WO2000007595A1

WO2000007595A1 - Pyridinones for the treatment of sexual dysfunction

Info

Publication number: WO2000007595A1
Application number: PCT/EP1999/005544
Authority: WO
Inventors: Neil R. Manowitz; Robert A. O'brien; Hugh E. Morgan
Original assignee: Basf Corporation
Priority date: 1998-08-03
Filing date: 1999-07-31
Publication date: 2000-02-17
Also published as: AU5509099A; CA2339484A1; EP1107759A1; JP2002522388A

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

PYRIDINONES FOR THE TREATMENT OF SEXUAL DYSFUNCTION

Description

This invention relates to pyridinone compounds with therapeutic activity, and to therapeutic compositions containing such compounds. More particularly, the invention relates to compositions and methods for treating sexual dysfunction in animals and humans, and still more particularly to the treatment of penile erectile dysfunction in human males.

Impotence is defined as a lack of the ability of a male to copulate, and very often involves an inability to achieve penile erection or ejaculation, or both. More specifically, penile erectile impotence or dysfunction may be defined as the inability to obtain or sustain an erection adequate for intercourse. The prevalence of male impotence is claimed to be between 2 and 7% of the human 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 USA alone, for example, it has been estimated that there are up to 10 million impotent males, with the majority suffering from problems of organic rather than psychogenic origin.

Reports of well-controlled clinical trials in man are few and the efficacy of orally administered drugs is low. Although many different drugs have been shown to induce penile erection, they are only effective after direct injection into the penis, e.g., in- traurethrally or intracavernosally (i.e.), and are not approved for erectile dysfunction. Current medical treatment is based on the i.e. injection of vasoactive substances and good results have been claimed with phenoxybenzamine, phentolamine, papaverine and prostaglandin Ei, either alone or in combination; however, pain, priapism and fibrosis of the penis are associated with the i.e. administration of some of these agents.

Potassium channel openers (KCO) and vasoactive intestinal poly- peptide (VIP) have also been shown to be active i.e., but cost and stability issues could limit development of the latter. An alternative to the i.e. route is the use of glyceryl trinitrate (GTN) patches applied to the penis, which has been shown to be effective but produces side-effects in both patient and partner.

As a general alternative to pharmacological intervention, a vari- ety of penile prostheses has been used to assist achievement of an erection. The short term success rate is good, but problems with infection and ischaemia, especially in diabetic men, make this type of treatment a final option rather than a first-line therapy.

More recently, orally administered drugs (e.g., Viagra®) compris- ing pyrazolopyrimidinones are being used to treat penile erectile dysfunction in human males. Such compounds are described, e.g., in WO 94/28902, the disclosure of which publication is expressly incorporated herein, in its entirety, by reference. These compounds are reportedly potent inhibitors of cyclic guanosine 3', 5 ' -monophosphate phosphodiesterases (cGMP PDEs) in contrast to their inhibition of cyclic adenosine 3', 5' -monophosphate phosphodiesterases (cAMP PDEs) . This selective enzyme inhibition leads to elevated cGMP levels.

However, these compounds, specifically Viagra®, have a short half-life (4-5 hours) in vivo. This short half-life requires that a tablet be taken about one hour before sexual intercourse. Furthermore, the Food and Drug Administration has limited use of Viagra® to one tablet per day, effectively precluding additional episodes of sexual intercourse in the same day. Thus, it would be desirable to have a drug for treatment of sexual dysfunction, particularly penile erectile dysfunction, that overcomes the disadvantages of prior treatment regimens and can be taken once a day, thereby providing effective treatment for the entire 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 Cι_₄ alkoxyearbonyl, allyl, propynyl or phenyl-lower alkyl in which the phenyl ring is optionally substituted by 1 or 2 Cι- alkoxy groups ;

