U.S. patent application number 09/741085 was filed with the patent office on 2002-01-17 for potassium channel inhibitors.
Invention is credited to Beaudoin, Serge, Gross, Michael, Reed, Aimee.
Application Number | 20020006929 09/741085 |
Document ID | / |
Family ID | 26867070 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020006929 |
Kind Code |
A1 |
Gross, Michael ; et
al. |
January 17, 2002 |
Potassium channel inhibitors
Abstract
Compounds useful as potassium channel inhibitors and especially
useful for the treatment of cardiac arrhythmias and cell
proliferative disorders are described.
Inventors: |
Gross, Michael; (Durham,
NC) ; Beaudoin, Serge; (Morrisville, NC) ;
Reed, Aimee; (Durham, NC) |
Correspondence
Address: |
BANNER & WITCOFF
1001 G STREET N W
SUITE 1100
WASHINGTON
DC
20001
US
|
Family ID: |
26867070 |
Appl. No.: |
09/741085 |
Filed: |
December 21, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60231296 |
Sep 8, 2000 |
|
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60171397 |
Dec 21, 1999 |
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Current U.S.
Class: |
514/256 ;
514/299; 514/351; 544/333; 546/112; 546/329 |
Current CPC
Class: |
C07D 213/40 20130101;
C07D 239/42 20130101; A61P 37/06 20180101; A61P 9/06 20180101; C07D
233/64 20130101; C07D 213/38 20130101; C07D 241/12 20130101; C07D
239/26 20130101; A61P 43/00 20180101; C07D 409/12 20130101; C07D
417/12 20130101; A61P 9/04 20180101; A61P 37/02 20180101 |
Class at
Publication: |
514/256 ;
514/299; 514/351; 544/333; 546/112; 546/329 |
International
Class: |
C07D 43/02; C07D 221/04;
C07D 213/36 |
Claims
We claim:
1. A compound having potassium channel inhibitory activity of
formula (I), or a pharmaceutically acceptable salt or prodrug
thereof: 36wherein, A, B, and D are selected from a substituted
carbon atom, a nitrogen atom or N.fwdarw.O, wherein at least one of
A, B, and D is a substituted carbon atom and at most only one of A,
B and D is N.fwdarw.O; E and G are each hydrogen, or E and G taken
together form a bond; R.sup.1 is selected from hydrogen, alkyl,
carbocycloalkyl, aryl, heterocyclo, heteroaryl, alkoxy, aryloxy,
and substituted amino; Y is selected from a bond, alkyl,
carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and
heterocyclo; X is one of C.dbd.O, C.dbd.S or SO.sub.2; R.sup.2 and
R.sup.3 are independently selected from hydrogen (H), alkyl,
carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;
substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl,
aminoalkanoyl, substituted aminoalkanoyl, alkanoylamidoalkyl,
alkanoyl(substituted amido)alkyl, aroylamidoalkyl,
aroyl(substituted amido)alkyl, heterocyclocarbonylamidoalkyl,
heterocyclocarbonyl(substituted amido)alkyl, heteroaroylamidoalkyl,
and heteroaroyl(substituted amido)alkyl; R.sup.4 is selected from
alkyl, carbocycloalkyl, aryl, (aryl)alkyl, heteroaryl and
heterocyclo; R.sup.5 and R.sup.6 are each independently selected
from hydrogen and alkyl; R.sup.7 is independently selected from
hydrogen, alkyl, hydroxy, alkoxy, amino, substituted amino, nitro,
cyano, halo, carboxy, alkoxycarbonyl, aminocarbonyl, substituted
aminocarbonyl and n is 1, 2 or 3; Z is selected from hydrogen,
alkyl, hydroxy, SH, alkoxy, aryloxy, alkylthio, amino, substituted
amino, alkoxycarbonyl, alkanoylamido, aroylamido,
heterocyclocarbonylamido, heteroaroylamido,
alkanoyl(alkylsubstituted) amido, aroyl(alkylsubstituted)amido,
heteroaroyl(alkylsubstituted)amido, and heterocyclocarbonyl(alkyl
substituted)amido; with the provisos that i) when R.sup.4 is aryl,
then R.sup.4 is not a 3,4-dialkoxy phenyl, or a 3-cycloalkylalkoxy,
4-alkoxy phenyl and ii) when A, B, and D are all CH, and Z is H,
OR.sup.a, or NR.sup.bR.sup.c wherein R.sup.a is one of H,
(CH.sub.2).sub.m--R.sup.8 or C(O)--(CH.sub.2).sub.m--R.sup.8, m is
1 to 5, R.sup.8 is N(R.sup.9).sub.2, N(R.sup.9).sub.3L or
CO.sub.2R.sup.9, each R.sup.9 being independently selected from one
of H or alkyl, and L is a counter ion, R.sup.b is H or alkyl;
R.sup.c is H, alkyl, or CO.sub.2R.sup.10, and R.sup.10 is alkyl;
then when R.sup.2 is hydrogen, or methyl, R.sup.3 is not hydrogen,
or alkyl, and when R.sup.3 is H, or alkyl then R.sup.2 is not H, or
methyl.
2. A compound having potassium channel inhibitory activity of
formula (II), or a pharmaceutically acceptable salt or prodrug
thereof 37wherein R.sub.1 is selected from hydrogen, alkyl,
carbocycloalkyl, aryl, heterocyclo, heteroaryl, alkoxy, aryloxy,
and substituted amino; Y is selected from a bond, alkyl,
carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and
heterocyclo; X is one of C.dbd.O, C.dbd.S or SO.sub.2; R.sup.2 and
R.sup.3 are independently selected from hydrogen, alkyl,
carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;
substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl and
aminoalkanoyl; R.sup.4 is selected from alkyl, carbocycloalkyl,
aryl, (aryl)alkyl, heteroaryl and heterocyclo; Z is selected from
hydrogen, alkyl, hydroxyl, amino and substituted amino; with the
provisos that i) when R.sup.4 is aryl, then R.sup.4 is not a
3,4-dialkoxy phenyl, or a 3-cycloalkylalkoxy, 4-alkoxy phenyl and
ii) when A, B, and D are all CH, and Z is H, OR.sup.a, or
NR.sup.bR.sup.c wherein R.sup.a is one of H,
(CH.sub.2).sub.m--R.sup.8 or C(O)--(CH.sub.2).sub.m--R.sup.8, m is
1 to 5, R.sup.8 is N(R.sup.9).sub.2, N(R.sup.9).sub.3L or
CO.sub.2R.sup.9, each R.sup.9 being independently selected from one
of H or alkyl, and L is a counter ion, R.sup.b is H or alkyl;
R.sup.c is H, alkyl, or CO.sub.2R.sup.10, and R.sup.10 is alkyl;
then when R.sup.2 is hydrogen, or methyl, R.sup.3 is not hydrogen,
or alkyl, and when R.sup.3 is H, or alkyl then R.sup.2 is not H, or
methyl.
3. A compound having potassium channel inhibitory activity of
formula (III), or a pharmaceutically acceptable salt or prodrug
thereof: 38wherein, A, B, and D are substituted carbon atoms, or
one of A, B, and D is a nitrogen atom, or N.fwdarw.O; E and G are
each hydrogen, or E and G taken together form a bond; R.sup.1 is
selected from hydrogen, alkyl, carbocycloalkyl, aryl, heterocyclo,
heteroaryl, alkoxy, aryloxy, and substituted amino; Y is selected
from a bond, alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, and heterocyclo; X is one of C.dbd.O, C.dbd.S or
SO.sub.2; R.sup.2 and R.sup.3 are independently selected from
hydrogen, alkyl, carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;
substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl and
aminoalkanoyl; R.sup.4 is selected from alkyl, carbocycloalkyl,
aryl, (aryl)alkyl, heteroaryl and heterocyclo; R.sup.5 and R.sup.6
are each independently selected from hydrogen and alkyl; R.sup.7 is
independently selected from hydrogen, alkyl, hydroxy, alkoxy,
amino, substituted amino, nitro, cyano, halo, carboxy,
alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl and n is
1, 2 or 3; Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy,
aryloxy, alkylthio, amino, substituted amino, alkoxyalkanoyl,
alkanoylamido, aroylamido, heteroaroylamido,
heterocyclocarbonylamido, alkanoyl(alkylsubstituted)amido,
aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido
and heterocyclocarbonyl(alkylsubstitut- ed)amido; with the provisos
that i) when R.sup.4 is aryl, then R.sup.4 is not a 3,4-dialkoxy
phenyl, or a 3-cycloalkylalkoxy, 4-alkoxy phenyl and ii) when A, B,
and D are all CH, and Z is H, OR.sup.a, or NR.sup.bR.sup.c wherein
R.sup.a is one of H, (CH.sub.2).sub.m--R.sup.8 or
C(O)--(CH.sub.2).sub.m--R.sup.8, m is 1 to 5, R.sup.8 is
N(R.sup.9).sub.2, N(R.sup.9).sub.3L or CO.sub.2R.sup.9, each
R.sup.9 being independently selected from one of H or alkyl, and L
is a counter ion, R.sup.b is H or alkyl; R.sup.c is H, alkyl, or
CO.sub.2R.sup.10, and R.sup.10 is alkyl; then when R.sup.2 is
hydrogen, or methyl, R.sup.3 is not hydrogen, or alkyl, and when
R.sup.3 is H, or alkyl then R.sup.2 is not H, or methyl.
4. A compound having potassium channel inhibitory activity of
formula (IV), or a pharmaceutically acceptable salt or prodrug
thereof: 39wherein A, B, and D are all CH, or one of A, B, and D is
a nitrogen atom or N.fwdarw.O; R' is selected from hydrogen, alkyl,
carbocycloalkyl, aryl, heterocyclo, heteroaryl, alkoxy, aryloxy and
substituted amino; Y is selected from a bond, alkyl,
carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and
heterocyclo; R.sup.1 and R.sup.3 are independently selected from
hydrogen, alkyl, carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;
substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl and
aminoalkanoyl; R.sup.4 is selected from aryl, heteroaryl and
heterocyclo; Z is selected from hydrogen, alkyl, hydroxy, SH,
alkoxy, aryloxy, alkylthio, amino, substituted amino,
alkoxyalkanoyl, alkanoylamido, aroylamido, heteroaroylamido,
heterocyclocarbonylamido, alkanoyl(alkylsubstituted)amido,
aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido
and heterocyclocarbonyl(alkylsubstitut- ed)amido; with the provisos
that i) when R.sup.4 is aryl, then R.sup.4 is not a 3,4-dialkoxy
phenyl, or a 3-cycloalkylalkoxy, 4-alkoxy phenyl and ii) when A, B,
and D are all CH, and Z is H, OR.sup.a, or NR.sup.bR.sup.c wherein
R.sup.a is one of H, (CH.sub.2).sub.m--R.sup.8 or
C(O)--(CH.sub.2).sub.m--R.sup.8, m is 1 to 5, R.sup.8 is
N(R.sup.9).sub.2, N(R.sup.9).sub.3L or CO.sub.2R.sup.9, each
R.sup.9 being independently selected from one of H or alkyl, and L
is a counter ion, R.sup.b is H or alkyl; R.sup.c is H, alkyl, or
CO.sub.2R.sup.10, and R.sup.10 is alkyl; then when R.sup.2 is
hydrogen, or methyl, R.sup.3 is not hydrogen, or alkyl, and when
R.sup.3 is H, or alkyl then R.sup.2 is not H, or methyl.
5. A compound having potassium channel inhibitory activity of
formula (V), or a pharmaceutically acceptable salt or prodrug
thereof: 40R.sup.1 is selected from hydrogen, alkyl,
carbocycloalkyl, aryl, heterocyclo, heteroaryl, alkoxy, aryloxy and
substituted amino; Y is selected from a single bond, alkyl,
carbocycloalkyl, aryl, heteroaryl and heterocyclo; R.sup.2 is
selected from aryl, aralkyl, heterocyclo, (heterocyclo)alkyl,
heteroaryl and heteroaralkyl; R.sup.3 is selected from hydrogen,
alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; R.sup.4 is
selected from aryl, heteroaryl and heterocyclo; Z is selected from
hydrogen and hydroxyl; with the provisos that when R.sup.4 is aryl,
then R.sup.4 is not a 3,4-dialkoxy phenyl, or a 3-cycloalkylalkoxy,
4-alkoxy phenyl.
6. The compound of claim 1, or a pharmaceutically acceptable salt
or prodrug thereof, wherein X is C.dbd.O.
