
3 substituents, selected from the group consisting of alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0157] The term "halogen" or "halo" refers to fluoro, bromo,
chloro, and iodo.
[0158] The term "acyl" denotes a group --C(O)R, in which R is
hydrogen, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted heterocyclyl, optionally
substituted aryl, and optionally substituted heteroaryl.
[0159] The term "heteroaryl" refers to an aromatic group (i.e.,
unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms
selected from oxygen, nitrogen and sulfur within at least one
ring.
[0160] Unless otherwise constrained by the definition for the
heteroaryl substituent, such heteroaryl groups can be optionally
substituted with 1 to 5 substituents, preferably 1, 2, or 3
substituents selected from the group consisting of alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,
acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl (an
alkyl ester), arylthio, heteroaryl, heteroarylthio,
heterocyclylthio, thiol, alkylthio, aryl, aryloxy, aralkyl,
heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,
heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
--SO-alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless otherwise
constrained by the definition, all substituents may optionally be
further substituted by 1, 2, or 3 substituents chosen from alkyl,
carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,
CF.sub.3, amino, substituted amino, cyano, and --S(O).sub.nR, where
R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Such heteroaryl
groups can have a single ring (e.g., pyridyl or furyl) or multiple
condensed rings (e.g., indolizinyl, benzothiazole, or
benzothienyl). Examples of nitrogen heterocycles and heteroaryls
include, but are not limited to, pyrrole, imidazole, pyrazole,
pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,
indole, indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,
phenothiazine, imidazolidine, imidazoline, and the like as well as
N-alkoxy-nitrogen containing heteroaryl compounds.
[0161] The term "heteroaryloxy" refers to the group
heteroaryl-O--.
[0162] The term "heterocyclyl" refers to a monoradical saturated or
partially unsaturated group having a single ring or multiple
condensed rings, having from 1 to 40 carbon atoms and from 1 to 10
hetero atoms, preferably 1 to 4 heteroatoms, selected from
nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
[0163] Unless otherwise constrained by the definition for the
heterocyclic substituent, such heterocyclic groups can be
optionally substituted with 1 to 5, and preferably 1, 2, or 3
substituents, selected from the group consisting of alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,
acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,
arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,
aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, --SO-alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless
otherwise constrained by the definition, all substituents may
optionally be further substituted by 1, 2, or 3 substituents chosen
from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,
halogen, CF.sub.3, amino, substituted amino, cyano, and
--S(O).sub.nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1
or 2. Heterocyclic groups can have a single ring or multiple
condensed rings. Preferred heterocyclics include tetrahydrofuranyl,
morpholino, piperidinyl, and the like.
[0164] The term "thiol" refers to the group --SH.
[0165] The term "substituted alkylthio" refers to the group
--S-substituted alkyl.
[0166] The term "heteroarylthiol" refers to the group
--S-heteroaryl wherein the heteroaryl group is as defined above
including optionally substituted heteroaryl groups as also defined
above.
[0167] The term "sulfoxide" refers to a group --S(O)R, in which R
is alkyl, aryl, or heteroaryl. "Substituted sulfoxide" refers to a
group --S(O)R, in which R is substituted alkyl, substituted aryl,
or substituted heteroaryl, as defined herein.
[0168] The term "sulfone" refers to a group --S(O).sub.2R, in which
R is alkyl, aryl, or heteroaryl. "Substituted sulfone" refers to a
group --S(O).sub.2R, in which R is substituted alkyl, substituted
aryl, or substituted heteroaryl, as defined herein.
[0169] The term "keto" refers to a group --C(O)--. The term
"thiocarbonyl" refers to a group --C(S)--.
[0170] The term "carboxy" refers to a group --C(O)--OH.
[0171] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not.
[0172] The term "compound of Formula I" is intended to encompass
the compounds of the invention as disclosed, and the
pharmaceutically acceptable salts, pharmaceutically acceptable
esters, and prodrugs of such compounds. Additionally, the compounds
of the invention may possess one or more asymmetric centers, and
can be produced as a racemic mixture or as individual enantiomers
or diastereoisomers. The number of stereoisomers present in any
given compound of Formula I depends upon the number of asymmetric
centers present (there are 2.sup.n stereoisomers possible where n
is the number of asymmetric centers). The individual stereoisomers
may be obtained by resolving a racemic or non-racemic mixture of an
intermediate at some appropriate stage of the synthesis, or by
resolution of the compound of Formula I by conventional means. The
individual stereoisomers (including individual enantiomers and
diastereoisomers) as well as racemic and non-racemic mixtures of
stereoisomers are encompassed within the scope of the present
invention, all of which are intended to be depicted by the
structures of this specification unless otherwise specifically
indicated.
[0173] "Isomers" are different compounds that have the same
molecular formula.
[0174] "Stereoisomers" are isomers that differ only in the way the
atoms are arranged in space.
[0175] "Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term "(.+-.)" is
used to designate a racemic mixture where appropriate.
[0176] "Diastereoisomers" are stereoisomers that have at least two
asymmetric atoms, but which are not mirror-images of each
other.
[0177] The absolute stereochemistry is specified according to the
Cahn-Ingold-Prelog R--S system. When the compound is a pure
enantiomer the stereochemistry at each chiral carbon may be
specified by either R or S. Resolved compounds whose absolute
configuration is unknown are designated (+) or (-) depending on the
direction (dextro- or laevorotary) which they rotate the plane of
polarized light at the wavelength of the sodium D line.
[0178] The term "compound of Formula I" is intended to encompass
the compounds of the invention as disclosed, and the
pharmaceutically acceptable salts, pharmaceutically acceptable
esters, polymorphs, and prodrugs of such compounds.
[0179] The term "therapeutically effective amount" refers to that
amount of a compound of Formula I that is sufficient to effect
treatment, as defined below, when administered to a mammal in need
of such treatment. The therapeutically effective amount will vary
depending upon the subject and disease condition being treated, the
weight and age of the subject, the severity of the disease
condition, the manner of administration and the like, which can
readily be determined by one of ordinary skill in the art.
[0180] The term "treatment" or "treating" means any treatment of a
disease in a mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms
of the disease not to develop;
(ii) inhibiting the disease, that is, arresting the development of
clinical symptoms; and/or
(iii) relieving the disease, that is, causing the regression of
clinical symptoms.
[0181] In many cases, the compounds of this invention are capable
of forming acid and/or base salts by virtue of the presence of
amino and/or carboxyl groups or groups similar thereto. The term
"pharmaceutically acceptable salt" refers to salts that retain the
biological effectiveness and properties of the compounds of Formula
I, and which are not biologically or otherwise undesirable.
Pharmaceutically acceptable base addition salts can be prepared
from inorganic and organic bases. Salts derived from inorganic
bases, include by way of example only, sodium, potassium, lithium,
ammonium, calcium and magnesium salts. Salts derived from organic
bases include, but are not limited to, salts of primary, secondary
and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl
amines, substituted alkyl amines, di(substituted alkyl)amines,
tri(substituted alkyl)amines, alkenyl amines, dialkenyl amines,
trialkenyl amines, substituted alkenyl amines, di(substituted
alkenyl)amines, tri(substituted alkenyl)amines, cycloalkyl amines,
di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkyl
amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl
amines, cycloalkenyl amines, di(cycloalkenyl)amines,
tri(cycloalkenyl)amines, substituted cycloalkenyl amines,
disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl
amines, aryl amines, diaryl amines, triaryl amines, heteroaryl
amines, diheteroaryl amines, triheteroaryl amines, heterocyclic
amines, diheterocyclic amines, triheterocyclic amines, mixed di-
and tri-amines where at least two of the substituents on the amine
are different and are selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl, heterocyclic, and the like. Also included are
amines where the two or three substituents, together with the amino
nitrogen, form a heterocyclic or heteroaryl group.
[0182] Specific examples of suitable amines include, by way of
example only, isopropylamine, trimethyl amine, diethyl amine,
tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine,
2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-alkylglucamines, theobromine, purines, piperazine,
piperidine, morpholine, N-ethylpiperidine, and the like.
[0183] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Salts
derived from organic acids include acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid,
and the like.
[0184] As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the
active ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also be
incorporated into the compositions.
