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`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
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`May 09, 2000
`
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`APPLICATION NUMBER: 60/123,244
`FILING DATE: March 08, 1999
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`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
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`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53 (0).
`
`Given Name (first and middle [Ii any])
`Elizabeth
`Joanne
`
`lNVENTOFt(S)
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`
`Stoner
`Waldstreicher
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`CASE NUMBER
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`2°G15PV
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`Residence (City and Either State or Foreign Country)
`Westfleld, New Jersey
`Scotch Plains, New Jersey
`
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`
`[3 Additional inventors are being named on the___ separately numbered sheets attached hereto
`TITLE OF THE INVENTION (280 characters max)
`METHODS AND COMPOSITONS FOR TREATING ERECTILE DYSFUNCTION
`
`CORRESPONDENCE ADDRESS
`
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`Merck & Co., Inc.
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`DATE
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`0002
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`FILING FEE
`AMOUNT ($)
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`0002
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`
`
`«W
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`‘
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`20315PV
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`
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`TITLE OF THE INVENTION
`
`METHODS AND COMPOSITIONS FOR TREATING ERECTILE
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`DYSFUNCTION
`
`FIELD OF THE INVENTION
`
`The present invention provides for novel methods for the
`
`treatment of erectile dysfunction comprising a drug combination. More
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`particularly, the drug combination of the present invention comprises
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`an agonist of the melanocortin receptor with a cyclic—GMP-specific
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`phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist.
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`The present invention also provides for pharmaceutical compositions
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`comprising such drug combinations useful in the methods to treat
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`erectile dysfunction. Moreover, the present invention provides for a
`method of manufacture of a medicament useful in the treatment of
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`erectile dysfunction.
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`BACKGROUND OF THE INVENTION
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`Erectile dysfunction denotes the medical condition of
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`inability to achieve penile erection sufficient for successful sexual
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`intercourse. The term “impotence” is oftentimes employed to describe
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`this prevalent condition. Approximately 140 million men worldwide,
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`and, according to a National Institutes of Health study, about 30 million
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`American men suffer from impotency or erectile dysfunction. It has
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`been estimated that the latter number could rise to 47 million men by the
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`year 2000. Erectile dysfunction can arise from either organic or
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`psychogenic causes, with about 20% of such cases being purely
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`psychogenic in origin. Erectile dysfunction increases from 40% at age
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`40, to 67% at age 75, with over 75% occurring in men over the age of 50.
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`In spite of the frequent occurrence of this condition, only a small
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`number of patients have received treatment because existing treatment
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`alternatives, such as injection therapies, penile prosthesis implantation,
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`and vacuum pumps, have been uniformly disagreeable [for a discussion,
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`see “ABC of sexual health - erectile dysfunction,” Brit. Med. J. 318: 387-
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`390 (1999)]. Only more recently have more viable treatment modalities
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`become available, in particular orally active agents, such as sildenafil
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`citrate, marketed by Pfizer under the brand name of Viagra®. Sildenafil
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`is a selective inhibitor of type V phosphodiesterase (PDE-V), a cyclic-
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`GMP-specific phosphodiesterase isozyme [see R.B. Moreland _ej:_a_l. ,
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`“Si1denafil: A Novel Inhibitor of Phosphodiesterase Type 5 in Human
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`Corpus Cavernosum Smooth Muscle Cells,” Life Sci., 62: 309-318 (1998)].
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`Prior to the introduction of Viagra on the market, less than 10% of
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`patients suffering from erectile dysfunction received treatment.
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`Sildenafil is also being evaluated in the clinic for the treatment of female
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`sexual dysfunction.
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`The regulatory approval of Viagra® for the oral treatment of
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`erectile dysfunction has invigorated efforts to discover even more
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`effective methods to treat erectile dysfunction. Several additional
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`selective PDE—V inhibitors are in clinical trials. UK-114542 is a sildenafil
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`backup from Pfizer with supposedly improved properties.
