Aminocyclohexylesters and uses thereof

Details Aminocyclohexylesters and uses thereof Aminocyclohexylesters and uses thereof

1999-03-17

2001-01-16

Kifle, Bruck (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S217120, C514S319000, C514S320000, C514S327000, C514S317000, C514S408000, C514S422000, C514S429000, C540S450000, C540S451000, C540S480000, C540S524000, C540S526000, C540S596000, C540S602000, C540S604000, C540S484000, C540S200000, C540S354000, C540S362000, C546S192000, C546S195000, C546S196000, C546S216000, C548S950000, C548S952000, C548S517000, C548S527000, C548S541000, C548S572000

Reexamination Certificate

active

06174879

ABSTRACT:

TECHNICAL FIELD
The present invention is generally directed toward aminocyclohexylester compounds, including thioesters, for use in cardiac arrhythmias, the blockade of ion channels and the preparation of pharmaceutical compositions and kits.
BACKGROUND OF THE INVENTION
Arrhythmia is a variation from the normal rhythm of the heart beat. The major cause of fatalities due to cardiac arrhythmias is the subtype of arrhythmias known as ventricular fibrillation. Conservative estimates indicate that, in the U.S. alone, approximately 300,000 individuals per year suffer heart attacks. Approximately half of these die from sudden cardiac death, the major cause of which is ventricular fibrillation.
Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia. For example, Class I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias. Treatment of ventricular arrhythmia is very important since such an arrhythmia, especially ventricular fibrillation, can be fatal. Serious ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) occur most often in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs in the setting of acute myocardial ischemia, before infarction fully develops. At present, lidocaine is the current drug of choice for prevention of ventricular fibrillation. However, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction. Therefore, there is a need in the art to identify new antiarrhythmic treatments, particularly treatments for ventricular arrhythmias. The present invention fulfills this need, and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compounds for a variety of uses. including the blockade of ion channels in vitro and in vivo, and for the treatment of arrhythmias
In an aspect of the present invention, aminocyclohexyl esters and thioesters are provided. In one embodiment, a compound comprises an enantiomer or geometric isomer of a compound of formula I, or a solvate or pharmaceutically acceptable salt thereof, the compound of the formula:
wherein X is a direct bond;
or —(CH
2
)
n
—Y—, where n=1, 2, or 3, and Y is a direct bond, O or S;
or —CH(R
12
)—Y—, where R
12
is alkyl of from one to six carbon atoms, a saturated carbocyclic ring of from three to six carbon atoms, phenyl or benzyl, and Y is a direct bond, O or S;
or —C(R
13
)═CH—, where R
13
is hydrogen, alkyl of from one to six carbon atoms, or phenyl;
R
1
and R
2
are independently hydrogen, alkyl of three to eight carbon atoms, alkoxyalkyl of three to eight carbon atoms, or aralkyl of seven to twelve carbon atoms;
or R
1
and R
2
, when taken together with the nitrogen atom to which they are attached, form a ring denoted by formula II:
where m is an integer from three to eight, and the ring may be substituted at any one carbon atom by hydroxy, oxo, alkyl of one to three carbon atoms or alkoxy of one to three carbon atoms, or may be fused at two adjacent carbon atoms with an aromatic or aliphatic carbocyclic ring of six carbon atoms;
or complete a saturated monocyclic nitrogen heterocyclic ring of five to eight ring atoms, containing only carbon, nitrogen and optionally oxygen ring atoms, and the heterocyclic ring containing not more than two nitrogen ring atoms, the second nitrogen being optionally substituted with an alkyl group of one to six carbon atoms or a phenyl ring;
or complete a ring selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, or 3-azabicyclo[3.2.0]heptan-3-yl;
R
3
and R
4
are independently attached to the cyclohexane ring at the 3-, 4-, 5-, or 6-positions, and are independently hydrogen, hydroxy, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms, or are points of attachment of a spiro five- or six-membered heterocyclic ring containing one oxygen or sulfur atom; and
A is an alkyl group of five to twelve carbon atoms, or is a saturated carbocyclic ring of three to six carbon atoms, or is selected from formulae III, IV, V, VI, VII or VII:
where R
5
, R
6
and R
7
are independently hydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, or aryl, and when X is a direct bond at least one of R
5
, R
6
and R
7
is a hydroxy, fluorine, chlorine, bromine, trifluoromethyl, alkyl of from one to six carbon atoms, or aryl substituent, and when X is —CH═CH—, and R
1
and R
2
when taken together with the nitrogen atom to which they are attached, form a N-phenylpiperazine ring, and R
3
and R
4
are hydrogen, at least one of R
5
, R
6
and R
7
is a substituent other than hydrogen;
where R
8
and R
9
are independently hydrogen, hydroxy, fluorine, chlorine, bromine, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms or aryl;
where R
8
and R
9
are defined as above;
where R
10
is hydrogen, hydroxy, fluorine, chlorine, bromine, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or aryl; Z is CH
2
, O, S, or N—R
11
where R
11
is hydrogen or alkyl of one to six carbon atoms;
only when X is a direct bond;
only when X is a direct bond;
with the proviso that, when X is —(CH
2
)
n
—Y—, and n=1, and Y is a direct bond, and R
1
and R
2
, when taken together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring, and R
3
and R
4
are hydrogen, A may not be 4-thianaphthenyl.
In another embodiment, a compound comprises an enantiomer or geometric isomer of a compound of formula I, or a solvate or pharmaceutically acceptable salt thereof, the compound of the formula:
wherein X is a direct bond;
or —(CH
2
)
n
—Y—, where n=1 and Y is a direct bond, O or S;
or —CH(R
12
)—, where R
12
is alkyl of from one to six carbon atoms;
or —C(R
13
)═CH—, where R
13
is hydrogen;
R
1
and R
2
are independently hydrogen, alkyl of three to eight carbon atoms, alkoxyalkyl of three to eight carbon atoms, or aralkyl of seven to twelve carbon atoms;
or R
1
and R
2
, when taken together with the nitrogen atom to which they are attached, form a ring denoted by formula II:
where m is an integer from three to eight, and the ring may be substituted at any one carbon atom by hydroxy, oxo, alkyl of one to three carbon atoms or alkoxy of one to three carbon atoms, or may be fused at two adjacent carbon atoms with an aromatic or aliphatic carbocyclic ring of six carbon atoms;
or complete a saturated monocyclic nitrogen heterocyclic ring of five to eight ring atoms, containing only carbon, nitrogen and optionally oxygen ring atoms, and the heterocyclic ring containing not more than two nitrogen ring atoms, the second nitrogen being optionally substituted with an alkyl group of one to six carbon atoms or a phenyl ring;
or complete a ring selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, or 3-azabicyclo[3.2.0]heptan-3-yl;
R
3
and R
4
are independently attached to the cyclohexane ring at the 3-, 4-, 5-, or 6-positions, and are independently hydrogen, hydroxy, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms, or are points of attachment of a spiro five- or six-membered heterocyclic ring containing one oxygen or sulfur atom; and
A is an alkyl group of five to twelve carbon atoms, or is a saturated carbocyclic ring of three to six carbon atoms, or is selected from:
formula III where R
5
, R
6
and R
7
are independently hydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, or aryl, and when X is a direct bond at least one of R
5
, R
6
and R
7
is a hydroxy, fluorine, chlorine, bromine, trifluoromethyl, alkyl of from one to six carbon atoms, or aryl substitu

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