Substituted alkyl piperazine derivatives

Details Substituted alkyl piperazine derivatives Substituted alkyl piperazine derivatives

2001-02-22

2002-09-17

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S400000

Reexamination Certificate

active

06451798

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, 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
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, NR
20
CO
2
R
22
, NR
20
CON(R
20
)
2
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, NR
20
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
20
, SR
20
, N(R
20
)
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
1-3
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
20
, CON(R
20
)
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
20
, N(R
20
)
2
, CO
2
R
20
, CON(R
20
)
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 with the proviso that 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 ring including from 1 to 3 carbon atoms;
R
17
is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF
3
, CN, OR
20
, SR
20
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, NR
20
CO
2
R
22
, C
1-2
alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF
3
, CN, OR
20
, and C
1-6
alkyl;
R
20
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, alkyl, CN, —O—C
1-6
alkyl, or CF
3
; and
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.
In still another embodiment, this invention is a substituted piperazine compound selected from the group consisting of 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmethoxy)propyl]piperazinyl}acetamide, 2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide, 2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide, 2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, 2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, 2-(4-{3-[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydoxy-3-(2-naphthylmethoxy)propyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmet

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