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`IC-351 (ICOS
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`Corp.) is claimed to have greater selectivity for PDE-V over PDE-VI than
`sildenafil. Other PDE—V inhibitors include M-54033 and M-54018 from
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`Mochida Pharmaceutical Co. and E-4010 from Eisai Co., Ltd.
`
`Other pharmacological approaches to the treatment of
`
`erectile dysfunction have been described [see, e.g., “Latest Findings on
`
`the Diagnosis and Treatment of Erectile Dysfunction,” Drug News &
`
`Perspectives, 9: 572-5 75 (1996); “Oral Pharmacotherapy in Erectile
`
`Dysfunction,” Current Opinion in Urology, 7: 349-353 (1997)]. Aproduct
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`under clinical development by Zonagen is an oral formulation of the
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`alpha-adrenoceptor antagonist phentolamine mesylate under the brand
`
`name of Vasomax®. Vasomax® is also being evaluated for the
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`treatment of female sexual dysfunction.
`
`Drugs to treat erectile dysfunction act either peripherally or
`
`centrally. They are also classified according to whether they “initiate” a
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`sexual response or “facilitate” a sexual response to prior stimulation [for
`
`a discussion, see “A Therapeutic Taxonomy of Treatments for Erectile
`
`Dysfunction: An Evolutionary Imperative,” Int. J. lm otence Res., 9:
`
`115-121 (1997)]. While sildenafil and phentolamine act peripherally and
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`are considered to be “enhancers” or “facilitators” of the sexual response
`
`to erotic stimulation, sildenafil appears to be efficacious in both mild
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`organic and psychogenic erectile dysfunction. Sildenafil has an onset of
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`action of 30-60 minutes after an oral dose with the effect lasting about 4
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`hours, whereas phentolamine requires 5-30 minutes for onset with a
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`duration of 2 hours. Although sildenafil is effective in a majority of
`
`patients, it takes a relatively long time for the compound to show the
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`desired effects. The faster-acting phentolamine appears to be less
`effective and to have a shorter duration of action than sildenafil. Oral
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`sildenafil is effective in about 70% of men who take it, whereas an
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`adequate response with phentolamine is observed in only 35-40% of
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`patients. Both compounds require erotic stimulation for efficacy. Since
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`sildenafil indirectly increases blood flow in the systemic circulation by
`
`enhancing the smooth muscle relaxation effects of nitric oxide, it is
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`contraindicated for patients with unstable heart conditions or
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`cardiovascular disease, in particular patients taking nitrates, such as
`
`nitroglycerin, to treat angina. Other adverse effects associated with the
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`clinical use of sildenafil include headache, flushing, dyspepsia, and
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`“abnormal vision,” the latter the result of inhibition of the type VI
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`phosphodiesterase isozyme (PDE—VI), a cyclic—GMP-specific
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`7)
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`phosphodiesterase that is concentrated in the retina. “Abnormal vision
`
`is defined as a mild and transient “bluish” tinge to vision, but also an
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`increased sensitivity to light or blurred vision. Moreover, since some
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`patients have developed a tolerance to prior phosphodiesterase
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`inhibitors, sildenafil may prove to have a similar outcome in some
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`percentage of patients when used over a long period of time.
`
`Synthetic melanocortin receptor agonists (melanotropic
`
`peptides) have been found to initiate erections in men with psychogenic
`
`erectile dysfunction [See H. Wessells _e1_a_l., “Synthetic Melanotropic
`
`Peptide Initiates Erections in Men With Psychogenic Erectile
`
`Dysfunction: Double-Blind, Placebo Controlled Crossover Study,” L
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`L_l;c_>l., 160: 389-393 (1998); Fifteenth American Peptide Symposium, June
`
`14-19, 1997 (Nashville TN)1 Activation of melanocortin receptors of the
`
`brain appears to cause normal stimulation of sexual arousal. In the
`
`above study, the centrally acting oumelanocyte-stimulating hormone
`
`analog, melanotan—II (MT-II), exhibited a 75% response rate, similar to
`
`results obtained with apomorphine, when injected intramuscularly or
`
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`0005
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`0005
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`subcutaneously to males with psychogenic erectile dysfunction. MT-II
`
`is a synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe-Arg-Trp—Lys]-
`
`NH2, which contains the 4-10 melanocortin receptor binding region
`
`common to oz-MSH and adrenocorticotropin, but with a lactam bridge.
