Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-22
2003-04-22
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254110, C544S377000, C544S400000
Reexamination Certificate
active
06552023
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is concerned with substituted piperazine compounds, therapeutic dosage forms including one or more of the compounds, and methods for treating diseases in mammals, and in particular, in a human in a therapy selected from the group including protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
2. Description of the Art
U.S. Pat. No. 4,567,264, the specification of which is incorporated herein by reference, discloses a class of substituted piperazine compounds that includes a compound known as ranolazine, (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced angina, and myocardial infarction.
U.S. Pat. No. 5,506,229, which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. In particular, ranolazine is particularly useful for treating arrhythmias, variant and exercise-induced angina, and myocardial infarction by partially inhibiting cardiac fatty acid oxidation. Conventional oral and parenteral ranolazine formulations are disclosed, including controlled release formulations. In particular, Example 7D of U.S. Pat. No. 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
Despite the important discovery that ranolazine is a very useful cardiac therapeutic agent, there remains a need for compounds that are partial fatty acid oxidation inhibitors that have a half-life greater than ranolazine and that have activities as least similar to ranolazine.
SUMMARY OF THE INVENTION
This invention includes novel substituted piperazine compounds that are partial fatty acid oxidation inhibitors with good therapeutic half-lives.
This invention also includes novel substituted piperazine compounds that can be administered to a mammal to protect skeletal muscles against damage resulting from trauma, to protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
This invention includes a class of substituted piperazine compounds having the
following formula:
wherein m=1 or 2 or 3;
R
1
, R
2
, R
3
, R
4
and R
5
are each independently selected from the group consisting of hydrogen, halo, NO
2
, CF
3
, CN, OR
23
, SR
23
, N(R
23
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
23
)
2
, NR
23
CO
2
R
22
, NR
23
CON(R
23
)
2
, COR
23
, CO
2
R
23
, CON(R
23
)
2
, NR
23
SO
2
R
22
, C
1-5
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO
2
, CF
3
, CN, OR
23
, SR
23
, N(R
23
)
2
, S(O)R
22
, and SO
2
R
22
;
R
6
, R
7
and R
8
each independently selected from the group consisting of hydrogen or C
1-5
alkyl;
R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
and R
16
are each independently selected from the group consisting of hydrogen, CO
2
R
23
, CON(R
23
)
2
, C
1-4
alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF
3
, CN, OR
23
, N(R
23
)
2
, CO
2
R
23
, CON(R
23
)
2
or aryl, wherein R
9
and R
10
may together form a carbonyl, or R
11
and R
12
may together form a carbonyl, or R
13
and R
14
may together form a carbonyl, or R
15
and R
16
may together form a carbonyl wherein R
11
and R
13
or R
9
and R
15
or R
9
and R
11
or R
11
and R
15
or R
9
and R
13
may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein R
9
and R
10
or R
11
and R
12
or R
13
and R
14
or R
15
and R
16
may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R
17
, R
18
, R
19
, R
20
, and R
21
are each independently selected from the group consisting of hydrogen, halo, NO
2
, CF
3
, CN, OR
23
, SR
23
, N(R
23
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
23
)
2
, NR
23
CO
2
R
22
, NR
23
CON(R
23
)
2
, COR
23
, CO
2
R
23
, CON(R
23
)
2
, NR
23
SO
2
R
22
, C
1-15
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO
2
, CF
3
, CN, OR
23
, SR
23
, N(R
23
)
2
, S(O)R
22
, and SO
2
R
22
or wherein R
17
and R
18
may join together to form —CH═CH—CH═CH—, or wherein R
17
and R
18
or R
18
and R
19
or R
19
and R
20
or R
20
and R
21
may combine to form a saturated ring including from 3 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom;
R
22
is selected from the group consisting of C
1-15
alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O—C
1-6
alkyl, CF
3
, or heteroaryl; and
R
23
is selected from the group consisting of H, C
1-15
alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alky, CN, —O—C
1-6
alky, or CF
3
.
In another embodiment, this invention is a substituted piperazine compound selected from the group consisting of N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide; 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide; N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-(4-{4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide, 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piper
Blackburn Brent K.
Elzein Elfatih
Ibrahim Prabha N.
Marquart Tim
Palle Venkata P.
Bernhardt Emily
CV Therapeutics Inc.
McDonnell & Boehnen Hulbert & Berghoff
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