Compositions and methods for modulating sexual activity

Details Compositions and methods for modulating sexual activity Compositions and methods for modulating sexual activity

1998-07-08

2002-06-04

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S252120, C514S252010, C514S247000

Reexamination Certificate

active

06399618

ABSTRACT:

TECHNICAL FIELD
The present invention is generally directed to N-alkylpiperazino derivatives of substituted acetic acids and pharmaceutical compositions thereof, to the preparation of such compounds and compositions, and to the use of such compounds and compositions to enhance sexual performance, as pro-libido agents and/or for the treatment and/or prevention of sexual dysfunction in male and/or female animals.
BACKGROUND OF THE INVENTION
At the present time there is a wide variety of pharmacological agents used and/or reportedly useful as pro-libido agents and/or for the treatment of sexual dysfunction. Some examples include: serotonin receptor agonists and antagonists (see, e.g., EP 385,658; WO 94/15,920; GB 2,248,449; and GB 2,276,165), dopamine receptor agonists (see, e.g., WO 93/23,035; WO 94/21,608; Pomerantz S. M., Pharmacol.
Biochem. Behav.
39:123-128, 1991; and Ferrari F. et al.
Psychopharmacology
113:172-176, 1993); adrenergic receptor agonists (see, e.g., WO 95/13,072; EP 611,248; U.S. Pat. No. 5,229,387; and WO 92/11,851); inhibitors of phoshodiesterase (see, e.g., DE 4,338,948; and WO 94/28,902); histamine receptor agonists (see, e.g., U.S. Pat. Nos. 4,013,659; 4,126,670; 4,767,778; WO 91/17,146; U.S. Pat. No. 5,047,418; and EP 0,458,661); neuropeptide Y antagonists (see, e.g., WO 95/00,161); angiotensin II receptor antagonists (see, e.g., EP 577,025); cholinesterase inhibitors (see, e.g., U.S. Pat. Nos. 5,177,070; and 4,633,318); combinations of agents with the different types of biological activity (see, e.g., U.S. Pat. No. 5,145,852; and WO 95/05,188); derivatives of vasoactive intestinal peptide (see, e.g., U.S. Pat. No. 5,147,855; EP 540,969; and EP 463,450); prostaglandins (see, e.g., WO 93/00,894; and EP 459,3770); antidepressants and antipsychotics (see, e.g., U.S. Pat. No. 4,931,445; GB 2,448,449; and Naganuma et al.
Clin. Exp. Pharm. Physiol.
20:177-183, 1993); nitric oxide donors (see, e.g., WO 92/21,346; DE 4,305,881; DE 4,212,582; and WO 94/16,729); calcitonin gene related peptide (see, e.g., Steif, C. G. et al.,
Urology,
41:397-400, 1993); and androgens (see, e.g., JP 06,211,675; HU 62,473; and WO 94/16,709).
Many or all of these pharmacological agents are associated with adverse effects, some examples of which are quoted below. Dopamine receptor agonists may aggravate schizophrenia or induce it de novo in some patients. Serotonin receptor agonists are capable of producing an effect that has been termed “serotonin syndrome” (Glennon, R. A.
J. Med. Chem.
30:1-9,1987). This latter effect has been thoroughly investigated in animals (Peroutka, S. J.
Science
212:827-829, 1981; Goddwin G. M. et al.,
Br. J. Pharmacol.
84:743-753, 1985; and Tricklebank, M. D.,
Eur. J. Pharmac.
117:15-24, 1985) and manifests itself in, for example, head twitches, “wet dog shakes”, forepaw treading, flat body posture, hind limb abduction, Straub tail and yawning. Histamine receptor agonists may induce central nervous system dysfunction and adverse effects in the endocrine system. Smooth muscle relaxants (such as papaverine) may induce pain, echytomosis and occasional episodes of priapism. &agr;-Adrenoreceptor blockers administered systemically have been reported to induce priapism characterized by a persistent erection that cannot be relieved by sexual intercourse or masturbation (Kaisary, A. V. et al.,
Br. J. Urol.
68:227, 1986).
Accordingly there is a need in the art to identify new pharmacological agents, compositions and/or treatments which are useful as pro-libido agents and/or are useful in the treatment and/or prevention of sexual dysfunction in males or females, and/or can enhance a patient's sexual performance. The present invention fulfills these needs and further provides related advantages.
SUMMARY OF THE INVENTION
Briefly, one aspect of the invention provides compounds of formula (I)
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence:
Ar is selected from a C
3
-C
13
carbocyclic ring, and ring systems selected from formulae (II), (III), (IV), (V), (VI), and (VII):
where R
7
, R
8
and R
9
are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C
2
-C
7
alkanoyloxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
2
-C
7
alkoxycarbonyl, C
1
-C
6
thioalkyl, aryl and N(R
15
,R
16
) where R
15
and R
16
are independently selected from hydrogen, acetyl, methanesulfonyl, and C
1
-C
6
alkyl;
where R
10
and R
11
are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C
2
-C
7
alkanoyloxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
2
-C
7
alkoxycarbonyl, C
1
-C
6
thioalkyl, and N(R
15
,R
16
) where R
15
and R
16
are independently selected from hydrogen, acetyl, methanesulfonyl, and C
1
-C
6
alkyl;
where R
12
is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C
2
-C
7
alkanoyloxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
2
-C
7
alkoxycarbonyl, C
1
-C
6
thioalkyl, and N(R
15
,R
16
) where R
15
and R
16
are independently selected from hydrogen, acetyl, methanesulfonyl, and C
1
-C
6
alkyl;
including isolated enantiomeric, diastereomeric, tautomeric and geometric isomers thereof, and mixtures thereof;
L is selected from the group of a direct bond, O, NH, and N(C
1
-C
6
alkyl);
R
1
is selected from the group of a direct bond, a C
1
-C
6
alkylene group, (such as —CH
2
— and —CH
2
CH
2
—), and 1,2-disubstituted C
5
-C
6
cycloalkyl; and
R
2
is C
1
-C
6
alkyl.
Another aspect of the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent in combination with a compound of formula (I):
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, having the definition set forth above.
Another aspect of the invention provides a method for treating and/or preventing sexual dysfunction in a male or female patient, where the method includes the step of administering to the patient in need thereof an amount of a compound of formula (I) or composition therefrom,
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, having the definition set forth above, and where the amount is effective to treat and/or prevent the sexual dysfunction. The sexual dysfunction may be, for example, male erectile dysfunction or impotence.
Another aspect of the invention provides a use of a compound for manufacture of a medicament for treating and/or preventing sexual dysfunction in a male or female patient, wherein the compound is of formula (I)
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above. The sexual dysfunction may be, for example, male erectile dysfunction or impotence.
Another aspect of the invention provides a method for increasing the libido of a male or female patient, where the method includes the step of administering to a male or female in need thereof an effective amount of a compound, or composition therefrom, of formula (I)
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above, and where the amount is effective to increase the libido of the patient.
Another aspect of the invention provides a use of a compound, or composition therefrom, for manufacture of a medicament for increasing the libido of a male or female patient, wherein the compound is of formula (I)
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above.
Another aspect of the invention provides a method for enhancing the sexual performance of a male or femal

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