R is hydrogen or lower alkyl; R₃ is (X)_m-S (0)_nR₄, COR₅, SR₆, or S (OH) (0)NR₇, wherein m is 0 or 1, n is 0, 1, or 2, X is oxygen or lower alkylene, R is C_!-₄ alkyl, R₅ is hydroxyl, lower alkyl carbonyl, amino, or lower alkyl amino, and Re and R are lower alkyl; and

ring A represents an optionally substituted phenyl ring of formula

wherein R₃, R₉ and R_J_Q, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, tri - fluoromethyl, lower alkylthio, lower alkylsulphinyl, loweralkyl- sulphonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano, phenyl, or phenyl substituted by 1 to 3 groups indepen- dently selected from lower alkyl, lower alkoxy and trifluoromethyl ; or

ring A represents an optionally substituted thiophene ring of formula

wherein R_n is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, phenyl, or phenyl substituted by halogen, or a pharmaceutically acceptable salt thereof.

The compounds of the general formula I have been found to have antihypertensive activity and cardiac activity in warm-blooded animals. The compounds, methods of making the compounds, antihy- pertensive and cardiac therapeutic compositions of the compounds, and methods for treating hypertension and heart failure using the compounds are described in US Patent 4,302,460, US Patent 4,522,884, US Patent 4,855,291, US Patent 4,877,793, US Patent 4,710,506, US Patent 4,772,614 and US Patent 4,997,840, the dis- closures of which patents are expressly incorporated herein, in their entirety, by reference. Unexpectedly, it has now been found that the compounds of formula I are useful in the treatment of sexual dysfunction in animals and humans, more particularly penile erectile dysfunction in human males. Although the compositions and methods of the invention are envisaged primarily for the treatment of erectile dysfunction or male sexual dysfunction, they may also be useful for the treatment of female sexual dysfunction including orgasmic dysfunction related to clitoral disturbances.

Thus, in one embodiment, the invention concerns pharmaceutical compositions useful for treating sexual dysfunction in humans animals, more particularly penile erectile dysfunction in human males, which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceuti- cally acceptable diluent or carrier.

In another embodiment, the invention concerns a method for treating sexual dysfunction in humans and animals, more particularly penile erectile dysfunction in human males, which comprises ad- ministering to a human or an animal in need of said treatment an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising either the compound or the salt.

In yet another embodiment, the invention concerns a process for preparing a pharmaceutical composition for treating sexual dysfunction in humans and animals, more particularly penile erectile dysfunction in human males, which comprises formulating 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 animals and humans, methods for treating sexual dysfunction in animals and humans, processes for preparing the pharmaceutical compositions, using the compounds of the general formula I.

I. Definitions

Certain terms employed in the specification, examples and appended claims are, for convenience, set forth as follows.

The terms "lower alkyl", "lower alkoxy", "lower alkanoyl", and "lower alkythio" denote such groups containing 1-8 carbon atoms, especially 2-4 carbon atoms for lower alkanoyl and 1-4 carbon atoms for 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, ethylthio, propylthio and n-butylthio.

As used hereinafter, the term "active compound" denotes a pyridinone compound of general formula I. In therapeutic use, the active compound may be administered orally, rectally or parenter- ally, preferably orally.

The term "treatment" is used herein in its broadest sense, and includes curative and/or prophylactic treatment of sexual dysfunction in animals and humans .

The term "animal" as used herein denotes all warm-blooded ani- mals, including mammals, more preferably human beings.

II. Description of Certain Preferred Embodiments

In a preferred embodiment, the invention provides pharmaceutical compositions comprising compounds of the general formula I, and methods using the compositions to treat sexual dysfunction in male animals and humans, more preferably penile erectile dysfunction in human males .

The compounds of the invention may contain one or more asymmetric centers and, therefore, can exist as enantiomers or diastereoi- somers . Furthermore, certain compounds of the invention containing alkenyl groups may exist as cis-isomers or trans-isomers . In each case, the invention includes both mixtures and separate in- dividual isomers. The compounds may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers .

Preferred compounds for use in the pharmaceutical compositions and methods of the invention are compounds having the general formulas II and III:

wherein Ri, R₃, Re, Rg, Rio and R_n are defined as above.

