DE19919828A1 - Treating male or female sexual dysfunction, especially erectile dysfunction, using propentofylline or corresponding alcohol as selective phosphodiesterase V inhibitor - Google Patents

Abstract

1-(-5-Oxohexyl)-3-methyl-7-propyl-xanthine (I) and/or 1-(5-hydroxyhexyl)-3-methyl-7-propyl-xanthine (II) is used for the treatment of sexual dysfunction in males or females. The use of one or more of 1-(-5-oxohexyl)-3-methyl-7-propyl-xanthine of formula (I) and 1-(5-hydroxyhexyl)-3-methyl-7-propyl-xanthine of formula (II) (as the racemate or the S- or S-enantiomer) is claimed for the preparation of a medicament for the prophylaxis or therapetic treatment of functional disorders affecting sexual intercourse in mammals, including men and women. An Independent claim is included for the use of (I) and/or (II) for the preparation of medicaments for selectively inhibiting phosphodiesterase type V isoenzyme.

Description

Under erection, the swelling and hardening of erectile tissue is caused by Understanding blood congestion, such as the stiffness of the male limb. Under Erectile dysfunction is particularly the physical sexual arousal in men, that is, the lack of erection of the penis in the situation of sexual intercourse Roger that. Erectile dysfunction is understood as the inability of a man no erection of the penis during sexual intercourse or a sufficient one Maintain erection.

Korenman and Viosca (J Am Gematr Soc (April 1993); 41; 363-366) describe them Efficacy of oral pentoxifilline administration in the treatment of erection disorders. Effects were observed with a delay of approximately 2 weeks and attributed to the increased blood supply in the penis. It is known that for the Erection of the secondary cellular messenger cyclic guanosine monophosphate (cGMP) responsible is the guanylate cyclase soluble by stimulating the enzyme endogenous nitrogen monoxide (NO) is formed. (Bush, P.A. et al. (1993) Circulation 87: V30-V32). Inhibitors of the phosphodiesterase isoenzyme type V, the preferentially breaks down the messenger cGMP, have been shown to be effective for the treatment of Erectile dysfunction has been demonstrated (Boolell, M. et al. (1996) Brit. J. Urol. 78: 257-261). Because it inhibiting cGMP degradation leads to a cGMP-increasing effect simultaneous administration of sildenafil and nitrates or NO donors is contraindicated. This can then lead to a hypotonic crisis (Laufs and Erdmann; Dtsch med Wschr; 123 (1998); 1562-1565).

Disadvantage of the known inhibitors of cGMP phosphodiesterase, isoenzyme of Type V is the vasodilation and hypotension that is exacerbated by exogenous NO unfavorable conditions leads to death.  

The invention aims at specific inhibitors of cGMP degrading Phosphodiesterase, type V isoenzyme, found to be essentially none Have increased effectiveness through exogenous NO.

The task is accomplished by providing certain xanthine derivatives, especially 1- (5-oxohexyl) -3-methyl-7-n-propyl-xanthine and 1- (5-hydroxyhexyl) -3-methyl-7-n-propyl- xanthine solved.

The invention therefore relates to the use of at least one compound of the formula I.

or at least one compound of the formula II,

wherein the compound of formula II is present as a racemate or as an S or R enantiomer, for the manufacture of a medicament for the prophylactic or curative treatment of Erectile dysfunction in male mammals, including males.

1- (5-Oxohexyl) -3-methyl-7-propylxanthine are very particularly preferred (Compound of the formula I, which is also known under the name propentofylline) and / or 1- (5-hydroxyhexyl) -3-methyl-7-n-propyl-xanthine (compound of the formula II) as  Racemate and / or as enantiomer R - (-) - 1- (5-hydroxyhexyl) -3-methyl-7-n-propyl-xanthine or mixtures thereof used according to the invention.

The compounds of formula I and formula II are by known methods manufactured (US 3,737,433; US 4,108,995; US 4,289,776; US 5,407,815; US 5,478,831). The starting materials of the manufacturing processes and implementations are known and can be easily produced by methods known from the literature. Mammals include, in particular, pets and animals living in the country and Cattle farming or kept in zoological gardens, for example, dogs, Cats, horses, monkeys, sheep, goats, cattle or pigs.

