DE4338948A1 - Treating erectile dysfunction without causing side-effects - Google Patents

Abstract

The use of phosphodiesterase III inhibitors (I) is claimed for treating erectile dysfunction.

Description

The invention relates to the use of inhibitors of Phosphodiesterase III (sPDE III) for the treatment of erectile Dysfunction.

The physiological information transfer for relaxation (Sagging) smooth muscle cells is caused by transfer agents blood (hormones) or nerves (neurotransmitters) causes. These neurotransmitters work within the smooth Muscle cell an increase in cAMP and cGMP, which is a Relaxation. cAMP and cGMP are in turn Phosphodiesterases (PDE) are broken down. Inhibitors of the PDE in turn decrease the breakdown of cAMP and cGMP, leading to an increase of these molecules within the cell and thereby one Relaxation of the smooth muscle cell leads. This is for example described by Torphy, and others in thorax 46, 512, 1991.

From this publication and from TIPS 12, 19, 1991 and Br. J. Pharmacol. 104, 471, 1991 is still a distinction the PDE into different sub-esterases, the specific ones Phosphodiesterases (sPDE), known. It is in five different sPDE differentiated, in the individual organs and Organ systems are distributed differently and depending on Distribution in the cell has different levels of effectiveness have. In the publications mentioned and in J. Histochem. Cytochem. 35, 72, 1987, J. Urol. 139, 1988 and J. Pharmacol. Exp. Therap. 247, 630, 1988 also the occurrence the different isoenzymes in various tissues discussed, including the presence of sPDE I in the ureter (Ureter).

About 5% of men in their 40s and 20% in their 60s  suffer from erectile dysfunction. By losing the Potency becomes the physical, mental and social Self-image of the man, especially the young man, shocked. Patients with chronic erectile dysfunction are unsettled in your sexuality and personality and to be regarded as sick.

Used to treat predominantly up to the 1970s Psychological causes were attributed to erectile dysfunction in addition to psychotherapy or testosterone Aphrodisiacs of controversial value used. Only through that Research into the physiology of the erection process has been done found that organic in more than 60% of patients Causes which cause erectile dysfunction, being autonomous Efferences from the parasympathetic part of the sacral marrow, Neurotransmitter, dilation of the penile arteries, relaxation of the cavernous spaces and constriction of the veins play a role. Vascular factors are the cause in over 70% of cases involved, such as pathological or arterial blood supplies abnormally increased venous outflow from the cavernous spaces. About 20% of neurogenic disorders are involved.

Oral therapy with these organically related dysfunctions vasoactive substances such as yohimbine, phenoxybenzamine, Terbutaline, Bethanechol, Levodopa, Verapamil or Theophyllin proved unsuccessful. In addition to using Prosthetic implantation or revascularization surgery an intra-cavernous injection of papaverine (Virag, Lancet, 2, 938, 1982), the α-receptor blocker phenoxybenzamine (Brindley, Br. J. Psychiatr., 143, 332, 1983) and one Combination of papaverine and the α-receptor blocker Phentolamine (Stief, Urologist A, 25, 63, 1986) as successful. The latter therapy method can be used independently by the patient perform and is also called erectile tissue Auto Injection Therapy (SKAT).

A disadvantage, however, has been found to be partially undesirable prolonged erection with the risk of priapism at the Use of papaverine, unwanted painfulness the use of phenoxybenzamine as well as a possible one  Cancerogenicity of this compound.

In animal experiments (cynomolgus), 1-2 Intra-cavernous papaverine injections weekly for 12 months extensive fibrosis of large parts of the erectile tissue found what is extremely negative in humans Long-term results would result from fibroization erection of the cavernous body is no longer possible.

The use of acetylcholine is only temporary Erection associated with strong systemic side effects and the injection of prostaglandin E₁ is due to the patient rejected to great pain.

The object of the invention was therefore to develop and manufacture of drugs for the treatment of neurogenic, arterial, neurotransmitter, myopathic, venous or psychogenic erectile dysfunction in mammals, preferred in humans, without the side effects mentioned.

It has now been found that there are three different sPDEs in the human corpus cavernosum (erectile tissue of the male limb), namely sPDE III, sPDE IV and sPDE V. Surprisingly, inhibition of sPDE III leads to relaxation of the corpus cavernosum even in the smallest doses. without noticeable effects on other organs in this dose were observed. Quazinone, an sPDE III inhibitor, as shown in FIG. 1, for example, has a markedly relaxing effect even at concentrations of 10 ^-5 mol / l, while the inhibitors of the other sPDE's do not yet have any noteworthy effect in these concentrations.