With regard to compounds of formula II, still more preferred compounds have formula IIA:

wherein R₃ is (X)_m-S (0)_nR₄, C0R₅, SR₆, or S (OH) (0) NR₇; and

(a) Rio is hydrogen and Rg is 6-lower alkoxy, 8-lower alkoxy, 5-halo or 6-halo;

(b) R₉ is hydrogen and R₁₀ is halo; lower alkyl, lower alkoxy, trifluoromethyl or lower alkyl-thio;

(c) Rio is halo, lower alkoxy or lower alkyl and Rg is 6-lower alkyl, 6-lower alkoxy or 6-halo of a different value from Rio; or

(d) Rg and Rio are hydrogen.

Preferred embodiments include compounds of formula IIA wherein R_x and R₂ are methyl, R₉ is hydrogen and Rio is halo, lower alkyl or trifluoromethyl. More preferably, R₁₀ is halo or Cι~C₄ alkyl. In yet another preferred embodiment, Rg is 6-lower alkoxy and R₁₀ is halo or lower alkoxy. In a further preferred embodiment, Rg is 6-halo and R_Xo is lower alkoxy. In another preferred embodiment, Rio is C₁-C₄ alkyl.

Thus, preferred embodiments include compounds of formula IIB, IIC, IID, HE, IIF. IIIA and IIIB as follows:

40

45

Preferred compounds of formula IIB are those in which m is 1, n is 2, and X is oxygen. Preferred compounds of formula IIC include those in which m is 0, n is 1 or 2 , and R is methyl. Preferred compounds of formula IID include those in which R₅ is amino or lower alkyl amino. Preferred compounds of formula HE include those in which R₆ is methyl. Preferred compounds of formula IIF include those in which R₇ is methyl. Preferred compounds of formula IIIA include those in which n is 1 and R₄ is methyl. Pre- ferred compounds of formula IIIB include those in which R₅ is amino or lower alkyl amino.

Specific preferred compounds of the invention include l-methyl-3-methylsulphinyl-4-quinolone, 7-fluoro-l-methyl-3-me- thylsulphinyl-4-quinolone, 7-fluoro-l-methyl-4-oxo-l, 4-dihydro- quinolone-3-carboxamide, 4-methyl-7-oxo-4 , 7-dihydro- thieno [3 , 2-b] pyridine-6-carboxamide, 4-methyl-6-methylsulphi - nyl-7 (4H) -thieno [3 , 2-b] pyridinone, 7-chloro-l-methyl-3-methylsul- phamoyl-4-quinolone, l-methyl-4-oxo-l, 4-dihydroquinol-3-yl metha- nesulphonate, 7-chloro-l-methyl-4-oxo-l, 4-dihydroquinoline-3-car- boxamide, 7-fluoro-l-methyl-3-methylsulphonyl-4-quinolone, or 7-fluoro-l-methyl-3-methylthio-4-quinolone, or pharmaceutically acceptable salts thereof.

The therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral, or topical/transdermal administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The composi- tions of the invention contain 0.1-90% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form.

Compositions for oral administration are the preferred composi- tions of the invention, and the active ingredient in such compositions is preferably administered in unit dosage 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 conve- niently contain a unit dosage of the active compound of 1-500 mg/kg, more preferably 5-100 mg/kg, still more preferably 5-50 mg/kg .

The excipients used in the preparation of the compositions of the invention are the excipients well known in the pharmacists' art. Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example, maize starch, and lubricating agents, for example, magnesium stearate, and tableting the mix- ture by known methods. Such tablets may, if desired, be provided with enteric coatings by known methods, for example, by the use of cellulose acetate phthalate. Similarly capsules, for example, hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner .

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 oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example, arachis oil.

Compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases .

Compositions of the invention suitable for parenteral (e.g., sub- lingual or buccal) administration are the known pharmaceutical forms for such administration, for example, sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent. Compositions of the invention suitable for topical/transdermal administration are the known pharmaceutical forms for such administration, for example, patches, gels, creams lotions, sprays, etc.