`
`5 MT-II (also referred to as PT-14) (Erectide®) is presently in clinical
`
`development by Palatin Technologies, Inc. and TheraTech, Inc. as a
`
`non-penile subcutaneous injection formulation. An oral transmucosal
`
`delivery system for the drug is also being developed. It is considered to
`
`be an “initiator” of the sexual response. The time to onset of erection
`
`10 with this drug is relatively short (10-20 minutes) with a duration of
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`action approximately 2.5 hours. Adverse reactions observed with MT-II
`
`include nausea, flushing, loss of appetite, stretching, and yawning.
`
`Adverse effects associated with MT-II may be the result of
`
`the lack of selectivity of the compound for a particular melanocortin
`
`15
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`receptor subtype. To date, five melanocortin receptor subtypes have been
`
`cloned. Evidence has been presented suggesting that the erectogenic
`
`properties of melanocortin agonists are mediated via binding to the MC-
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`4R subtype. Whereas MC-3R is expressed in the brain, gut, and
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`placenta, the MC—4R subtype is uniquely expressed in the brain, and
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`20
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`inactivation has been found to cause obesity.
`Because of the unresolved deficiencies of the various
`
`pharmacological agents discussed above, there is a continuing need in
`
`the medical arts for improved methods and compositions to treat
`
`individuals suffering from psychogenic and/or organic erectile
`
`25
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`dysfunction. Such methods should have wider applicability, enhanced
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`convenience and ease of compliance, short onset of action, reasonably
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`long duration of action, and minimal side effects with few
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`contraindications, as compared to agents now available.
`
`It is therefore an object of the present invention to provide
`
`30 methods of treating erectile dysfunction which comprise the
`
`administration to a human subject in need thereof a centrally—acting
`
`agent that ‘initiates” an erectogenic response in combination with
`
`another centrally~acting agent or a peripherally—acting agent that
`
`“facilitates” or “enhances” the response to erotic ‘stimulation. The
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`35
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`human subject may be either male or female.
`
`-4.
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`0006
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`0006
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`20315PV
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`It is another object of the present invention to provide
`
`pharmaceutical compositions comprising the combination that are
`
`useful in the methods of the present invention.
`
`It is still a further object of the present invention to provide a
`method of manufacture of a medicament useful in the treatment of
`
`erectile dysfunction.
`
`SUMMARY OF THE INVENTION
`
`10
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`15
`
`The present invention provides for methods of treating
`
`erectile dysfunction in a human subject in need of such treatment
`
`comprising administration of a therapeutically effective amount of an
`
`agonist of the melanocortin receptor in combination with a
`
`therapeutically effective amount of a cyclic-GMP-specific
`
`phosphodiesterase inhibitor or an alpha—adrenergic receptor antagonist.
`
`Further, the present invention provides for pharmaceutical
`
`compositions useful in the methods of the present invention, as well as a
`method of manufacture of a medicament useful to treat erectile
`
`dysfunction.