The invention also relates to medicaments for the treatment of erectile dysfunction at least an effective amount of a compound of formula I or at least one Compound of formula II, wherein the compound of formula 11 as a racemate or as S- or R enantiomer is present, in addition to pharmaceutically suitable and physiological compatible carriers, diluents and / or other active and Contain auxiliaries.

The invention also relates to methods of producing a medicament for treatment of erectile dysfunction characterized by having at least one Compound of formula I or II with a physiologically acceptable carrier and other suitable active ingredients, additives or auxiliaries in a suitable dosage form brings.

The invention further relates to the use of at least one compound of the formula I. or at least one compound of formula II, wherein the compound of formula II as Racemate or as an S or R enantiomer, for perfection, refinement or increase erectile ability in men. This application is not on the therapeutic use and does not apply to erectile dysfunction, especially not the use for the treatment of erectile dysfunction in Man. This application affects the man who does not have erectile dysfunction and a normal ability to swell and solidify erectile tissue  and the man who will increase his physical well-being and well-being would like to improve his quality of life.

Although the invention primarily involves the use of at least one compound of the Formula I or at least one compound of formula II, wherein the compound of Formula II is present as a racemate or as an S or R enantiomer, for the preparation of a Medicinal product to treat erectile dysfunction in men or for Perfection, refinement or increase in erectile ability in men concerns, the above-mentioned compounds are also for prophylactic or curative Treatment of female dysfunction during intercourse, in particular malfunctions of the female erectile organ.

The invention further relates to the use of at least one compound of the formula I. or at least one compound of formula II, wherein the compound of formula II as Racemate or as an S or R enantiomer, for perfection, refinement or increase the excitability of the female erectile organ. This application is focused on non-therapeutic use and does not affect use in female dysfunction during intercourse, especially not the Use for the treatment of functional disorders of the erectile organ in the Mrs. This application affects women who are not dysfunctional Intercourse suffers and a normal swelling and ability Solidification of erectile tissue and the woman showing her physical Wants to increase well-being and well-being in order to improve their quality of life.

The invention further relates to the use of at least one compound of Formula I or at least one compound of formula II, wherein the compound of Formula II is present as a racemate or as an S or R enantiomer, to increase the Erectile ability in male mammals. This application comes in particular in the breeding of pets, in the breeding of animals in the area of or animal husbandry or for the conservation of species in zoological gardens.  

Suitable solid or liquid pharmaceutical preparation forms for the above Uses are, for example, granules, powders, coated tablets, tablets, (Micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions as well as preparations with protracted release of active substances, in the case of which Production of customary auxiliaries, such as carriers, explosives, binders, coatings, swellings, Lubricants or lubricants, flavors, sweeteners or solubilizers, Find use. As commonly used auxiliaries such. B. magnesium carbonate, Titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, Cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and Solvents such as sterile water and mono- or polyhydric alcohols, e.g. B. Called glycerin. The suppositories are preferably hydrogels or xerogels, containing block copolymers of methacrylic acid and methyl methacrylates, who have a long stay in the rectum.

The above galenical forms of preparation become parenteral, oral, rectal or optionally applied topically, in particular orally or rectally. The rectal Application leads to the rapid reaching of sufficient blood levels of the above Compounds of formula I and II.

The galenical preparation forms mentioned are preferably in dosage form units manufactured and administered, each unit being an active ingredient contains a certain dose of at least one compound of formula I or II. With fixed Dosage units such as tablets, capsules, coated tablets or suppositories is this Dose up to about 1000 mg, but preferably about 100 mg to 600 mg, and at Injection solutions in ampoule form up to 300 mg, preferably 20 mg to 200 mg. For the treatment of a patient (70 kg) is an intravenous in the early phases Infusion treatment indicated from 100 mg to 2000 mg per day. In the later Treatment phase is oral or rectal administration of 3 times 300 mg or 400 mg per day, particularly indicated by 1- (5-oxohexyl) -3-methyl-7-propylxanthine. Oral or rectal administration from 1 to 3 are for non-therapeutic use times 200 mg to 500 mg per day, especially 1- (5-oxohexyl) -3-methyl-7- propylxanthine, sufficient.  

However, higher or lower doses may also be appropriate. The The dose can be administered either as a single dose or as a single dose Dosage unit or several smaller dosage units as well Multiple doses are divided at certain intervals.

