Quinoline inhibitors of cGMP phosphodiesterase

Details Quinoline inhibitors of cGMP phosphodiesterase Quinoline inhibitors of cGMP phosphodiesterase

2003-04-14

2004-12-28

Desai, Rita (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S134000

Reexamination Certificate

active

06835737

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to quinoline 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, the use of certain medicaments including some types of antihypertensive agents, digoxin, or 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.
A penile erection is dependent upon the presence of adequate levels of cyclic guanosine 3′,5′-monophosphate (cGMP), especially in corpora cavernosa tissue. Thus, administering 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 used in treating other disorders responding to the inhibition of cGMP PDE, such as various cardiovascular disorders.
SUMMARY OF THE INVENTION
The present invention provides quinoline compounds of the following formula (I) or salts thereof, for use as inhibitors of cGMP PDE, especially Type 5:
wherein:
R
2
, R
6
, R
7
and R
8
are independently hydrogen, halogen, alkyl, substituted alkyl, alkoxy, nitro, cyano, aryl, heteroaryl, or heterocyclo;
R
3
is —(CH
2
)
z
Y, wherein z is 0, 1, 2, or 3;
R
4
and R
5
(i) are independently hydrogen, alkyl, substituted alkyl, cycloalykl, substituted cycloalkyl, aryl, or heteroaryl, with the proviso that R
4
and R
5
are not both hydrogen; or (ii) taken together form a heterocyclo ring;
Y is selected (i) independently from —OR
9
, —CO
2
R
9
, —CH(CO
2
R
9
)
2
, —O(C═O)NR
10
R
11
, —NR
10
R
11
, —NR
10
(C═O)NR
11
R
12
, —CH[(C═O)NR
10
R
11
]
2
, —(C═O)NR
10
R
11
, —NR
10
(C═O)R
12
, —S(O)
m
R
9
, —SO
2
NR
10
R
11
, imidazole, substituted imidazole, triazole, substituted triazole, or cyano, or (ii) together with one of R
4
and R
5
to form a heterocylo ring therewith;
m is 0, 1, or 2;
R
9
is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, or pentafluorophenyl; and
R
10
, R
11
, and R
12
(i) are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl; or (ii) taken together wherein R
10
forms a three- to seven-membered heterocyclo ring with R
11
or R
12
, or R
11
forms a three- to seven-membered heterocyclo ring with R
12
.
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
2
and R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
and R
12
are as defined above and R
3
is selected from hydrogen and —(CH
2
)
z
Y, with the proviso that at least one of R
2
, R
3
, R
6
, R
7
, and R
8
is not hydrogen. 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
2
and R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
and R
12
are as defined above and R
3
is selected from hydrogen and —(CH
2
)
z
Y, with the proviso that at least one of R
2
, R
3
, R
6
, R
7
, and R
8
is not hydrogen.


REFERENCES:
patent: 3362954 (1968-01-01), Surrey et al.
patent: 4343804 (1982-08-01), Munson, Jr. et al.
patent: 4840972 (1989-06-01), Effland et al.
patent: 5296484 (1994-03-01), Coghlan et al.
patent: 5482941 (1996-01-01), Terrett
patent: 5488055 (1996-01-01), Kumar et al.
patent: 5576322 (1996-11-01), Takase et al.
patent: 5716993 (1998-02-01), Ozaki et al.
patent: 6002008 (1999-12-01), Wissner et al.
patent: 6087368 (2000-07-01), Macor et al.
patent: 6316438 (2001-11-01), Yu et al.
patent: 0336544 (1989-10-01), None
patent: 0480052 (1992-04-01), None
patent: 2258855 (1975-08-01), None
patent: 11-80156 (1999-03-01), None
patent: WO94/22855 (1994-10-01), None
patent: WO96/05176 (1996-02-01), None
patent: WO98/07430 (1998-02-01), None
patent: WO98/08848 (1998-03-01), None
patent: WO98/16514 (1998-04-01), None
patent: WO98/47874 (1998-10-01), None
patent: WO99/43674 (1999-09-01), None
patent: WO00/09506 (2000-02-01), None
patent: WO01/21642 (2001-03-01), None
patent: WO01/68186 (2001-09-01), None
Nasr M et al. Journal of Medicinal Chemistry 1978 vol. 21 No 3.*
Jain P. C. et al Substituted Alkylamino . . . 1968 Div of Med Chem.*
Savini et al., Il Farmaco, 48 (6) pp. 805-825 (1993).
Eggert et al., Arch. Pharm. (Weinheim) 323 pp. 611-617 (1990).
Marecki et al., American Pharmaceutical Asso., Journal of Pharmaceutical Sciences, vol. 73, No. 8, pp. 1141-1143 (1984).
Jain et al., J. of Medicinal Chemistry, American Chemical Soc., vol. 11, No. 1 pp. 87-92 (1968).
Wright et al., J. of Medicinal Chemistry, American Chemical Soc., vol. 14, No. 11 pp. 1060-1066 (1971).
Terrett et al., Bioorganic & Medicinal Chemistry Letters, vol. 6, No. 15, pp. 1819-1824 (1996).
Elworthy et al., J. Med. Chem. vol. 40, pp. 2674-2687 (1997).
Ife et al., American Chemical Society, pp. 3413-3422 (1992).

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