Fused pyridine inhibitors of cGMP phosphodiesterase

Details Fused pyridine inhibitors of cGMP phosphodiesterase Fused pyridine inhibitors of cGMP phosphodiesterase

1999-09-10

2001-12-04

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S212080, C514S218000, C514S228500, C514S234200, C514S253040, C514S278000, C540S527000, C540S575000, C544S061000, C544S127000, C544S362000, C546S020000, C546S120000

Reexamination Certificate

active

06326379

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to fused pyridine compounds, to methods of using such compounds in the treatment of cGMP-associated conditions such as erectile dysfunction, and to pharmaceutical compositions containing such compounds.
BACKGROUND OF THE INVENTION
Erectile dysfunction is the inability to obtain and maintain a penile erection sufficient for sexual intercourse or other sexual expression. A number of factors can place an individual at risk for this disorder, for example, trauma, pelvic surgery, hypercholesterolemia, ischemic heart disease, peripheral vascular disease, chronic renal failure, diabetes, or the use of medicaments such as certain antihypertensive medications or digoxin, or illicit drugs, cigarettes or alcohol. Methods for the treatment of erectile dysfunction include the use of vacuum devices and penile implants, as well as the administration of medicaments such as yohimbine, papaverine and apomorphine. Improved methods for the treatment of this disorder are sought, however, as the aforementioned methods do not provide sufficient efficacy, and/or are accompanied by drawbacks or side effects such as erosion, pain, priapism or gastrointestinal discomfort.
As penile erection is dependent upon the presence of adequate levels of cyclic guanosine 3′, 5′-monophosphate (cGMP), especially in corpora cavernosa tissue, administration of an inhibitor of a cGMP phosphodiesterase (cGMP PDE) (and particularly, a selective inhibitor of cGMP PDE Type V (cGMP PDE V)) provides a means for achieving and maintaining an erection, and therefore for treating erectile dysfunction. See Trigo-Rocha et al., “Nitric Oxide and cGMP: mediators of pelvic nerve-stimulated erection in dogs,”
Am. J. Physiol
., Vol. 264 (February 1993); Bowman et al., “Cyclic GMP mediates neurogenic relaxation in the bovine retractor-penis muscle,”
Br. J. Pharmac
., 81, 665-674 (1984); and Rajfer et al., “Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission,”
New England J. Med
., 326, 2, 90-94 (January 1992). Sildenafil, for example, has been described as a phosphodiesterase Type V inhibitor useful for the treatment of erectile dysfunction. See
Drugs of the Future
, 22, 138-143 (1997).
The present invention provides novel compounds which are potent and selective inhibitors of cGMP PDE V which may be employed in the treatment of erectile dysfunction. In view of their activity, the present compounds can also be employed in the treatment of other disorders responding to the inhibition of cGMP PDE such as various cardiovascular disorders.
SUMMARY OF THE INVENTION
This invention is directed to the novel fused pyridine compounds of formulas I and II shown below including pharmaceutically acceptable salts thereof, pharmaceutical compositions containing one or more fused pyridines of formulas I and II, and the use of such compounds as inhibitors of cGMP PDE, especially type V.
This invention is also directed to the use of the fused pyridine compounds of formula III shown below including pharmaceutically acceptable salts thereof as inhibitors of cGMP PDE, especially type V.
In the above formulas:
E
1
is —O—R
1
, —S—R
1
, —NH—A
1
-cycloalkyl, —NH—A
1
-substituted cycloalkyl, —NH—A
1
-heterocyclo, or —NH—A
1
-heteroaryl.
E
2
is —NH—A
1
-alkoxy, —NH—A
1
—CO
2
alkyl,
 —NH—A
1
-aryl, or —NH—A
1
-substituted aryl.
R
1
is —A
1
-cycloalkyl, —A
1
-subsituted cycloalkyl, —A
1
-alkoxy,
 —A
1
-aryl, —A
1
-substituted aryl, —A
1
-heterocyclo, or —A
1
-heteroaryl.
X
1
is —O—A
1
—R
2
, —O—R
9
, —N (R
9
) (R
10
),
 a monocylic ring
 a fused bicyclic ring
 or a spiro ring
X
2
is —O—A
1
—R
25
,
 a monocyclic ring
 a fused bicyclic ring
 or a spiro ring
X
3
is —O—R