The invention therefore relates to the use of Inhibitors of sPDE III, preferably from

• 1. 6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one (Anagrelide),
• 2. [1,6-dihydro-2-methyl-6-oxo [3,4'-bipyridine] -5-carbonitrile (Milrinon),
• 3. 4-ethyl-5-isonicotinoyl-4-imidazolin-2-one (piroximone),
• 4. 4,5-dihydro-6- [2- (4-methoxyphenyl) -5-benzimidazolyl] -5-  methyl-3 (2H) -pyridazinone (pimobendan),
• 5. N-Cyclohexyl-4 - [- (1,2-dihydro-2-oxo-6-quinolyl) oxy] -N- methylbutyramide (cilostamide),
• 6. N- [4- (4,5-Dihydro-5-oxopyrazinyl) phenyl] acetamide (SKF 94120),
• 7. N-cyano-N'-methyl-N '' - [4- (1,4,5,6-tetrahydro-4-methyl-6- oxo-3-pyridazinyl) phenyl] guanidine (Siguazodan),
• 8. N-Cyclohexyl-N-methyl-4 - [(1,2,3,5-tetrahydro-2- oxoimidazo [2,1-b] quinazolin-7-yl) oxy] butanamide (Lixazinone),
• 9. 4,5-dihydro-6- [4- (1-imidazolyol) phenyl] -3 (2H) pyridazinone (Imazodan),
• 10. N-Hydroxy-5,6-dimethoxy-benzo (b) thiophene-2-carboximidamide (Org 30029),
• 11. N- [4- (1,6-Dihydro-6-oxo-3-pyridazinyl) phenyl] -N'-methyl urea (ICI 118233),
• 12. 6- [4- (difluoromethoxy) -3-methoxyphenyl] -3 (2H) pyridazinone (Zardaverine),
• 13. 6- (3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4,4-dimethyl-quinoline (EMD 54622),
• 14. 3,3-dimethyl-5- (1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl) -2- indolinone (indolidane),
• 15. 4-Methyl-5- [4- (methylthio) benzoyl] -4-imidazolin-2-one (Enoximon) and
• 16. (R) -6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazoline 2- (3H) -one (quazinone),

and their pharmacologically acceptable salts, for Manufacture of drugs for the treatment of erectile Dysfunctions in mammals, preferably in humans, as well the treatment of erectile dysfunction in mammals and Humans using sPDE III inhibitors.

The pharmacologically acceptable salts are more common Way by neutralizing the bases with inorganic or get organic acids. As inorganic acids come to Example hydrochloric acid, sulfuric acid, phosphoric acid or Hydrobromic acid, as organic acids for example Carboxylic, sulfonic or sulfonic acids such as acetic acid, tartaric acid, Lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, Fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-  Phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, Mandelic acid, citric acid, malic acid, salicylic acid, 3- Aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, Isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2- disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid in question.

In addition to the usual auxiliary, carrier and Additives an effective dose of sPDE III inhibitors or their salts for the treatment of said dysfunctions used. The dosage depends on the species, Body weight, age, individual condition and Application type.

Oral, intravenous, intracavernous or topical preparations in question. Latter are, for example, lotions, creams, solutions, gels, sprays, elastic liquid plasters, transdermal systems or Coatings for condoms.

Preparations for parenteral administration contain 0.5 µg to 1 mg, preferably 5 to 500 µg of the compounds of the general Formula II per dose unit and can be in separate Dosage unit forms such as B. ampoules or vials. Solutions of the active ingredient are preferably used, prefers aqueous solutions and especially isotonic solutions, but also suspensions. These injection forms can be used as Finished product can be made available or only directly before use by mixing the active compound to Example of the lyophilizate, optionally with other solid ones Carriers, with the desired solution or Suspensions are prepared.

The usual galenic ones are used for oral use Forms of preparation such as tablets, coated tablets, capsules, dispersible powders, granules, aqueous or oily Suspensions, syrups, juices or drops.

Solid dosage forms can be inert excipients and carriers  included, such as B. calcium carbonate, calcium phosphate, Sodium phosphate, lactose, starch, alginates, gelatin, guar rubber, magnesium or aluminum stearate, talc, silicone oil, or vegetable or animal fats and oils.

Liquid dosage forms can be sterilized and / or optionally auxiliaries such as preservatives, Stabilizers, wetting agents, penetrants, emulsifiers, Spreading agents, solubilizers, salts for regulating the osmotic pressure or for buffering and / or Viscosity regulators included.

