MXPA01001263A - Pyridinones for the treatment of sexual dysfunction - Google Patents

Abstract

Compositions which contain a pyridinone of general formula (I), and pharmaceutically acceptable salts thereof, show penile erectile activity. The specification describes and claims pharmaceutical compositions containing the pyridinone compounds in particular flosequinan and derivatives thereof and methods of treating sexual dysfunction in animals and humans, particularly penile erectile dysfunction in human males.

Description

PIRIDINONES FOR THE TREATMENT OF SEXUAL DYSFUNCTION Description This invention relates to pyridinone compounds with therapeutic activity, and also to therapeutic compositions containing such compounds. More particularly, the invention relates to compositions and methods for the treatment of sexual diffusion in animals and humans, and even more particularly, to the treatment of erectile dysfunction in human males. Impotence is defined as a deficiency of a male's ability to relate sexually, and often involves an inability to achieve erection of the penis or ejaculation, or both. More specifically, the dysfunction or impotence of the erection of the penis can be defined as the inability to obtain or maintain an adequate erection for intercourse. The prevalence of masulin impotence, it is claimed, is between 2 and 7% of the male population, increasing with age, up to 50 years of age, and between 18 and 75% between 55 and 80 years of age. In the United States, for example, it has been estimated that there are up to 10 million impotent men, most suffering from problems of organic rather than psychogenic origin. There are few reports of well-controlled clinical trials in men and the efficacy of orally administered medications is low. Although many different drugs have been shown to induce penile erection, these are only effective after direct injection into the penis, for example, intraurethrally or intracavernosally (i.c), and are not approved for erectile dysfunction. Current medical treatments are based on the i.c. of vasoactive substances and it has been claimed that they give good results with phenoxybenzamine, phentolamine, papaverine and prostaglandin Ei, alone or in combination; however, pain, priapism and penile fibrosis are associated with i.c. administration. of some of these agents. They also showed to be active i.c. potassium channel openers (KCO) and intestinal vasoactive polypeptides (VIP), but cost and stability aspects could limit the development of the latter. An alternative for the route i.c. is the use of glyceryl trinitrate patches (GTN (applied to the penis, which have been shown to be effective but produce lataral effects in the patient and the couple.) As a general alternative to pharmacological intervention, a variety of penile prostheses have been used to help the erection, the success rate is good in short periods, but problems with infection and ischemia, especially in diabetic men, make this type of treatment a final option rather than a first-line therapy. Orally administered drugs (eg, Viagra®) contain pyrazolopyrimidinones which are being used to treat erectile dysfunctions of the penis in human males Such compounds are described, for example, in WO 94/208902, 7.a description of this publication is expressly incorporated in the present, in its integrity as a reference, these compounds are potent inhibitors, as has been reported, of cyclic guanosine 3 ', 5' -monophosphate phosphodiestera a (cGMP PDE) in contrast to its inhibition of cyclic adenosine 3 ', 5' -monophosphate phosphodiesterases (cAMP PDE). This selective enzyme inhibition leads to elevated cGMP levels. However, these compounds, specifically Viagra®, have a short half vica (4-5 hours) in vivo. This short half-life requires that one tablet be taken approximately 1 hour before sexual contact. In addition, the Food and Drug Administration has limited the use of viagra® to one tablet per day, effectively preventing additional episodes of same-day sexual contact. In this way, it is desired to have a medicament for the treatment of sexual dysfunction, particularly penile erection dysfunction, which overcomes the disadvantages of the previous treatment regimens and can be taken once a day, thus providing effective treatment throughout the day. The invention is directed to pyridinone compounds with therapeutic activity, and to therapeutic compositions containing such compounds, wherein the compounds have the general formula I: Ri is hydrogen, lower alkyl optionally substituted by hydroxy or C 1 alkoxycarbonyl, allyl, propynyl or phenyl lower alkyl in which the phenyl ring is optionally substituted by one or two C 1 alkoxy groups; R2 is hydrogen or a lower alkyl; R3 is (X; m-S (0) nR4, COR5, SR6, or S (0H) (0) NR7, where m is 0 or 1, n is 0, 1, or 2, X is oxygen or lower alkylene, R 4 is C 1 -4 alkyl, R 5 is hydroxyl, lower alkylcarbonyl, amino, or lower alkyl amino, and R? and R7 are lower alkyls; and ring A represents an optionally substituted phenyl ring of formula: wherein Re, R_ and Rio, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, lower alkylsulfini L, lower alkylsulfonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano, phenyl, phenyl substituted by 1 to 3 groups independently selected from lower alkyl, lower alkoxy and trifluoromethyl; or the ring? represents an optionally substituted thiophene ring of the formula: wherein Rn is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, phenyl, or phenyl substituted by hydrogen, or a pharmaceutically acceptable salt thereof. The compounds of the formula I were found to have anti- hypertensive activity and cardiac activity in warm-blooded animals. The compounds, methods of preparing the compounds, therapeutic compositions of the antihypertensive and cardiac compounds, and methods for treating hypertension and heart failure using the compounds are described in U.S. Patent 4,302,460, U.S. Patent 4,522,884, U.S. Patent 4,855,291, U.S. Pat. US 4,877,793, US Patent 4,710,506, US Patent 4,772,614 and US Patent 4,997,840, the description of such patents is expressly incorporated herein by reference in its entirety. Unexpectedly, it has now been found that the compounds of the formula I are useful in the treatment of sexual dysfunction in animals and humans, more particularly erectile dysfunction of the penis in human males. Although the compositions and methods of the invention are intended primarily for the treatment of erectile dysfunction or male sexual dysfunction, they may be useful for female sexual dysfunction, including orgasmic dysfunction related to clitoral disorders. Thus, in one embodiment, the invention relates to pharmaceutical compositions useful for treating sexual dysfunction in human animals, more specifically erectile dysfunction of the penis in males, which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