[0185] "Fatty acid oxidation inhibitors" refers to compounds that
suppress ATP production from the oxidation of fatty acids and
consequently stimulate ATP production from the oxidation of glucose
and lactate. In the heart, most of the ATP production is acquired
through the metabolism of fatty acids. The metabolism of glucose
and lactate provides a lesser proportion of ATP. However, the
generation of ATP from fatty acids is less efficient with respect
to oxygen consumption than the generation of ATP from the oxidation
of glucose and lactate. Thus, the use of fatty acid oxidation
inhibitors results in more energy production per molecule of oxygen
consumed, allowing the heart to be energized more efficiently.
Fatty acid oxidation inhibitors are especially useful, therefore,
for treating an ischemic environment in which oxygen levels are
reduced.
Nomenclature
[0186] The naming and numbering of the compounds of the invention
is illustrated with a representative compound of Formula I in which
where R.sup.1 is 2,6-dimethylphenyl, R.sup.2 is 2-fluorophenyl,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
hydrogen, A is methylene, T is oxygen, X is a covalent bond,
Y.sup.1 and Y.sup.2 are both methylene, and Z is --NHC(CO)--:
##STR3## which is named: [0187]
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonyl
amino]-2-hydroxypropyl}-piperazinyl)acetamide.
Synthesis of the Compounds of Formula I
[0188] One method of preparing the compounds of Formula I, in which
Y.sup.1 is methylene and Z is --NR.sup.2(CO)--, is shown in
Reaction Scheme I. ##STR4## Step 1--Preparation of a Compound of
Formula (2)
[0189] The compound of formula (2) is prepared conventionally by
reaction of a compound of formula (1), for example allyl amine,
with benzylchloroformate. In general, the reaction is conducted in
an inert solvent, for example dichloromethane, and a tertiary
organic base, for example triethylamine, or an inorganic base, for
example potassium carbonate, at a temperature of about 0.degree. C.
for about 2 hours, followed by about room temperature for about 1-4
hours. When the reaction is substantially complete, the product of
formula (2) is isolated and purified by conventional means, for
example by removal of the solvent under reduced pressure followed
by chromatography of the residue on silica gel.
Step 2--Preparation of a Compound of Formula (3)
[0190] The compound of formula (3) is prepared from (2) by reaction
with an agent capable of epoxidizing the terminal double bond of
(2), such as m-chloroperoxybenzoic acid. In general, the reaction
is conducted in an inert solvent, for example dichloromethane,
initially at about 0.degree. C., followed by reaction at about room
temperature for 12-24 hours. When the reaction is substantially
complete, the product of formula (3) is isolated and purified by
conventional means, for example by removal of the solvent under
reduced pressure, followed by chromatography of the residue on
silica gel.
Step 3--Preparation of a Compound of Formula (5)
[0191] The compound of formula (5) is prepared by reaction of
epoxide (3) with a compound of formula (4). In general, the
reaction is carried out in a protic solvent, such as ethanol, in
the presence of a tertiary organic base, such as triethylamine, or
an inorganic base, for example potassium carbonate, at a
temperature of about 50-120.degree. C., preferably at reflux
temperature. When the reaction is substantially complete, the
product of formula (5) is isolated and purified by conventional
means, for example by removal of the solvent under reduced
pressure, followed by chromatography of the residue on silica
gel.
Step 4--Preparation of a Compound of Formula (6)
[0192] The compound of formula (5) is deprotected with an
appropriate agent, for example by hydrogenation in the presence of
a catalyst, for example palladium on carbon. In general, the
reaction is conducted in a protic solvent at room temperature. When
the reaction is substantially complete, the product of formula (6)
is isolated by conventional means, for example by removal of the
solvent under reduced pressure, followed by chromatography of the
residue on silica gel.
Step 5--Preparation of a Compound of Formula I
[0193] The compound of formula (6) is reacted with an acid chloride
of the formula R.sup.2C(O)Hal, where Hal is a halogen (e.g.,
R.sup.2C(O)Cl). In general, the reaction is carried out in an inert
solvent, for example dichloromethane, in the presence of a tertiary
organic base, such as triethylamine, or an inorganic base, for
example potassium carbonate, at a temperature of about
50-120.degree. C., preferably at reflux temperature. When the
reaction is substantially complete, the product of Formula I is
isolated by conventional means, for example by removal of the
solvent under reduced pressure, followed by preparative thin layer
chromatography.
Starting Materials
[0194] The compounds of formula (1), (2), (3) and (4) are either
commercially available or can be made by conventional methods well
known to those of ordinary skill in the art. For example, the
precursor to a compound of formula (4) where R.sup.3 and R.sup.7
when taken together represent a bridging methylene group, i.e.:
##STR5## is commercially available
[(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane], or can be made by a
procedure disclosed in J. Org. Chem., 1990, 55, 1684-7. Similarly,
the precursor to a compound of formula (4) where R.sup.3 and
R.sup.7 when taken together represent a bridging methylene group,
and the precursor to a compound of formula (4) where R.sup.3 and
R.sup.9 when taken together represent a bridging methylene group,
can be made by published procedures found in J. Med. Chem., 1974,
17, 481-7.
[0195] Alternatively, a precursor to the intermediate of formula
(4), where A is a CH.sub.2 group can be prepared as shown in
Reaction Scheme 1A below. ##STR6## where Bz is benzyl and BOC is
benzyloxycarbonyl.
[0196] Alkylation of compound (A) with an alkyl halide of the
formula R.sup.3Hal, using t-BuLi as a base, affords the compound of
formula (B) in which R.sup.3 is alkyl and R.sup.4 is hydrogen.
Reaction with a second alkyl halide of formula R.sup.4Hal provides
a compound of formula B in which both R.sup.3 and R.sup.4 are
alkyl. The reaction is described in more detail in Pohlman et. al.
(J. Org. Chem, 1997, 62, 1016-1022).
[0197] BOC deprotection of (B) with trifluoroacetic acid affords a
compound of formula (C). Reduction of (C), for example with
diborane, provides the compound of formula (D). This reduction is
described in more detail in Jacobson et. al, J. Med. Chem, 1999,
42, 1123-1144. Chiral compounds of formula (D) can also be prepared
following a similar procedure.
[0198] Precursor (D) can also be prepared through standard coupling
(eg. EDC or PyBroP) of D or L amino acids and standard deprotection
as outlined in Reaction Scheme 1B below, as described in Cledera,
P. et al. Tetrahedron, 1998 p. 12349-12360; and Smith, R. A. et al
Bioorg. Med. Chem. Lett. 1998, p. 2369-2374. ##STR7##
[0199] Conventional reduction of the diketopiperazine (G) with
diborane affords the N-benzyl protected version of precursor (D).
Precursor (D) can also be prepared as shown in Reaction Scheme 1C
below. ##STR8##
[0200] Bromination of an aldehyde of the formula (H) provides the
compound of formula (J), which is reacted with ethylene diamine to
provide the compound of formula (K). Catalytic hydrogenation of (K)
provides a compound of formula (D). The reaction is described in
more detail in Bogeso, K. P., et al, J. Med. Chem. 1995, 38, p
4380-4392. Aldehydes of formula (I) are either commercially
available, or may be prepared by means well know in the art.
[0201] Precursor (D) also includes the bicyclic homologs of
piperazine (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane,
3,8-diazabicyclo[3.2.1]octane, and 2,5-diazabicyclo[2.2.2]octane.
##STR9##
[0202] Commercially available bicyclic analogs include
(1S,4S)-(+)-2,5-diazabicyclo-[2.2.1]heptane (L). Compounds (M) and
(N) and the (1R,4R) isomer of (L) can be prepared by published
procedures (for (M) and (N) 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).
[0203] A method of preparing the compounds of Formula I, in which
Y.sup.1 is methylene and Z is --(CO)NR.sup.20--, is shown in
Reaction Scheme II. ##STR10## Step 1--Preparation of a Compound of
Formula (9)
[0204] The compound of formula (9) is prepared conventionally by
reaction of a compound of formula (8), for example butenoic acid,
with an amine of formula HN(R.sup.2)(R.sup.20), where R.sup.2 and R
are as defined above, for example 4-methoxyaniline or
2-fluoroaniline. In general, the reaction is conducted in an inert
solvent, for example dichloromethane, in the presence of an agent
capable of promoting amide bond formation, for example
N,N'-dicyclohexylcarbodiimide (DCC), at about room temperature for
about 8-48 hours, preferably about 18 hours. When the reaction is
substantially complete, the product of formula (9) is isolated by
conventional means, for example by filtration, removal of the
solvent under reduced pressure, followed by chromatography of the
residue on silica gel.