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`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention is concerned with the combination of
`
`an agonist of the melanocortin receptor with a cyclic-GMP—specif1c
`phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist
`
`for the treatment of erectile dysfunction in a male or female human
`
`subject. This particular combination produces unexpectedly superior
`
`pharmacokinetic and pharmacodynamic results in the treatment of
`
`male or female erectile dysfunction. Thus, it is an object of the instant
`
`invention to describe the combination of the two drugs in the treatment of
`
`erectile dysfunction. In addition, it is an object of the instant invention to
`
`describe preferred embodiments within each category of compounds
`which are used as elements in the instant combination. It is a further
`
`object of this invention to describe compositions containing each of the
`
`compounds for use in the treatment of erectile dysfunction. It is a still
`
`further object of this invention to describe a method of manufacture of a
`
`medicament containing the present drug combination which is useful
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`0007
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`‘20315PV
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`for the treatment of erectile dysfunction. Further objects will become
`
`apparent from a reading of the following description.
`
`The instant combination for the treatment of erectile
`
`dysfimction contains as a first element an agonist of the melanocortin
`
`receptor. Representative agonists of the melanocortin receptor are
`
`disclosed in the following publications, which are incorporated by
`
`reference herein in their entirety:
`
`(1) M. E. Hadley egg, “Discovery and Development of Novel
`
`Melanogenic Drugs,” in Integration of Pharmaceutical Discove_1_'_v_ and
`
`Development: Case Studie , edited by Borchardt et al., Plenum Press,
`
`New York, 1998;
`
`(2) RT. Dorr, _(at_al_., “Evaluation of Melanotan-II, A Superpotent Cyclic
`
`Melanotropic Peptide in a Pilot Phase-I Clinical Study,” Life Sci., 58:
`
`1777-1784 (1996); and
`
`(3) R.A.H. Adan, “Identification of Antagonists for Melanocortin MC3,
`
`MC4, and MC5 Receptors,” European J. Pharmacol., 269: 331-337 (1994).
`
`Compositions and methods for the treatment of psychogenic
`
`erectile dysfunction comprising melanotropic peptides are disclosed in
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`U.S. Patent No. 5,576,290 and CA 2,158,425, which are incorporated by
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`reference herein in their entirety.
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`In the instant combination for the treatment of erectile
`
`dysfunction, the first element of the combination is an agonist of the
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`melanocortin receptor. In one embodiment of the combination of the
`
`present invention, the agonist of the melanocortin receptor is
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`melanotan—II (MT—II).
`
`In another embodiment of the combination of the present
`
`invention, the agonist of the melanocortin receptor is selective for the
`
`MC-4.-R subtype. Selective MC-4R agonists have been described, and
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`reference is made to the following disclosures, which are incorporated
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`30
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`by reference herein in their entirety:
`
`(1) C. Haskell-Luevano, et al., “Discovery of Prototype Peptidomimetic
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`Agonists at the Human Melanocortin Receptors MC1R and MC4R,”
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`J .Med. Chem., 40'. 2133-2139 (1997); and
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`(2) HB. Schioth, et al., “Discovery of Novel Melanocortin—4 Receptor
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`35v
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`Selective MSH Analogues,” Brit. J. Pharmacol., 124: 75-82 (1998).
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`-6-
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`0008
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`if21ii
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`In the instant combination for the treatment of erectile
`
`dysfunction, the second element of the combination is composed of either
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`a cyclic—GMP—specific phosphodiesterase inhibitor or an alpha-
`
`adrenergic receptor antagonist.
`
`In a further embodiment of the
`
`combination of the present invention, the second element of the
`
`combination is a cyclic—GMP-specific phosphodiesterase inhibitor
`
`selective for the type V phosphodiesterase isozyme (PDE—V).
`
`Representative PDE—V inhibitors are disclosed in the patent and
`
`scientific literature. The Pfizer pyrazolo[4,3-d]pyrimidin—7-one PDE—V
`
`inhibitors are disclosed in WO 94/28902; W0 96/16644; WO 96/16657; EP
`
`0,702,555; EP 0,463,756; CA 2,163,446; and US. Patent No. 5,250,534; all of
`
`which are incorporated by reference herein in their entirety. Sildenafil
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`is the generic name for 1—[4—ethoxy-(6,7-dihydro-1-methyl-7-oxo-3-propyl-
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`1I-I-pyrazolo[4,3-d]pyrimidin-5—yl)phenylsulfonyl]-4-methyl-piperazine.
