Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-11-15
2002-04-23
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S305000
Reexamination Certificate
active
06376555
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel series of 4-substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation. Such disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
2. Description of the Prior Art
Modulation of potassium channels remains at the forefront of current approaches for controlling resting cell membrane potential and affecting cell excitability. A wide variety of discrete potassium channels exist and these have been thoroughly classified according to structure, function, pharmacological properties, and gating mechanisms in several recent reviews: Rudy, B.
Neuroscience
1988, 25, 729-749; Atwal, K.,
Medicinal Research Reviews
1992, 12, 569-591; Gopalakrishnan, M. et al.,
Drug Development Research
1993, 28, 95-127; Primeau, J. et al.,
Current Pharmaceutical Desian
1995, 1, 391-406; Edwards, G. et al.,
Exp. Opin. Invest. Drugs
1996, 5(11), 1453-1464. Therapeutic potential for potassium channel modulators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is being vastly explored.
A series of N-aryl and N-heteroaryl-1,2-diaminocyclobutene-3,4-diones disclosed by Butera et al., in U.S. Pat. Nos. 5,354,763; 5,397,790; 5,401,753; 5,403,853; 5,403,854; 5,466,712; 5,506,252 and 5,532,245 and additionally by Antane et al., in U.S. Pat. Nos. 5,464,867 and 5,512,585 have the ability to hyperpolarize smooth muscle tissue via activation of the ATP-dependent potassium channel (K
ATP
). Also disclosed is the potential utility of the N-aryl and N-heteroaryl-1,2-diaminocyclobutene-3,4-diones as useful agents for the treatment of cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder.
A series of 1,2-diamino derivatives of cyclobutene-3,4-diones disclosed by Butera et al., in U.S. Pat. No. 5,763,474 have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, hypertension, stroke and similar diseases which are amenable to treatment with potassium channel activating compounds.
Kinney et al., in U.S. Pat. No. 5,240,946 discloses 3,4-diamino-3-cyclobutene-1,2-diones as NMDA antagonists.
Algieri et al., in U.S. Pat. No. 4,390,701 discloses 1-(substituted-amino)-2-(amino or substituted amino)cyclobutene-3,4-diones which are histamine H
2
antagonists useful in the treatment of peptic ulcers. Additionally, Nohara, et al., in U.S. Pat. No. 4,673,747 disclose substituted aminoalkylphenoxy derivatives which exert antagonism against histamine H
2
receptors.
A series of p-substituted phenyl-cyclobutenediones are reported as substrates and intermediates for monothionation reactions by Muller et al.
Synthesis
1997, 1, 50-52. Related compounds are described by Schmidt et al.
Synthesis
1990, 7, 579-582 in a paper on Meerwein-arylation of semisquaric acids and semisquaric amides. Unsubstituted phenyl-cyclobutenediones are reported as reaction products between cyclobutenediones and aziridines by Ried et al.
Liebias Ann. Chem
. 1975, 1863-1872.
In an effort to generate multiple core structure libraries by combinatorial chemistry, P. A. Tempest et al.
J. Am. Chem. Soc
. 1997, 119, 7607-7608, using Wang resin, disclose a library of p-hydroxylated phenyl-cyclobutenediones which are prepared and cleaved from the Wang resin to afford hydroxylated phenyl-cyclobutenediones.
N-Substituted-3-amino-4-phenylcyclobutenediones are reported by J. E. Thorpe
J. Chem. Soc
. (B), 1534-1535(1968) in conjunction with proton nuclear magnetic resonance spectra studies of squaramides.
A series of p-halophenylcyclobutenediones disclosed as intermediates for the preparation of stilbene analogs which are described as having utility as non-linear optical elements with good heat and light resistance are reported in EP-0761643-A2. Additionally, Pu, in U.S. Pat. No. 5,106,997, and Nishikata et al., in U.S. Pat. Nos. 5,616,802, 5,659,085 and 5,811,552 and in JP-A-7-309819 disclose a series of cyclobutenedione derivatives useful for the preparation of nonlinear optical elements.
A series of biphenylcyclobutenediones containing an additional heterocyclic ring as a substituent on the second phenyl ring of the bicyclic moiety and having utility as angiotensin II antagonists are reported in WO9401436-A1.
Additionally, 3-acyl-3-cyclobutene-1,2-diones are reported in several synthetic methodology papers: L. S. Liebeskind et al.
J. Org. Chem
. 1993, 58(13), 3543-3549; L. Sunset al.,
J. Org. Chem
. 1995, 60(25), 8194-8203.
The 4-substituted-3-disubstituted-amino-cyclobut-3-ene-1,2-diones described herein are useful in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation.
SUMMARY OF THE INVENTION
Accordingly, the present invention discloses compounds represented by Formula (I):
wherein:
R
1
, R
2
, and R
3
, are, independently hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen), cycloalkyl of 3 to 10 carbon atoms, —OR
7
, amino, alkylamino of 1 to 10 carbon atoms, —SO
3
H, —SO
2
NH
2
, —SONH
2
, —NHSO
2
R
7
,
—SO
2
R
7
, carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 12 carbon atoms;
A is a moiety selected from the group consisting of a bond, —CH
2
—, —CH═CH— and —CHCOR
6
; p
1
W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with —R
1
—R
2
and —R
3
.
R
4
is a alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms, nitro, halogen, cyano, —OR
7
,
trifluoromethyl or trifluoromethoxy;
R
5
is hydrogen, alkyl of 1 to 10 carbon atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms.
—SO
2
R
7
, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
R
6
is alkyl of 1 to 10 carbon or aryl of 6 to 12 carbon atoms;
R
7
is alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, —CF
3
, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
with the following provisos that A is not a bond and W is not a carbon bearing a hydrogen;
a) when R
1
and R
2
are H; R
3
is selected from the group consisting of: H, 4-methyl, 4-chloro, 4-nitro and 4-methoxy; and R
4
and R
5
are simultaneously methyl or ethyl;
b) when R
1
, R
2
, R
3
and R
5
are H; and R
4
is butyl;
c) when R
1
, R
2
and R
5
are H; R
3
is 4-halo (chloro, bromo, fluoro, or iodo) and R
4
is alkyl of 1 to 4 carbon atoms; and
d) when R
1
is selected from the group consisting of H, 2-methyl, 2-ethyl and 2-methoxy; R
2
and R
5
are H; R
3
is 4-dimethylamino and R
4
is 2-propyl;
or pharmaceutically acceptable salts thereof.
Preferred groups of compounds of Formula (I) of this invention are those in the subgroups:
a) compounds having the general formula:
wherein R
1
, R
2
, R
3
, R
4
, and R
5
are as hereinbefore defined;
b) compounds having the general formula:
wherein R
Butera John A.
Jenkins Douglas J.
Lennox Joseph R.
American Home Products Corporation
Davis Zinna Northington
Moran Daniel B.
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