Step 2--Preparation of a Compound of Formula (10)
[0205] The compound of formula (9) is reacted with an agent capable
of epoxidizing the terminal double bond, such as
m-chloroperoxybenzoic acid. In general, the reaction is conducted
in an inert solvent, for example dichloromethane, initially at
about 0.degree. C., followed by reaction at about room temperature
for 12-24 hours. When the reaction is substantially complete, the
product of formula (3) is isolated by conventional means, for
example by removal of the solvent under reduced pressure, followed
by chromatography of the residue on silica gel.
Step 3--Preparation of a Compound of Formula I
[0206] The epoxide of formula (10) is then reacted with the
compound of formula (4). In general, the reaction is carried out in
a protic solvent, such as ethanol, in the presence of a tertiary
organic base, such as triethylamine, or an inorganic base, for
example potassium carbonate, at a temperature of about
50-120.degree. C., preferably at about 80.degree. C. When the
reaction is substantially complete, the product of Formula I is
isolated by conventional means, for example by removal of the
solvent under reduced pressure, followed by chromatography of the
residue on silica gel.
[0207] A method of preparing the compounds of Formula I in which
X.sup.1 is ethylene is shown in Reaction Scheme III. ##STR11## Step
1--Preparation of a Compound of Formula (13)
[0208] The compound of formula (13) is prepared conventionally by
reaction of a compound of formula (4) with a compound of formula
(12), for example 4-(2-methoxyphenyl)-1-butene-3-one. In general,
the reaction is conducted in a protic solvent, for example ethanol,
at a temperature of about 50-120.degree. C., preferably at about
80.degree. C., for about 8-48 hours, preferably about 18 hours.
When the reaction is substantially complete, the compound of
formula (13) is isolated by conventional means, for example by
removal of the solvent under reduced pressure, followed by
chromatography of the residue on silica gel.
Step 2--Preparation of a Compound of Formula I
[0209] A compound of Formula I is prepared from a compound of
formula (13) conventionally by reduction with a reducing agent
capable of selectively reducing the ketone carbonyl in the presence
of an amide, such as sodium borohydride. In general, the reaction
is conducted at reflux in a protic solvent, for example ethanol, at
a temperature of about 50-120.degree. C., preferably at about
80.degree. C., for about 8-48 hours, preferably about 18 hours.
When the reaction is substantially complete, the product of Formula
I is isolated by conventional means, for example by filtration,
removal of the solvent under reduced pressure, followed by
chromatography of the residue on silica gel.
[0210] Another method of preparing the compounds of Formula I, is
shown in Reaction Scheme IV. ##STR12## Step 1--Preparation of a
Compound of Formula (16)
[0211] The compound of formula (16) is prepared conventionally by
reaction of a compound of formula (4) with a halo ketone of formula
(15). In general, the reaction is carried out in a protic solvent,
such as ethanol, in the presence of a tertiary organic base, such
as triethylamine, or an inorganic base, for example potassium
carbonate, at a temperature of about 50-120.degree. C., preferably
about 80.degree. C., for about 8-48 hours, preferably about 18
hours. When the reaction is substantially complete, the ketone
product of formula (16) is isolated by conventional means, for
example by removal of the solvent under reduced pressure, followed
by chromatography of the residue on silica gel. Alternatively,
after filtration the product can be crystallized from the
filtrate.
Step 2--Preparation of a Compound of Formula I
[0212] A compound of Formula I is prepared from a compound of
formula (16) by reduction with a reducing agent capable of
selectively reducing the ketone carbonyl in the presence of an
amide, such as sodium borohydride. In general, the reaction is
conducted at about room temperature in a protic solvent, for
example ethanol, for about 8-48 hours, preferably about 18 hours.
When the reaction is substantially complete, the product of Formula
I is isolated by conventional means, for example by removal of the
solvent under reduced pressure, followed by chromatography of the
residue on silica gel.
General Utility
[0213] The compounds of Formula I are effective in the treatment of
conditions known to respond to administration of fatty acid
oxidation inhibitors, including protection of skeletal muscles
against damage resulting from trauma, intermittent claudication,
shock, and cardiovascular diseases including atrial and ventricular
arrhythmias, Prinzmetal's (variant) angina, stable angina, ischemia
and reperfusion injury in cardiac, kidney, liver and the brain,
unstable angina, congestive heart disease, and myocardial
infarction. The compounds of Formula I can also be used to preserve
donor tissue and organs used in transplants, and may be
coadministered with thrombolytics, anticoagulants, and other
agents.
Testing
[0214] Activity testing is conducted as described in those patents
and patent applications referenced above, and in the Examples
below, and by methods apparent to one skilled in the art.
Pharmaceutical Compositions
[0215] The compounds of Formula I are usually administered in the
form of pharmaceutical compositions. This invention therefore
provides pharmaceutical compositions that contain, as the active
ingredient, one or more of the compounds of Formula I, or a
pharmaceutically acceptable salt or ester thereof, and one or more
pharmaceutically acceptable excipients, carriers, including inert
solid diluents and fillers, diluents, including sterile aqueous
solution and various organic solvents, permeation enhancers,
solubilizers and adjuvants. The compounds of Formula I may be
administered alone or in combination with other therapeutic agents.
Such compositions are prepared in a manner well known in the
pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences,
Mace Publishing Co., Philadelphia, Pa. 17.sup.th Ed. (1985) and
"Modern Pharmaceutics", Marcel Dekker, Inc. 3.sup.rd Ed. (G. S.
Banker & C. T. Rhodes, Eds.).
Administration
[0216] The compounds of Formula I may be administered in either
single or multiple doses by any of the accepted modes of
administration of agents having similar utilities, for example as
described in those patents and patent applications incorporated by
reference, including rectal, buccal, intranasal and transdermal
routes, by intra-arterial injection, intravenously,
intraperitoneally, parenterally, intramuscularly, subcutaneously,
orally, topically, as an inhalant, or via an impregnated or coated
device such as a stent, for example, or an artery-inserted
cylindrical polymer.
[0217] One mode for administration is parental, particularly by
injection. The forms in which the novel compositions of the present
invention may be incorporated for administration by injection
include aqueous or oil suspensions, or emulsions, with sesame oil,
corn oil, cottonseed oil, or peanut oil, as well as elixirs,
mannitol, dextrose, or a sterile aqueous solution, and similar
pharmaceutical vehicles. Aqueous solutions in saline are also
conventionally used for injection, but less preferred in the
context of the present invention. Ethanol, glycerol, propylene
glycol, liquid polyethylene glycol, and the like (and suitable
mixtures thereof), cyclodextrin derivatives, and vegetable oils may
also be employed. The proper fluidity can be maintained, for
example, by the use of a coating, such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and by the use of surfactants. The prevention of the action of
microorganisms can be brought about by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
sorbic acid, thimerosal, and the like.
[0218] Sterile injectable solutions are prepared by incorporating
the compound of Formula I in the required amount in the appropriate
solvent with various other ingredients as enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum-drying and freeze-drying techniques which
yield a powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered solution thereof.
[0219] Compounds of Formula I may be impregnated into a stent by
diffusion, for example, or coated onto the stent such as in a gel
form, for example, using procedures known to one of skill in the
art in light of the present disclosure.
[0220] Oral administration is another route for administration of
the compounds of Formula I. Administration may be via capsule or
enteric coated tablets, or the like. In making the pharmaceutical
compositions that include at least one compound of Formula I, the
active ingredient is usually diluted by an excipient and/or
enclosed within such a carrier that can be in the form of a
capsule, sachet, paper or other container. When the excipient
serves as a diluent, it can be in the form of a solid, semi-solid,
or liquid material (as above), which acts as a vehicle, carrier or
medium for the active ingredient. Thus, the compositions can be in
the form of tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), ointments containing, for example, up
to 10% by weight of the active compound, soft and hard gelatin
capsules, sterile injectable solutions, and sterile packaged
powders.
[0221] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as
methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents.