In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example, as obtained by fluid energy milling. In other formulations, it may be beneficial to use pharmaceutically ac- ceptable salts of the compounds.

The pharmaceutically acceptable salts of the compounds of the invention which contain a basic center are, for example, non-toxic acid addition salts formed with inorganic acids such as hydro- chloric, hydrobromic, sulfuric and phosphoric acid, with organo- carboxylic acids, or with organo-sulphonic acids. 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 may, if desired, be associated with other compatible pharmacologically active ingredients.

For veterinary use, the compounds of the invention, or non-toxic salts thereof, are administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinary surgeon will determine the dosing regimen and route of administration most appropriate for a particular animal.

The therapeutic activity of the compounds of general formula I has been demonstrated by means of tests on standard laboratory animals. Such tests include, for example, the oral and/or intra- duododenal administration of the compounds to rabbits and marmo- sets. Penile erection was elicited in both species upon administration of the compounds of the invention.

It is reported in WP 94/28902 that investigations have been conducted to isolate and characterize the cyclic nucleotide PDEs of human corpus cavernosum, relaxation of which leads to penile erection. These investigations, including studies of substrate specificity, response to activators and inhibitor sensitivity, have demonstrated that human corpus cavernosum contains three distinct PDE enzymes. The predominant PDE is the cGMP-specific PDEy, although cGMP-stimulated cAMP PDEs were also found. By contrast, the compounds of the invention are arteriovenous dilators whose clinically relevant pharmacologic mechanism is distinct from compounds such as the pyrazolopyriimidinones of WO 94/28902 that produce vasodilatation by inhibiting the hydrolysis of cyclic GMP by one or more phosphodiesterase isoenzymes. Unlike such agents (e.g., Viagra®), studies in both arterial and venous systems indicate that compounds in accordance with the invention, e.g., flosequinan (7-fluoro-l-methyl-3- (methyl - sulfinyl) -4 (1H) -quinolinone) , at clinically relevant concentra- tions effect vasodilatation by inhibiting the formation of inosi- tol 1,4, 5-triphosphate (ITP) from phosphatidylinositol 4,5 bi- phosphate and by inhibition of protein kinase C (Lang, D. and Lewis M.J., Eur. J. Clin . Pharmacol . , 226, 259-264 (1992); and Haas, G.J. and Leier, V.C., Drug Therapy, 47-59 (1995)). Because ITP is critical for calcium release from the sarcoplasmic reticu- lum and therefore for vasoconstriction, the action of flosequinan to alter intracellular calcium kinetics results in vasodilatation in the absence of changes of cGMP or cAMP. (Richards, N.T., Poston, L., and Hilton, P.J. Bri t . J. Pharmacol 98, (Proc. Suppl.), 734P (1989)). Although flosequinan has been noted in some studies to increase intracellular cGMP and cAMP at supra- pharmacologic concentrations by non-selective inhibition of phosphodiesterase activity, the clinical significance of this observation is unknown.

All patents, published patent applications and other references disclosed herein are hereby expressly incorporated, in their entirety, by reference.

The invention now being generally described will be more readily understood by reference to the following examples, which are included merely 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 Patent 4,855,291.

4-methyl-7-oxo-4 , 7-dihydrothieno [3 , 2-b] pyridine-6-carboxamide was prepared as described in Example 1 of US Patent 4,877,793.

4-methyl-6-methylsulphinyl-7 (4H) -thieno [3 , 2-b] pyridinone was pre- pared as described in Example 2 of US Patent 4,710,506. 7-chloro-l-methyl-3-methylsulphamoyl-4-quinolone was prepared as described in Example 4 of US Patent 4,772,614.

7-chloro-l-methyl-4-oxo-l, 4-dihydroquinoline-3-carboxamide was 5 prepared as described in Example 4 of US Patent 4,855,291.