In another embodiment, the invention relates to a method for treating sexual dysfunction in humans and animals, more particularly erectile dysfunction of the penis in human males, which consists of the administration to a human or an animal in need of said treatment, of a effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either the compound or the salt. In still another embodiment, the invention relates to a process for preparing the pharmaceutical composition for the treatment of sexual dysfunction in humans and animals, more particularly erectile dysfunction of the penis in human males, which comprises the formulation of a compound of formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable diluent or carrier. The present invention provides pharmaceutical compositions for the treatment of sexual dysfunction in humans and animals, methods for treating sexual dysfunction in animals and humans, processes for preparing pharmaceutical compositions using the compounds of general formula I.

I. Definitions Certain terms used in the specification, examples and the attached clauses are, for convenience, declared as follows. The terms "lower alkyl", "lower alkoxy", "lower alkanoyl", and "lower alkylthio" denotes that such groups contain 1-8 carbon atoms, especially 2-4 carbon atoms: carbon for lower alkanoyl and 1-4 carbon atoms p = .ra the other groups. Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-heptyl, n-octyl, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, acetyl, propionyl, butyryl, methylthio , etiitium, propylthio and n-butylthio. As used hereafter, the term "active compound" denotes a pyridinone compound of general formula I.

In therapeutic use, the active compound can be administered orally, rectally or parenterally, preferably orally. The term "treatment" is used in its broadest sense, and includes curative and / or prophylactic treatment of sexual dysfunction in animals and humans. The term "animal" as used herein includes all warm-blooded animals, including mammals, more preferably humans.

II. DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS In a preferred embodiment, the invention provides pharmaceutical compositions comprising compounds of the formula I, and methods using the compositions for treating sexual dysfunction in human and male animals, more preferably male penile erectile dysfunction. The compounds of the invention may contain one or more asymmetric centers and, therefore, may exist as enantiomers or diastereoisomers. In addition, certain compounds of the invention containing alkenyl groups can exist as cis isomers or trans isomers. In each case, the invention includes separate mixtures and individual isomers. The compounds can also exist in tautomeric form and the invention includes separate individual mixtures and tautomers. Preferred compounds for use in the methods and pharmaceutical compositions of the invention are compounds having the general formulas II and III: where Ri, R3, Re, R_, Rio. and Rn. They are as defined before.