[0222] The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art. Controlled release drug delivery
systems for oral administration include osmotic pump systems and
dissolutional systems containing polymer-coated reservoirs or
drug-polymer matrix formulations. Examples of controlled release
systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;
4,902,514; and 5,616,345. Another formulation for use in the
methods of the present invention employs transdermal delivery
devices ("patches"). Such transdermal patches may be used to
provide continuous or discontinuous infusion of the compounds of
the present invention in controlled amounts. The construction and
use of transdermal patches for the delivery of pharmaceutical
agents is well known in the art. See, e.g., U.S. Pat. Nos.
5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed
for continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0223] The compositions are preferably formulated in a unit dosage
form. The term "unit dosage forms" refers to physically discrete
units suitable as unitary dosages for human subjects and other
mammals, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient (e.g., a
tablet, capsule, ampoule). The compounds of Formula I are effective
over a wide dosage range and are generally administered in a
pharmaceutically effective amount. Preferably, for oral
administration, each dosage unit contains from 1 mg to 2 g of a
compound of Formula I, and for parenteral administration,
preferably from 0.1 to 700 mg of a compound of Formula I. It will
be understood, however, that the amount of the compound of Formula
I actually administered will be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound
administered and its relative activity, the age, weight, and
response of the individual patient, the severity of the patient's
symptoms, and the like.
[0224] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules.
[0225] The tablets or pills of the present invention may be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action, or to protect from the acid
conditions of the stomach. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer that serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0226] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. Preferably the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in preferably
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be inhaled directly from the
nebulizing device or the nebulizing device may be attached to a
face mask tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions may be
administered, preferably orally or nasally, from devices that
deliver the formulation in an appropriate manner.
[0227] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
EXAMPLE 1
Preparation of a Compound of Formula I
[0228] A. Preparation of a Compound of Formula (2) in which Y.sup.2
is --CH.sub.2-- and R.sup.20 is Hydrogen ##STR13##
[0229] To a solution of allylamine (58 mmoles, 3.34 g) at 0.degree.
C. in dichloromethane (100 mL) was added triethylamine (120 mmoles,
16 mL). The mixture was stirred for two minutes, then
benzylchloroformate (58 mmoles, 8.25 mL) added dropwise. The
resulting solution was stirred at 0.degree. C. for 2 hours, and at
ambient temperature for an additional 90 minutes. A white
precipitate formed, which was filtered off. Solvent was removed
from the filtrate under reduced pressure, and the residue
chromatographed on a silica gel column, eluting with 20% ethyl
acetate/hexanes, to give benzyl allylcarbamate, a compound of
formula (2), as a clear oil. Yield: 5.0 g. B. Preparation of a
Compound of Formula (3) in which Y.sup.2 is --CH.sub.2-- and
R.sup.20 is Hydrogen ##STR14##
[0230] To a solution of benzyl allylcarbamate (26.1 mmoles, 5 g) at
0.degree. C. in dichloromethane (110 mL) was added 77% w/w
m-chloroperbenzoic acid (52.2 mmoles, 11.71 g), and the mixture was
stirred for 18 hours while gradually allowing the mixture to warm
to ambient temperature. The reaction mixture was diluted with
dichloromethane (500 mL) and the organic phase washed with 2.5N
NaOH solution (2.times.200 mL). The organic layer was then dried
over MgSO.sub.4, filtered, and the filtrate evaporated to give a
pale yellow oil that was purified by column chromatography on
silica gel, eluting with 30% ethyl acetate/hexanes, to give pure
benzyl oxiran-2-ymethylcarbamate, a compound of formula (3). Yield:
4.8 g. C. Preparation of a Compound of Formula (5) in which A and Y
are --CH.sub.2--, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, and R.sup.20 are Hydrogen, T is oxygen, X is a Covalent
Bond, and R.sup.1 is 2,6-Dimethylphenyl ##STR15##
[0231] To a solution of benzyl oxiran-2-ymethylcarbamate (12
mmoles, 2.5 g) in ethanol (100 mL) was added triethylamine (24
mmoles, 3.34 mL), followed by the addition of
N-(2,6-dimethylphenyl)-2-piperazinylacetamide (24 mmoles, 5.94 g),
a compound of formula (4). The resulting mixture was refluxed for
18 hours, then solvent removed from the reaction mixture under
reduced pressure. The residue was purified by column chromatography
on silica gel, eluting with 5% MeOH/dichloromethane to give
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(phenylmethoxy)carbonylamino]pr-
opyl}piperazinyl)acetamide, a compound of formula (5), as an
off-white solid. Yield: 2.25 g. D. Preparation of a Compound of
Formula (6) in which A and Y.sup.2 are --CH.sub.2--, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.20 are
Hydrogen, T is Oxygen, X is a Covalent Bond and R.sup.1 is
2,6-Dimethylphenyl ##STR16##
[0232] To a solution of
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(phenylmethoxy)-carbonylamino]p-
ropyl}piperazinyl)acetamide in methanol (70 mL) at room temperature
was added under a steady flow of nitrogen Pd/C (10% w/w, 0.337 g).
Hydrogen gas was bubbled through the reaction mixture via a septum
with a needle as outlet for 2 minutes, and the reaction was stirred
under a positive hydrogen pressure for two hours. Nitrogen was
blown over the suspension before it was filtered over celite. The
filtrate was evaporated to give
2-[4-(3-amino-2-hydroxypropyl)piperazin-1-yl]-N-(2,6-dimethylphenyl)aceta-
mide, a compound of formula (6), as a clear oil (2.0 g). E.
Preparation of a Compound of Formula I in which A, Y.sup.1 and
Y.sup.2 are --CH.sub.2--, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, and R.sup.20 are Hydrogen, T is Oxygen, X is a
Covalent Bond, Z is --NHC(O)--, R.sup.1 is 2,6-Dimethylphenyl, and
R.sup.2 is 2-Fluorophenyl ##STR17##
[0233] To a solution of
2-[4-(3-amino-2-hydroxypropyl)piperazin-1-yl]-N-(2,6-dimethylphenyl)-acet-
amide (0.312 mmoles) in ethanol (2 mL) was added triethylamine (100
.mu.L) followed by 2-fluorobenzyl chloride (0.312 mmoles), and the
solution was stirred at 90.degree. C. for 18 hours. Solvent was
removed under reduced pressure, and the residue purified by
preparative TLC, eluting with 5% methanol/dichloromethane, to yield
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)-carbonylamino]-2-hydroxy-
propyl}piperazinyl)acetamide, a compound of Formula I.