`
`For a discussion of its efficacy in the treatment of male erectile
`
`dysfunction, reference is made to I. Goldstein $11., N. Engl. J. Med.,
`
`338: 1397-1404 (1998) and M. Boolell §_t_a_l., “Sildenafil: an orally active type
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`5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of
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`penile erectile dysfunction,” Int. J. Impotence Res., 8: 47-52 (1996).
`
`The ICOS Corp. tetracyclic PDE—V inhibitors are disclosed
`
`in WO 95/19978; WO 97/03675; and W0 97/1997 8; all of which are
`
`incorporated by reference herein in their entirety.
`
`IC—351 represents
`
`(6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl—6—(3,4-
`
`methylenedioxyphenyl)—pyrazino[2’,1’: 6,1]pyrido[3,4-b]indo1e-1,4-dione
`
`and is disclosed in WO 97/03675 for the treatment of impotence.
`
`The Mochida Pharmaceutical Co. pyridocarbazole series of
`
`PDE—V inhibitors, of which M—54018 and M-54033 are members, is
`
`disclosed in WO 97/45427, which is incorporated by reference herein in
`
`its entirety. Other structural classes of PDE—V inhibitors are disclosed
`
`in WO 98/16224 (E. Merck GmbH), WO 99/02161 (Forssmann), WO
`
`98/07430 (Eisai), and JP 8225541 (Eisai), all of which are incorporated by
`
`reference herein in their entirety.
`
`In a class of this embodiment of the present invention, the
`
`combination for the treatment of erectile dysfunction comprises an
`
`agonist of the melanocortin receptor and a PDE—V inhibitor selected from
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`the group consisting of sildenafil citrate, IC-351, M-54018, and M-54033.
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`In a subclass of this class of the present invention, the agonist of the
`
`melanocortin receptor is MT-II. In another subclass of this class of the
`
`present invention, the combination of the present invention comprises a
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`selective agonist of the melanocortin-4 receptor and a PDE-V inhibitor
`
`selected from the group consisting of sildenafil citrate, IC-351, M-54018,
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`and M-54033. An especially preferred combination is a selective agonist
`
`of the melanocortin-4 receptor (MC—4R) and sildenafil citrate.
`
`In another embodiment of the combination of the present
`
`invention, the second element of the combination is an alpha-adrenergic
`
`receptor antagonist. In a class of this embodiment of the present
`
`invention, the alpha-adrenergic receptor antagonist is selective for the
`
`alpha-2 receptor subtype. In a subclass of this class of the present
`
`invention, the alpha-2 receptor antagonist is yohimbine or delquamine.
`
`The efficacy of yohimbine in the treatment of psychogenic erectile
`
`dysfunction is reported in Lancet, pp. 42-43 (1987). Delquamine is an
`
`alpha adrenoreceptor antagonist, with a greater affinity for the alpha-2
`receptor subtype [see A. Morales et_a_11., “Oral and topical treatment of
`
`erectile dysfunction,” Urol. Clin. North Am., 22: 879-885 (1995)].
`
`In another subclass of this class of the present invention,
`
`the alpha-2 receptor antagonist is an arylquinolizine derivative disclosed
`
`in U.S. Patent Nos. 4,824,849 and 4,710,504, both of which are
`
`incorporated by reference herein in their entirety. In a subclass of this
`
`subclass of the present invention, the alpha-2 receptor antagonist is the
`
`benzofuroquinolizine analog, MK—912, disclosed in US. Patent No.