Such additives are, for example, tartrate and citrate buffers, Ethanol, complexing agents (such as ethylenediamine tetraacetic acid and their non-toxic salts). Come to regulate the viscosity high molecular weight polymers such as liquid Polyethylene oxide, carboxymethyl celluloses, polyvinyl pyrrolidones, Dextrans or gelatin. Solid carriers are for example Starch, lactose, mannitol, methyl cellulose, talc, highly disperse Silicas, higher molecular fatty acids (such as stearic acid), Gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers (like polyethylene glycol).

Oily suspensions for parenteral or topical applications can be vegetable synthetic or semi synthetic oils like for example liquid fatty acid esters with 8 to 22 C- Atoms in the fatty acid chains, for example palmitin, laurin, Tridecyl, margarine, stearin, arachine, myristic, behen, Pentadecyl, linoleic, elaidic, brasidic, erucic or oleic acid, those with monohydric to trihydric alcohols with 1 to 6 carbon atoms such as methanol, ethanol, propanol, butanol, Pentanol or its isomers, glycol or glycerol esterified his. Such fatty acid esters are, for example commercially available miglyols, isopropyl myristate, isopropyl palmitate, Isopropyl stearate, PEG 6-capric acid, caprylic / capric acid ester of saturated fatty alcohols, polyoxyethylene glycerol trioleates, Ethyl oleate, waxy fatty acid esters such as artificial Duckling glandular fat, isopropyl coconut fatty acid, Oleic acid oleyl ester, oleic acid decyl ester, lactic acid ethyl ester,  Dibuthyl phthalate, adipic acid diisopropyl ester, polyol Fatty acid esters a. Silicone oils are also suitable different viscosity or fatty alcohols like Isotridexyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or Oleyl alcohol, fatty acids such as oleic acid. Farther Vegetable oils such as castor oil, almond oil, olive oil, Use sesame oil, cottonseed oil, peanut oil or soybean oil Find. The substances mentioned also have the properties a spreading agent, that is, it is a particularly good one Distribution on the skin.

As solvents, gelling agents and solubilizers come in Question water or water-miscible solvents. Suitable are, for example, alcohols such as ethanol or Isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, Polyethylene glycols, phthalates, adipates, propylene glycol, Glycerin, di- or tripropylene glycol, waxes, Methyl cellosolve, cellosolve, ester, morpholines, dioxane, Dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, Cyclohexanone etc.

Cellulose ethers can be used as film formers in both water and organic solvents can dissolve or swell and after drying a kind of film form, such as hydroxypropyl cellulose, Methyl cellulose, ethyl cellulose or soluble starches.

Mixed forms between gel and film formers are quite also possible. Ionic macromolecules in particular come here to use such. B. sodium carboxymethyl cellulose, Polyacrylic acid, polymethacrylic acid and their salts, Sodium amylopectin semiglycolate, alginic acid or propylene glycol Alginate as sodium salt, gum arabic, xanthan gum, guar Gum or carrageenan.

The following can be used as additional formulation aids: Glycerin, paraffin of different viscosity, Triethanolamine, collagen, allantoin, novantisol acid, Perfume oils.  

Also the use of surfactants, emulsifiers or wetting agents may be necessary for the formulation, such as Na- Lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-β- iminodipropionate, polyoxyethylated castor oil or sorbitan Monooleate, sorbitan monostearate, cetyl alcohol, lecithin, Glycerol monostearate, polyoxyethylene stearate, Alkylphenol polyglycol ether, cetyltrimethylammonium chloride or Mono / dialkyl polyglycol ether orthophosphoric acid monoethanolamine salts.

Stabilizers such as montmorillonites or colloidal silicas to stabilize emulsions or to prevent the Breakdown of active substances such as antioxidants, for example tocopherols or butylated hydroxyanisole, or Preservatives such as p-hydroxybenzoic acid esters can also for the preparation of the desired formulations may be required.

To promote penetration contain transdermal Formulations preferably organic, well tolerated by the skin Solvents such as ethanol, methylpyrrolidone, polyethylene glycol, Oleyl alcohol, octanol, linoleic acid, triacetin, propylene glycol, Glycerin, Solketal or Dimethylsulfoxid.

The manufacture, filling and sealing of the preparations takes place under the usual antimicrobial and aseptic Conditions. Also for topical or transdermal If possible, they are packaged in separate packages Dose units to facilitate handling, also here how in the case of parenteral forms, if necessary for reasons of stability by separate packaging of the active ingredients or their Combinations as a lyophilisate, optionally with solid ones Carriers, and the necessary solvents etc.