The advantage of the compounds of the formula I and II used according to the invention is a high selective inhibition of the cGMP-degrading phosphodiesterase, isoenzyme of type V, while the predominantly cyclic adenosine monophate (cAMP) degrading phosphodiesterase, isoenzyme of type III, only at significantly higher concentrations of the compounds of the formula I and II is inhibited. It is also advantageous that the activity of the compounds of the formula I and II is not significantly increased in the presence of NO donors, but remains essentially unchanged. This leads to a significantly lower drop in blood pressure. Furthermore, the compounds of the formulas I and II used according to the invention have a significantly earlier onset of action than comparable inhibitors of cGMP-degrading phosphodiesterase, isoenzyme of type V. These pharmacological properties such as a strong relaxing effect on the isolated erectile tissue of the rabbit and the potent inhibition of cGMP-degrading phosphodiesterase, Type V isoenzyme in the therapeutically relevant concentration range of the IC ₅₀ from 1 µM to 3 µM show that the compounds of the formula I and II are suitable for the prophylaxis and treatment of erectile dysfunction, for the selective inhibition of the phosphodiesterase type V, for the relaxation of erectile tissue and to perfect, refine or increase erectile ability.

Pharmacological examples example 1 Relaxation of the constriction of the isolated rabbit induced by noradrenaline Erectile tissue

The relaxation of the constriction of the isolated erectile tissue (corpus cavernosum) of the rabbit penis induced by noradrenaline is suitable as a pharmacological model for testing potential drugs for the treatment of erectile dysfunction (Saenz De Tejada, I. et al. (1989) J. Urology 148: 1117- 1121). The experiments were carried out based on the method of Kim, N. et al. (1991) J. Clin. Invest. 88: 112-118 as follows: Penile erectile tissue strips of chinchilla bastard rabbits (body weight about 3.5 kg) were suspended in organ baths in cancer buffer solution, connected to electronic isometric force transducers and pre-stretched to a passive tensile stress of 2 g. After an equilibration phase of 1.5 hours to hours, the tissue strips were contracted by administration of noradrenaline (1 to 3 µM). After reaching the maximum contraction strength, the test substance was added cumulatively to the organ bath solution in increasing concentrations from 10 ^-9 M to 10 ^-4 M, and the relaxation of the tissue strips was measured. The relaxation achieved by the test substance is related to the contraction caused by noradrenaline and expressed in% relaxation of the noradrenaline-induced contraction. The measure of the potency of the test substance is the concentration graphically determined from the concentration-effect curve, at which a 50% relaxation was achieved (IC ₅₀ ).

As shown in Table 1, propentofylline brought about a marked concentration-dependent relaxation of the erectile tissue strips with an IC ₅₀ of about 3 µM.

Table 1

Example 2 Inhibition of type V and type III phosphodiesterase isoenzymes Enzyme preparation

The phosphodiesterase isoenzyme type V and type III were from fresh human platelets chromatographically according to the method of Tenor, H. et al. (1995) J. Invest. Dermatol. 105: 70-74 won.

Measurement of phosphodiesterase activity

The determination of the activity of phosphodiesterase, isoenzyme type V and type III, was carried out according to the method of Ukena, D. et al. ((1993) Biochem. Pharmacol. 45: 847). The hydrolysis of the ³ H-labeled substrate cGMP or cAMP by the phosphodiesterases, isoenzyme of type V and type III, is determined by means of the radiobiochemical measurement of the degradation products separated by ion exchange chromatography (QAE Sephadex A 25, Pharmacia Biotech). The test substance is added to the enzyme-substrate solution in increasing concentrations and the inhibitory activity is given in percent (%) of the remaining enzyme activity.

As shown in Table 2, propentofylline significantly inhibited the activity of the phosphodiesterase isoenzyme type V, depending on the concentration. The calculated IC _{50 was} 1.1 μM. The calculated IC ₅₀ for the determined inhibition of the phosphodiesterase isoenzyme type III is 77 µM.

Table 2

Table 3 shows the inhibition of the activities of the phosphodiesterase type V and type III isoenzyme by a racemate containing both the R enantiomer and the S enantiomer of 1- (5'-hydroxyhexyl) -3-methyl-7-n- propyl-xanthine (A 720287). The calculated IC ₅₀ for type V is 5.0 µM. The calculated IC ₅₀ for the determined inhibition of the phosphodiesterase isoenzyme type III is 53 µM.