7. A pharmaceutical composition comprising the compound of claim 1,
or a pharmaceutically acceptable salt or prodrug thereof and a
pharmaceutically acceptable diluent or carrier.
8. A pharmaceutical composition comprising the compound of claim 2,
or a pharmaceutically acceptable salt or prodrug thereof and a
pharmaceutically acceptable diluent or carrier.
9. A pharmaceutical composition comprising the compound of claim 3,
or a pharmaceutically acceptable salt or prodrug thereof and a
pharmaceutically acceptable diluent or carrier.
10. A pharmaceutical composition comprising the compound of claim
4, or a pharmaceutically acceptable salt or prodrug thereof and a
pharmaceutically acceptable diluent or carrier.
11. A pharmaceutical composition comprising the compound of claim
5, or a pharmaceutically acceptable salt or prodrug thereof and a
pharmaceutically acceptable diluent or carrier.
12. A pharmaceutical composition comprising the compound of claim
6, or a pharmaceutically acceptable salt or prodrug thereof and a
pharmaceutically acceptable diluent or carrier.
13. A method for inhibiting potassium transport across cellular
membranes possessing potassium channels comprising exposing a cell
membrane possessing said channels to the presence of the compound
of claim 1, or a pharmaceutically acceptable salt or prodrug
thereof.
14. The method of claim 13 wherein the potassium channel is a
voltage gated potassium channel.
15. The method of claim 14 wherein the potassium channel is
selected from a potassium channel responsible for cardiac I.sub.Kur
potassium current, a potassium channel responsible for T-lymphocyte
I.sub.Kn potassium current and potassium channels containing one of
Kv1.5 or Kv1.3 .alpha.-subunit gene products.
16. A method for inhibiting potassium transport across cellular
membranes possessing potassium channels comprising exposing a cell
membrane possessing said channels to the presence of the compound
of claim 2, or a pharmaceutically acceptable salt or prodrug
thereof.
17. The method of claim 16 wherein the potassium channel is a
voltage gated potassium channel.
18. The method of claim 17 wherein the potassium channel is
selected from a potassium channel responsible for cardiac I.sub.Kur
potassium current, a potassium channel responsible for T-lymphocyte
I.sub.Kn potassium current and potassium channels containing one of
Kv1.5 or Kv1.3 .alpha.-subunit gene products.
19. A method for inhibiting potassium transport across cellular
membranes possessing potassium channels comprising exposing a cell
membrane possessing said channels to the presence of the compound
of claim 3, or a pharmaceutically acceptable salt or prodrug
thereof.
20. The method of claim 19 wherein the potassium channel is a
voltage gated potassium channel.
21. The method of claim 20 wherein the potassium channel is
selected from a potassium channel responsible for cardiac I.sub.Kur
potassium current, a potassium channel responsible for T-lymphocyte
I.sub.Kn potassium current and potassium channels containing one of
Kv1.5 or Kv1.3 .alpha.-subunit gene products.
22. A method for treating cardiac arrhythmias which comprises
administering to a patient in need thereof, a pharmaceutically
effective amount of the compound of claim 1, or a pharmaceutically
acceptable salt or prodrug thereof.
23. A method for treating a cell proliferative disorder which
comprises administering to a patient in need thereof, a
pharmaceutically effective amount of the compound of claim 1, or a
pharmaceutically acceptable salt or prodrug thereof.
24. A method for treating cardiac arrhythmias which comprises
administering to a patient in need thereof, a pharmaceutically
effective amount of the compound of claim 2, or a pharmaceutically
acceptable salt or prodrug thereof.
25. A method for treating a cell proliferative disorder which
comprises administering to a patient in need thereof, a
pharmaceutically effective amount of the compound of claim 2, or a
pharmaceutically acceptable salt or prodrug thereof.
26. A method for treating cardiac arrhythmias which comprises
administering to a patient in need thereof, a pharmaceutically
effective amount of the compound of claim 3, or a pharmaceutically
acceptable salt or prodrug thereof.
27. A method for treating a cell proliferative disorder which
comprises administering to a patient in need thereof, a
pharmaceutically effective amount of the compound of claim 3, or a
pharmaceutically acceptable salt or prodrug thereof.
28. A method for treating cardiac arrhythmias which comprises
administering to a patient in need thereof, a pharmaceutically
effective amount of the compound of claim 4, or a pharmaceutically
acceptable salt or prodrug thereof.
29. A method for treating cardiac arrhythmias which comprises
administering to a patient in need thereof, a pharmaceutically
effective amount of the compound of claim 5, or a pharmaceutically
acceptable salt or prodrug thereof.
30. A method for treating cardiac arrhythmias which comprises
administering to a patient in need thereof, a pharmaceutically
effective amount of the compound of claim 6, or a pharmaceutically
acceptable salt or prodrug thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. 119
(e)(1) of prior filed provisional applications 60/231,296 filed
Sep. 8, 2000 and 60/171,397 filed on Dec. 21, 1999.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is broadly directed to a class of
compounds useful as potassium channel inhibitors.
[0004] 2. Description of Related Art
[0005] The importance of potassium channels was first recognized
almost fifty years ago when Hodgkin and Huxley discovered that
potassium ions contributed to the current that excited the squid
giant axon. Research in the area, however, was hampered by the lack
of selective, high affinity ligands for potassium channels. But the
advent of recombinant DNA techniques and single cell and whole cell
voltage clamp techniques has changed the slow pace of the field.
Indeed, potassium channels which exhibit functional,
pharmacological and tissue distribution characteristics have been
cloned. These cloned potassium channels are useful targets in
assays for identifying candidate compounds for the treatment of
various disease states. Potassium channels have turned out to be
the most diverse family of ion channels discovered to date. They
modulate a number of cellular events such as muscle contraction,
neuro-endocrine secretion, frequency and duration of action
potentials, electrolyte homeostasis, and resting membrane
potential.
[0006] Potassium channels are expressed in eukaryotic and
prokaryotic cells, and are elements in the control of electrical
and nonelectrical cellular functions. Potassium channels have been
classified according to their biophysical and pharmacological
characteristics. Subclasses of these channels have been named based
on amino acid sequence and functional properties. Salient among
these are the voltage dependent potassium channels, for example
voltage gated potassium channels (e.g., Kv1, Kv2, Kv3, Kv4).
Subtypes within these subclasses have been characterized as to
their putative function, pharmacology and distribution in cells and
tissues (Chandy and Gutman, "Voltage-gated potassium channel genes"
in Handbook of Receptors and Channels-Ligand and Voltage-gated Ion
Channels, ed. R. A. North, 1995; Doupnik et al., Curr. Opin.
Neurobiol. 5:268, 1995). For example, the Kvl class of potassium
channels is further subdivided depending on the molecular sequence
of the channel, for example Kv 1.1, Kv 1.3, Kv 1.5. Functional
voltage-gated K+ channels can exist as multimeric structures formed
by the association of either identical or dissimilar subunits. This
phenomenon is thought to account for the wide diversity of K+
channels. However, subunit compositions of native K+ channels and
the physiologic role that particular channels play are, in most
cases, still unclear.
[0007] Membrane depolarization by Kv 1.3 inhibition has been shown
to be an effective method to prevent T-cell proliferation and
therefore has applications in many autoimmune conditions.
Inhibition of K+ channels in the plasma membrane of human T
-lymphocytes has been postulated to play a role in eliciting
immunosuppressive responses by regulating intracellular Ca++
homeostasis, which has been found to be important in T-cell
activation.
[0008] The Kv 1.3 voltage-gated potassium channel is found in
neurons, blood cells, osteoclasts and T-lymphocytes. The Chandy and
Cahalan laboratories proposed a hypothesis that blocking the Kv 1.3
channel would elicit an immunosuppressant response. (Chandy et al.,
J. Exp. Med. 160, 369, 1984; Decoursey et al., Nature, 307, 465,
1984). However, the K+channel blockers employed in their studies
were non-selective. Until research with the peptide margatoxin, a
peptide found in scorpion venom, no specific inhibitor of the Kv
1.3 channel existed to test this hypothesis. Although a laboratory
(Price et al, Proc. Natl. Acad. Sci. USA, 86, 10171, 1989) showed
that charybdotoxin would block Kv 1.3 in human T cells,
charybdotoxin was subsequently shown to inhibit four different K+
channels (Kv 1.3 and three distinct small conductance Ca++
activated K+ channels) in human T-lymphocytes, limiting the use of
this toxin as a probe for the physiological role of Kv 1.3 (Leonard
et al, Proc. Natl. Acad. Sci. USA, 89, 10094, 1992). Margatoxin, on
the other hand, blocks only Kv 1.3 in T-cells, and has
immunosuppressant activity in both in vitro and in vivo models.
(Lin et al., J. Exp. Med., 177, 637, 1993). The therapeutic utility
of this compound, however, is limited by its potent toxicity.
Recently, a class of compounds has been reported that may be an
attractive alternative to the above-mentioned drugs, see for
example U.S. Pat. Nos. 5,670,504; 5,631,282; 5,696,156; 5,679,705;
and 5,696,156. While addressing some of the activity/toxicity
problems of previous drugs, these compounds tend to be of large
molecular weight and are generally produced by synthetic
manipulation of a natural product, isolation of which is cumbersome
and labor intensive.
[0009] Immunoregulatory abnormalities have been shown to exist in a
wide variety of autoimmune and chronic inflammatory diseases,
including systemic lupus erythematosis, chronic rheumatoid
arthritis, type I and II diabetes mellitus, inflammatory bowel
disease, biliary cirrhosis, uveitis, multiple sclerosis and other
disorders such as Crohn's disease, ulcerative colitis, bullous
pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves
ophthalmopathy and asthma.
[0010] Although the underlying pathogenesis of each of these
conditions may be quite different, they have in common the
appearance of a variety of auto-antibodies and self-reactive
lymphocytes. Such self-reactivity may be due, in part, to a loss of
the homeostatic controls under which the normal immune system
operates. Similarly, following a bone-marrow or an organ
transplantation, the host lymphocytes recognize the foreign tissue
antigens and begin to produce antibodies which lead to graft
rejection.
[0011] One end result of an autoimmune or a rejection process is
tissue destruction caused by inflammatory cells and the mediators
they release. Anti-inflammatory agents such as NSAID's act
principally by blocking the effect or secretion of these mediators
but do nothing to modify the immunologic basis of the disease. On
the other hand, cytotoxic agents, such as cyclophosphamide, act in
such a nonspecific fashion that both the normal and autoimmune
responses are shut off. Indeed, patients treated with such
nonspecific immunosuppressive agents are as likely to succumb from
infection as they are from their autoimmune disease.
[0012] Cyclosporin A (CsA), which was approved by the US FDA in
1983 is currently the leading drug used to prevent rejection of
transplanted organs. In 1993, FK-506 (Prograf) was approved by the
US FDA for the prevention of rejection in liver transplantation.
CsA and FK-506 act by inhibiting the body's immune system from
mobilizing its vast arsenal of natural protecting agents to reject
the transplant's foreign protein. In 1994, CsA was approved by the
US FDA for the treatment of severe psoriasis and has been approved
by European regulatory agencies for the treatment of atopic
dermatitis. Though they are effective in fighting transplant
rejection, CsA and FK-506 are known to cause several undesirable
side effects including nephrotoxicity, neurotoxicity, and
gastrointestinal discomfort. Therefore, a selective
immunosuppressant without these side effects still remains to be
developed. Potassium channel inhibitors promise to be the solution
to this problem.
[0013] Atrial fibrillation (AF) is the most common sustained
cardiac arrhythmia in clinical practice and is likely to increase
in prevalence with the aging of the population. Currently, AF
affects more than 1 million Americans annually, represents over 5%
of all admissions for cardiovascular diseases and causes more than
80,000 strokes each year in the United States. While AF is rarely a
lethal arrhythmia, it is responsible for substantial morbidity and
can lead to complications such as the development of congestive
heart failure or thromboembolism. Currently available Class I and
Class III antiarrhythmic drugs reduce the rate of recurrence of AF,
but are of limited use because of a variety of potentially adverse
side effects including ventricular proarrhythmia. Because current
therapy is inadequate and fraught with side effects, there is a
clear need to develop new therapeutic approaches.