`
`4,824,849. MK-912 represents 1’,3’-dimethylspiro(1,3,4,5’,6,6’,7,12b-
`
`octahydro—2H-benzo[b]-furo[2,3-a]quinolizine)-2,4’-pyrimidin-2’—one and
`
`is a potent, orally active agent with a pharmacologic profile consistent
`
`With alpha-2 antagonism [see D.J. Pettibone, gag” “Pharmacological
`
`profile of a new potent and specific alphaz-adrenoceptor antagonist, L-
`
`657,743,” Naunyn-Schmiederberg’s Arch. Pharmacol., 336: 169-175
`
`(1987)]. The effect of the drug on penile erections i.n healthy male
`
`volunteers was observed by B.J. Gertz 91. and reported in _Q_liI_1_.
`
`Pharmacol. Then, 46: 566-575 (1989). An especially preferred
`
`10
`
`15
`
`20
`
`25
`
`30
`
`0010
`
`0010
`
`
`
`0011
`
`1.
`
`203 15PV
`
`combination is a selective agonist of the melanocortin-4 receptor (MC-4R)
`and MK—912.
`
`The instant combination of an agonist of the melanocortin
`
`receptor and a cyclic—GMP-specific phosphodiesterase inhibitor or an
`
`alpha-adrenergic receptor antagonist is useful in the therapeutic
`
`treatment of erectile dysfunction. Although the methods and
`compositions comprising drug combinations of the present invention are
`
`envisaged primarily for the treatment of male erectile dysfunction, they
`
`may also be useful for the treatment of female sexual dysfunction,
`
`including orgasmic dysfunction related to clitoral disturbances.
`
`The combination of an agonist of the melanocortin receptor
`
`and a cyclic-GMPvspecific phosphodiesterase inhibitor or an alpha-
`
`adrenergic receptor antagonist provides an unexpectedly superior effect
`
`in the treatment of erectile dysfunction. The combination provides for
`
`effective treatment of either psychogenic or organic erectile dysfunction
`
`in a greater percentage of the affected population than either element of
`
`the combination separately. The combination provides for a shorter
`
`onset of action and longer duration of action than either element of the
`
`combination separately. The combination also has fewer side effects and
`
`contraindications than either member of the combination separately.
`
`For use in medicine, the salts of the compounds of this
`
`invention refer to non—toxic "pharmaceutically acceptable salts." Other
`
`salts may, however, be useful in the preparation of the compounds
`
`according to the invention or of their pharmaceutically acceptable salts.
`
`Salts encompassed within the term "pharmaceutically acceptable salts"
`
`refer to non-toxic salts of the compounds of this invention which are
`
`generally prepared by reacting the free base with a suitable organic or
`
`inorganic acid. Representative salts include the following:
`
`Acetate, Benzenesulfonate, Benzoate, Bicarbonate,
`
`Bisulfate, Bitartrate, Borate, Bromide, Camsylate, Carbonate, Chloride,
`
`Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate,
`
`Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
`
`Glycollylarsanilate, I-Iexylresorcinate, Hydrabamine, Hydrobromide,
`
`Hydrochloride, I-Iydroxynaphthoate, Iodide, Isothionate, Lactate,
`
`Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
`
`10
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`20
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`35
`
`-9.
`
`
`
`0011
`
`
`
`Ix
`
`20315PV
`
`Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate,
`
`Nitrate, N—methylglucamine ammonium salt, Oleate, Oxalate, Pamoate
`
`(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
`
`Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate,
`
`Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
`
`Furthermore, Where the compounds of the invention carry an acidic
`
`moiety, suitable pharmaceutically acceptable salts thereof may include
`
`alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal
`
`salts, e.g., calcium or magnesium salts; and salts formed with suitable
`
`10
`
`15
`
`organic ligands, e.g., quaternary ammonium salts.
`
`The compounds of the present invention may have chiral
`
`centers and occur as racemates, racemic mixtures and as individual
`
`diastereomers, or enantiomers with all isomeric forms being included
`
`in the present invention. Therefore, where a compound is chiral, the
`
`separate enantiomers, substantially free of the other, are included
`
`within the scope of the invention; further included are all mixtures of
`
`the two enantiomers. Also included within the scope of the invention are
`
`polymorphs and hydrates of the compounds of the instant invention.