In relation to the compounds of formula II, even more preferred compounds have the formula IIA: R wherein R3 is (X) mS (0) nR, C0R5, SR6, or S (0H) (0) NR7, and (a) Rio is hydrogen and Rg is lower alkoxy-6, lower alkoxy-8, halo- 5 or halo-6; (b) R9 is hydrogen and Rio is halo; lower alkyl, lower alkoxy, difluoromethyl or lower alkylthio; (c) Rio is halo, lower alkoxy or halo-6 of a value other than Rio; or (d) Rg and Rio are hydrogen. Preferred embodiments include compounds of formula IIA wherein Ri and R2 are methyl, Rg is hydrogen and Rio is halo, lower alkyl or trifluoromethyl. More preferably, Rio is halo or C? _ Alkyl. In yet another preferred embodiment, Rg is lower alkoxy-6 and Rio is halo or lower alkoxy. In a more preferred embodiment, Rg is halo-6 and Rio is lower alkoxy. In another preferred embodiment, Rio is C? - alkyl. Thus, preferred embodiments include compounds of formula IIB, IIC, IID, HE, IIF, IIIA and IIIB as follows: 25 Preferred compounds of formula IIB are those in which m is 1, n is 2, and X is oxygen. Preferred compounds of the formula IIC include those in which m is 0, n is 1 or 2 and R 4 is methyl. Preferred compounds of formula IIB include those in which R5 is amino or lower alkylamino. Preferred compounds of the formula HE include those in which Rd is methyl. Preferred compounds of formula IIF include those in which R7 is methyl. Preferred compounds of formula IIIB include those in which n is 1 and R4 is methyl. Preferred compounds of formula IIIB include those in which R5 is amino or lower alkyl amino. Preferred specific compounds of the invention include l-β-ethyl-3-methylsulfinyl-4-quinolone, 7-fluoro-l-methyl-3-methylsulfinyl-4-quinolone, 7-fluoro-l-methyl-4-oxo-1,4-dihydroquinolone-3-carboxamide, -methyl-7-oxo-4, 7- dihydrothien [3, 2-b] pyridine-6-carboxamide, 4-methyl-6-methylsulfinyl-7 (4H) -thien [3,2- b] pyridinone, 7-chloro-l-methyl-3-methylsulfamoyl- 4-quinolone, l-methyl-4-oxo-l, 4-dihydroquinol-3-ylmetanesulfonate, 7-chloro-l-methyl-4-oxo-l, 4-dihydroquinoljn-3-carboxamide, 7-fluoro -1-methy1-3-methylsulfonyl-4-quinolone or 7-fluoro-l-methyl-3-methylthio-4-quinolone, or pharmaceutically acceptable salts thereof. The therapeutic compositions of the present invention can take the form of any known pharmaceutical composition, oral, rectal, parenteral, or topical / transdermal administration. Suitable pharmaceutically acceptable diluents for use in such compositions are well known in the art of pharmacy. The compositions of the invention contain 0.1-90% by weight of the active compound. The compositions of the invention are generally presented in a single dose form. Compositions for oral administration are the preferred compositions of the invention, and the active ingredient of such compositions is preferably administered in a single dose form. Preferred compositions are the known pharmaceutical forms for such administration. , for example, tablets, capsules, syrups and aqueous or oily suspensions. The tablets and capsules may conveniently contain a unit dose of the active compound of 1-500 mg / kg, more preferably 5-100 mg / kg, even more preferably 5-50 mg / kg. The excipients used in the preparation of the compositions of the invention are excipients well known in the art of pharmacy. The tablets can be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example, corn starch, lubricating agents, for example, magnesium stearate, and tabletting the mixture by known methods. Such tablets may, if desired, be provided with enteric coatings by the known methods, for example, by the use of cellulose acetate :: talate. Similarly capsules, for example, hard or soft gelatin capsules, containing the active compound with or without the addition of excipients, for example, can be prepared by conventional means and, if desired, provided with enteric coatings in a manner known Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethyl cellulose, and suspensions in oil containing a compound of the present invention. invention in a suitable vegetable oil, for example, peanut oil. Compositions of the invention suitable for rectal administration are pharmaceutically known forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases. Compositions of the invention suitable for parenteral (eg, sublingual or buccal) administration are pharmaceutically known forms for such administration, eg, sterile suspensions in aqueous media and oily media or sterile solutions in a suitable solvent. Compositions of the invention suitable for topical / transdermal administration are pharmaceutically known forms for such administration, for example, patches, gels, cream lotions, aerosols, and the like. In some formulations it may be beneficial to use the compounds of the present invention in the form of very small particles, for example, as obtained by grinding by fluid energy. In other formulations, the use of pharmaceutically acceptable salts of the compounds may be beneficial. The pharmaceutically acceptable salts of the compounds of the invention which contain a basic center, for example, are non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, with organocarboxylic acids, or with organosulfonic acids. The compounds of the invention can also provide pharmaceutically acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include sodium and potassium salts. In the compositions of the present invention the active compound can, if desired, be associated with other pharmacologically compatible active ingredients. For veterinary use, the compounds of the invention, or the non-toxic salts thereof, are administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinary surgeon will determine the dosage regimen and route of administration. more appropriate for a particular animal. The therapeutic activity of the compounds of the general formula I have been demonstrated by means of tests on laboratory animals. Such tests include, for example, oral and / or intraduodenal administration of the compounds to rabbits and marmosets. The erection of the penis was produced in both species by the administration of the compounds of the invention. It is reported in WP 94/28902 that investigations have led to separate and characterize the cyclic nucleotides PDE of the human corpus cavernosum, the relaxation of which leads to the erection of the penis. This research, including studies of substrate specificity, response to activators and sensitivity to the inhibitor have shown that the human corpus cavernosum contains three different types of PDE enzymes. The predominant PDE is the cGMP specific test, although the cAMP PDEs stimulated by cGMP are also found. In contrast, the compounds of the invention are arteriovenous dilators whose clinically relevant pharmacological mechanism is distinct from compounds such as pyrazolopyrimidinones of WO 94/28902 which produces vasodilation by inhibiting the hydrolysis of cyclic GMP by one or more phosphodiesterase isozymes. Unlike these agents (eg, Viagra®), studies in both arterial and venous systems indicate that the compounds according to the invention, for example, flosequinate (7-fluoro-l-methyl-3- (methyl-sulfinyl) -4- (1H) -quinolinone), at clinically relevant concentrations, carries out vasoc'ylation by inhibiting the formation of inositol 1, 4, 5-triphosphate (ITP) from phosphatidylinositol 4,5-bisphosphate and by inhibition of protein kinase C (Lang, D. and Lewis MJ Eur. J. Clin. Pharmacol. 226, 259-264 (1992); and Hass, G.J. and Leier, V.C.