[0014] Antiarrhythmic agents of Class III are drugs that cause a
selective prolongation of the duration of the action potential
without significant cardiac depression. Available drugs in this
class are limited in number. Examples such as sotalol and
amiodarone have been shown to possess interesting Class III
properties (Singh B. N., Vaughan Williams E. M. "A Third Class Of
Anti-Arrhythmic Action: Effects On Atrial And Ventricular
Intracellular Potentials And Other Pharmacological Actions On
Cardiac Muscle, of MJ 1999 and AH 3747" Br. J Pharmacol 1970;
39:675-689. and Singh B. N., Vaughan Williams E. M, "The Effect Of
Amiodarone, A New Anti-Anginal Drug, On Cardiac Muscle", Br J
Pharmacol 1970; 39:657-667.), but these are not selective Class III
agents. Sotalol also possesses Class II effects which may cause
cardiac depression and is contraindicated in certain susceptible
patients. Amiodarone, also is not a selective Class III
antiarrhythmic agent because it possesses multiple
electrophysiological actions and is severely limited by side
effects (Nademanee, K. "The Amiodarone Odessey". J. Am. Coll.
Cardiol. 1992; 20:1063-065.) Drugs of this class are expected to be
effective in preventing ventricular fibrillation. Selective class
III agents, by definition, are not considered to cause myocardial
depression or an induction of arrhythmias due to inhibition of
conduction of the action potential as seen with Class I
antiarrhythmic agents.
[0015] Class III agents increase myocardial refractoriness via a
prolongation of cardiac action potential duration. Theoretically,
prolongation of the cardiac action potential can be achieved by
enhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter
I.sub.Na and I.sub.Ca, respectively) or by reducing outward
repolarizing potassium (K+) currents. The delayed rectifier (IK) K+
current is the main outward current involved in the overall
repolarization process during the action potential plateau, whereas
the transient outward (I.sub.to) and inward rectifier (IKI) K+
currents are responsible for the rapid initial and terminal phases
of repolarization, respectively. Cellular electrophysiologic
studies have demonstrated that IK consists of two pharmacologically
and kinetically distinct K+ current subtypes, lKr (rapidly
activating and deactivating) and IKs (slowly activating and
deactivating)(Sanguinetti and Jurkiewicz, Two Components Of Cardiac
Delayed Rectifier K+ Current: Differential Sensitivity To Block By
Class IH Antiarrhythmic Agents, J Gen Physiol 1990, 96:195-215).
Class III antiarrhythmic agents currently in development, including
d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and
methanesulfonamide-N-[I'-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-d-
ihydro4-hydroxyspiro[2H-1-benzopyran-2,4'-piperidin]-6yl]
monochloride, predominantly, if not exclusively, block IKr.
Although, amiodarone is a blocker of IKs (Balser J. R. Bennett, P.
B., Hondeghem, L. M. and Roden, D. M. "Suppression Of
Time-Dependent Outward Current In Guinea Pig Ventricular Myocytes:
Actions Of Quinidine And Amiodarone. Circ. Res. 1991, 69:519-529),
it also blocks I.sub.Na, and I.sub.Ca, effects thyroid function, is
a nonspecific adrenergic blocker, and acts as an inhibitor of the
enzyme phospholipase (Nademanee, K. "The Amiodarone Odessey". J Am.
Coll. Cardiol. 1992; 20:1063-1065). Therefore, its method of
treating arrhythmia is uncertain. Most Class III agents that are
known to be in development predominantly block IKr.
[0016] Reentrant excitation (reentry) has been shown to be a
prominent mechanism underlying supraventricular arrhythmias in man.
Reentrant excitation requires a critical balance between slow
conduction velocity and sufficiently brief refractory periods to
allow for the initiation and maintenance of multiple reentry
circuits to coexist simultaneously and sustain AF. Increasing
myocardial refractoriness by prolonging action potential duration
(APD), prevents and/or terminates reentrant arrhythmias. Most
selective Class III antiarrhythmic agents currently in development,
such as d-sotalol and dofetilide predominantly, if not exclusively,
block IKr, the rapidly activating component of IK found both in
atrium and ventricle in man.
[0017] Since these IKr blockers increase APD and refractoriness
both in atria and ventricle without affecting conduction per se,
theoretically they represent potential useful agents for the
treatment of arrhythmias like AF. These agents have a liability in
that they have an enhanced risk of proarrhythmia at slow heart
rates. For example, torsades de points has been observed when these
compounds are utilized (Roden, D. M. "Current Status of Class III
Antiarrhythmic Drug Therapy", Am J. Cardiol, 1993; 72:44B-49B).
This exaggerated effect at slow heart rates has been termed
"reverse frequency-dependence", and is in contrast to
frequency-independent or frequency-dependent actions (Hondeghem, L.
M. "Development of Class III Antiarrhythmic Agents" J. Cadiovasc.
Cardiol. 20 (Suppl. 2):S17-S22).
[0018] The slowly activating component of the delayed rectifier
(IKs) potentially overcomes some of the limitations of IKr blockers
associated with ventricular arrhythmias. Because of its slow
activation kinetics however, the role of IKs in atrial
repolarization may be limited due to the relatively short APD of
the atrium. Consequently, although IKs blockers may provide
distinct advantage in the case of ventricular arrhythmias, their
ability to affect SVT is considered to be minimal.
[0019] The ultra-rapidly activating delayed rectifier K+ current
(I.sub.kur) is believed to represent the native counterpart to a
cloned potassium channel designated Kv1.5 and, while present in
human atrium, it appears to be absent in human ventricle.
Furthermore, because of its rapidity of activation and limited slow
inactivation, I.sub.kur is believed to contribute significantly to
repolarization in human atrium. Consequently, a specific blocker of
I.sub.kur, that is a compound which blocks Kv 1.5, would overcome
the shortcoming of other compounds by prolonging refractoriness by
retarding repolarization in the human atrium without causing the
delays in ventricular repolarization that underlie arrhythmogenic
after depolarizations and acquired long QT syndrome observed during
treatment with current Class III drugs.
[0020] In intact human atrial myocytes an ultra-rapidly activating
delayed rectifier K+ current I.sub.kur which is also known as the
sustained outward current, I.sub.sus or I.sub.so, has been
identified and this current has properties and kinetics identical
to those expressed by the human K+ channel clone (hKv1.5, HK2) when
isolated from human heart and stably expressed in human (HEK-293)
cell lines. (Wang, Fermini and Natel, 1993, Circ Res 73:1061-1076;
Fedida et al., 1993, Circ Res 73:210-216; Snyders, Tamkun and
Bennet, 1993, J Gen Physiol 101:513-543) and originally cloned from
rat brain (Swanson et al., 10, Neuron 4:929-939). Although various
antiarrythmic agents are now available on the market, those having
both satisfactory efficacy and a high margin of safety have not
been obtained. For example, antiarrythmic agents of Class I
according to the classification scheme of Vaughan-Williams
("Classification Of Antiarrhythmic Drugs" In: Cardiac Arrhythrnias,
edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra,
Sodertalje, pp449-472, 1981) which cause a selective inhibition of
the maximum velocity of the upstroke of the action potential (max)
are inadequate for preventing ventricular fibrillation. In
addition, they have problems regarding safety, namely, they cause a
depression of myocardial contractility and have a tendency to
induce arrhythmias due to an inhibition of impulse conduction.
Beta-adrenoceptor blockers and calcium antagonists which belong to
Class II and IV, respectively, have a defect in that their effects
are either limited to a certain type of arrhythmia or are
contraindicated because of their cardiac depressant properties in
certain patients with cardiovascular disease. Their safety,
however, is higher than that of the antiarrhythmic agents of Class
I.
[0021] The present invention is related to compounds which are
useful as inhibitors of potassium channel function. The compounds
of the invention are especially active as inhibitors of
voltage-gated potassium channels. The potassium channel inhibitors
of the invention may therefore be utilized for the treatment of
diseases in which prolongation of cellular action potentials would
be beneficial, which include, but are not limited to, cardiac
arrhythmias. In addition, compounds of the invention may be
utilized for treating disorders in which induction of cell membrane
depolarization would be beneficial, which include, but are not
limited to, cell proliferative disorders.
[0022] WO 98/04521 (see U.S. Pat. No. 6,083,986) describes a class
of indane potassium channel inhibitors said to be useful for
treating cardiac arrhythmias and cell proliferative disorders.
[0023] It is an object of the present invention to provide
compounds which are useful for the treatment of diseases in
mammals, including humans, and especially for the management of
diseases which can be treated by inhibiting cell membrane potassium
channels, such as the potassium channels responsible for cardiac
I.sub.Kur potassium current, or the potassium channels responsible
for T-lymphocyte I.sub.Kn potassium current, and potassium channels
containing one of Kv1.5 or Kv1.3 .alpha.-subunit gene products.
[0024] Another object of the invention is to provide a method of
treating diseases in mammals, including humans, which respond to
the inhibition of potassium channel function, which method
comprises administering to a mammal in need thereof a compound of
the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0025] This invention describes compounds and their utility as
inhibitors of voltage-dependent potassium channel function,
particularly potassium channels (i.e., I.sub.Kur, Kv1.5) that could
serve as targets for the treatment of cardiac arrhythmias
especially those occurring in the atria (e.g., atrial flutter and
atrial fibrillation) (Wang et al., Circ. Res. 73:1061, 1993; Fedida
et al., Circ. Res. 73:210, 1993; Wang et al., J. Pharmacol. Exp.
Ther. 272:184, 1995), as well as the potassium channels (i.e.,
I.sub.Kn, Kv1.3) that could serve as targets for the treatment of
immunologic diseases (Kaczorowski and Koo, Perspectives in Drug
Discovery and Design 2:233, 1994). Consequently, the present
invention also provides a method for treating diseases which
respond to the inhibition of potassium channel function, such as
cardiac arrhythmias and various immunologic diseases, using the
compounds of the invention.
[0026] The invention is particularly based on our discovery that
the compounds of the following formula (I) are inhibitors of
potassium channel function. In particular, these compounds have
demonstrated activity against the human potassium channels/currents
I.sub.Kur, I.sub.Kn, Kv1.5, Kv1.3. As a result, these compounds are
useful in the treatment of cardiac arrhythmias and cell
proliferative disorders.
[0027] Thus, in a first aspect, the present invention concerns
compounds having potassium channel inhibitory activity of the
formula (1), or a pharmaceutically acceptable salt or prodrug
thereof 1
[0028] A, B, and D are selected from a substituted carbon atom, a
nitrogen atom or N .vertline.O, wherein at least one of A, B, and D
is a substituted carbon atom and at most only one of A, B and D is
N .vertline.O;
[0029] E and G are each hydrogen or E and G taken together form a
bond (site of unsaturation);
[0030] R.sup.1 is selected from hydrogen, alkyl, carbocycloalkyl,
aryl, heterocyclo, heteroaryl, alkoxy, aryloxy, and substituted
amino;
[0031] Y is selected from a bond (i.e., R.sup.1 and X are directly
linked), alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, and heterocyclo;
[0032] X is one of C.dbd.O, C.dbd.S or SO.sub.2;
[0033] R.sup.1 and R.sup.3 are independently selected from hydrogen
(H), alkyl, carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;
substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl,
aminoalkanoyl, substituted aminoalkanoyl, alkanoylamidoalkyl,
alkanoyl(substituted amido)alkyl, aroylamidoalkyl,
aroyl(substituted amido)alkyl, heterocyclocarbonylamidoalkyl,
heterocyclocarbonyl(substituted amido)alkyl, heteroaroylamidoalkyl,
and heteroaroyl(substituted amido)alkyl;
[0034] R.sup.4 is selected from alkyl, carbocycloalkyl, aryl,
(aryl)alkyl, heteroaryl and heterocyclo;
[0035] R.sup.5 and R.sup.6 are each independently selected from
hydrogen and alkyl;
[0036] R.sup.7 is independently selected from hydrogen, alkyl,
hydroxy, alkoxy, amino, substituted amino, nitro, cyano, halo,
carboxy, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl
and n is 1, 2 or 3;
[0037] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy,
aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl,
alkanoylamido, aroylamido, heterocyclocarbonylamido,
heteroaroylamido, alkanoyl(alkylsubstituted) amido,
aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido,
and heterocyclocarbonyl(alkyl substituted)amido;
[0038] with the provisos that
[0039] i) when R.sup.4 is aryl, then R.sup.4 is not a 3,4-dialkoxy
phenyl, or a 3-cycloalkylalkoxy, 4-alkoxy phenyl and
[0040] ii) when A, B, and D are all CH, and Z is H, OR.sup.a, or
NR.sup.bR.sup.c, wherein R.sup.a is one of H,
(CH.sub.2).sub.m--R.sup.8 or C(O)--(CH.sub.2).sub.m--R.sup.8, m is
1 to 5, R.sup.8 is N(R.sup.9).sub.2, N(R.sup.9).sub.3L or
CO.sub.2R.sup.9, each R.sup.9 being independently selected from one
of H or alkyl, and L is a counter ion, R1 is H or alkyl; R.sup.c is
H, alkyl, or CO.sub.2R.sup.10, and R.sup.10 is alkyl; then when
R.sup.2 is hydrogen, or methyl, R.sup.3 is not hydrogen, or alkyl
(especially methyl), and when R.sup.3 is H, or alkyl (especially
methyl) then R.sup.2 is not H, or methyl.