F. Preparation of a Compound of Formula I in which A, Y.sup.1 and
Y.sup.2 are --CH.sub.2--, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, and R.sup.20 are Hydrogen, T is Oxygen, X is a
Covalent Bond, Z is --NHC(O)--, R.sup.1 is 2,6-Dimethylphenyl, and
R.sup.2 is 4-Methoxyphenyl or 3,4,5-Trimethoxyphenyl
[0234] Similarly, following the procedure of 1E above, replacing
2-fluorobenzoyl chloride with other compounds of formula
R.sup.2--C(O)Cl, the following compounds of Formula I were made:
[0235]
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-methoxyphenyl)carbonylamino]-2-hydroxy-
propyl}piperazinyl)acetamide; [0236]
N-(2,6-dimethylphenyl)-2-(4-{3-[(3,4,5-trimethoxyphenyl)carbonylamino]-2--
hydroxypropyl}piperazinyl)acetamide. [0237]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]-
-propyl}piperazinyl)acetamide; [0238]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)-carbon-
ylamino]propyl}piperazinyl)acetamide; [0239]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[3-
-methoxy-5-(trifluoromethyl)phenyl]acetamide; [0240]
N-[(2,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2--
hydroxypropyl}piperazinyl)acetamide; [0241]
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-{3-[(2-fluorophenyl)carbonyla-
mino]-2-hydroxypropyl}piperazinyl)acetamide; [0242]
N-(3,4-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}-piperazinyl)acetamide; [0243]
N-(3,5-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}piperazinyl)acetamide; [0244]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[5-
-methoxy-3-(trifluoromethyl)phenyl]acetamide; [0245]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-na-
phthylacetamide; [0246]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-in-
dan-5-ylacetamide; [0247]
N-(2-chloro-4-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hyd-
roxypropyl}piperazinyl)acetamide; [0248]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-be-
nzylacetamide; [0249]
N-cyclohexyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}-pip-
erazinyl)acetamide; [0250]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-ph-
enylacetamide; [0251]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(3-
,4,5-trichlorophenyl)acetamide; [0252]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(2-
-phenylethyl)acetamide; [0253]
N-[2-(2,4-dichlorophenyl)ethyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-
-hydroxypropyl}piperazinyl)acetamide; [0254]
2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[4-
-(trifluoromethyl)phenyl]acetamide; [0255]
N-(4-chloro-2-methoxy-5-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylam-
ino]-2-hydroxypropyl}piperazinyl)acetamide; [0256]
N-cyclopentyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}pip-
erazinyl)-acetamide; [0257]
2-(4-{3-[(2,4-difluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)--
N-(2,6-dimethylphenyl)acetamide; [0258]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)carbony-
lamino]-propyl}piperazinyl)acetamide; [0259]
2-{4-[3-(benzothiazol-5-ylcarbonylamino)-2-hydroxypropyl]piperazinyl}-N-(-
2,6-dimethylphenyl)acetamide; [0260]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]-
propyl}-piperazinyl)acetamide; [0261]
N-[(4-chlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydr-
oxypropyl}piperazinyl)acetamide; [0262]
N-[(3,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2--
hydroxypropyl}piperazinyl)acetamide; [0263]
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}piperazinyl)acetamide; [0264]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-hydroxyphenyl)carbonylamino]-
propyl}-piperazinyl)acetamide; and [0265]
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)carbonylamino]-
propyl}-piperazinyl)acetamide. F. Preparation of a Compound of
Formula I in which T is Oxygen, X is a Covalent Bond, and Z is
--NHC(O)--
[0266] Similarly, following the procedure of 1A-E above, other
compounds of Formula I are made.
EXAMPLE 2
Preparation of a Compound of Formula (11)
[0267] A. Preparation of a Compound of Formula (9) in which Y is
--CH.sub.2--, R.sup.20 is Hydrogen and R.sup.2 is 4-Methoxyphenyl
##STR18##
[0268] To a solution of vinylacetic acid (8) (0.35 g), in
dichloromethane (5 mL) was added dicyclohexylcarbodiimide resin (4
g), and p-methoxy aniline (4 mmoles) and the mixture stirred at
ambient temperature for 18 hours. The resulting suspension was
filtered, the filtrate was washed with 10% citric acid (1 mL) and
saturated sodium bicarbonate (1 mL). The organic layer containing
crude N-(4-methoxyphenyl)but-3-enamide, a compound of formula (9),
was used in the next step without further workup. B. Preparation of
a Compound of Formula (10) in which Y is --CH.sub.2--, R.sup.20 is
hydrogen and R.sup.2 is 4-methoxyphenyl ##STR19##
[0269] The solution of N-(4-methoxyphenyl)but-3-enamide (9) from
the previous reaction was treated with m-chloroperbenzoic acid (2
eq.) and stirred at room temperature for 18 hours. The reaction
mixture was diluted with dichloromethane, and washed with 1N sodium
hydroxide. The organic phase was separated, dried over magnesium
sulfate, filtered, and the filtrate evaporated under reduced
pressure to give crude N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide,
a compound of formula (10). C. Preparation of a Compound of Formula
I in which A and Y are --CH.sub.2--, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, and R.sup.20 are Hydrogen, T is Oxygen,
X is a Covalent Bond, R.sup.1 is 2,6-Methylphenyl and R.sup.2 is
4-Methoxyphenyl ##STR20##
[0270] To a solution of crude
N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide (10) in ethanol (2.5 mL)
was added triethylamine (0.5 mL), followed by
N-(2,6-dimethylphenyl)-2-piperazinylacetamide, a compound of
formula (4) (150 mg), and the mixture was heated to reflux for 18
hours. Solvent was removed from the reaction mixture under reduced
pressure, and the residue purified by column chromatography on
silica gel, eluting with 5% MeOH/dichloromethane, to give
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}-piperazinyl)-3-hydroxy-N-(-
4-methoxyphenyl)butanamide, a compound of Formula I as an off-white
solid.
D. Preparation of a Compound of Formula I in which A and Y are
--CH.sub.2--, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
and R.sup.20 are Hydrogen, T is Oxygen, X is a Covalent Bond,
varying R.sup.1 and R.sup.2
[0271] Similarly, following the procedures of 2B and 2C above, but
optionally replacing N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide
with other compounds of formula (10), and optionally replacing
N-(2,6-dimethylphenyl)-2-piperazinylacetamide with other compounds
of formula (4), the following compounds of Formula I were prepared.
[0272]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-
-fluorophenyl)butanamide; [0273]
4-[4-({N-[(3,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-f-
luorophenyl)-3-hydroxybutanamide; [0274]
4-[4-({N-[(2,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-f-
luorophenyl)-3-hydroxybutanamide; [0275]
4-(4-{[N-(3,5-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophe-
nyl)-3-hydroxybutanamide; [0276]
4-(4-{[N-(3,4-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophe-
nyl)-3-hydroxybutanamide; [0277]
4-(4-{[N-(4-chloro-2-methoxy-5-methylphenyl)carbamoyl]methyl}piperazinyl)-
-N-(2-fluorophenyl)-3-hydroxybutanamide; [0278]
N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[3-methoxy-5-(trifluoromethyl)pheny-
l]carbamoyl}-methyl)piperazinyl]butanamide; [0279]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-naphthylcarbamoyl)methyl]piperaziny-
l}butanamide; [0280]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-indan-5-ylcarbamoyl)methyl]piperazi-
nyl}butanamide; [0281]
4-(4-{[N-(2-chloro-4-methylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluo-
rophenyl)-3-hydroxybutanamide; [0282]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophe-
nyl)-3-hydroxybutanamide; [0283]
N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-benzylcarbamoyl]methyl}piperazinyl)-
butanamide; [0284]
4-{4-[(N-cyclohexylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hyd-
roxybutanamide; [0285]
4-{4-[(N-cyclopentylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hy-
droxybutanamide; [0286]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-phenylcarbamoyl)methyl]piperazinyl}-
butanamide; [0287]
N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(3,4,5-trichlorophenyl)carbamoyl]me-
thyl}-piperazinyl)butanamide; [0288]
N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(2-phenylethyl)carbamoyl]methyl}-pi-
perazinyl)butanamide; [0289]
4-[4-({N-[2-(2,4-dichlorophenyl)ethyl]carbamoyl}methyl)piperazinyl]-N-(2--
fluorophenyl)-3-hydroxybutanamide; [0290]
N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[4-(trifluoromethyl)phenyl]carbamoy-
l}methyl)-piperazinyl]butanamide; [0291]
4-[4-({N-[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}methyl)piperazinyl-
]-N-(2-fluorophenyl)-3-hydroxybutanamide; [0292]
N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-(1H-indazol-5-yl)carbamoyl)methyl]--
piperazinyl}butanamide; and [0293]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophe-
nyl)-3-hydroxybutanamide.
EXAMPLE 3
Preparation of a Compound of Formula I
[0294] A. Preparation of a Compound of Formula (13) in which A and
Y are --CH.sub.2--, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
and R.sup.8 are Hydrogen, T is Oxygen, X and Z are Covalent Bonds,
R.sup.1 is 2,6-Dimethylphenyl, and R.sup.2 is 2-Methoxyphenyl
##STR21##
[0295] A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide
(100 mg, 0.4 mmol) and 1-(2-methoxyphenyl)but-3-en-2-one (100 mg,
0.56 mmol), a compound of formula (12), in ethanol (2 mL) was
heated at reflux for 16 hours. Ethanol was removed under reduced
pressure and the residue was purified by preparative TLC, using 10%
methanol in dichloromethane as mobile phase, to afford
N-(2,6-dimethylphenyl)-2-{4-[4-(2-methoxyphenyl)-3-oxobutyl]piperazin-1-y-
l}acetamide, a compound of formula (13). B. Preparation of a
Compound of Formula I in which A and Y are --CH.sub.2--, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are Hydrogen, T is
Oxygen, X and Z are Covalent Bonds, R.sup.1 is 2,6-Methylphenyl,
and R.sup.2 is 2-Methoxyphenyl ##STR22##
[0296] To a solution of
N-(2,6-dimethylphenyl)-2-{4-[4-(2-methoxyphenyl)-3-oxobutyl]piperazin-1-y-
l}acetamide (100 mg, 0.23 mmol) in ethanol (2 mL) was added sodium
borohydride (50 mg), and the mixture was stirred for 16 hours.
