Apomorphine derivatives and methods for their use

Details Apomorphine derivatives and methods for their use Apomorphine derivatives and methods for their use

2001-03-29

2003-01-14

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S034000, C514S080000, C546S077000, C546S078000

Reexamination Certificate

active

06506765

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to apomorphine derivative compounds; pharmaceutically active compositions of apomorphine derivative compounds; and the use of apomorphine derivative compounds in methods for treating sexual dysfunction or for enhancing apomorphine effectiveness for patients treated with apomorphine. The apomorphine derivatives may be esters, ethers, amides, mixed anhydrides, hemiacetals, glucuronates, sulfates or phosphonates. A preferred apomorphine derivative is norapomorphine.
BACKGROUND OF THE INVENTION
The human sexual response in both males and females results from a complex interplay of psychological, hormonal and other physiological influences. Efforts are ongoing to provide effective treatments which are convenient and simple to use, do not require a constant dosage regimen or even multiple doses to achieve desired results, are non-invasive and allow a rapid and predictable capacity for sexual function on demand and in response to normal sexual stimulation.
For males, methods involving various external devices for the treatment of impotence have been suggested such as tourniquets (see U.S. Pat. No. 2,818,855). In addition, penile implants, such as hinged or solid rods and inflatable, spring driven or hydraulic models, have been used for some time.
Drug treatments are also known. For example, U.S. Pat. No. 4,127,118 discloses a method of treating male impotence by local injection of an appropriate vasodilator, in particular, an adrenergic blocking agent or a smooth muscle relaxant to effect and enhance an erection, and U.S. Pat. No. 4,801,587 discloses the application of an ointment to relieve impotence. The ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and a carrier to assist absorption of the primary agent through the skin. U.S. Pat. No. 5,256,652 discloses the use of an aqueous topical composition of a vasodilator such as papaverine together with hydroxypropyl-&bgr;-cyclodextrin.
The effect of apomorphine on impotence, or male sexual dysfunction has been extensively studied and reported upon. However, apomorphine has been shown to have very poor oral bioavailability. See, for example, Baldessarini et al., in Gessa et al., eds.,
Apomorphine and Other Dopaminomimetics, Basic Pharmacology,
Vol. 1, Raven Press, N.Y. (1981), pp. 219-228.
Therefore, the efficacy of the use of apomorphine for treatment of sexual dysfunction is reduced by the problems of low bioavailability and undesirable side effects. An increased bioavailability leads to an increase in plasma concentration of the drug and an increase in undesirable side effects. Therefore, for the treatment of sexual dysfunction, use of apomorphine has to date been qualified by specific concentration parameters and/or methods of administration to overcome this problem.
For example, apomorphine has been disclosed for the amelioration of female sexual dysfunction in U.S. Pat. No. 5,945,117. Apomorphine has also been disclosed for the amelioration of male erectile dysfunction in U.S. Pat. Nos. 5,624,677; 5,888,534; 5,770,606; 5,985,889 and 5,994,363. In U.S. Pat. No. 5,624,677, mint flavoring may be added to the formulation to attenuate some of the local emesis receptors. In U.S. Pat. No. 5,888,534, a slow release sublingual tablet is disclosed. The slow release of the tablet is said to reduce the undesirable side effects of the drug. The adverse effects of apomorphine were minimized by gradual acclimatization to apomorphine as disclosed in U.S. Pat. No. 5,994,363. Apomorphine was disclosed for treatment of impotence in a fast release oral formulation when the patient was first pre-treated with domperidone in WO 98/31368. The treatment of erectile dysfunction with certain nasal formulations of apomorphine is disclosed in WO 99/27905. However there is still a need for effective treatments of sexual dysfunction.
It is therefore an object of this invention to provide an effective treatment for sexual dysfunction.
It is a further object of this invention to provide a method for enhancing use of apomorphine, when apomorphine is used to treat patients with Parkinson's disease or sexual dysfunction, among other maladies.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of the structure
wherein n is an integer of from one to four;
R
1
is selected from the group consisting of hydrogen, alkyl, —PO
3
H
2
, —SO
3
H, and glucuronyl; and,
R
2
at each occurrence is independently selected from the group consisting of hydrogen, alkyl, —PO
3
H
2
, —SO
3
H and glucuronyl;
or a pharmaceutically acceptable salt thereof.
Preferably, the compound is of the structure
wherein R
1
is selected from the group consisting of hydrogen, alkyl, —PO
3
H
2
, —SO
3
H and glucuronyl; and
R
3
and R
4
are each independently selected from the group consisting of hydrogen, alkyl, —PO
3
H
2
, —SO
3
H and glucuronyl;
or a pharmaceutically acceptable salt thereof.
The invention is also directed to pharmaceutical compositions comprising a compound of Formula I in a pharmaceutically acceptable carrier.
The invention is also directed to a method of treating sexual dysfunction in a patient in need of such treatment comprising administering a therapeutically effective amount of at least one compound of Formula I to said patient. The compound may be an apomorphine derivative which is an ester, ether, amide, mixed anhydride, hemiacetal, glucuronate, sulfate or phosphonate. In the method, apomorphine or a pharmaceutically acceptable salt thereof may also be administered to said patient. A presently preferred compound is norapomorphine.
The invention is also directed to a method for enhancing apomorphine effectiveness in a patient treated with apomorphine comprising the step of co-administering a therapeutically effective amount of a combination of at least one compound of Formula I with apomorphine to said patient. The compound may be an apomorphine derivative which is an ester, ether, amide, mixed anhydride, hemiacetal, glucuronate, sulfate or phosphonate. In the method, apomorphine or a pharmaceutically acceptable salt thereof may also be administered to said patient. A presently preferred compound is norapomorphine.
Presently preferred apomorphine derivatives include apomorphine N-glucuronide, apomorphine O-glucuronide, apomorphine O-sulfate, apomorphine N-sulfate, norapomorphine, norapomorphine O-glucuronide, norapomorphine N-glucuronide, norapomorphine O-sulfate, norapomorphine N-sulfate and combinations thereof. For the practice of the method, the patients may be those treated for Parkinson's disease or sexual dysfunction.
When the method is used for the treatment of sexual dysfunction and the patient is male, the therapeutically effective amount may be an amount sufficient to induce an erection adequate for vaginal penetration. Alternatively, if the patient is female the therapeutically effective amount may be an amount sufficient to induce clitoral erectogenesis and vaginal engorgement. In the methods, apomorphine may administered intranasally, orally, sublingually or administered by inhalation to the lungs.
DETAILED DESCRIPTION OF THE INVENTION
Definitions of Terms
The term “alkyl” as used herein alone or in combination refers to C
1
-C
12
straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a C
x
-C
y
designation. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.
The term “glucuronyl” as used herein refers to a group of the general structure —C(O)(CH(OH))
4
—CO
2
H. Glucuronyl derivatives (or glucuronides) are obtained by reacting glucuronic acid through the aldehyde moiety with the compound to be derivatized. Alcohol or amine functionalities on a compound may be glucuronidated.
Use of the above terms is meant to encompass substituted and unsubstituted moieties. Substitution may be by

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