9
, —O—A
1
—O—R
9
, —N(R
9
)(R
10
),
 or a monocyclic ring
A
1
is an alkylene or substituted alkylene bridge of 1 to 10 carbons.
Y is nitrogen or C(R
6
).
Z is nitrogen or C(R
7
) with the proviso that at least one of Y or Z is nitrogen.
R
3
is hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, substituted alkyl, —A
1
-aryl, —A
1
-substituted aryl, —A
1
-cycloalkyl, or —A
1
-substituted cycloalkyl.
R
6
and R
7
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, —A
1
-cycloalkyl, —A
1
-substituted cycloalkyl, —A
1
-aryl, A
1
-substituted aryl, —A
1
-heterocyclo, and A
1
-heteroaryl.
R
4
is hydrogen, —N(R
12
)(R
13
), —OR
12
or 1- or 3-imidazolyl.
A
2
is a direct bond, an alkylene or substituted alkylene bridge of 1 to 10 carbons, an alkenyl or substituted alkenyl bridge of 2 to 10 carbons having one or more double bonds, or an alkynyl or substituted alkynyl bridge of 2 to 10 carbons having one or more triple bonds.
R
2
is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclo, heteroaryl, cycloalkyl-A
3
-cycloalkyl, cycloalkyl-A
3
-substituted cycloalkyl, cycloalkyl-A
3
-aryl, cycloalkyl-A
3
-substituted aryl, cycloalkyl-A
3
-heterocyclo, cycloalkyl-A
3
-heteroaryl, substituted cycloalkyl-A
3
-cycloalkyl, substituted cycloalkyl-A
3
-substituted cycloalkyl, substituted cycloalkyl-A
3
-aryl, substituted cycloalkyl-A
3
-substituted aryl, substituted cycloalkyl-A
3
-heterocyclo, substituted cycloalkyl-A
3
-heteroaryl, aryl-A
3
-cycloalkyl, aryl-A
3
-substituted cycloalkyl, aryl-A
3
-aryl, aryl-A
3
-substituted aryl, aryl-A
3
-heterocyclo, aryl-A
3
-heteroaryl, substituted aryl-A
3
-cycloalkyl, substituted aryl-A
3
-substituted cycloalkyl, substituted aryl-A
3
-aryl, substituted aryl-A
3
-substituted aryl, substituted aryl-A
3
-heterocyclo, substituted aryl-A
3
-heteroaryl, heterocyclo-A
3
-cycloalkyl, heterocyclo-A
3
-substituted cycloalkyl, heterocyclo-A
3
-aryl, heterocyclo-A
3
-substituted aryl, heterocyclo-A
3
-heterocyclo, heterocyclo-A
3
-heteroaryl, heteroaryl-A
3
-cycloalkyl, heteroaryl-A
3
-substituted cycloalkyl, heteroaryl-A
3
-aryl, heteroaryl-A
3
-heterocyclo, heteroaryl-A
3
-heteroaryl, cyano, —OR
9
, —SR
9
, —(C═O)R
9
, —N(R
9
)(R
10
), —CO
2
R
9
, —(C═O)N(R
12
)(R
13
), —SO
2
N(R
12
)(R
13
), —NR
11
(C═O)R
19
, —NR
11
(C═O)N(R
12
)(R
13
), —O—(C═O)N(R
12
)(R
13
) provided that A
2
is not a direct bond, —NR
11
CO
2
R
19
, —(C═O)N(R
11
)CH
2
CO
2
R
19
, nitrogen when A
2
is alkynyl ending in a triple bond, or NH when A
2
is alkenyl ending in a double bond.
R
25
is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclo, heteroaryl, cycloalkyl-A
3
-cycloalkyl, cycloalkyl-A
3
-substituted cycloalkyl, cycloalkyl-A
3
-aryl, cycloalkyl-A
3
-substituted aryl, cycloalkyl-A
3
-heterocyclo, cycloalkyl-A
3
-heteroaryl, subsituted cycloalkyl-A
3
-cycloalkyl, substituted cycloalkyl-A
3
-substituted cycloalkyl, substituted cycloalkyl-A
3
-aryl, substituted cycloalkyl-A
3
-substituted aryl, substituted cycloalkyl-A
3
-heterocyclo, substituted cycloalkyl-A
3
-heteroaryl, aryl-A
3
-cycloalkyl, aryl-A
3
-substituted cycloalkyl, aryl-A
3
-aryl, aryl-A
3
-substituted aryl, aryl-A
3
-heterocyclo, aryl-A
3
-heteroaryl, substituted aryl-A
3
-cycloalkyl, substituted aryl-A
3
-substituted cycloalkyl, substituted aryl-A
3
-aryl, substituted aryl-A
3
-substituted aryl, substituted aryl-A
3
-heterocyclo, substituted aryl-A
3
-heteroaryl, heterocyclo-A
3
-cycloalkyl, heterocyclo-A
3
-substituted cycloalkyl, heterocyclo-A
3
-aryl, heterocyclo-A
3
-substituted aryl, heterocyclo-A
3
-heterocyclo, heterocyclo-A
3
-heteroaryl, heteroaryl-A
3
-cycloalkyl, heteroaryl-A
3
-substituted cycloalkyl, heteroaryl-A
3
-aryl, heteroaryl-A
3
-substituted aryl, heteroaryl-A
3
-heterocyclo, heteroaryl-A
3
-heteroaryl, cyano, —S—R
9
, —(C═O)R
11
, —CO
2
R
19
, —(C═O)N(R
12
)(R
13
), —SO
2
N(R
12
)R
13
), —NR
9
(C═O)R
10
, —NR
11
(C═O)N(R
12
)(R
13
), —O—(C═O)N(R
12
)(R
13
) provided that A
2
is not a direct bond, —NR
11
CO
2
R
19
, —(C═O)N(R
11
l)CH
2
CO
2
R
19
, nitrogen when A
2
is alkynyl ending in a triple bond, or NH when A
2
is alkenyl ending in

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