[0041] In a preferred class of compounds of formula (I), A, B and D
are substituted carbon atoms, E, G, R.sup.5, R.sup.6 and R.sup.7
are each a hydrogen, Z is selected from hydrogen, alkyl, hydroxyl,
amino and substituted amino and the remaining substituents and
provisos are as defined above in connection with formula (I), as is
represented in the following formula (II), (and again including the
pharmaceutically acceptable salts or prodrugs thereof) 2
[0042] In a more preferred subset of compounds of formula (II) (and
their pharmaceutically acceptable salts, or prodrugs), R.sup.1 is
selected from H alkyl, carbocycloalkyl, aryl, and heteroaryl; X is
C.dbd.O; Y is selected from a bond (i.e., R.sup.1 and X are
directly linked), alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, and heterocyclo; R.sup.2 and R.sup.3 are independently
selected from H, alkyl, carbocycloalkyl, aryl, (aryl)alkyl,
heterocyclo, (heterocyclo)alkyl, heteroaryl and
(heteroaryl)alkyl;
[0043] R.sup.4 is selected from aryl and heteroaryl; Z is selected
from H, OH, amino and substituted amino.
[0044] In another aspect, the present invention concerns indane
compounds having potassium channel inhibition activity of the
formula (III)), or pharmaceutically acceptable salts or prodrugs
thereof: 3
[0045] wherein all of the variables have the meaning ascribed to
them in connection with formula (I) and formula (III) is subject to
the same provisos as formula (1).
[0046] Yet another preferred subclass of compounds (including their
pharmaceutically acceptable salts or prodrugs) falling within the
compounds of formula (I) is represent by the following formula
(IV): 4
[0047] A, B, and D are all CH, or one of A, B, and D is a nitrogen
atom or N.quadrature.O;
[0048] R.sup.1 is selected from hydrogen, alkyl, carbocycloalkyl,
aryl, heterocyclo, heteroaryl, alkoxy, aryloxy and substituted
amino;
[0049] Y is selected from a bond, alkyl, carbocycloalkyl, alkenyl,
alkynyl, aryl, heteroaryl and heterocyclo;
[0050] R.sup.2 and R.sup.3 are independently selected from
hydrogen, alkyl, carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;
substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl and
aminoalkanoyl;
[0051] R.sup.4 is selected from aryl, heteroaryl and
heterocyclo;
[0052] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy,
aryloxy, alkylthio, amino, substituted amino, alkoxyalkanoyl,
alkanoylamido, aroylamido, heteroaroylamido,
heterocyclocarbonylamido, alkanoyl(alkylsubstituted)amido,
aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido
and heterocyclocarbonyl(alkylsubstitut- ed)amido;
[0053] with the provisos that
[0054] i) when R.sup.4 is aryl, then R.sup.4 is not a 3,4-dialkoxy
phenyl, or a 3-cycloalkylalkoxy, 4-alkoxy phenyl and
[0055] ii) when A, B, and D are all CH, and Z is H, OR.sup.a, or
NR.sup.bR.sup.c, wherein R.sup.a is one of H,
(CH.sub.2).sub.m--R.sup.8 or C(O)--(CH.sub.2).sub.m--R.sup.8, m is
1 to 5, R.sup.8 is N(R.sup.9).sub.2, N(R.sup.9).sub.3L or
CO.sub.2R.sup.9, each R.sup.9 being independently selected from one
of H or alkyl, and L is a counter ion, R.sup.b is H or alkyl;
R.sup.c is H, alkyl, or CO.sub.2R.sup.10, and R.sup.10 is alkyl;
then when R.sup.2 is hydrogen, or methyl, R.sup.3 is not hydrogen,
or alkyl (especially methyl), and when R.sup.3 is H, or alkyl
(especially methyl) then R.sup.2 is not H, or methyl.
[0056] Preferably, R.sup.4 in the prior embodiments is phenyl per
se or a phenyl substituted with one or more groups in the 2
(ortho), 3 (meta), or 4 (para) positions, wherein said groups are
selected from C.sub.1-5 alkyl, C.sub.1-5 alkoxy, cyano, halo and
trifluoromethyl. Alternatively, R.sup.4 is an optionally
substituted heteroaryl, an optionally substituted heterocyclo or an
optionally substituted carbocycloalkyl, wherein said optionally
substituted moieties may be substituted with C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, cyano, halo and trifluoromethyl.
[0057] In a preferred class of the compounds of formula (IV)
(subject to the same provisos and including pharmaceutically
acceptable salts or prodrugs thereof), A, B and D are all --CH--; Z
is selected from hydrogen and hydroxyl, Y is selected from a single
bond, alkyl, aryl, heteroaryl and heterocyclo, R.sup.2 is selected
from aryl, aralkyl, heteroaryl and heteroaralkyl, and R.sup.3 is
selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl and
heteroaralkyl, and the remaining substituents are as defined above,
as is represented in the following formula (V): 5
[0058] In other aspects, the present invention concerns compounds
having potassium channel inhibitory activity of the formula (VI),
or a pharmaceutically acceptable salt or prodrug thereof 6
[0059] A, B, and D are selected from a substituted carbon atom, a
nitrogen atom or N.fwdarw.O, wherein at least one of A, B, and D is
a substituted carbon atom and at most only one of A, B and D is
N.fwdarw.O;
[0060] E and G are each hydrogen or E and G taken together form a
bond (site of unsaturation);
[0061] R.sup.1 is selected from hydrogen, alkyl, carbocycloalkyl,
aryl, heterocyclo, heteroaryl, alkoxy, aryloxy, and substituted
amino;
[0062] Y is selected from a bond (i.e., R.sup.1 and X are directly
linked), alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, and heterocyclo;
[0063] X is one of C.dbd.O, C.dbd.S or SO.sub.2;
[0064] R.sup.2 is selected from carbocycloalkyl, aryl, (aryl)alkyl,
heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl,
aminoalkyl; substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl,
aminoalkanoyl, substituted aminoalkanoyl, alkanoylamidoalkyl,
alkanoyl(substituted amido)alkyl, aroylamidoalkyl,
aroyl(substituted amido)alkyl, heterocyclocarbonylamidoalkyl,
heterocyclocarbonyl(substitut- ed amido)alkyl,
heteroaroylamidoalkyl, and heteroaroyl(substituted amido)alkyl;
[0065] R.sup.3 is selected from hydrogen (H), alkyl,
carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;
substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl,
aminoalkanoyl, substituted aminoalkanoyl, alkanoylamidoalkyl,
alkanoyl(substituted amido)alkyl, aroylamidoalkyl,
aroyl(substituted amido)alkyl, heterocyclocarbonylamidoalkyl,
heterocyclocarbonyl(substituted amido)alkyl, heteroaroylamidoalkyl,
and heteroaroyl(substituted amido)alkyl;
[0066] R.sup.4 is selected from alkyl, carbocycloalkyl, aryl,
(aryl)alkyl, heteroaryl and heterocyclo;
[0067] R.sup.5 and R.sup.6 are each independently selected from
hydrogen and alkyl;
[0068] R.sup.7 is independently selected from hydrogen, alkyl,
hydroxy, alkoxy, amino, substituted amino, nitro, cyano, halo,
carboxy, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl
and n is 1, 2 or 3;
[0069] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy,
aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl,
alkanoylamido, aroylamido, heterocyclocarbonylamido,
heteroaroylamido, alkanoyl(alkylsubstituted) amido,
aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido,
and heterocyclocarbonyl(alkyl substituted)amido;
[0070] In a preferred class of compounds of formula (VI), A, B and
D are substituted carbon atoms, E, G, R.sup.5, R.sup.6 and R.sup.7
are each a hydrogen, Z is selected from hydrogen, alkyl, hydroxyl,
amino and substituted amino and the remaining substituents are as
defined above in connection with formula (VI), as is represented in
the following formula (VII), (and again including the
pharmaceutically acceptable salts or prodrugs thereof) 7
[0071] In a more preferred subset of compounds of formula (VI) (and
their pharmaceutically acceptable salts, or prodrugs), R.sup.1 is
selected from H alkyl, carbocycloalkyl, aryl, and heteroaryl; X is
C.dbd.O; Y is selected from a bond (i.e., R.sup.1 and X are
directly linked), alky, carbocycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, and heterocyclo; R.sup.2 is selected from
carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl and (heteroaryl)alkyl; and R.sup.3
is selected from H, alkyl, carbocycloalkyl, aryl, (aryl)alkyl,
heterocyclo, (heterocyclo)alkyl, heteroaryl and (heteroaryl)alkyl;
R.sup.4 is selected from aryl and heteroaryl; Z is selected from H,
OH, amino and substituted amino.
[0072] In still another aspect, the present invention concerns
indane compounds having potassium channel inhibition activity of
the formula (VIII)), or pharmaceutically acceptable salts or
prodrugs thereof: 8
[0073] wherein all of the variables have the meaning ascribed to
them in connection with formula (VI).
[0074] Yet another preferred subclass of compounds (including their
pharmaceutically acceptable salts or prodrugs) falling within the
compounds of formula (VI) is represent by the following formula
(IX): 9
[0075] A, B, and D are all CH, or one of A, B, and D is a nitrogen
atom or N.fwdarw.O;
[0076] R.sup.1 is selected from hydrogen, alkyl, carbocycloalkyl,
aryl, heterocyclo, heteroaryl, alkoxy, aryloxy and substituted
amino;
[0077] Y is selected from a bond, alkyl, carbocycloalkyl, alkenyl,
alkynyl, aryl, heteroaryl and heterocyclo;
[0078] R.sup.2 is selected from carbocycloalkyl, aryl, (aryl)alkyl,
heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl,
aminoalkyl; substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl
and aminoalkanoyl;
[0079] R.sup.3 is selected from hydrogen, alkyl, carbocycloalkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl,
(heteroaryl)alkyl, aminoalkyl; substituted aminoalkyl,
carboxyalkyl, alkoxyalkanoyl and aminoalkanoyl;
[0080] R.sup.4 is selected from aryl, heteroaryl and heterocyclo;
and
[0081] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy,
aryloxy, alkylthio, amino, substituted amino, alkoxyalkanoyl,
alkanoylamido, aroylamido, heteroaroylamido,
heterocyclocarbonylamido, alkanoyl(alkylsubstituted)amido,
aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido
and heterocyclocarbonyl(alkylsubstitut- ed)amido.
[0082] Preferably, R.sup.4 in the prior embodiments is phenyl per
se or a phenyl substituted with one or more groups in the 2
(ortho), 3 (meta), or 4 (para) positions, wherein said groups are
selected from C.sub.1-5 alkyl, C.sub.1-5 alkoxy, cyano, halo and
trifluoromethyl. Alternatively, R.sup.4 is an optionally
substituted heteroaryl, an optionally substituted heterocyclo or an
optionally substituted carbocycloalkyl, wherein said optionally
substituted moieties may be substituted with C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, cyano, halo and trifluoromethyl.
[0083] In a preferred class of the compounds of formula (IX)
(including pharmaceutically acceptable salts or prodrugs thereof),
A, B and D are all --CH--; Z is selected from hydrogen and
hydroxyl, Y is selected from a single bond, alkyl, aryl, heteroaryl
and heterocyclo, R.sup.2 is selected from aryl, aralkyl, heteroaryl
and heteroaralkyl, and R.sup.3 is selected from hydrogen, alkyl,
aryl, aralkyl, heteroaryl and heteroaralkyl, and the remaining
substituents are as defined above, as is represented in the
following formula (X): 10
[0084] Compounds, (including pharmaceutically acceptable salts or
prodrugs thereof), of the prior formulae VI through X, subject to
the provisos attributed to formulae I through V also are
contemplated as additional aspects of the present invention.
[0085] Specific examples of molecules embraced under formulae (I)
through (X) are illustrated below.