Excess borohydride was then quenched by the addition of saturated
ammonium chloride solution. Dichloromethane (20 mL) was added, the
mixture shaken, and the organic layer was separated, washed with
water and concentrated under reduced pressure. The residue obtained
was purified by preparative TLC using 10% methanol in
dichloromethane as mobile phase to afford
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-
-1-yl}acetamide, a compound of Formula I.
C. Preparation of a Compound of Formula I in which A and Y are
--CH.sub.2--, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and
R.sup.8 are Hydrogen, T is Oxygen, X and Z are Covalent Bonds,
varying R.sup.1 and R.sup.2
[0297] Similarly, following the procedures of 3A and 3B above, the
following compounds of Formula I were prepared: [0298]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(3,4,5-trimethoxyphenyl)butyl]pi-
perazin-1-yl}acetamide; [0299]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-
-1-yl}acetamide; [0300]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazi-
n-1-yl}acetamide; [0301]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-
yl}acetamide; [0302]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-
-1-yl}acetamide; [0303]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazi-
n-1-yl}acetamide; [0304]
N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazin-1-yl]aceta-
mide; [0305]
2-{4-[4-(4-tert-butylphenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimeth-
ylphenyl)acetamide; [0306]
2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylph-
enyl)acetamide. [0307]
N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]ace-
tamide; [0308]
N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazinyl]acetamid-
e; [0309]
2-(4-{4-[4-(tert-butyl)phenyl]-4-hydroxybutyl}piperazinyl)-N-(2,6-dimethy-
lphenyl)acetamide; [0310]
N-(2,6-dimethylphenyl)-2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperaziny-
l}acetamide; [0311]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-
yl}acetamide; [0312]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-
yl}acetamide; [0313]
N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazi-
nyl}acetamide; [0314]
N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]pipe-
razinyl}-acetamide; [0315]
N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-
piperazinyl}-acetamide; [0316]
N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-
-piperazinyl}acetamide; [0317]
N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl-
}acetamide; [0318]
N-benzothiazol-2-yl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl-
}acetamide; [0319]
N-cyclohexyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetam-
ide; [0320]
N-cyclopentyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}aceta-
mide; [0321]
N-[(3,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-
acetamide; [0322]
N-[(2,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-
acetamide; [0323]
N-[(4-chlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acet-
amide; [0324]
N-(1H-indazol-5-yl)-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;
[0325]
N-benzothiazol-2-yl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]ace-
tamide; [0326]
N-cyclohexyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;
[0327]
N-cyclopentyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;
[0328]
2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-N-(2-phenylethyl)aceta-
mide; [0329]
N-[2-(2,4-dichlorophenyl)ethyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl-
]acetamide; [0330]
2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-N-(2-phenylethyl)a-
cetamide; [0331]
N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl-
]-piperazinyl}acetamide; [0332]
N-benzothiazol-2-yl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-
acetamide; [0333]
N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piper-
azinyl}acetamide; [0334]
N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]--
piperazinyl}acetamide; [0335]
N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]--
piperazinyl}acetamide; [0336]
N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-
acetamide; [0337]
N-cyclohexyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetami-
de; [0338]
N-cyclopentyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetam-
ide; [0339]
N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-
-piperazinyl}acetamide; [0340]
2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-(2-phenylethyl)ac-
etamide; and [0341]
2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-{2-[4-(trifluorom-
ethyl)phenyl]ethyl}acetamide. D. Preparation of a Compound of
Formula I
[0342] Similarly, following the procedures of 3A and 3B above,
other compounds of Formula I are prepared.
EXAMPLE 4
Preparation of a Compound of Formula (17)
[0343] A. Preparation of a Compound of Formula (16) in which Y and
Z Taken Together are a Covalent Bond, A is --CH.sub.2--, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are Hydrogen, T is
Oxygen, X is a Covalent Bond, R.sup.1 is 2,6-Methylphenyl, and
R.sup.2 is Phenyl ##STR23##
[0344] A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide
(4) (100 mg, 0.4 mmol), 4-chloro-1-phenylbutan-1-one (12) (100 mg,
0.55 mmol), and triethylamine (0.4 mL) in ethanol (3 mL) was heated
at reflux for 16 hours. Ethanol was removed under reduced pressure
and the residue was purified by preparative TLC using 10% methanol
in dichloromethane as mobile phase to afford
N-(2,6-dimethylphenyl)-2-[4-(4-oxo-4-phenylbutyl)piperazin-1-yl]acetamide-
, a compound of formula (16).
B. Preparation of a Compound of Formula (17)
[0345] Similarly, following the procedure of Example 4A above, but
replacing 4-chloro-1-phenylbutan-1-one with
4-chloro-1-(4-tert-butylphenyl)butan-1-one and
4-chloro-1-(4-chloro-butylphenyl)butan-1-one, the following
compounds of formula (16) were prepared: [0346]
2-{4-[4-(4-tert-butylphenyl)-4-oxobutyl]piperazin-1-yl}-N-(2,6-dimethylph-
enyl)acetamide; and [0347]
2-{4-[4-(4-chlorophenyl)-4-oxobutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl-
)acetamide. C. Preparation of a Compound of Formula I in which Y
and Z Taken Together are a Covalent Bond, A is --CH.sub.2--,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
Hydrogen, T is Oxygen, X is a Covalent Bond, R.sup.1 is
2,6-Methylphenyl group and R.sup.2 is Phenyl ##STR24##
[0348]
N-(2,6-dimethylphenyl)-2-[4-(4-oxo-4-phenylbutyl)piperazin-1-yl]ac-
etamide (16) was reduced to
N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazin-1-yl]aceta-
mide (17) with sodium borohydride under the same conditions shown
as Example 3B.
[0349] Similarly,
2-{4-[4-(4-tert-butylphenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimeth-
ylphenyl)acetamide and
2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylph-
enyl)acetamide were prepared.
[0350] The following examples illustrate the preparation of
representative pharmaceutical formulations containing a compound of
Formula I, such as those prepared in accordance with Examples 1-4
above.
EXAMPLE 5
[0351] Hard gelatin capsules containing the following ingredients
are prepared: TABLE-US-00001 Quantity Ingredient (mg/capsule)
Active Ingredient 30.0 Starch 305.0 Magnesium stearate 5.0
[0352] The above ingredients are mixed and filled into hard gelatin
capsules.
EXAMPLE 6
[0353] A tablet formula is prepared using the ingredients below:
TABLE-US-00002 Quantity Ingredient (mg/tablet) Active Ingredient
25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide
10.0 Stearic acid 5.0
[0354] The components are blended and compressed to form
tablets.
EXAMPLE 7
[0355] A dry powder inhaler formulation is prepared containing the
following components: TABLE-US-00003 Ingredient Weight % Active
Ingredient 5 Lactose 95
The active ingredient is mixed with the lactose and the mixture is
added to a dry powder inhaling appliance.
EXAMPLE 8
[0356] Tablets, each containing 30 mg of active ingredient, are
prepared as follows: TABLE-US-00004 Quantity Ingredient (mg/tablet)
Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose
35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10% solution in sterile
water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg
Talc 1.0 mg Total 120 mg
The active ingredient, starch and cellulose are passed through a
No. 20 mesh U.S. sieve and mixed thoroughly. The solution of
polyvinylpyrrolidone is mixed with the resultant powders, which are
then passed through a 16 mesh U.S. sieve. The granules so produced
are dried at 50.degree. C. to 60.degree. C. and passed through a 16
mesh U.S. sieve. The sodium carboxymethyl starch, magnesium
stearate, and talc, previously passed through a No. 30 mesh U.S.
sieve, are then added to the granules which, after mixing, are
compressed on a tablet machine to yield tablets each weighing 120
mg.
