Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-16
2003-11-04
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S251000
Reexamination Certificate
active
06642244
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pyrazolopyridopyrimidine compounds, to methods of using such compounds in treating 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 certain medicaments including some types of antihypertensive agents, digoxin, as well as the excessive use of narcotics, alcohol, tobacco, etc. Methods for treating 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 treating 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 (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 PDE 5 inhibitor useful for treating erectile dysfunction. See
Drugs of the Future,
22, 138-143 (1997).
Recent examples of other compounds claimed as PDE 5 inhibitors include fused pyridazine compounds (WO 96/05176 and U.S. patent application Ser. No. 09/393,833), anthranilic acid derivatives (U.S. Pat. No. 5,716,993), fused pyridopyridazine compounds (U.S. patent application Ser. No. 09/526,162), and quinazolinone compounds (U.S. Pat. No. 6,087,368).
The present invention provides compounds that are potent and selective inhibitors of cGMP PDE 5. These compounds may be employed in treating erectile dysfunction. In view of their activity, these compounds can also be employed in treating other disorders responding to the inhibition of cGMP PDE, such as various cardiovascular disorders.
SUMMARY OF THE INVENTION
The present invention provides pyrazolopyridopyrimidine compounds of the following formula (I) or salts thereof, for use as inhibitors of cGMP PDE, especially Type 5:
wherein:
R
1
is hydrogen, alkyl or substituted alkyl;
R
2
is hydrogen, halogen, —OR
5
or —NR
5
R
6
;
R
3
at each occurrence is selected from hydrogen, halogen, alkyl, substituted alkyl and —OR
7
;
R
4
is hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclo;
R
5
, R
6
and R
7
are independently selected from hydrogen, alkyl and substituted alkyl;
Y is —SO
2
— or —(C═O)—; and
n is 4.
The invention further provides pharmaceutical compositions adapted for use in treating cGMP-associated conditions comprising a pharmaceutically acceptable diluent or carrier and at least one compound of the formula (I) or salt thereof, wherein R
1
, R
2
, R
3
and R
4
are as defined above. The invention further provides methods for treating cGMP-associated conditions comprising administering to a mammal in need of such treatment a therapeutically-effective amount of one or more compounds of the formula (I) or salt thereof, wherein R
1
, R
2
, R
3
and R
4
are as defined above.
DETAILED DESCRIPTION OF THE INVENTION
The following are definitions of 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 “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, hydroxy, alkoxy, alkylthio, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)
2
, carbonyl, carboxy, —CO
2
-alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, or heterocycle. The term “substituted alkyl” also includes an alkyl group as defined above substituted with N(substituted alkyl) or N(substituted alkyl)
2
, or in other words, the groups (CH
2
)
n
NHR′ and (CH
2
)
n
NR′R″, wherein each of R′ and R″ comprises a substituted alkyl or form a heterocyclo ring.
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, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)
2
, carboxy, —CO
2
-lower alkyl, aryl, heterocyclo, heteroaryl, 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 “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 “aryl” includes such rings having from zero, one, two or three substituents, selected from the group consisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro, cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)
2
, carboxy, —(C═O)alkyl, —CO
2
-alkyl, cycloalkyl, substituted cycloalkyl, —(C═O)NH
2
, —(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)
2
, —NH—CH
2
-carboxy, —NH—CH
2
—CO
2
-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, heterocyclo, and heteroaryl.
The term “heterocyclo” refers to substituted and unsubstituted non-aromatic 3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heterocyclo group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Each heterocyclo group may be attached at any available nitrogen or carbon atom. Each heterocyclo group may contain one, two or three substituents selected from the group consisting of halo, amino, cyano, alkyl, substituted alkyl, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)
2
, alkoxy, alkylthio, hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, carboxy, —CO
2
-alkyl, cycloalkyl, substituted cycloalkyl, —(C═O)NH
2
, —(C═O)NH(alkyl
Bi Yingzhi
Macor John E.
Bristol-Myers Squibb Co.
Davis Stephen B.
LandOfFree
Pyrazolopyridopyrimidine inhibitors of cGMP phosphodiesterase does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pyrazolopyridopyrimidine inhibitors of cGMP phosphodiesterase, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyrazolopyridopyrimidine inhibitors of cGMP phosphodiesterase will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3173542