[0086] As used herein, when a particular radical generally
understood to have a single point of attachment to a core
structure, such as an alkyl group, is identified in connection with
a structure that must have two points of attachment in the
structural core (such as with the element Y in formula (I)), it is
understood that the named radical, e.g., alkyl, refers to the
parent radical with a hydrogen or a site of unsaturation removed to
create the second point of attachment so as to provide the required
structure.
[0087] The term "alkyl," as used alone or in combination herein,
refers to an unsubstituted or optionally substituted, straight, or
branched chain saturated hydrocarbon group containing from one to
eight carbon atoms, preferably from one to five carbons, such as
methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl, the
various branch chain isomers thereof, such as isopropyl, isobutyl,
sec-butyl, tert-butyl, isohexyl and the like. The alkyl group may
be optionally substituted by one or more substituents, and
generally no more than three, and most often just one substituent.
Preferred optional substituents include halo, alkoxy, amino, mono-
and di-substituted amino, aryl, carboxylic acid, heterocyclo,
heteroaryl, carbocycloalkyl, hydroxy, trifluoromethoxy and the
like. The term "lower alkyl" refers to such alkyl groups containing
from one to five carbon atoms.
[0088] The term "alkoxy," as used alone or in combination herein,
refers to an alkyl group, as defined above, covalently bonded to
the parent molecule through an --O-- linkage, such as methoxy,
ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.
[0089] The term "alkoxyalkyl" refers specifically to an alkyl group
substituted with an alkoxy group.
[0090] The term "aryloxy," as used alone or in combination herein,
refers to an aryl group, as defined below, covalently bonded to the
parent molecule through an --O-- linkage. An example of an aryloxy
is phenoxy.
[0091] The term "cycloalkoxy," as used alone or in combination
herein, refers to a carbocycloalkyl group, preferably a cycloalkyl
group, as both defined below, covalently bonded to the parent
molecule through an --O-- linkage.
[0092] The term "alkylthio," as used alone or in combination
herein, refers to an alkyl group, as defined above, covalently
bonded to the parent molecule through an --S-- linkage.
[0093] The term "alkenyl," as used alone or in combination herein,
refers to an alkyl group, as defined above, containing one or more
carbon-to-carbon double bonds, preferably one or two double bonds.
Examples of alkenyl include ethenylene, propenylene,
1,3-butadienyl, and 1,3,5-hexatrienyl.
[0094] The term "alkynyl," as used alone or in combination herein,
refers to an alkyl group, as defined above, containing one or more
carbon-to-carbon triple bonds, preferably one or two triple
bonds.
[0095] The term "cycloalkyl," as used alone or in combination
herein, refers to an unsubstituted or optionally substituted,
saturated cyclic hydrocarbon group containing three to eight carbon
atoms. The cycloalkyl group may optionally be substituted by one or
more substituents, and generally no more than three, and most often
just one substituent. Preferred optional substituents include
alkyl, halo, amino, mono- and di-substituted amino, aryl, hydroxy
and the like.
[0096] The term "haloalkyl" is a species of alkyl as defined
herein, and particularly refers to an alkyl, preferably a lower
alkyl, substituted with one or more halogen atoms, and preferably
is a C.sub.1 to C.sub.4 alkyl substituted with one to three halogen
atoms. One example of a haloalkyl is trifluoromethyl.
[0097] The term "alkanoyl" as used alone or in combination herein
refers to an acyl radical derived from an alkanecarboxylic acid
(alkyl-C(O)--), particularly a lower alkanecarboxylic acid, and
includes such examples as acetyl, propionyl, butyryl, valeryl, and
4-methylvaleryl.
[0098] The term "aroyl" means an acyl radical derived from an
aromatic carboxylic acid, such as optionally substituted benzoic or
naphthoic acids and specifically including benzoyl and
1-naphthoyl.
[0099] The term "aminocarbonyl" means an amino-substituted carbonyl
(carbamoyl or carboxamide) wherein the amino group is a primary
amino (--NH.sub.2). Substituted aminocarbonyl refers to secondary
(mono-substituted amino) or tertiary amino (di-substituted amino)
group, as defined below, preferably having as a substituent(s) a
lower alkyl.
[0100] The term "aminoalkanoyl" means an amino-substituted alkanoyl
wherein the amino group is a primary amino (-alkyl-C(O)--NH.sub.2).
The term "substituted aminoalkanoyl" refers to related secondary
(mono-substituted amino) or tertiary amino (di-substituted amino)
group, as defined below.
[0101] The term "carbocycloalkyl" when used alone or in combination
refers to an unsubstituted or optionally substituted, stable,
saturated or partially unsaturated monocyclic, bridged monocyclic,
bicyclic, and spiro ring carbocycles of 3 to 15 carbon atoms such
as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclohexyl, bicyclooctyl, bicyclononyl, spirononyl and
spirodecyl. Cycloalkyls are thus one specific subset of
carbocycloalkyls, and in the context of the present invention
constitute a highly preferred subset. The term "optionally
substituted" as it refers to "carbocycloalkyl" herein indicates
that the carbocycloalkyl group may be substituted at one or more
substitutable ring positions by one or more groups independently
selected from alkyl (preferably lower alkyl), alkoxy (preferably
lower alkoxy), nitro, monoalkylamino (preferably a lower
alkylamino), dialkylamino (preferably a di[lower]alkylamino),
cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl
amido (preferably lower alkyl amido), alkoxyalkyl (preferably a
lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower
alkoxycarbonyl), alkylcarbonyloxy (preferably a lower
alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being
optionally substituted by halo, lower alkyl and lower alkoxy
groups. Generally, there is no more than one optional
substituent.
[0102] The term "heterocyclo" as used, alone or in combination,
herein refers to an unsubstituted or optionally substituted,
stable, saturated, or partially unsaturated, monocyclic, bridged
monocyclic, bicyclic, and spiro ring system containing carbon atoms
and other atoms selected from nitrogen, sulfur and/or oxygen.
Preferably, a heterocyclo is a 5 or 6-membered monocyclic ring or
an 8-11 membered bicyclic ring which consists of carbon atoms and
contains one, two, or three heteroatoms selected from nitrogen,
oxygen and/or sulfur. Heterocyclo includes benz-fused monocyclic
carbocycloalkyl groups having at least one such heteroatom. The
term "optionally substituted" as it refers to "heterocyclo" herein
indicates that the heterocyclo group may be substituted at one or
more substitutable ring positions by one or more groups
independently selected from alkyl (preferably lower alkyl and
including haloalkyl (preferably trifluoromethyl)), alkoxy
(preferably lower alkoxy), nitro, monoalkylamino (preferably a
lower alkylamino), dialkylamino (preferably a di[lower]alkylamino),
cyano, halo, alkanoyl, aminocarbonyl, monoalkylaminocarbonyl,
dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido),
alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl
(preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a
lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl
being optionally substituted by halo, lower alkyl and lower alkoxy
groups. Generally, there is no more than one optional substituent.
Several non-limiting examples of such heterocyclo groups are
illustrated below: 11
[0103] The heterocyclo group may be, and generally is attached to
the parent structure through a carbon atom, or alternatively may be
attached through any heteroatom of the heterocyclo that results in
a stable structure.
[0104] The term "heteroaryl" as used alone or in combination,
herein refers to an unsubstituted or optionally substituted,
stable, aromatic monocyclic or bicyclic ring system containing
carbon atoms and other atoms selected from nitrogen, sulfur and/or
oxygen. Preferably, a heteroaryl is a 5 or 6-membered monocyclic
ring (optionally benzofused) or an 8-11 membered bicyclic ring
which consists of carbon atoms and contains one, two, or three
heteroatoms selected from nitrogen, oxygen and/or sulfur. The term
"optionally substituted" as it refers to "heteroaryl" herein
indicates that the heteroaryl group may be substituted at one or
more substitutable ring positions by one or more groups
independently selected from alkyl (preferably lower alkyl and
including haloalkyl (preferably trifluoromethyl)), alkoxy
(preferably lower alkoxy), nitro, monoalkylamino (preferably a
lower alkylamino), dialkylamino (preferably a di[lower]alkylamino,
cyano, halo, alkanoyl, aminocarbonyl, monoalkylaminocarbonyl,
dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido),
alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl
(preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a
lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl
being optionally substituted by halo, lower alkyl and lower alkoxy
groups. Generally, there is no more than one optional substituent.
Several non-limiting examples of such heteroaryl groups are
illustrated below: 12
[0105] The heteroaryl group may be, and generally is attached to
the parent structure through a carbon atom or alternatively may be
attached through any heteroatom of the heteroaryl that results in a
stable structure. In the foregoing structures it also is
contemplated that a nitrogen could be replaced with an N-oxide.
[0106] Both heterocyclo and heteroaryl also are intended to embrace
benzo fused structures such as 1,2-methylenedioxybenzene and
1,4-benzodioxan.
[0107] The specific chemical nature of the optionally substituted
heterocyclo and heteroaryl groups for the terminal moieties R.sup.1
and R.sup.2 in the prior identified potassium channel inhibitor
compounds is not narrowly critical and, as noted above, a wide
variety of substituent groups are contemplated. Preferably, the
substituents for the heterocyclo and heteroaryl groups are selected
such that the total number of carbon and hetero atoms comprising
the substituted heterocyclos and heteroaryls is no more than about
20.
[0108] The terms "halo" and "halogen" as used herein to identify
substituent moieties, represent fluorine, chlorine, bromine or
iodine, preferably chlorine or fluorine.
[0109] The term "aryl," when used alone or in combination, refers
to an unsubstituted or optionally substituted monocyclic or
bicyclic aromatic hydrocarbon ring system having 6 to 12 ring
carbon atoms. Preferred are optionally substituted phenyl,
1-naphthyl, or 2-naphthyl groups. The aryl group may optionally be
substituted at one or more substitutable ring positions (generally
at no more than three positions and most often at one or two
positions) by one or more groups independently selected from alkyl
(including haloalkyl (preferably trifluoromethyl and
difluoromethyl)), alkenyl, alkynyl, alkoxy, aryloxy, nitro,
hydroxy, amino, mono- and di-substituted amino, cyano, halo,
alkanoyl, aminocarbonyl, carboxylic acid, carboxylic acid esters,
carboxylic acid amide, an optionally substituted phenyl (optionally
substituted by halo, lower alkyl and lower alkoxy groups),
heterocyclo, or heteroaryl. Preferably, the aryl group is phenyl
optionally substituted with up to four and more usually with one or
two groups, preferably selected from lower alkyl, lower alkoxy, as
well as cyano, trifluoromethyl and halo.
[0110] The terms "aralkyl" and "(aryl)alkyl," alone or in
combination are a species of alkyl as defined herein, and
particularly refers to an alkyl group as defined above in which one
hydrogen atom is replaced by an aryl group as defined above, and
includes benzyl, and 2-phenylethyl.
[0111] The terms "(heterocyclo)alkyl" and "(heteroaryl)alkyl" alone
or in combination can be considered a species of alkyl as defined
herein, and particularly refers to an to an alkyl group as defined
above in which one hydrogen atom is replaced by a heterocyclo group
as defined above, or by a heteroaryl group as defined above.
[0112] The term "alkoxycarbonyl" alone or in combination means a
radical of the formula --C(O)-alkoxy, in which alkoxy is as defined
above.
[0113] The term "alkylcarbonyloxy" alone or in combination means a
radical of the formula --O--C(O)-alkyl, in which alkyl is as
defined above.
[0114] The term "alkoxyalkanoyl" alone or in combination means a
radical of the formula --alkyl-C(O)--O-alkyl.
[0115] The term "carboxyalkyl" alone or in combination means a
radical of the formula-alkyl-C(O)--OH.
[0116] As used in connection with formula (I) and elsewhere in this
application, the term "substituted carbon atom" means a ring carbon
substituted with one of the group R.sup.7, or the radical
--N(R.sup.2)(XYR.sup.1).
[0117] The term "substituted amino" embraces both "mono and
di-substituted amino." These terms, alone, or in combination, mean
a radical of the formula --NR'R", where, in the case of
mono-substitution, one of R' and R" is a hydrogen and the other is
selected from alkyl, carbocycloalkyl, aryl, heterocyclo,
(aryl)alkyl, (heterocyclo)alkyl, heteroaryl and hetero(aryl)alkyl;
in the case of di-substitution, R' and R" are independently
selected from alkyl, carbocycloalkyl, aryl, heterocyclo, and
heteroaryl, or R' and R" together with the nitrogen atom to which
they are both attached form a three to eight-membered heterocyclo
or heteroaryl radical.