The five compounds described in Example 1 were tested for penile erectile activity in marmosets as follows.

10 Example 2. Assay Methods

A. Animals

Common marmosets (callithrix jacchus) were used. The animals were 15 11 to 12 months of age 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, diet was offered approximately 3 hours after dose administration. Tap water was 20 available at all times from a water bottle. The marmosets were housed individually.

During the study, the temperature of the room in which the marmosets were housed was 20-24°C and the relative humidity was within 25 the range of 40-87%. Lighting was by fluorescent light on a 12 hour/12 hour light/dark cycle, which switched on automatically at 0700 hour GMT.

B. Test Substances 30

The test substance was milled.

The control article and vehicle for the test substance was a 0.4% solution of Cellosize (hydroxyethyl cellulose Q.P. 15000), in pu- 35 rified water B.P. The solution was prepared and used for periods up to 14 days .

The content of solutions and suspension of test substance (ranging from 2-40 mg/ml) in 0.4% aqueous Cellosize solution was de- 40 termined.

C . Treatment

The test substance was administered as an oral dose in the ve- 45 hide, at a dose volume of 0.5 ml per 100 g body weight. The control group received the vehicle orally, at the same dosage volume. The doses were administered by oral gavage, using a Franklin 10FG catheter and a plastic syringe. Doses in the range of 1 mg/kg to 250 mg/kg were employed as appropriate.

D. Observations

The male marmosets were observed continuously for at least 6 hours after each dose for the occurrence of penile erection.

The dose which caused penile erection was noted. The results for the five compounds of Example 1 are shown below. Penile erection was observed between 13 minutes after dosing and 2.5 hours from dosing. In certain cases penile erection 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, 4-dihydroquinol-3-yl methanesulpho- nate was found to elicit penile erection in the rabbit.

Equivalents

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

Claims

What is claimed is :

1. A pharmaceutical composition for treating sexual dysfunction in humans and animals which comprises a compound of formula I:

Ri is hydrogen, lower alkyl optionally substituted by hydroxy or C╬╣-₄ alkoxyearbonyl, allyl, propynyl or phenyl-lower alkyl in which the phenyl ring is optionally substituted by 1 or 2 C╬╣-₄ alkoxy groups;

R is hydrogen or lower alkyl;

R₃ is (X)_m-S (0)_nR₄, COR₅, SR₆, or S (OH) (0)NR₇, wherein is 0 or 1, n is 0, 1, or 2, X is oxygen or lower alkylene, R is C₁-₄ alkyl, R₅ is hydroxyl, lower alkyl carbonyl, amino, or lower alkyl amino, and Rg and R₇ are lower alkyl; and

ring A represents an optionally substituted phenyl ring of formula

wherein Ra, R₉ and Ro, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, lower alkylsulphinyl, loweralkylsulphonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano, phenyl, or phenyl substituted by 1 to 3 groups independently selected from lower alkyl, lower alkoxy and trifluoromethyl; or

ring A represents an optionally substituted thiophene ring of formula

wherein R_u is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkyl hio, phenyl, or phenyl substituted by halogen, or a pharmaceutically acceptable salt thereof,

in combination with a pharmaceutically acceptable diluent or carrier.

2. The composition of claim 1, wherein the compound has formula II:

3. The composition of claim 1, wherein the compound has formula III:

The composition of claim 2, wherein the compound has formula IIA:

wherein R₃ is (X)_m-S (0)_nR₄, COR₅, SR₆, or S(0H) (0)NR₇; and

(a) Rio is hydrogen and Rg is 6-lower alkoxy, 8-lower alkoxy, 5-halo or 6-halo;

5

(b) Rg is hydrogen and R₁₀ is halo; lower alkyl, lower alkoxy, trifluoromethyl or lower alkyl-thio;

(c) Rio is halo, lower alkoxy or lower alkyl and Rg is 6-lower 10 alkyl, 6-lower alkoxy or 6-halo of a different value from

Rio; or

(d) Rg and R₁₀ are hydrogoen.