`
`The present invention includes Within its scope prodrugs of
`the compounds of this invention.
`In general, such prodrugsi will be
`
`20
`
`functional derivatives of the compounds of this invention which are
`
`readily convertible Q1 into the required compound. Thus, in the
`
`methods of treatment of the present invention, the term "administering"
`
`25
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`30
`
`shall encompass the treatment of erectile dysfunction with the
`
`compound specifically disclosed as an element of the combination or
`
`with a compound which may not be specifically disclosed, but which
`
`converts to the specified compound _i_I_1_ @ after administration to the
`
`patient. Conventional procedures for the selection and preparation of
`
`suitable prodrug derivatives are described, for example, in "Design of
`
`Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these
`
`compounds include active species produced upon introduction of
`
`compounds of this invention into the biological milieu.
`
`The term "therapeutically effective amount" shall mean
`
`that amount of a drug or pharmaceutical agent that Will elicit the
`
`-10-
`
`0012
`
`
`
`
`
`.ii...iiii:1iiH
`
`0012
`
`
`
`20315PV
`
`
`
`ii1:ii11
`
`
`
`biological or medical response of a tissue, system, animal or human that
`
`is being sought by a researcher or clinician.
`
`As used herein, the term "composition" is intended to
`
`encompass a product comprising the specified ingredients in the
`
`specified amounts, as Well as any product which results, directly or
`
`indirectly, from combination of the specified ingredients in the specified
`amounts.
`
`In the combination of the present invention, the agonist of
`
`the melanocortin receptor may be administered separately or in
`
`conjunction with the cyclic-GMP-specific phosphodiesterase inhibitor or
`
`the alpha—adrenergic receptor antagonist. In addition, the
`
`administration of one element of the combination of the present
`
`invention may be prior to, concurrent to, or subsequent to the
`administration of the other element of the combination.
`
`The elements of the combination of the present invention
`
`may be administered by oral, parenteral (e.g., intramuscular,
`
`intraperitoneal, intravenous or subcutaneous injection, or implant),
`
`buccal, nasal, vaginal, rectal, sublingual, or topical (e.g., ocular
`
`eyedrop) routes of administration and may be formulated, alone or
`
`together, in suitable dosage unit formulations containing conventional
`
`non-toxic pharmaceutically acceptable carriers, adjuvants and Vehicles
`appropriate for each route of administration.
`I
`
`The pharmaceutical compositions for the administration of
`
`the compounds of this invention may conveniently be presented in
`
`dosage unit form and may be prepared by any of the methods well known
`
`in the art of pharmacy. All methods include the step of bringing the
`
`active ingredient into association with the carrier which constitutes one
`
`or more accessory ingredients.
`
`In general, the pharmaceutical
`
`compositions are prepared by uniformly and intimately bringing the
`
`active ingredient into association with a liquid carrier or a finely divided
`
`solid carrier or both, and then, if necessary, shaping the product into the
`
`desired formulation.
`
`In the pharmaceutical composition the active
`
`object compound is included in the combination in an amount sufficient
`
`to produce the desired pharmacologic effect upon the process or
`
`10
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`25
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`35
`
`condition of erectile dysfunction..
`
`-11-
`
`0013
`
`0013
`
`
`
`20315PV
`
`
`
`
`iiI!ll
`
`The pharmaceutical compositions containing the active
`
`ingredient suitable for oral administration may be in the form of discrete
`
`units such as hard or soft capsules, tablets, troches or lozenges, each
`
`containing a predetermined amount of the active ingredient; in the form
`
`of a dispersible powder or granules; in the form of a solution or a
`suspension in an aqueous liquid or non—aqueous liquid; in the form of
`
`syrups or elixirs; or in the form of an oil-in—water emulsion or a water-
`
`in-oil emulsion. Compositions intended for oral use may be prepared
`
`according to any method known to the art for the manufacture of
`
`pharmaceutical compositions and such compositions may contain one
`
`or more agents selected from the group consisting of sweetening agents,
`
`flavoring agents, coloring agents and preserving agents in order to
`
`provide a pharmaceutically elegant and palatable preparation.