[0118] The term "amido" refers to the group (--NH--) and the term
"substituted amido" embraces a radical of the formula (--NR'--)
where R' has the meaning above in connection with substituted
amino.
[0119] The terms "alkanoylamido," "aroylamido,"
"heterocyclocarbonylamido" and "heteroaroylamido" mean groups of
the formula R--C(O)--NH--where R is an alkyl, aryl, heteroaryl or
heterocyclo.
[0120] The terms "heteroaroyl" and "heterocyclocarbonyl" when used
alone or in combination means groups of the formula R--C(O)--where
R is a heteroaryl or heterocyclo.
[0121] Unless otherwise defined, the term "optionally substituted"
as used herein, refers to the substitution of a ring system at one
or more positions with one or more groups selected from: C.sub.1-5
alkyl, C.sub.1-5 alkoxy, an optionally substituted phenyl, cyano,
halo, trifluoromethyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkyl
carbonyloxy, mono- and bis-(C.sub.1-5 alkyl)-carboxamide, C.sub.1-5
alkyl amido, nitro, and mono- and bis-(C.sub.1-5 alkyl)-amino.
[0122] Applicants recognize that there may be some overlap in some
of the definitions of the various radical groups. Specific groups
are mentioned, however, such as (aryl)alkyl, and may be
particularly identified in the claims, in order to emphasize their
positive inclusion in the described subject matter, as not only an
optional substituent.
[0123] The term "treating" as used herein, describes the management
and care of a patient afflicted with a condition, disease or
disorder for which the administration of a compound of the present
invention alters the action or activity of a potassium channel to
prevent the onset of symptoms or complications associated with the
condition, disease or disorder, to alleviate the symptoms or
complications caused by the condition, disease or disorder, or to
eliminate the condition, disease or disorder altogether.
[0124] Certain indane compounds of the previous formulae useful as
potassium channel inhibitors in accordance with the present
invention can be prepared in accordance with the following Scheme
1: 13
[0125] Compounds of the invention of formula II where Z is hydrogen
may be prepared starting with a nitro indanone (A), which in step
(1) is reductively aminated in the presence of ammonium acetate
(employing a molar ratio of nitro indanone:ammonium acetate within
the range from about 1:1 to about 1:30) and a reducing agent such
as sodium cyanoborohydride in an inert organic solvent such as
methanol to form the nitro-amino compound (B). The nitro-amino
compound (B) then is reacted with a sulfonylating agent (employing
a molar ratio of Step (1) product to sulfonylating agent within the
range from about 1:1 to about 10:1) in the presence of a base such
as triethylamine or pyridine and in an inert organic solvent such
as tetrahydrofuran or dichloromethane to form the sulfonylated
compound (C).
[0126] The sulfonylated compound (C) is then subjected to
nitro-reduction by treatment with a suitable reducing agent such as
sodium borohydride in the presence of nickel chloride in an organic
solvent such as tetrahydrofuran and/or methanol to form the aniline
(D). Aniline (D) is then derivatized by treatment with an
alkylating agent such as an alkyl halide (R.sup.2X where X is Cl,
Br, or I) in the presence of a base such as potassium carbonate in
an inert solvent such as acetonitrile to form the secondary amine
(E). Alternatively, aniline (D) can be derivatized by reductive
alkylation using an aldehyde and a drying agent such as sodium
sulfate followed by treatment with a reducing agent such as sodium
borohydride in an organic solvent such as methanol or ethanol.
[0127] The secondary amine (E) thereafter undergoes an acylation in
step (5) by reacting the secondary amine (E) with an acylating
agent such as an acid chloride (which may be prepared in situ from
the corresponding carboxylic acid by methods known in the
literature) in the presence of a base such as triethylamine or
pyridine in an inert organic solvent such as tetrahydrofuran or
dichloromethane to form the amide compounds (F) of formula II where
X is C.dbd.O. The secondary amine (E) can also be reacted with a
sulfonylating agent under conditions described above to form
sulfonamide compounds of formula II (compound (F)) where X is
SO.sub.2. The secondary amine (E) can also be reacted with an
isocyanate in an organic solvent such as tetrahydrofuran or
dichloromethane to form urea compounds of formula II where X is
C.dbd.O, Y is a bond, and R.sup.1 is a substituted amino.
[0128] The starting nitro indanone, compound (A), the amino
compound (B), the sulfonamide (C), and the aniline (D) in General
Scheme 1 may be prepared as described in N. Castle et al., WO
9804521, see also U.S. Pat. No. 6,083,986 incorporated herein by
reference.
[0129] A synthetic approach to prepare compounds of formula II
where Z is hydroxyl is provided by the following Scheme 2 (Steps
1-8). In step (1), reduction of a nitro indanone (using NaBH.sub.4
for example) gives the corresponding alcohol; 14
[0130] In the next step (2), the product of step (1) is subjected
to an acid catalyzed dehydration (pTSA/Toluene) to give the
corresponding indene. 15
[0131] Then in step (3) the double bond of the indene product of
step (2) is oxidized (e.g. using M-CPBA/CH.sub.2Cl.sub.2) to give
the corresponding epoxide. 16
[0132] In step (4), the epoxide of step (3) is aminated (for
instance using ammonium hydroxide) to give the corresponding amino
alcohol. 17
[0133] The amino-alcohol of step (4) is sulfonylated, for example
using a sulfonyl chloride, to attach an R.sup.4--SO.sub.2-- moiety.
The amino-alcohol is reacted in a suitable solvent with the
sulfonyl chloride (or a sulfonyl anhydride) in the presence of an
acid scavenger. Suitable solvents in which the reaction can be
conducted include methylene chloride and tetrahydrofuran. Suitable
acid scavengers include triethylamine and pyridine. 18
[0134] In step (6), the nitro moiety of the sulfonylated product of
step (5) is reduced (SnCl.sub.2) to give the corresponding aniline.
19
[0135] The aniline formed in step (6) can then be derivatized (step
(7)) by treatment with an alkylating agent such as an alkyl halide
(R.sup.2X where X is Cl, Br, or I) in the presence of a base such
as potassium carbonate in an inert solvent such as acetonitrile to
form a secondary amine. Alternatively, the aniline formed in step
(6) can be derivatized by reductive alkylation using an aldehyde
and a drying agent such as sodium sulfate followed by treatment
with a reducing agent such as sodium borohydride in an organic
solvent such as methanol or ethanol. 20
[0136] As in Scheme 1, the so-formed secondary amine thereafter
undergoes an acylation in step (8) with an acylating agent such as
an acid chloride (which may be prepared in situ from the
corresponding carboxylic acid by methods known in the literature)
in the presence of a base such as triethylamine or pyridine in an
inert organic solvent such as tetrahydrofuran or dichloromethane to
form the desired amide where X is C.dbd.O. The resulting amide (X
is C.dbd.O) can be readily converted to the corresponding thioamide
(X is C.dbd.S) via known literature procedures (e.g., through the
use of Lawesson's reagent. The secondary amine could also be
reacted with a sulfonylating agent under conditions described above
to form the related sulfonamide compounds where X is SO.sub.2.
Additionally, the secondary amine could also be reacted with an
isocyanate in an organic solvent such as tetrahydrofuran or
dichloromethane to form a urea where X is C.dbd.O, Y is a bond, and
R' is a substituted amino. 21
[0137] Those skilled in the art will appreciate additional
techniques and raw materials suitable for preparing other compounds
falling within the scope of the present invention, as for example
are illustrated in the subsequent specific examples. For instance,
the skilled worker will readily appreciate the advantage of
employing protecting groups, and will readily understand their
application in a specific synthetic approach to improve the yield
of desired products. For example, one skilled in the art will
recognize that there are a variety of protecting groups as
discussed in "Protective Groups in Organic Synthesis", T. W. Green
and P. G. M. Wuts (1999).
[0138] It is recognized that there is generally at least one and
often more than one chiral center in the compounds falling within
the scope of the present invention and thus such compounds will
exist as various stereoisomeric forms. Applicants intend to include
all the various stereoisomers within the scope of the invention.
Thus, this invention is intended to include the cis and trans
isomers and the corresponding enantiomers of the compounds of
formula I-V. Though the compounds may be prepared as racemates and
can conveniently be used as such, individual enantiomers also can
be isolated or preferentially synthesized by known techniques if
desired. Such racemates and individual enantiomers and mixtures
thereof are intended to be included within the scope of the present
invention.
[0139] The present invention also encompasses the pharmaceutically
acceptable prodrugs of the compounds of Formula I. A prodrug is a
drug which has been chemically modified and may be biologically
inactive at its site of action, but which is degraded or modified
by one or more enzymatic or other in vivo processes to the parent
bioactive form. Generally, a prodrug has a different
pharmacokinetic profile than the parent drug such that, for
example, it is more easily absorbed across the mucosal epithelium,
it has better salt formation or solubility and/or it has better
systemic stability (e.g., an increased plasma half-life).
[0140] Those skilled in the art recognize that chemical
modifications of a parent drug to yield a prodrug include: (1)
terminal ester or amide derivatives which are susceptible to being
cleaved by esterases or lipases; (2) terminal peptides which may be
recognized by specific or nonspecific proteases; or (3) a
derivative that causes the prodrug to accumulate at a site of
action through membrane selection, and combinations of the above
techniques. Conventional procedures for the selection and
preparation of prodrug derivatives are described in H. Bundgaard,
Design of Prodrugs, (1985). Those skilled in the art are
well-versed in the preparation of prodrugs and are well-aware of
its meaning.
[0141] The compounds of the present invention can be used in their
neat form or in the form of pharmaceutically-acceptable salts
derived from inorganic or organic acids, or in the form of their
esters, amides, complexes, chelates, hydrates, stereoisomers,
crystalline or amorphous forms, metabolites, metabolic precursors,
or prodrugs. In the practice of the present invention, compounds of
the present invention in their neat form will generally have a
molecular weight of 800 or below, usually 600 or below.
[0142] Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts of compounds of the
present invention include such inorganic acids as hydrochloric
acid, sulphuric acid and phosphoric acid and such organic acids as
maleic acid, succinic acid and citric acid. These salts thus
include, but are not limited to, the following: acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, p-toluenesulfonate and
undecanoate.
[0143] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chlorides, bromides and iodides;
dialkyl sulfates, like dimethyl, diethyl, dibutyl and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides and others. Water or oil soluble or
dispersible products are thereby generally obtained.
[0144] The pharmaceutically acceptable salts of the compounds of
the present invention also can exist as various solvates, such as
with water, methanol, ethanol, dimethylformamide, ethyl acetate and
the like. Mixtures of such solvates also can be prepared. Such
solvates are within the scope of the present invention.
[0145] The pharmacological profile of the potassium channel
inhibitory activity of the compounds of the present invention can
be readily assessed by those skilled in the art using routine
experimentation, such as the procedures and techniques illustrated
in the examples which follow. Assays for assessing the activity of
particular compounds may employ cells stably transfected to express
a specific potassium channel, as well as native mammalian cells. In
particular, stable transfected cells, transfected to express a
specific potassium channel, which have been treated with a voltage
dependent fluorescent dye, such as bis-(1,3-dibutylbarbituric
acid)trimethine oxonol, can be used to gauge the inhibitory
activity of potassium channel inhibitor compounds, possibly in
comparison to known inhibitors. Alternatively, such cells can be
primed with a detectible species, such as .sup.86Rb, and then
challenged with a particular compound, under conditions otherwise
suitable for activating the potassium channel, to assess the
potassium inhibitory activity of the compound. The potassium
channel inhibitory activity of a compound also can be determined
using isolated mannalian cells and the whole cell configuration of
the known patch clamp technique (Hamill et al., Pflugers Archiv
391:85, 1981). These and other known techniques can be readily
employed by those skilled in the art to assess the activity level
of the potassium channel inhibitor compounds of the present
invention.
[0146] The compounds of the present invention may be administered
by a variety of routes including orally, parenterally,
sublingually, intranasally, by inhalation spray, rectally, or
topically in dosage unit formulations containing conventional
nontoxic pharmaceutically acceptable carriers, adjuvants, and
vehicles as desired. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intracardiac
injection, or infusion techniques. Topical administration may also
involve the use of transdermal administration such as transdermal
patches or iontophoresis devices.
[0147] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,2-propanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0148] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable nonirritating excipient
such as cocoa butter and polyethylene glycols which are solid at
ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
[0149] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose, lactose, or starch. Such dosage
forms may also comprise, as is normal practice, additional
substances other than inert diluents, e.g., lubricating agents such
as magnesium stearate. In the case of capsules, tablets, and pills,
the dosage forms may also comprise buffering agents. Tablets and
pills can additionally be prepared with enteric coatings.
