Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-11-10
2001-04-03
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S019300, C514S020800, C530S330000, C530S331000, C548S312100, C548S338100, C548S496000, C564S153000, C564S157000
Reexamination Certificate
active
06211156
ABSTRACT:
TECHNICAL FIELD
The present invention relates to peptides that can be administered to treat erectile dysfunction in male animals.
BACKGROUND OF THE INVENTION
The etiology of erectile dysfunction (ED) or impotence, is complex and it is usually divided into the primary or the more frequent secondary dysfunction.
The major cause of ED is vascular but other frequent causes include hormonal disorders, drug use and neurologic disorders.
Treatments for ED can be classified as central or peripheral initiators, central or peripheral conditioners and others. For a comprehensive review of the subject, with discussion on the role of neurotransmitters and neuropeptides, see A. Argiolas and M. R. Melis, Progress in Neurobiology, 47, 235-255 (1995). For classification of treatments, see J. P. W. Heaton et al., Int. J. Impotence Research 9, 115-121(1997).
Among neuropeptides that act centrally to induce penile erection, the best known are ACTH/MSH peptides and oxytocin. These centrally active peptides however are not specific in their action and cannot be used therapeutically because of their important side effects.
Non-peptidyl products are known to be useful for the treatment of ED. Among these, alprostadil (PGE
1
) is used topically, and apomorphine and sildenafil are administered by sublingual or oral application. All known agents are not devoid important drawbacks such as emetic properties (apomorphine) and cardiovascular side effects (sildenafil).
A treatment is clearly needed that is as specific as possible, causes a minimum of side effects and is easy to administer.
SUMMARY OF THE INVENTION
The present invention relates to the surprising finding that small peptides that do not belong to any of the previously known classes of peptides affecting penile erections can cause penile erections in male animals when injected into the paraventricular nucleus of the hypothalamus or when given systemically (intravenously or subcutaneously) to such animals.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In this description, the following abbreviations are used: D is the dextro enantiomer, Aib is &agr;-Aminoisobutyryl, TXM is tranexamyl (i.e. 4-(aminomethyl) cyclohexanecarbonyl), INIP is isonipecotinyl, GAB is &ggr;-aminobutyryl, IMA is imidazolylacetyl, Mrp is 2-methyl-Trp, &bgr;-Nal is &bgr;-(2-naphthyl) alanine, Trp is tryptophan, Phe is phenylalanine, Lys is lysine, Arg is arginine, H is hydrogen, and NH
2
is terminal amide.
The peptides which are useful in the present invention include those having the general formula:
X-A-B-C-Y-NH
2
in which:
X is Aib, TXM, INIP, GAB, H, or IMA;
A is D-Mrp, D-&bgr;Nal, or D-Trp;
B is D-Mrp, D-&bgr;Nal, D-Trp, or is not present;
C is D-Mrp, Phe, or is not present;
Y is Lys or Arg;
in which:
Preferred peptides of the present invention include:
GAB-D-Mrp-D-&bgr;Nal-Phe-Lys-NH
2
;
GAB-D-Mrp-D-Mrp-D-Mrp-Lys-NH
2
;
GAB-D-Mrp-D-&bgr;Nal-Phe-Arg-NH
2
; and
GAB-D-Mrp-D-Mrp-Lys-NH
2
.
Any pharmaceutically acceptable salts of the peptides of the present invention can be used, if desired. Such salts would include but are not limited to organic or inorganic addition salts such as, for example, hydrochloride, hydrobromide, phosphate, sulfate, acetate, succinate, ascorbate, tartrate, gluconate, benzoate, malate, fumarate, stearate, and pamoate salts.
The above peptides can be conveniently prepared according to the usual methods of peptide chemistry by solid phase synthesis using Fmoc-aminoacids (Fmoc is fluorenylmethoxy carbonyl) as described Atherton and Sheppard “
Solid Phase Peptide Synthesis
” (IRL Press at Oxford University Press, 1989), or in J. Jones “
The Chemical Synthesis of Peptides
” (Clarendon Press, Oxford, 1994).
The solid-phase synthesis starts from the C-terminal end of peptide. A suitable starting material can be prepared, for example, by attaching the required protected alpha-amino acid to a chloromethylated resin, a hydroxymethylated resin, a benzhydrylamine resin (BHA), or to a para-methylbenzhydrylamine resin (p-Me-BHA). As an example, an available chloromethylated resin is BIOBEADS® SX 1 by BioRad Laboratories, Richmond, Calif. The preparation of the hydroxymethyl resin is described by Bodansky et al., Chem. Ind. (London) 38, 15997 (1966). The BHA resin is described by Pietta and Marshall, Chem. Comm., 650 (1970) and is commercially available by Peninsula Laboratories Inc., Belmont, Calif.
After the starting attachment, the protecting group of the alpha-amino acid can be removed by means of different acid reagents, comprising trifluoroacetic acid (TFA) or hydrochloric acid (HCl) dissolved in organic solvents at room temperature. After the removal of the protecting group of the alpha-amino acid, the remaining protected amino acids can be coupled step by step in the desired order. Each protected amino acid can generally be reacted in excess of about three times using a suitable carboxyl activating group, such as dicyclohexylcarbodiimiide (DCC) or diisopropylcarbodiimide (DIC) dissolved, for example, in methylene chloride (CH2Cl2), dimethylformamide (DMF) or their mixtures. After the desired aminoacidic sequence has been completed, the desired peptide can be cleaved from the supporting resin by treatment with a reagent such as hydrogen fluoride (HF) which cleaves not only the peptide from the resin, but also the protecting groups of the lateral chains. When a chloromethylated resin or a hydroxymethylated resin is used, the treatment with HF leads to the formation of the terminal acid peptide in free form. When a BHA or p-Me-BHA resin is used, treatment with HF directly leads to the formation of the terminal amide peptide in free form.
The above peptides can be administered systemically, sublingually, buccally, orally intranasally, intrapulmonary or intraocularly at doses between 0.02 and 2 mg/kg of body weight appropriately formulated with pharmaceutically acceptable excipients or in the form of aqueous solutions or as solid powders in micronized form. Other dosage forms, though not specifically listed, are known to those skilled in the art and are within the scope of the present invention.
Medicaments useful for treating erectile dysfunction or for inducing an erection in a male animal including a human can comprise a peptide of the present invention or a pharmaceutically acceptable salt thereof, or combinations of peptides of the present invention or pharmaceutically acceptable salts thereof, optionally, in admixture with a carrier, excipient, vehicle, diluent, matrix, or delayed release coating. Examples of such carriers, excipients, vehicles, and diluents, can be found in Remingtons Pharmaceutical Sciences, 18
th
edition, A. R. Gennaro, Ed., Mack Publishing Company, Easton, Pa., 1990.
REFERENCES:
patent: 5576290 (1996-11-01), Hadley
patent: 5795957 (1998-08-01), Deghenghi
patent: 5807985 (1998-09-01), Deghenghi
patent: 5932548 (1999-08-01), Deghenghi
patent: 5955421 (1999-09-01), Deghenghi
patent: 6124263 (2000-09-01), Muccioli et al.
Argiolas Antonio
Deghenghi Romano
Asta Medica A.G.
Pennie & Edmonds LLP
Russel Jeffrey E.
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