`
`Solid dosage forms for oral administration include
`
`capsules, tablets, pills, powders and granules.
`
`In such solid dosage
`
`forms, the active compounds are admixed with at least one inert
`
`pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
`
`Such dosage forms can also comprise, as is normal practice, additional
`
`substances other than inert diluents, e.g., lubricating agents such as
`
`magnesium stearate, In the case of capsules, tablets and pills, the
`
`dosage forms may also comprise buffering agents.
`
`Tablets containing the active ingredient in admixture with
`
`non-toxic pharmaceutically acceptable excipients may also be
`
`manufactured by known methods. The excipients used may be for
`
`example, (1) inert diluents such as calcium carbonate, lactose, calcium
`
`phosphate or sodium phosphate; (2) granulating and disintegrating
`
`agents, such as corn starch or alginic acid; (3) binding agents such as
`
`starch, gelatin or acacia; and (4) lubricating agents such as magnesium
`
`stearate, stearic acid or talc. The tablets may be uncoated or they may be
`
`coated by known techniques to delay disintegration and absorption in the
`
`gastrointestinal tract and thereby provide a sustained action over a
`
`longer period. For example, a time delay material such as glyceryl
`
`monostearate or glyceryl distearate may be employed. They may also be
`
`coated by the techniques described in the U.S. Pat. Nos. 4,256,108;
`
`10
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`30
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`-12-
`
`0014
`
`0014
`
`
`
`n20315PV
`
`
`
`10
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`15
`
`20
`
`25
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`30
`
`4,160,452; and 4,265,874 to form osmotic therapeutic tablets for controlled
`release.
`
`In some cases, formulations for oral use may be in the form
`
`of hard gelatin capsules wherein the active ingredient is mixed with an
`
`inert solid diluent, for example calcium carbonate, calcium phosphate
`
`or kaolin. They may also be in the form of soft gelatin capsules wherein
`
`the active ingredient is mixed with water or an oil medium, for example
`
`peanut oil, liquid parafiin, or olive oil.
`
`Liquid dosage forms for oral administration include
`
`pharmaceutically acceptable emulsions, solutions, suspensions, syrups,
`
`and elixirs containing inert diluents commonly used in the art, such as
`
`water. Besides such inert diluents, compositions can also include
`
`adjuvants, such as wetting agents, emulsifying and suspending agents,
`
`and sweetening, flavoring, and perfuming agents.
`
`Aqueous suspensions normally contain the active materials
`
`in admixture with excipients suitable for the manufacture of aqueous
`
`suspensions. Such excipients may be
`
`1)
`
`suspending agents such as sodium carboxymethyl-
`
`cellulose, methylcellulose, hydroXypropylmethyl-
`
`cellulose, sodium alginate, polyvinyl—pyrrolidone,
`
`gum tragacanth and gum acacia;
`
`(2)
`
`dispersing or wetting agents which may be
`
`(a)
`
`a naturally—occurring phosphatide such as
`
`lecithin,
`
`(b)
`
`a condensation product of an alkylene oxide
`
`with a fatty acid, for example, polyoxyethylene
`
`stearate,
`
`(c)
`
`a condensation product of ethylene oxide with a
`
`long chain aliphatic alcohol, for example,
`
`heptadecaethyleneoxycetanol,
`
`(d)
`
`a condensation product of ethylene oxide with a
`
`partial ester derived from a fatty acid and a
`
`hexitol such as polyoxyethylene sorbitol
`
`monooleate, or
`
`- 13-
`
`0015
`
`0015
`
`
`
`I
`
`2031‘-SPV
`
`
`
`x:
`
`ml!
`
`
`
`(e)
`
`a conde