[0150] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring and perfuming agents.
[0151] The compounds of the present invention can also be
administered in the form of liposomes. As is known in the art,
liposomes are generally derived from phospholipids or other lipid
substances. Liposomes are formed as mono- or multi-lamellar
hydrated liquid crystals that are dispersed in an aqueous medium.
Any non-toxic physiologically acceptable and metabolizable lipid
capable of forming liposomes can be used. The present compositions
in liposome form can contain, in addition to a compound of the
present invention, stabilizers, preservatives, excipients, and the
like. The preferred lipids are the phospholipids and phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.
(1976), p. 33, et seq.
[0152] To select preferred compounds from less preferred compounds,
one uses by example the in vitro assays detailed under the
sub-heading BioAssays hereafter described. Typically, a preferred
compound will produce half maximal blocking activity at a
concentration below about 5 .mu.M, preferably below about 1 .mu.M,
more preferably below about 100 nM and most preferably below about
10 nM in the in vitro assays described. One of ordinary skill will
recognize that the final and optimum dose and regimen will be
determined empirically for any given drug.
[0153] Total daily dose administered to a host in single or divided
doses may be an amount, for example, from 0.001 to 100 mg of active
ingredient per kg body weight on a daily basis and more usually
0.01 to 10 mg/kg/day. Dosage unit compositions may contain such
amounts of submultiples thereof to make up the daily dose. It is
anticipated that a therapeutically effective serum concentration of
active ingredient will be 10 nM to 10 .mu.M (5 ng/ml to 5
.mu.g/ml).
[0154] The amount of active ingredient that may be combined with
carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[0155] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, and diet of the patient, the time
of administration, the route of administration, the rate of
excretion, whether a drug combination is used, and the severity of
the particular disease.
[0156] Using the processes described hereinabove, the following
compounds (each assigned a unique number identifier) can be
synthesized: 22
[0157] The present invention is further explained in greater detail
in the Examples which follow. These experimental examples are
intended as illustrative of the invention, and are not to be taken
as limiting thereof. Unless otherwise indicated, all references to
parts and percentages are based on weight and all temperatures are
expressed in degrees Celsius. The scope of the invention is not
construed as merely consisting of the following examples.
EXAMPLES
[0158] Compound Preparation 23
[0159] Compounds 97 and 98 and related amino indanes are prepared
as described in N. Castle et al WO9804521 (See also U.S. Pat. No.
6,083,986 incorporated herein by reference); D. Buckle et al J Med.
Chem. 1991, 34, 919-926 (and references cited therein) and J.
Tedder et al., EP0321175
[0160] Separation of the enantiomers of compound 97 and compound 98
can be accomplished by chiral HPLC using a Chiralpak AS column
(Chiral Technologies, Inc.) for compound 97 and a Chiralpak OJ
column (Chiral Technologies, Inc.) for compound 98. Asymmetric
synthetic methods can also be used to separate the enantiomers of
compound 97 and compound 98. For example, see N. Castle et al., WO
98/04521 (See also U.S. Pat. No. 6,083,986).
[0161] The resolution of racemic
trans-2-phenylcyclopropanecarboxylic acid to give the (+)-(S) and
(--)-(R) isomers is accomplished as described in Macromolecules,
1971, 4, 718-719.
Example 1
[0162] Preparation of Compound 99 24
[0163] To a stirred solution of Compound 97 (200 mg, 0.948 mmol) in
methanol (5 mL) at room temperature was added
1-methyl-2-imidazolecarboxa- ldehyde (125 mg, 1.13 mmol) and
anhydrous sodium sulfate (673 mg, 4.74 mmol). The reaction mixture
was heated at 50EC for six hours under nitrogen. The excess sodium
sulfate was filtered from the reaction mixture while it was still
warm and the filtrate was cooled to room temperature. Sodium
borohydride (103 mg, 2.72 mmol) was added to the filtrate and it
was stirred for 15 hours at room temperature. The solution was
quenched with saturated aqueous sodium bicarbonate solution and the
methanol was removed by rotary evaporation. The resulting mixture
was diluted with water and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated. The residue was recrystallized from a minimum
amount of hot ethyl acetate to give Compound 99 (229 mg, 59%) as a
white solid. The mother liquor was concentrated and subjected to
flash column chromatography on silica gel using 9:1 ethyl
acetate:methanol as the eluent to provide additional Compound 99
(39 mg). .sup.1H NMR (300 MHZ, d.sub.6-acetone) .delta. 7.90 (d, 2
H, J=8.2 Hz), 7.47 (d, 2 H, J=8.1 Hz), 6.99 (s, 1 H), 6.92 (d, 1 H,
J=8.2 Hz), 6.82 (d, 1 H, J=0.8 Hz), 6.67 (dd, 1 H, J=2.0, 8.1 Hz),
6.50 (s, 1 H), 5.14 (s, 1 H), 4.70 (m, 2H), 4.21 (s, 2H), 3.70 (s,
3H), 2.75, (q 2H, J=7.6 Hz), 2.67 (dd, 1 H, J=3.3, 8.9 Hz), 2.56
(m, 1 H), 2.12 (m, 1 H), 1.69 (m, 1 H), 1.25 (t, 3H, J=7.6 Hz).
.sup.13C NMR (75 MHZ, d.sub.6-acetone) .delta. 149.4, 147.4, 145.8,
143.4, 139.4, 131.5, 128.3, 126.9, 125.6, 124.6, 121.8, 113.5,
108.1, 58.7, 40.4, 34.2, 31.9, 28.5, 28.3, 14.3.
[0164] The following compounds in Example 2 and Example 3 were
synthesized using the procedures described in Example 1 using
Compound 97 and the appropriate aldehyde.
Example 2
[0165] Preparation of Compound 100 25
[0166] Compound 100 was obtained by reacting Compound 97 with
3-pyridine carboxaldehyde under the reaction conditions described
in Example 1 in 78% yield. Purification was accomplished by flash
column chromatography on silica gel using 6:2:2 ethyl
acetate:dichloromethane:hexanes as the eluent. 1H NMR (300 MHZ,
CDCl.sub.3) .delta. 8.47 (s, 1 H), 8.45 (d, J=4.8 Hz, 1 H), 7.81
(d, J=8.1 Hz, 2H), 7.63 (d, J=7.8 Hz, 1 H), 7.31 (d, J=8.1 Hz, 2
H), 7.26-7.20 (m, 1 H), 6.94 (d, J=8.1 Hz, 1 H), 6.45 (d, J=7.8 Hz,
1 H), 6.41 (s, 1 H), 5.43 (s, J=9.0 Hz, 1 H), 4.73 (q, J=7.8 Hz, 1
H), 4.19 (s, 2H), 2.78-2.54 (m, 4H), 2.30-2.20 (m, 1 H), 1.73-1.61
(m, 1 H), 1.23 (t, J=7.5 Hz, 3H);. .sup.13C NMR (75 MHZ,
CDCl.sub.3) .delta. 149.5, 149.0, 148.6, 147.0, 143.6, 138.7,
135.4, 134.9, 132.1, 128.6, 127.2, 125.4, 123.6, 113.6, 108.4,
58.9, 46.0, 35.0, 29.1, 28.8, 15.2
Example 3
[0167] Preparation of Compound 101 26
[0168] Compound 101 was obtained by reacting Compound 97 with
6-methyl-2-pyridine carboxaldehyde under the reaction conditions
described in Example 1 in 66% yield. Purification was accomplished
by recrystallization from ethyl acetate/hexane. .sup.1H NMR (300
MHZ, CDCl.sub.3) .delta. 7.81 (d, J=7.8 Hz, 2 H), 7.50 (t, J=7.8
Hz, 1 H), 7.31 (d, J=7.8 Hz, 2H), 7.06 (d, J=7.02 (d, J=7.8 Hz, 1
H), 6.92 (d, J=8.4 Hz, 1 H), 6.50 (d, J=7.8, 1 H), 6.38 (s, 1 H),
5.10 (d, J=8.7 Hz, 1 H), 4.72 (q, J=7.5 Hz, 1 H), 4.24 (s, 2 H),
2.70 (q, J=7.2 Hz, 2H), 2.63-2.56 (m, 2H), 2.56 (s, 3H), 2.25-2.22
(m, 1H), 1.71-1.62 (m, 1H), 1.24 (t, J=7.2 Hz, 3H); .sup.13C NMR
(75 MHZ, CDCl.sub.3) .delta. 158.0,157.5,149.4,147.4,143.3, 138.6,
136.9, 131.4, 128.6, 127.3, 125.2, 121.7, 118.7, 113.8, 108.3,
58.9, 49.4, 35.0, 29.1, 28.8, 24.5, 15.2
Example 4
[0169] Preparation of Compound 102 27
[0170] To a stirred solution of Compound 98 (294 mg, 0.88 mmol) in
methanol (10 mL) at room temp was added 3-pyridine carboxaldehyde
(0.12 mL, 1.27 mmol) followed by anhydrous sodium sulfate (480 mg,
3.38 mmol). ). The reaction mixture was heated at 55EC for 24 hours
under nitrogen at which time TLC analysis indicated that no
starting material remained. The reaction was cooled to OEC and
treated with sodium borohydride (53 mg, 1.40 mmol) in one portion.
After 15 minutes at OEC the cooling bath was removed and the
reaction was stirred at room temperature for three hours. The
methanol was removed by rotary evaporation and the residue was
treated with ethyl acetate and water. The organic layer was
separated, washed with saturated sodium chloride solution, dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by flash column chromatography on silica gel
using 8:1:1 ethyl acetate:hexane:acetonitrile as the eluent to
provide Compound 102 (197 mg, 53%) as a white foam. .sup.1H NMR
(300 MHZ, CDCl.sub.3) .delta. 8.41 (S, 1 H), 8.33 (d, J=4.2 HZ, 1
H), 7.82 (d, J=8.1 Hz, 2H), 7.57 (d, J=7.8 Hz, 1 H), 7.25 (d, J=8.1
Hz, 2H), 7.16 (dd, J=4.8 and 7.5 Hz, 1 H), 6.86 (d, J=8.1 Hz, 1 H),
6.59 (d, J=7.8 Hz, 1 H), 6.41 (d, J=6.9 Hz, 1 H), 6.20 (s, 1 H),
3.95 (t, J=6.9 Hz, 1 H, 4.30 (q, J=7.5 Hz, 1 H), 4. 11 (s, 2H),
3.92 (broad s, 1 H), 3.01 (dd, J=7.5 and 15.3 Hz, 1 H), 2.67-2.60
(m, 3H), 1. 19 (t, J=7.5 Hz, 3H); .sup.13C NMR (75 MHZ, CDCl.sub.3)
.delta. 149.7, 148.7, 148.2, 147.3, 140.2, 137.6, 135.5, 135.1,
128.7, 128.3, 127.4, 125.7, 123.7, 113.7, 108.2, 80.8, 65.6, 45.8,
37.0, 28.8, 15.2
Example 5
[0171] Preparation of Compound 103 28
[0172] To a solution of Compound 97 (100 mg, 0.32 mmol) in
1-methyl-2-pyrrolidinone (0.7 mL) at room temperature was added
2-chloropyrimidine (40 mg, 0.35 mmol). The reaction mixture was
heated at 140EC for 21 hours. The crude reaction mixture was
directly subjected to flash column chromatography on silica gel
eluting with hexane:ethyl acetate (3:2 then 1:1) to give Compound
103 (49 mg, 39%) as a white solid. .sup.1H NMR (300 MHZ,
CDCl.sub.3) 6 (ppm): 8.33 (2 H, d, J=4.9 Hz), 7.87 (2 H, d, J=8.3
Hz), 7.40 (1 H, dd, J=1.9, 8.0), 7.33 (2 H, d, J=8 Hz), 7.31 (1 H,
s), 7.14 (1 H, d, J=8.2 Hz), 6.69 (1 H, t, J=4.8), 5.18 (1 H, d,
J=8.9 Hz), 4.83 (1 H, q, J=8.4 Hz), 2.91-2.81 (1 H, m), 2.74-2.64
(1 H, m), 2.71 (2 H, q, J=7.7 Hz), 2.41-2.31 (1 H, m), 1.87-1.72 (2
H, m), 1.25 (3 H, t, J=7.7 Hz).
