Fused pyridopyridazine inhibitors of cGMP phosphodiesterase

Details Fused pyridopyridazine inhibitors of cGMP phosphodiesterase Fused pyridopyridazine inhibitors of cGMP phosphodiesterase

2000-03-15

2001-11-13

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S234000, C544S115000, C514S248000, C514S232800, C514S218000, C514S217050, C540S599000, C540S575000, C540S524000

Reexamination Certificate

active

06316438

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to fused pyridopyridazine compounds, to methods of using such compounds in the treatment of cGMP-associated conditions such as sexual dysfunction including erectile dysfunction and female sexual arousal disorder, to pharmaceutical compositions containing such compounds, and to intermediates for and methods of preparing 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 certain medicaments including some types of antihypertensive agents, digoxin, as well as the excessive use of narcotics, alcohol, tobacco, etc. 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) particularly, a selective inhibitor of cGMP PDE Type 5 (cGMP PDE 5), 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).
Female sexual arousal is part of the female sexual response cycle, and is characterized by increased vaginal lubrication, and increased clitoral and labial engorgement and sensation. Studies suggest a potential role for nitric oxide as a mediator of clitoral cavernosal and vaginal wall smooth muscle relaxation. Recently, PDE5 has been isolated in human clitoral smooth muscle culture. Therefore, a selective inhibitor of cGMP PDE5 provides means to restore diminished physiological arousal changes and improve subjective parameters of arousal in both pre- and post-menopausal women.
The present invention provides novel compounds which are potent and selective inhibitors of cGMP PDE 5. These compounds may be employed in the treatment of sexual dysfunction including erectile dysfunction and female sexual arousal disorder. In view of their activity, these 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
The present invention is directed to the fused pyridopyridazine compounds of the formula I and salts thereof, for use as inhibitors of cGMP PDE, especially Type 5,
wherein:
Y is nitrogen or —C(R
5
)—;
Z is nitrogen or —C(R
6
)— provided that at least one of Y and Z is nitrogen;
R
1
and R
2
are independently selected from the group consisting of hydrogen, chloro, —SR
7
, —OR
7
, —NR
8
R
9
, and
with the proviso that at least one of R
1
or R
2
is —SR
7
, —OR
7
, —NR
8
R
9
or
R
3
is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl;
R
4
is hydrogen, halogen, alkyl, substituted alkyl, —OR
10
, or —NR
11
R
12
;
R
5
and R
6
are independently selected from the group onsisting of hydrogen, halogen, alkyl, and substituted alkyl;
R
7
, R
8
, and R
9
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclo, heterocycloalkyl, heteroaryl and heteroarylalkyl;
R
8
and R
9
together with the N atom to which they are attached can form a heterocyclo ring, a substituted or unsubstituted imidazole, a substituted or unsubstituted pyrazole, or a substituted or unsubstituted triazole;
R
10
, R
11
and R
12
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclo, heterocycloalkyl, heteroaryl and heteroarylalkyl;
R
13
is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclo, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
DETAILED DESCRIPTION OF THE INVENTION
The following are definitions of the terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The term “alkyl” refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most preferred. The term alkyl when used at the end of a term, i.e. cycloalkylalkyl, arylalkyl, heterocycloalkyl, refers to a straight or branched chain carbon bridge of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and most preferably 1 to 4 carbon atoms such as
The term “alkoxy” refers to an alkyl group as defined above bonded through an oxygen (—O—). The term “alkylthio” refers to an alkyl group as defined above bonded through a sulfur (—S—).
The term “cycloalkyl” refers to fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7, carbon atoms as well as such rings having a fused aryl ring such as indan.
The term “substituted cycloalkyl” refers to such rings having one, two or three substituents, preferably one, selected from the group consisting of alkyl, alkoxy, alkylthio, halo, hydroxy, cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)
2
,
carboxy, —CO
2
-lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclo, heterocycloalkyl, heteroaryl, heteroarylalkyl, keto, ═N—OH, ═N—O-lower alkyl, and a five or six membered ketal, i.e 1,3-dioxolane or 1,3-dioxane.
The term “substituted alkyl” refers to an alkyl group as defined above having one, two or three substituents selected from the group consisting of halo, amino, cyano, —(CH
2
)
m
-hydroxy, alkoxy, alkylthio, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)
2
,
carboxy and —CO
2
-alkyl.
The term “halo” refers to chloro, bromo, fluoro and iodo.
The term “aryl” refers to phenyl, 1-naphthyl and 2-naphthyl, with phenyl being preferred. The term “substituted aryl” refers to such rings having one, two or three substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, halo, hydroxy, nitro, cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)
2
, carboxy, —CO
2
-alkyl,
—NH—CH
2
-carboxy, —NH—CH
2
—CO
2
-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, heterocyclo, heterocycloalkyl, heteroaryl, and heteroarylalkyl, as well as pentafluorophenyl.
The term “heterocyclo” refers to substituted and unsubstituted saturated or partially saturated 3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups and 10 to 15 membered tricyclic gr

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