15 5. The composition of claim 4, wherein Ri and R₄ are methyl.

6. The composition of claim 4, wherein Rg is hydrogen and Rio is halo, lower alkyl or trifluoromethyl .

20 7. The composition of claim 6, wherein R₁₀ is halo.

8. The composition of claim 4, wherein R₉ is 6-lower alkoxy and R₅ is halo or lower alkoxy.

25 9. The composition of claim 4, wherein Rg is 6-halo and Rio is lower alkoxy.

10. The composition of claim 6, wherein R₁₀ is C₁-C₄ alkyl.

30 11. The composition of claims 5, 6, 7, 8, 9, or 10, wherein R₃ is -(X)_m-S(0)_nR₄.

12. The composition of claim 11, wherein m is 1, n is 2, and X is oxygen .

35

13. The composition of claim 11, wherein m is 0.

14. The composition of claim 13, wherein n is 1 or 2.

40 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 alkyl amino. 45

17. The composition of claims 5, 6, 7, 8, 9 or 10, wherein R₃ is SR₆.

18. The composition of claim 17 wherein Rg is methyl. 5

19. The composition of claims 5, 6, 7, 8, 9 or 10, wherein R₃ is S (OH) (0)NR₇.

20. The composition of claim 19, wherein R₇ is methyl. 10

21. The composition of claim 3, wherein R₃ is S(0)_nR .

22. The composition of claim 21, wherein n is 1 and R₄ is methyl.

15 23. The composition of claim 3, wherein R₃ is COR₅.

24. The composition of claim 23, wherein R₅ is amino or lower alkyl amino.

20 25. A pharmaceutical composition for treating sexual dysfunction in humans and animals which comprises l-methyl-3-methylsul - phinyl-4-quinolone, 7-fluoro-l-methyl-3-methylsulphi - nyl-4-quinolone, 7-fluoro-l-methyl-4-oxo-l, 4-dihydroquino- lone-3-carboxamide, 4-methyl-7-oxo-4, 7-dihydro-

25 thieno [3 , 2-b] pyridine-6-carboxamide, 4-methyl-6-methylsulphi - nyl-7 (4H) -thieno [3 , 2-b] pyridinone, 7-chloro-l-methyl-3-me- thylsulphamoyl-4-quinolone, l-methyl-4-oxo-l, 4-dihydroqui - nol-3-yl methanesulphonate, 7-chloro-l-methyl-4-oxo-l, 4-dihy- droquinoline-3-carboxamide, 7-fluoro-1-methyl-3-methylsulpho-

30 nyl-4-quinolone, or 7-fluoro-l-methyl-3-methylthio-4-quino- lone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

35 26. The composition of claim 1, 2, 3, 4 or 25, wherein said sexual dysfunction is erectile dysfunction.

27. The composition of claim 26, wherein said sexual dysfunction is penile erectile dysfunction in a human male.

40

28. The composition of claim 27 in unit dosage form.

29. The composition of claim 28, wherein the unit dosage of active ingredient is 1-500 mg/kg.

45

30. The composition of claim 29, wherein the unit dosage is 5-100 mg/kg .

31. The composition of claim 30 in the form of tablets, capsules, suppositories, transdermal patches or topical creams.

32. A method for treating sexual dysfunction in humans and animals which comprises administering to a human or an animal in need of said treatment with an effective amount of a compound of formula I:

Ri is hydrogen, lower alkyl optionally substituted by hydroxy or C╬╣-₄ alkoxyearbonyl, allyl, propynyl or phenyl-lower alkyl in which the phenyl ring is optionally substituted by 1 or 2 C╬╣_₄ alkoxy groups ;

R is hydrogen or lower alkyl;

R₃ is (X)_m-S (0)_nR₄, COR₅, SR₆, or S (OH) (0)NR₇, wherein m is 0 or 1, n is 0, 1, or 2 , X is oxygen or lower alkylene, R is C₁-₄ alkyl, R₅ is hydroxyl, lower alkyl carbonyl, amino, or lower alkyl amino, and Rg and R₇ are lower alkyl; and

ring A represents an optionally substituted phenyl ring of formula

wherein Rg , Rg and Ro, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, lower alkylsulphinyl, loweralkylsulphonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano, phenyl, or phenyl substituted by 1 to 3 groups independently selected from lower alkyl, lower alkoxy and trifluoromethyl; or

ring A represents an optionally substituted thiophene ring of formula

wherein R_u is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, phenyl, or phenyl substituted by halogen, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising either said compound or said salt.