Example 6
[0173] Preparation of Compound 10 29
[0174] To a stirred solution of Compound 99 (65 mg, 0.16 mmol) in
anhydrous THF (1.5 mL) at room temperature was added triethylamine
(0.027 mL, 0.20 mmol) followed by hydrocinnamoyl chloride (29 mg,
0.17 mmol). The reaction mixture was stirred at room temperature
for 6 hours. Saturated aqueous sodium bicarbonate solution was
added and the resulting mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel using 10:1:1 ethyl
acetate:dichloromethane:hexanes as the eluent to give Compound 10
(59 mg, 69%) as a white foam. .sup.1H NMR (300 MHZ,
d.sub.6-acetone) .delta. 7.87 (d, 2H, J=8.4 Hz), 7.48 (d, 2H,
J=8.2-Hz), 7.26 (m, 4H), 7.15 (d, 1 H, J=7.2 Hz), 7.08 (d, 2H,
J=7.7 Hz), 6.94 (s, 1 H), 6.76 (d, 1 H, J=7.8 Hz), 6.65 (d, 1 H,
J=7.8 H z), 4.92 (m, 1 H) 4.77 (m, 2 H), 3.59 (s, 3 H), 2.81 (q, 2
H, J=6.9 H z), 2.74 (m, 4H), 2.24 (m, 3H), 1.76 (m, 1H), 1.26 (t,
3H, 7.6 Hz). .sup.13C NMR (75 MHZ, d.sub.6-acetone) .delta. 170.8,
149.2, 144.2, 143.7, 142.8, 141.5, 140.0, 128.6, 128.4, 128.3,
128.3, 127.2, 126.9, 125.9, 125.2, 124.3, 121.6, 58.3, 35.8, 34.4.,
32.2, 31.2, 29.8, 28.4, 14.8.
[0175] The following compounds in Example 7 to Example 10 were
synthesized using the procedures described in Example 6 using
Compound 99 and the appropriate acid chloride.
Example 7
[0176] Preparation of Compound 37 30
[0177] Compound 37 was obtained by reacting Compound 99 with
3-chlorobenzoyl chloride in the presence of triethylamine as
described in Example 6 in 67% yield. Purification was accomplished
by flash column chromatography using EtOAc as the eluent. .sup.1H
NMR (300 MHZ, d.sub.6-acetone) .delta. 7.87 (d, 2 H, J=8.2 Hz),
7.48 (d, 2 H, J=8.4 Hz), 7.26 (m, 1 H), 7.14 (m, 1 H), 7.08 (d, 1
H, J=8.7 Hz), 7.00 (s, 1 H), 6.96 (d, 1 H, J=8. 0 Hz), 6.86 (d, 1
H, J=11.1 Hz), 6.79 (s, 1 H), 5.11 (d, 1 H, J=15.2 Hz), 4.94 (d, 1
H, J=15.2 Hz) 4.69 (m, 1 H), 3.75 (s, 3H), 2.77 (q, 2H, J=7.7 Hz),
2.72 (m, 1 H), 2.63 (m, 1 H), 2.22 (m, 1 H), 1.72 (m, 1H) 1.27 (t,
3H, 7.7 Hz). .sup.13C NMR (75 MHZ, d.sub.6-acetone) .delta.
167.9,149.2,144.1, 143.6, 141.9, 141.5, 139.9, 138.5, 133.2, 129.4,
129.3, 128.6, 128.4, 128.3, 127.2, 127.1, 126.9, 124.8, 123.8,
121.6, 58.3, 45.2, 34.5, 32.3, 14.8.
Example 8
[0178] Preparation of Compound 45 31
[0179] Compound 45 was obtained by reacting Compound 99 with
m-anisoyl chloride in the presence of triethylamine as described in
Example 6 in 90% yield. Purification was accomplished by flash
column chromatography using 10:1 ethyl acetate:hexanes as the
eluent. .sup.1H NMR (300 MHZ, d.sub.6-acetone) .delta. 7.89 (d, 2H,
J=8.2 Hz), 7.48 (d, 2H, J=8.2 Hz), 7.24 (d, 1 H, J=8.6 Hz), 7.07
(t, 1 H, J=8.0 Hz), 7.01 (s, 1 H), 6.91 (d, 1 H, J=8.0 Hz), 6.79
(m, 5H), 5.16 (d, 1 H, J=15.1 Hz), 4.92 (d, 1 H, J=15.2 Hz), 4.68
(dd, 1 H, J=7.8, 15.8 Hz), 3.77 (s, 3H), 3.63 (s, 3H), 2.76 (q, 2H,
J=7.7 Hz), 2.71 (dd, 1 H, J 3. 1, 8.4 Hz), 2.63 (m, 1 H), 2.24 (m,
1 H), 1.73 (m, 1 H), 1.26 (t, 3H, J 7.6 Hz).
Example 9
[0180] Preparation of Compound 46 32
[0181] Compound 46 was obtained by reacting Compound 99 with
3-cyclopentylpropionyl chloride in the presence of triethylamine as
described in Example 6 in 44% yield. Purification was accomplished
by flash column chromatography using 10:1 ethyl acetate:hexanes as
the eluent. .sup.1H NMR (300 MHZ, d.sub.6-acetone) .delta. 7.89 (d,
2H, J=8.1 Hz), 7.45 (d, 2H, J=8.2 Hz), 7.28 (m, 1 H), 7.13 (d, 1 H,
J=8.0 Hz), 6.97 (s, 1 H), 6.91 (d, 1 H, J=8. 0 Hz), 6.89 (d, 1 H,
J=6.7 Hz), 6.68 (d, 1 H, J=14.8 Hz), 4.94 (d, 1 H, J=15.0 Hz), 4.78
(m, 2H), 3.68 (s, 3H), 2.88 (m, 4H), 2.76 (q, 2H, J=7.5 Hz), 2.70
(m, 1 H), 2.29 (m, 1 H), 1.95 (m, 2H), 1.82 (m, 1 H), 1.50 (m, 8H),
1.26 (t, 3H, J=7.6 Hz).
Example 10
[0182] Preparation of Compound 47 33
[0183] Compound 47 was obtained by reacting Compound 99 with
3,3-dimethylacryloyl chloride in the presence of triethylamine as
described in Example 6 in 37% yield. Purification was accomplished
by flash column chromatography using 10:1 ethyl acetate: hexanes as
the eluent. .sup.1H NMR (300 MHZ, d.sub.6-acetone) .delta. 7.88 (d,
2H, J=8.3 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.26 (d, 1 H, J=8.6 Hz),
7.10 (d, 1 H, J=7.9 Hz), 6.96 (s, 1 H), 6.89 (d, 1 H, J=8.0 Hz),
6.71 (s, 1 H), 5.39 (s, 1 H), 4.98 (d, 1 H, J=15.1 Hz), 4.78 (m, 2
H), 3.71 (s, 3 H), 2.76(m, 4H), 2.30 (m, 1H), 2.09 (s, 3H), 1.82
(m, 1H), 1.63 (s, 3H), 1.25 (t, 3H, J=7.6 Hz).
Example 11
[0184] Preparation of Compound 2 34
[0185] To a stirred solution of Compound 100 (47 mg, 0.12 mmol) in
anhydrous tetrahydrofuran (8 mL) at OEC was added triethylamine
(0.03 mL, 0.21 mmol) followed by hydrocinnamoyl chloride (34 mg;
0.20 mmol). The reaction was allowed to stir for 21 hours slowly
warming to room temperature. The solvent was removed by rotary
evaporation and the residue was treated with ethyl acetate and
saturated aqueous sodium chloride solution. The organic layer was
separated, dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by flash column
chromatography on silica gel using 8:1:1 ethyl acetate:
dichloromethane:acetonitrile as the eluent to give Compound 2 (45
mg, 73%) as a white foam. .sup.1H NMR (300 MHZ, CDCl.sub.3) .delta.
8.36 (d, J=3.6 Hz, 1 H), 8.12 (s, 1 H), 7.78 (d, J=8.1 Hz, 2H),
7.53 (d, J=7.8 Hz, 1 H), 7.29 (d, J=8.1 Hz, 2H), 7.22-7.11 (m, 4H),
7.03-7.00 (m, 2H),6.55 (s, 1H), 6.48 (d, J=7.8 Hz, 1H), 5.91 (d,
J=9.3 Hz, 1H), 4.85-4.59 (m, 3H), 2.88-2.59 (m, 6H), 2.30-2.22 (m,
4H), 1.75-1.67 (m, 1 H), 1.25 (t, J=7.8 Hz, 3H) .sup.13C NMR (75
MHZ, CDCl.sub.3) .delta. 172.2, 149.7, 148.5, 144.5, 142.9, 141.0,
140.4, 138.6, 137.0, 133.1, 128.7, 128.6, 128.41, 128.35, 127.2,
126.27 125.8, 124.1, 123.7, 58.3, 50.4, 36.0, 34.7, 31.7, 29.7,
28.8, 15.2.
Example 12
[0186] Preparation of Compound 49 35
[0187] To a stirred solution of Compound 103 (49 mg, 0.13 mmol) in
anhydrous tetrahydrofuran (1 mL) at room temperature were added
triethylamine (0.028 mL, 0.20 mmol) and hydrocinnamoyl chloride
(0.024 mL, 0.16 mmol). After 24 hours, additional triethylamine
(0.028 mL, 0.20 mmol) and hydrocinnamoyl chloride (0.024 mL, 0.16
mmol) were added and the reaction mixture was allowed to stir an
additional 24 hours. The reaction was diluted with ethyl acetate
and the organic layer was washed with saturated aqueous sodium
bicarbonate solution, water, and saturated aqueous sodium chloride
solution. The organic was concentrated and the residue was purified
by flash column chromatography on silica gel using 2:1
hexanes:ethyl acetate as the eluent to give Compound 49 (40 mg,
58%) as a colorless oil.
[0188] .sup.1H NMR (300 MHZ, CDCl.sub.3) 6 (ppm): 8.63 (2 H, d,
J=4.9 Hz), 7.81 (2 H, d, J=8.3 Hz), 7.31-7.17 (8 H, m), 7.09 (1 H,
t, J=4.7 Hz), 7.01 (1 H, dd, J=1.7, 7.9 Hz), 6.91 (1 H, s), 5.02 (1
H, d, J=9 Hz), 4.82 (1 H, q, J=8.0 Hz), 3.06-2.63 (6 H, m), 2.71 (2
H, q, J=7.5 Hz), 2.35-2.25 (1 H, m), 1.78-1.71 (1 H, m), 1.26 (3 H,
t, J=7.5 Hz).
[0189] 13C NMR (75 MHZ, CDCl.sub.3) 8 (Ppm): 174.14, 161.34,
158.39, 143.61, 142.62, 141.15, 139.95, 138.31, 128.78, 128.68,
128.59, 128.51, 128.34, 127.27, 126.21, 125.76, 124.34, 117.69,
58.60, 38.67, 35.04, 31.63, 29.86, 28.85, 15.17.
[0190] BioAssays
[0191] The cloning, construction and testing of CHO cells that
express human voltage-gated potassium channels are described in
prior U.S. patent application Ser. No. 08/893,160 (published as WO
98/04521), as are assays measuring .sup.86rubidium efflux from cell
monolayers; fluorescence measurement of cell membrane potential;
electrophysiological studies and lymphocyte proliferation
studies.
[0192] The efficacy of various compounds of the present invention
as inhibitors of Kv1.5 are shown in Table 1 (using the known patch
clamp techniques cited above and described in detail in WO
98/04521, the disclosure of which is incorporated herein by
reference.
1 TABLE 1 % Inhibition Compound at 0.1 .mu.M (n2) 2 55 4 50 10 53
33 59 37 53 46 35 49 66 75 48 86 55 93 33 94 53 148 58 154 37 157
40
[0193] The principles, preferred embodiments and modes of operation
of the present invention have been described in the foregoing
specification. The invention which is intended to be protected
herein, however, is not to be construed as limited to the
particular forms disclosed, since they are to be regarded as
illustrative rather than restrictive. Variations and changes may be
made by those skilled in the art without departing from the spirit
of the invention. Those skilled in the art will recognize
variations in the processes as described above and will recognize
appropriate modifications based on the above disclosure for making
and using the compounds of the invention.
[0194] In the forgoing specification, the following abbreviations
are used:
2 Designation Reagent or Fragment m-CPBA meta-chloroperoxybenzoic
acid Me methyl Et ethyl NaBH.sub.4 sodium borohydride
CH.sub.2Cl.sub.2 dichloromethane SnCl.sub.2 tin (II chloride
dihydrate CDCl.sub.3 chloroform-d
* * * * *