Table 3

The surprisingly strong relaxing effects of propentofylline on the isolated erectile tissue of the rabbit and the potent inhibition of cGMP-degrading phosphodiesterase V by propentofylline and 1- (5'-hydroxyhexyl) -3-methyl-7-n-propyl-xanthine (A 720287) in therapeutic relevant concentration range of the IC ₅₀ of about 1 µM or 5 µM by A 720287 show that propentofylline and A 720287 are suitable for the prophylaxis and treatment of erectile dysfunction.

Example 3 The effect of propentofylline on the relaxation caused by sodium nitroprusside pre-contracted erectile tissue from rabbit on noradrenaline

The relaxing effect of propentofylline on that caused by sodium nitroprusside Relaxation on the pre-contracted erectile tissue (corpus cavemosum) The rabbit penis was carried out essentially as described in Example 1. Penile erectile tissue tissue strips from chinchilla bastard rabbits (body weight 3.5 kg) were suspended in organ baths in cancer buffer solution electronic isometric force transducers and connected to a passive Pre-stretched tension of 2 g. After an equilibration phase from 1 hour to The tissue strips were administered for 1.5 hours by administration of noradrenaline (1 to 3 μM) contracted. After reaching the maximum contraction strength, sodium Nitroprusside (SNP; 0.3 µM or 1 µM) alone or propentofylline (3 µM, 30 min. Preincubation) and sodium nitroprusside added to the organ bath solution and measured the relaxation of the tissue strips. The relaxation achieved thereby was related to the contraction caused by norepinephrine and in% Relaxation of the noradrenaline-induced contraction is indicated.

Table 4 shows the results.  

Table 4

The results show that the relaxing effect of a NO donor (SNP) is not significantly enhanced by propentofylline. Therefore, propentofylline can also be used in The presence of NO donors does not lead to hypotension.

Claims (10)

1. Use of at least one compound of the formula I.
and / or at least one compound of the formula II,
wherein the compound of formula II is present as a racemate or as an S or R enantiomer,
for the manufacture of a medicament for the prophylactic or curative treatment of erectile dysfunction in male mammals, including men. 2. Use according to claim 1, characterized in that 1- (5-oxohexyl) - 3-methyl-7-propylxanthine or 1- (5-hydroxyhexyl) -3-methyl-7-n-propylxanthine as Racemate or as enantiomer R - (-) - 1- (5-hydroxyhexyl) -3-methyl-7-n-propyl- xanthine or a mixture thereof is used. 3. Use according to claim 1 or 2, characterized in that 1- (5-Oxohexyl) -3-methyl-7-propylxanthine is used.   4. Use of at least one compound of the formula I and / or II according to Claim 1 for the manufacture of a medicament for the selective inhibition of Phosphodiesterase, isoenzyme type V. 5. Use of at least one compound of the formula I and / or II according to Claim 1 for the manufacture of a medicament for relaxing Erectile tissue. 6. Use of at least one compound of formula I or at least a compound of formula II, the compound of formula II as a racemate or is present as an S or R enantiomer, according to claim 1 Perfection, refinement or increase in erectile ability in Man, using for curative or prophylactic treatment is excluded from erectile dysfunction. 7. Use of at least one compound of formula I or at least a compound of formula II, the compound of formula II as a racemate or is present as an S or R enantiomer, according to claim 1 for the preparation of a Medicinal product for the prophylactic or curative treatment of female Malfunctions during sexual intercourse, especially malfunctions of the female erectile organ. 8. Use of at least one compound of the formula I or at least a compound of formula II, the compound of formula II as a racemate or is present as an S or R enantiomer, according to claim 1 Perfection, refinement or increase in excitability of the female erectile organ, being used for curative or prophylactic Treatment is excluded.   9. Use of at least one compound of the formula I or at least one Compound of formula II, wherein the compound of formula II as a racemate or is present as an S or R enantiomer, according to claim 1 to increase the Erectile ability in male mammals. 10. Use according to one or more of claims 1 to 9, wherein the galenical preparation is suitable for oral or rectal application.