Drug Theraphy, 47-59 (1995)). Because ITP is critical for the release of calcium from the sarcoplasmic reticulum and, therefore, for vasoconstriction, the action of flosequinin to alter the kinetics of intracellular calcium results in vasodilation in the absence of cGMP or cAMP changes. (Richards, N.T., Poston, L. and Hilton, P.J. Brit. J. Pharmacol 98, (Proc. Suppl.), 734p (1989)). Although it was observed in some studies that flosequine increases cGMP and intracellular cAMP in supra pharmacological concentrations: by non-selective inhibition of phosphodiesterase activity, the clinical importance of this observation is unknown. All patents, published patent applications and other references described in the patent are hereby expressly incorporated, in their entirety, by reference. Now, the invention being described generally will be more readily understood by reference to the following examples, which are included only for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

Example 1. Preparation of compounds 7-Fluoro-l-methyl-4-oxo-l, 4-dihydroquinolone-3-carboxamide was prepared as described in Example 1 of US Pat. No. 4,855,291. As described in Example 1 of US Pat. No. 4,877,793, 4-methyl-7-oxo-4,7-dihydrothien [3,2- b] pyridine-6-carboxamide was prepared. was prepared as described in Example 2 of U.S. Patent 4,710,506, 4-methyl-6-methylsulfinyl-7 (4H) -thien [3,2-b] pyridinone. Prepared as described in Example 4 of U.S. Patent 4,772,614, 7-chloro-l-methyl-3-methylsulfamoyl-4-quinolone. Prepared as described in Example 4 of U.S. Patent 4,855,291, 7-chloro-l-methyl-4-oxo-l, 4-dihydroquinoline-3-carboxamide. The five compounds described in Example 1 were tested for penile erectile activity in marmosets as follows: Example 2. Test methods A. Animals Common marmosets (callithrix jacchus) were used. The animals were 11 to 12 months old and the weight range was 250 to 300 g. Each animal was provided with 80 g of solid diet (predominantly fruit) daily. During the treatment periods, the diet was offered approximately 3 hours after the administration of the dose. The water supply was available all the time from a bottle of water. The tit..es were lodged individually. During the study, the temperature of the room in which the tities were housed was 20-24 ° C and the relative humidity was within the range of 40-87%. The lighting was by fluorescent light in a light / dark cycle of 12 hours / 12 hours that automatically changed to 0700 hours GMT. [sic] B. Test substances The test substances were ground. The control article and vehicle for the test substance was a 0.4% solution of Cellosize (hydroxyethylcellulose Q.P. 15000), in purified B.P. The solution was prepared and used for periods of up to 14 days. The content of the solutions and suspensions of the test substance (varying from 2-40 mg / ml) in 0.4% aqueous Cellosize solution was determined.

