Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-03
2001-09-11
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S383000, C514S410000, C548S252000, C548S266400, C548S421000
Reexamination Certificate
active
06288099
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to a series of substituted tetracyclic heteroaromatic benzofuranoindoles and indenoindoles 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 Design
1995, 1, 391-406; Edwards, G. et al.
Exp. Opin. Invest. Drugs
1996, 5 (11), 1453-1464]. Activation of these channels augments transmembrane K
+
flux, thus effecting hyperpolarization of the cell membrane towards the Nernst K
+
equilibrium potential (−90 mV), and subsequent closure of the voltage-gated Ca
2+
channels. As a result, the hyperactive cell becomes less excitable and therefore less prone to further stimulation; thus leading to relaxation in the case of smooth muscle. As a result of this pharmacologic action, therapeutic potential for potassium channel activators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is being vastly explored.
A series of heterotetracyclic methylamnino benzofuranoindoles compounds are reported by Bair, K. W., in WO 91/14688 and EP-447703-A1 and are useful as antitumor and biocidal agents.
An example disclosed is 2-methyl-2-(((10-methyl- 10
H
-benzofuro(3,2-
b
)indol-6-yl)methyl)amino)-1,3-propanediol.
A series of indenoindoles claimed as useful medicinal antioxidants and free-radical scavengers are disclosed by Sainsbury et al. in EP-404536-A1.
A series of indenoindoles useful as a component in an organic electroluminescent element are disclosed in JP-06-228554.
X is —O—, —S, -, SO
2
-, or —NR
9
A related series of tetrahydro indeno-indole analogs is disclosed by Sainsbury, M. in WO 90/15799 and in EP-409410-B1.
These compounds are also claimed as useful antioxidants for the treatment of atherosclerosis, thrombosis, embolism and Parkinson's disease.
The synthesis and antioxidant properties of a series of indeno-indoles and indolines are reported in several papers [Brown, D. W. et al.,
Tetrahedron
1991, 47 (25), 4383-4408; Brown, D. W. et al.,
Tetrahedron
1993, 49 (39), 8919-8932; Graupner, P. R. et al.,
Tetrahedron Lett.
1995, 36 (32) 5827-5830; Shertzer, H. G. et al.,
Fd. Chem. Tox.
1991, 29 (6) 391-400]. Reported also by Brown, F. C. et al.,
Tetrahedron Lett.
1991, 32 (6) 801-802 are flash-vacuum pyrolysis methods for the synthesis of substituted indeno[1,2-b]indoles.
The present invention differs from the prior art by requiring the Z substituent, defined below as a carboxylic acid moiety, a bioisosteric equivalent of a carboxylic acid, or a derivative thereof to be substituted at position a of the tetracyclic heteroaromatic benzofuranoindoles and indenoindoles of Formulae (I) and (II). The compounds of this invention have reported potassium channel activation and the resulting smooth muscle relaxing properties are uniquely tissue-selective for bladder tissue.
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, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen), amino, alkylamino of 1 to 10 carbon atoms, —SO
3
H, —SO
2
NH
2
, —NHSO
2
R
14
,
R
15
SO
2
-, carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, 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;
Y is —O— and-NR
4
;
X is —O—, when Y is —NR
4
;
X is —NR
4
, when Y is —O—;
R
4
is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, 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 and arylalkylsulfonyl of 7 to 12 carbon atoms;
R
5
and R
6
are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine;
Z substituted at position a is selected from the group consisting of
M is an alkali metal cation or an alkaline earth metal cation;
R
7
is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
R
8
and R
9
are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
R
10
, R
11
, R
12
and R
13
are independently, alkyl of 1 to 10 carbon atoms;
R
14
is a straight chain alkyl of 1 to 10 carbon atoms;
R
15
is a straight chain 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 alkylamnino of 1 to 10 carbon atoms;
provided that R
1
, R
2
and R
3
are not hydrogen when Z is —CHO, Y is —O— and X is —N—CH
3
;
or a pharmaceutically acceptable salt thereof.
A preferred aspect of this invention includes compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroup below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a) Y is —NR
4
when X is —O—;
More preferred aspects of this invention includes compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
Z is —CO
2
H;
R
1
is halogen or nitro;
a) X is —O—, when Y is —NR
4
; and
b) X is —NR
4
, when Y is —O—;
Specifically preferred compounds of this invention according to general Formula (I) are the following compounds or a pharmaceutically acceptable salt thereof:
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Iodo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Chloro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Nitro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid dihydrate;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methyl ester;
(8-Bromo-10H-benzo[4,5]furo[3,2-b]indol-1-yl)-methanol;
8-Bromo-10H-benzo[4,5&
Antane Schuyler A.
Butera John A.
Lennox Joseph R.
American Home Products Corporation
Moran Daniel B.
Stockton Laura L.
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