Example 1 - solution for injection

50 mg quazinone are mixed with 750 mg NaCl in distilled water dissolved, adjusted to pH 3.7 with 1N HCl and with distilled Make up to 100 ml of water and pack it in 0.5 ml ampoules.  

Example 2 - Solution for topical application

From 500 mg quazinone, 2 ml isopropyl myristate and 10 ml ethanol a solution for topical application is prepared and prepared Packed dose units of 2 ml each.

Example 3 - Spray

In a mixture of 3.5 ml Miglyol 812 and 0.08 g 200 µg quazinone are suspended in benzyl alcohol. These Suspension is filled into a container with a metering valve. There are now 5 ml of Freon 12 under pressure through the valve in the Container filled. By shaking the freon in the Miglyol-benzyl alcohol mixture dissolved.

The effectiveness of the pharmaceuticals for the teaching according to the invention is proven by the following pharmacological examinations:

Human corpus cavernosum freshly removed during the operation is cut into small strips (approx. 3 × 10 mm). These are then installed in a bath with a nutrient solution that ensures the survival of the organ strips. By coupling the organ strips to a sensor, changes in the length of the organ strip can be registered, and the effects of medications that are added to the organ bath nutrient solution can be examined based on the change in length (increase or decrease) of the organ strip. At the start of the experiment, the organ strips are z. B. contracted noradrenaline. After contraction of the organ strips has occurred, an inhibitor of a specific phosphodiesterase is then added to the organ bath solution in increasing doses (10 ^-7 , 10 ^-6 , 10 ^-5 etc. mol / l) and the relaxation triggered thereby is measured. The results obtained are essentially transferable to the whole organism, since human tissue has been used and the metabolic processes investigated in the whole organism run faster and therefore the medication works even faster.

1 shows the results of these organ bath tests  shown. There have been studies with specific inhibitors the sPDE III (Quazinon), the sPDE IV (Rolipram) and the sPDE V (Zaprinast) with 5 to 7 measurements for each Measuring points. From the illustration it can be seen that a Inhibitor of sPDE III already at much lower Concentrations leads to a more pronounced relaxation than that Inhibitors of the other sPDE's.

Evidence of whether a compound for the invention Purpose is d. H. is an inhibitor of sPDE III, takes place according to known methods, such as. B. described by Galwan et al., Arch. Pharmacol. 1990, 342, 221-227 or Nicholson, Br. J. Pharmacol., 1989, 79, 889-897, for example according to the following general method:

Fresh tissue obtained intraoperatively is homogenized and then ultracentrifuged. Then the supernatant pipetted off and chromatographed. Of the 100 fractions of 70 to 1000 mM (millimolar) are then 5 batches of 30 ul the enzyme preparation; each enzyme preparation one Fraction becomes radioactive with a) cAMP, b) radioactive labeled cGMP, c) radioactively labeled cAMP plus calcium plus calmodulin, d) radioactively labeled cGMP plus calcium plus Calmodulin or e) radioactively labeled cAMP plus cGMP plus calcium plus calmodulin added. After incubation and The reaction is terminated and centrifugation repeated Radioactivity of the samples measured. The determination of Radioactivity allows the calculation of enzyme activity in pmol / ml × min. The plot of the activity curve allows the Identification of fractions where the Phosphodiesterase activity is particularly high. The Phosphodiesterase activity of each peak shows one different composition with regard to the activity of the 5th different approaches. This special composition of the Phosphodiesterase activity allows an assignment to one specific phosphodiesterase (sPDE). An inhibitor of one sPDE is now the substance, its concentration, the necessary is to inhibit 50% of substrate hydrolysis (IC₅₀), in which relevant peak fraction, which is the specific  Contains phosphodiesterase at least 20 times smaller than with other peak fractions. Again, do this as above described, enzyme preparations prepared. Before incubation the enzyme batches according to a) to e) of the peak fractions now added the compound to be tested. The renewed Determination and application of the enzyme activity then allows according to the above definition the identification of a Substance as an inhibitor of specific phosphodiesterase.

Claims (2)

1. Use of inhibitors of phosphodiesterase III in the Treatment of erectile dysfunctions. 2. Use of anagrelide, milrinone, pimobendan, cilostamide, Siguazodan, Lixazinone, Imazodan, Zardaverin, Indolidan, Enoximon, Quazinon, SKF 94120, Org 30029, ICI 118233 or EMD 54622 or their pharmacologically acceptable salts according to Claim 1.