C. Treatment The test substance was administered as an oral dose in the vehicle, at a dose volume of 0.5 ml per 100 g of body weight. The control group received the vehicle orally, in the same dose volume. The doses were administered by oral priming, using a Franklin 10FG catheter and a plastic syringe. The dose in the range of 1 mg / kg to 250 mg / kg was used as appropriate.

D. Observations Male tities were observed continuously for at least 6 hours after each dose for the presence of penile erection. The dose that caused the erection of the penis was noted. The results for the five compounds of Example 1 are shown below. The erection of the penis was between 13 minutes after dosing and 2.5 hours after dosing. In certain cases, the erection of the penis was maintained for a period of up to 3.5 hours after dosing, in certain cases for up to 7.5 hours after dosing.

Table 1 In addition, l-methyl-4-oxo-l, -dihydroquinol-3-yl-methanesulfonate was found to produce penile erection in the rabbit.

Equivalents Those skilled in the art will recognize, or may be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are proposed to be included by the following clauses.

Claims (1)

1. CLAIMS A pharmaceutical composition for the treatment of sexual dysfunction in humans and animals that contains a compound of formula I: Ri is hydrogen, lower alkyl optionally substituted by hydroxy or C? -4 alco alkoxycarbonyl, allyl, propynyl or phenyl lower alkyl in which the phenyl ring is optionally substituted by one or two C? -4 alco alkoxy groups; R2 is hydrogen or a lower alkyl; R3 is (X) mS (0) nR4, COR5, SR6, or S (OH) (0) NR7, where m is 0 or '.., n is 0, 1, or 2, X is oxygen or lower alkylene R 4 is C 4 alkyl, R 5 is hydroxyl, lower alkylcarbonyl, amino, or lower alkyl amino, and R 6 and R 7 are lower alkyl; and ring A represents an optional substituted phenyl ring of formula: wherein R8, Rg and Rio, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano , phenyl, phenyl substituted by 1 to 3 groups independently selected from lower alkyl, lower alkoxy and trifluoromethyl; or the ring A represents an optionally substituted thiophene ring of the formula: wherein Rn is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthyl, phenyl, or phenyl substituted by hydrogene, or a pharmaceutically acceptable salt thereof. in combination with a pharmaceutically acceptable diluent or carrier. The composition of claim 1, wherein the compound has the formula II: The composition of claim 1, wherein the compounds have the formula III: The composition of claim 2, wherein the compound has the formula HA: wherein R3 is (X) m-S (O) nR4, COR5, SR6, or S (OH) (0) NR7, and (a) Rio is hydrogen and Rg is lower alkoxy-6, lower alkoxy-8, halo-5 or halo-6; (b) Rg is hydrogen and Rio is halo; lower alkyl, lower alkoxy, difluoromethyl or lower alkylthio; (c) Rio is halo, lower alkoxy or lower alkyl and Rg is lower alkyl-β, lower alkoxy-6 or halo-6 of a value other than Rio; or (d) Rg and Rio, are hydrogen. The composition of claim 4, wherein Ri and R are methyl. 6. The composition of claim 4, wherein Rg is hydrogene and Rio is halo, lower alkyl or trifluoromethyl. The composition of claim 6, wherein Rio is halo. The composition of claim 4, wherein Rg is lower alkoxy-6 and R5 is halo or lower alkoxy. 9. The composition of claim 4, wherein R9 is halo-6 and Rio is lower alkoxy. 10. The composition of claim 6, wherein Rio is C? - alkyl. 11. The composition of claims 5, 6, 7, 8, 9 or 10, wherein R3 is - (X) m-S (O) nR4. The composition of claim 11, wherein m is 1, n is 2, and X is oxygen. The composition of claim 11, wherein m is 0. 14. The composition of claim 13, wherein n is 1 or 2. 15. The composition of claims 5, 6, 7, 8, 9 or 10, wherein R3 is COR5. 16. The composition of claim 15, wherein R5 is amino or lower alkylamino. 17. The composition of claims 5, 6, 7, 8, 9 or 10, wherein R3 is SR6. 18. The composition of claim 17, wherein Re is methyl. 