EXAMPLE 9
[0357] Suppositories, each containing 25 mg of active ingredient
are made as follows: TABLE-US-00005 Ingredient Amount Active
Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve
and suspended in the saturated fatty acid glycerides previously
melted using the minimum heat necessary. The mixture is then poured
into a suppository mold of nominal 2.0 g capacity and allowed to
cool.
EXAMPLE 10
[0358] Suspensions, each containing 50 mg of active ingredient per
5.0 mL dose are made as follows: TABLE-US-00006 Ingredient Amount
Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl
cellulose (11%) 50.0 mg Macrocrystalline cellulose (89%) Sucrose
1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water
to 5.0 mL
The active ingredient, sucrose and xanthan gum are blended, passed
through a No. 10 mesh U.S. sieve, and then mixed with a previously
made solution of the microcrystalline cellulose and sodium
carboxymethyl cellulose in water. The sodium benzoate, flavor, and
color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
EXAMPLE 11
[0359] A subcutaneous formulation may be prepared as follows:
TABLE-US-00007 Ingredient Quantity Active Ingredient 5.0 mg Corn
Oil 1.0 mL
EXAMPLE 12
[0360] An injectable preparation is prepared having the following
composition: TABLE-US-00008 Ingredients Amount Active ingredient
2.0 mg/ml Mannitol, USP 50 mg/ml Gluconic acid, USP q.s. (pH 5-6)
Water (distilled, sterile) q.s. to 1.0 ml Nitrogen Gas, NF
EXAMPLE 13
[0361] A topical preparation is prepared having the following
composition: TABLE-US-00009 Ingredients grams Active ingredient
0.2-10 Span 60 2.0 Tween 60 2.0 Mineral oil 5.0 Petrolatum 0.10
Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy
anisole) 0.01 Water q.s. to 100
All of the above ingredients, except water, are combined and heated
to 60.degree. C. with stirring. A sufficient quantity of water at
60.degree. C. is then added with vigorous stirring to emulsify the
ingredients, and water then added q.s. 100 g.
EXAMPLE 14
Sustained Release Composition
[0362] The sustained release Formulations of this invention are
prepared as follows: TABLE-US-00010 Weight Ingredient Range (%)
Active ingredient 50-95 Microcrystalline cellulose (filler) 1-35
Methacrylic acid copolymer 1-35 Sodium hydroxide 0.1-1.0
Hydroxypropyl methylcellulose 0.5-5.0 Magnesium stearate
0.5-5.0
[0363] Compound and pH-dependent binder and any optional excipients
are intimately mixed (dry-blended). The dry-blended mixture is then
granulated in the presence of an aqueous solution of a strong base
which is sprayed into the blended powder. The granulate is dried,
screened, mixed with optional lubricants (such as talc or magnesium
stearate), and compressed into tablets. Preferred aqueous solutions
of strong bases are solutions of alkali metal hydroxides, such as
sodium or potassium hydroxide, for example sodium hydroxide, in
water (optionally containing up to 25% of water-miscible solvents
such as lower alcohols).
[0364] The resulting tablets may be coated with an optional
film-forming agent, for identification, taste-masking purposes and
to improve ease of swallowing. The film forming agent will
typically be present in an amount ranging from between 2% and 4% of
the tablet weight. Suitable film-forming agents are well known to
the art and include hydroxypropyl methylcellulose, cationic
methacrylate copolymers (dimethylaminoethyl
methacrylate/methyl-butyl methacrylate copolymers-Eudragit.RTM.
E-Rohm. Pharma), and the like. These film-forming agents may
optionally contain colorants, plasticizers, and other supplemental
ingredients.
EXAMPLE 15
Mitochondrial Assays
[0365] Rat heart mitochondria were isolated by the method of
Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).
[0366] 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 micro molar, 30 micro
molar, and 3 micro molar. 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.
[0367] The compounds of the invention showed activity as fatty acid
oxidation inhibitors in this assay. Representative examples of test
data is shown below, along with their NMR. [0368]
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxyp-
ropyl}piperazinyl)acetamide;
[0369] MS (ESI): 443.56 (M+H.sup.+), 465.56 (M+Na.sup.+). .sup.1H
NMR (.delta., 400 MHz, CDCl.sub.3): 8.82 (brs, 1H); 8.03 (t, 1H);
7.48 (dd, 1H); 7.30-7.18 (m, 2H); 7.18-7.01 (m, 4H); 4.00-3.90 (m,
1H); 2.78-3.69 (m, 1H); 3.50-3.40 (m, 1H); 3.20 (s, 2H); 2.80-2.25
(m, 10H); 2.18 (s, 6H).
Inhibition was found to be 24% at 100 .mu.M of test compound.
[0370]
4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hyd-
roxy-N-(2-fluorophenyl)butanamide;
[0371] TLC: R.sub.f=0.21 (5% MeOH in CH.sub.2Cl.sub.2); MS (ESI+):
443.54 (M+H.sup.+), 465.52 (M+Na.sup.+). .sup.1H NMR (.delta., 400
MHz, CDCl3): 8.80 (brs, 1H); 8.60 (brs, 1H); 8.30 (t, 1H);
7.17-6.99 (m, 6H); 4.20-4.12 (m, 1H); 3.20 (s, 2H); 2.80-2.25 (m,
12H); 2.21 (s, 6H).
Inhibition was found to be 36% at 100 .mu.M of test compound.
[0372]
N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)pipera-
zinyl]acetamide
[0373] TLC: R.sub.f=0.45 (5% MeOH in CH.sub.2Cl.sub.2); MS (ESI+):
388.61 (M+H.sup.+); .sup.1H NMR (.delta., 400 MHz, CDCl3): 8.70
(brs, 1H); 7.10 (s, 3H); 3.82-3.78 (m, 1H); 3.20 (s, 2H); 2.80-2.68
(brs, 4H); 2.58-2.38 (brs, 2H); 2.26 (t, 2H); 2.20 (s, 6H);
2.01-0.98 (m, 15H).
Inhibition was found to be 8% at 100 .mu.M of test compound.
EXAMPLE 16
Perfusate
[0374] Langendorff perfusion is conducted using a Krebs-Henseleit
solution containing: (mM) NaCl (118.0), KCl (4.7), KH.sub.2PO.sub.4
(1.2), MgSO.sub.4 (1.2), CaCl.sub.2 (2.5), NaHCO.sub.3 (25.0) and
glucose (5.5 or 11) (Finegan et al. 1996). The working heart
perfusate consists of a Krebs-Henseleit solution with the addition
of palmitate (0.4 or 1.2 mM) pre-bound to 3% bovine serum albumin
(essentially fatty acid free BSA) and insulin (100 .mu.U/ml).
Palmitate is initially dissolved in an ethanol:water mixture
(40%:60%) containing 0.5-0.6 g Na.sub.2CO.sub.3 per g of palmitate.
Following heating to evaporate the ethanol, this mixture is then
added to the 3% BSA-Krebs-Henseleit mixture (without glucose) and
allowed to dialyze (8000 MW cut-off) overnight in 10 volumes of
glucose-free Krebs-Henseleit solution. The next day, glucose is
added to the solution and the mixture was filtered through glass
microfiber filters (GF/C, Whatman, Maidstone, England) and kept on
ice, or refrigerated, prior to use. The perfusate is continuously
oxygenated with a 95% CO.sub.2, 5% O.sub.2 gas mixture while in the
perfusion apparatus to main aerobic conditions.
EXAMPLE 17
Heart Perfusion Protocols
[0375] Rats are anesthetized with pentobarbital (60 mg/kg,
intraperitoneally) and hearts rapidly removed and placed in
ice-cold Krebs-Henseleit solution. The hearts are then rapidly
cannulated via the aortic stump and Langendorff perfusion at
constant pressure (60 mm Hg) is initiated and continued for a
10-min equilibration period. During this equilibration period, the
pulmonary artery is cut, and excess fat and lung tissue removed to
reveal the pulmonary vein. The left atrium is cannulated and
connected to the preload line originating from the oxygenation
chamber. After the 10-min equilibration period, hearts are switched
to working mode (by clamping off the Langendorff line and opening
the preload and afterload lines) and perfused at 37.degree. C.
under aerobic conditions at a constant left atrial preload (11.5 mm
Hg) and aortic afterload (80 mm Hg). The compliance chamber is
filled with air adequate to maintain developed pressure at 50-60 mm
Hg. Perfusate is delivered to the oxygenation chamber via a
peristaltic pump from the reservoir chamber that collected aortic
and coronary flows as well as overflow from the oxygenator.