19. The composition of claims 5, 6, 7, 8, 9 or 10, wherein R3 is S (OH) (0) NR7. The composition of claim 19, wherein R7 is methyl. 21. The composition of claim 3, wherein R3 is S (0) nR4. 22. The composition of claim 21, wherein n is 1 and R4 is instyle. 23. The composition of claim 3, wherein R3 is COR5. 24. The composition of claim 23, wherein R5 is amino or lower alkylamino. 25. A pharmaceutical composition for treatment of sexual dysfunction in humans and animals that contains 1-methyl-3-methylsulfinyl-4-quinolone, 7-fluoro-l-methyl-3-methylsulinyl-4-quinolone, 7-fluoro-l-methoxy-4-oxo-l, 4-dihydroquinolone-3-carboxamide, 4-methyl-7-oxo-4, 7 -dihydrothien [3, 2-b] pyridine-6-carboxamide, 4-methyl-6-methylsulfinyl-7 (4H) -thien [3,2- b] pyridinone, 7-chloro-l-methyl-3-methylsulfamoyl- 4-quinolone, l-methyl-4-oxo-l, 4-dihydroquinol-3-yl-metasulfonate, 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, 7-fluoride- l-methyl-3-methylsulonyl-4-quinolone or 7-fluoro-l-methyl-3-methylthio-4-quinolone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. The composition of claim 1, 2, 3, 4 or 25, wherein the sexual dysfunction is erectile dysfunction. The composition of claim 26, wherein the sexual dysfunction is penile erectile dysfunction in a male. The composition of claim 27, in unit dose form. The composition of claim 28, wherein the single dose of the active ingredient is 1-500 mg / kg. The composition of claim 29, wherein the single dose is 5-100 mg / kg. The composition of claim 30, in the form of tablets, capsules, suppositories, transdermal patches or topical creams. A method for treating sexual dysfunction in humans and animals that consists in the administration to a human or animal in need of said treatment, of an effective amount of a compound of formula I: Ri is hydrogen, optionally substituted lower alkyl by hydroxy or C 1 alkoxycarbonyl, allyl, propynyl or lower alkyl-phenyl in which the phenyl ring is optionally substituted by one or two C? - alkoxy groups; R2 is hydrogen or a lower alkyl; R3 is (X) mS (0) nR4, COR5, SR5, or S (OH) (0) NR7, where m is 0 or J., n is 0, 1, or 2, X is oxygen or lower alkylene, R 4 is C 4 alkyl, R 5 is hydroxyl, lower alkyl, amino, or lower alkyl, and R and R7 are lower alkyl; and ring A represents an optionally substituted phenyl ring of formula: wherein Rs, Rg and Rio, may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl [sic], lower halogenated alkyl, lower alkoxy halogenated, cyano, phenyl, or phenyl substituted by 1 to 3 groups independently selected from lower alkyl, lower alkoxy and trifluoromethyl; or ring A represents optionally substituted thiophene ring of formula: wherein Rn is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthyl, phenyl, or phenyl substituted by halogen, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of said compounds or said salt. The method of claim 32, wherein the compound has the formula II: The method of claim 32, wherein the compound has the formula III: The method of claim 33, wherein the compound has the formula HA: wherein R3 is (X) m-S (0) nR4, C0R5, SR6 or S (0H) (0) NR7; Y (a) Rio is hydrogen and Rg is a lower alkoxy 6, lower alkoxy 8, halo-5 or halo-6; (b) R9 is hydrogen and Rio is halo; lower alkyl, lower alkoxy, trifluoromethyl or lower alkylthio; (c) Rio is halo, lower alkoxy or lower alkyl and Rg is a lower alkyl-6, lower alkoxy-6 or halo-6 or a different value of R 0; or (d) Rg and Rio are hydrogen. 36. The method of claim 35, wherein Ri and R4 are methyl. 37. The method of claim 35, wherein Rg is hydrogen and Rio is halo, lower alkyl or trifluoromethyl. 38. The method of claim 37, wherein Rio is halo. 39. The method of claim 35, wherein Rg is lower alkoxy-6 and R5 is halo or lower alkoxy. 40. The method of claim 35, wherein Rg is halo-6 and Rio is lower alkoxy. 41. The method of claim 37, wherein Rio is C 4 -4 alkyl. 42. The method of claim 36, 37, 38, 39, 40 or 41, wherein R3 is - (X) m-S (O) nR4. 43. The method of claim 42, wherein m is 1, n is 2 and X is oxygen. 44. The method of claim 42, wherein m is 0. 45. The method of claim 44, wherein n is 1 or 2. 46. The method of claim 36, 37, 38, 39, 40 or 41, wherein R3 is COR5. 47. The method of claim 46, wherein R5 is amino or lower alkylamino. 48. The method of claim 36, 37, 38, 39, 40 or 41, wherein R3 is SR6. 49. The method of claim 48 wherein Re is methyl. 50. The method of claim 36-41, wherein R3 is S (OH) (0) NR7. 51. The method of claim 50, wherein R7 is methyl. 52. The method of claim 34, wherein R3 is S (0) nR4. 53. The method of claim 52, wherein n is 1 and R4 is methyl. 54. The method of claim 34, wherein R3 is COR5. 55. The method of claim 54, wherein R5 is amino or lower alkylamino. 56. A method for treating sexual dysfunction in humans and animals comprising administration to a human or animal in need of such treatment with an effective amount of l-methyl-3-methylsulfinyl-4-quinolone., 7-fluoro-l-methyl-3-methylsulfinyl-4-quinolone, 7-fluoro-1-methoxy-4-oxo-1,4-dihydroquinolone-3-carboxamide, 4-methyl-7-oxo-4, 7 -dihydrothien [3,2- b] pyridine-6-carboxamide, 4-methyl-6-methylsulfinyl-7 (4H) -thien [3,2- b] pyridinone, 7-chloro-1-methyl-3-methylsulfamoyl- 4-quinolone, l-methyl-4-oxo-l, 4-dihydroquinol-3-yl-metasulfonate, 7-chloro-1-methyl-4-oxo-1, -dihydroquinoline-3-carboxamide, 7-fluoride-l -methyl-3-methylsulfonyl-4-quinolone or 7-fluoro-l-methyl-3-methylthio-4-quinolone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. thereof, or a pharmaceutical composition comprising any of said compounds or said salt. 57. The method of claim 32, 33, 34, 35 or 56, wherein the sexual dysfunction is erectile dysfunction. 58. The method of claim 57, wherein the sexual dysfunction is erectile dysfunction of the penis in a male. 59. The method of claim 58, wherein the compound is administered in a single dose form. 60. The method of claim 59, wherein the amount of the compound is 1-500 mg. 61. The method of claim 60, wherein the amount of compound is 5-100 mg. 62. The method of claim 58, wherein the compound is administered in the form of a tablet, capsule, suppository, transdermal patch or topical cream. 63. A process for preparing a pharmaceutical composition for treatment of sexual dysfunction in humans and animals comprising the formulation of a compound of formula I: (I) Ri is hydrogen, lower alkyl optionally substituted by hydroxy or C? _4 alkoxycarbonyl, allyl, propynyl, or phenylalkyl lower wherein the phenyl ring is optionally substituted by 1 or 2 C? -C 4 alkoxy groups; R2 is hydrogen or lower alkyl; R3 is; X) mS (0) nR4, COR5, SR6 or S (OH) (0) NR7, where m is 0 or 1, n is 0, 1 or 2, X is oxygen or lower alkylene, R4 is alkyl of C1-4, R5 is hydroxyl, lower alkylcarbonyl, amino, or lower alkylamino, and R6 and R7 are lower alkyl; and ring A represents an optionally substituted phenyl ring of the formula: wherein Re, Rg and Rio, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano , phenyl, substituted phenyl by 1 to 3 independently selected groups of lower alkyl, lower alkoxy and trifluoromethyl; or the ring A represents an optionally substituted thiophene ring of the formula: wherein Ru is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, phenyl, or phenyl substituted by halogen, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier. The process of claim 63, wherein the compound has the formula II: The process of claim 63, wherein the compound has the formula III: The process of claim 64, wherein the compound has the formula HA: wherein R3 is (X) m-S (0) nR4, C0R5, SR6 or S (OH) (0) NR7; Y (a) Ro is hydrogen and Rg is lower alkyl-6, lower alkoxy-8, halo-5, or halo-6; (b) Rg is hydrogen and Rio is halo; lower alkyl, lower alkoxy, trifluoromethyl or lower alkylthio; (c) Rio is halo, lower alkoxy or lower alkyl and Rg is lower alkyl-6, lower alkoxy-6 or halo-6 of a different value from R10; or (d) Rg and Rio are hydrogen.