[0376] Typically, hearts are perfused under aerobic conditions for
60 min. Hearts are paced at 300 beats/min throughout each phase of
the perfusion protocol (voltage adjusted as necessary) with the
exception of the initial 5 min of reperfusion when hearts are
allowed to beat spontaneously.
[0377] At the end of the perfusion protocol, hearts are rapidly
frozen using Wollenberger clamps cooled to the temperature of
liquid nitrogen. Frozen tissues are pulverized and the resulting
powders stored at -80.degree. C.
EXAMPLE 18
Myocardial Mechanical Function
[0378] Aortic systolic and diastolic pressures are measured using a
Sensonor (Horten Norway) pressure transducer attached to the aortic
outflow line and connected to an AD Instruments data acquisition
system. Cardiac output, aortic flow and coronary flow (cardiac
output minus aortic flow) are measured (ml/min) using in-line
ultrasonic flow probes connected to a Transonic T206 ultrasonic
flow meter. Left ventricular minute work (LV work), calculated as
cardiac output x left ventricular developed pressure (aortic
systolic pressure-preload pressure), is used as a continuous index
of mechanical function. Hearts are excluded if LV work decreased
more than 20% during the 60-min period of aerobic perfusion.
EXAMPLE 19
Myocardial Oxygen Consumption and Cardiac Efficiency
[0379] Measuring the atrial-venous difference in oxygen content of
the perfusate and multiplying by the cardiac output provides an
index of oxygen consumption. Atrial oxygen content (mmHg) is
measured in perfusate in the preload line or just prior to entering
the left atria. Venous oxygen content is measured from perfusate
exiting the pulmonary artery and passing through in-line O.sub.2
probes and meters Microelectrodes Inc., Bedford, N. H. Cardiac
efficiency is calculated as the cardiac work per oxygen
consumption.
EXAMPLE 20
Measurement of Glucose and Fatty Acid Metabolism
[0380] Determining the rate of production of .sup.3H.sub.2O and
.sup.14CO.sub.2 from [.sup.3H/.sup.14C]glucose in the isolated
working rat model allows a direct and continuous measure of the
rates of glycolysis and glucose oxidation. Alternatively, the
measure of the production of .sup.3H.sub.2O from
[5-.sup.3H]palmitate provides a direct and continuous measure of
the rate of palmitate oxidation. Dual labelled substrates allows
for the simultaneous measure of either glycolysis and glucose
oxidation or fatty acid oxidation and glucose oxidation. A 3-ml
sample of perfusate is taken from the injection port of the
recirculating perfusion apparatus at various time-points throughout
the protocol for analysis of .sup.3H.sub.2O and .sup.14CO.sub.2 and
immediately placed under mineral oil until assayed for metabolic
product accumulation. Perfusate is supplemented with
[.sup.3H/.sup.14C]glucose or [5-.sup.3H]palmitate to approximate a
specific activity of 20 dpm/mmol. Average rates of glycolysis and
glucose oxidation are calculated from linear cumulative
time-courses of product accumulation between 15 and 60 min for
aerobic perfusion. Rates of glycolysis and glucose oxidation are
expressed as .mu.mol glucose metabolized/min/g dry wt.
EXAMPLE 21
Measurement of Myocardial Glycolysis
[0381] Rates of glycolysis are measured directly as previously
described (Saddik & Lopaschuk, 1991) from the quantitative
determination of .sup.3H.sub.2O liberated from radiolabeled
[5-.sup.3H]glucose at the enolase step of glycolysis. Perfusate
samples are collected at various time-points throughout the
perfusion protocol. .sup.3H.sub.2O is separated from the perfusate
by passing perfusate samples through columns containing Dowex 1-X 4
anion exchange resin (200-400 mesh). A 90 g/L Dowex in 0.4 M
potassium tetraborate mixture is stirred overnight after which 2 ml
of the suspension is loaded into separation columns and washed
extensively with dH.sub.2O to remove the tetraborate. The columns
are found to exclude 98-99.6% of the total [.sup.3H]glucose (Saddik
& Lopaschuk, 1996). Perfusate samples (100 .mu.l) are loaded
onto the columns and washed with 1.0 ml dH.sub.2O. Effluent is
collected into 5 ml of Ecolite Scintillation Fluid (ICN,
Radiochemicals, Irvine, Calif.) and counted for 5 min in a Beckman
LS 6500 Scintillation Counter with an automatic dual
(.sup.3H/.sup.14C) quench correction program. Average rates of
glycolysis for each phase of perfusion are expressed as .mu.mol
glucose metabolized/min/g dry wt as described above.
EXAMPLE 22
Measurement of Myocardial Glucose Oxidation
[0382] Glucose oxidation is also determined directly as previously
described (Saddik & Lopaschuk, 1991) by measuring
.sup.14CO.sub.2 from [.sup.14C]glucose liberated at the level of
pyruvate dehydrogenase and in the Krebs cycle. Both .sup.14CO.sub.2
gas exiting the oxygenation chamber and [.sup.14C]bicarbonate
retained in solution are measured. Perfusate samples are collected
at various time-points throughout the perfusion protocol.
.sup.14CO.sub.2 gas is collected by passing the gas exiting the
oxygenator through a hyamine hydroxide trap (20-50 ml depending on
perfusion duration). Perfusate samples (2.times.1 ml), which are
stored under oil to prevent the escape of gas by equilibration with
atmospheric CO.sub.2, are injected into 16.times.150 mm test tubes
containing 1 ml of 9 N H.sub.2SO.sub.4. This process releases
.sup.14CO.sub.2 from the perfusate present as
H.sup.14CO.sub.3.sup.-. These duplicate tubes are sealed with a
rubber stopper attached to a 7-ml scintillation vial containing a
2.times.5 cm piece of filter paper saturated with 250 .mu.l of
hyamine hydroxide. The scintillation vials with filter papers are
then removed and Ecolite Scintillation Fluid (7 ml) added. Samples
are counted by standard procedures as described above. Average
rates of glucose oxidation for each phase of perfusion are
expressed as .mu.mol glucose metabolized/min/g dry wt as described
above.
EXAMPLE 23
Measurement of Myocardial Fatty Acid Oxidation
[0383] Rates of palmitate oxidation are measured directly as
previously described (Saddik & Lopaschuk, 1991) from the
quantitative determination of .sup.3H.sup.-H.sub.2O liberated from
radiolabeled [5-3H]palmitate. .sup.3H.sub.2O is separated from
[5-3H]palmitate following a chloroform:methanol (1.88 ml of 1:2
v/v) extraction of a 0.5 ml sample of buffer then adding 0.625 ml
of chloroform and 0.625 ml of a 2M KCL:HCl solution. The aqueous
phase is removed and treated with a mixture of chloroform, methanol
and KCl:HCl (1:1:0.9 v/v). Duplicate samples are taken from the
aqueous phase for liquid scintillation counting and rates of
oxidation are determined taking into account a dilution factor.
This results in >99% extraction and separation of .sup.3H.sub.2O
from [5-.sup.3H]palmitate. Average rates of glucose oxidation for
each phase of perfusion are expressed as .mu.mol glucose
metabolized/min/g dry wt as described above.
Dry to Wet Ratios
[0384] Frozen ventricles are pulverized at the temperature of
liquid nitrogen with a mortar and pestle. Dry to wet determinations
are made by weighing a small amount of frozen heart tissue and
re-weighing that same tissue after 24-48 hr of air drying and
taking the ratio of the two weights. From this ratio, total dry
tissue can be calculated. This ratio is used to normalize, on a per
g dry weight basis, rates of glycolysis, glucose oxidation and
glycogen turnover as well as metabolite contents.
[0385] The compounds of the invention show activity as fatty acid
oxidation inhibitors in this assay.
[0386] While the present invention has been described with
reference to the specific embodiments thereof, it will be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the
true spirit and scope of the invention. In addition, many
modifications may be made to adapt a particular situation,
material, composition of matter, process, process step or steps, to
the objective, spirit and scope of the present invention. All such
modifications are intended to be within the scope of the claims
appended hereto. All patents and publications cited above are
hereby incorporated by reference.
* * * * *