33. The method of claim 32, wherein the compound has formula II:

34. The method of claim 32, wherein the compound has formula III:

35. The method of claim 33, wherein the compound has formula IIA:

wherein R₃ is (X)_m-S (0)_nR₄, COR₅, SRg, or S(OH) (0)NR₇; and

10

(a) Rio is hydrogen and Rg is 6-lower alkoxy, 8-lower alkoxy, 5-halo or 6-halo;

(b) Rg is hydrogen and R₁₀ is halo; lower alkyl, lower alkoxy,

15 trifluoromethyl or lower alkyl-thio;

(c) R o is halo, lower alkoxy or lower alkyl and Rg is 6-lower alkyl, 6-lower alkoxy or 6-halo of a different value from Rio ; or

20

(d) Rg and Rio are hydrogen.

36. The method of claim 35, wherein Ri and R₄ are methyl.

25 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 R o is halo.

30 39. The method of claim 35, wherein Rg is 6-lower alkoxy and R₅ is halo or lower alkoxy.

40. The method of claim 35, wherein Rg is 6-halo and Rio is lower alkoxy.

35

41. The method of claim 37, wherein Rio is C₁-C₄ alkyl.

42. The method of claim 36, 37, 38, 39, 40, or 41, wherein R₃ is -(X)_m-S(0)_nR₄.

40

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

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 alkyl 5 amino .

48. The method of claim 36, 37, 38, 39, 40, or 41, wherein R₃ is SRg.

10 49. The method of claim 48 wherein Rg 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. 15

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.

20 54. The method of claim 34, wherein R₃ is C0R₅.

55. The method of claim 54, wherein R₅ is amino or lower alkyl amino.

25 56. A method for treating sexual dysfunction in humans and animals which comprises administering to a human or an animal in need of said treatment with an effective amount of l-methyl-3-methylsulphinyl-4-quinolone, 7-fluoro-l-methyl-3-methylsulphinyl-4-quinolone,

30 7-fluoro-l-methyl-4-oxo-l, 4-dihydroquinolone-3-carboxamide, 4-methyl-7-oxo-4 , 7-dihydrothieno [3, 2-b]pyridine-6-carboxa- mide, 4-methyl-6-methylsulphinyl-7 (4H) -thieno [3, 2-b] pyridinone, 7-chloro-l-methyl-3-methylsulphamoyl-4-quinolone, l-methyl-4-oxo-l, 4-dihydroquinol-3-yl methanesulphonate,

35 7-chloro-l-methyl-4-oxo-l, 4-dihydroquinoline-3-carboxamide, 7-fluoro-l-methyl-3-methylsulphonyl-4-quinolone, or 7-fluoro-l-methyl-3-methylthio-4-quinolone, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising either said compound or said salt.

40

57. The method of claim 32, 33, 34, 35 or 56, wherein said sexual dysfunction is erectile dysfunction.

58. The method of claim 57, wherein said sexual dysfunction is 45 penile erectile dysfunction in a human male.

59. The method of claim 58, wherein the compound is administered in unit dosage form.

60. The method of claim 59, wherein the amount of the compound is 5 1-500 mg.

61. The method of claim 60, wherein the amount of the compound is 5-100 mg.

10 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 15 treating sexual dysfunction in humans and animals which comprises formulating a compound of formula I:

25

Ri is hydrogen, lower alkyl optionally substituted by hydroxy or C╬╣-₄ alkoxyearbonyl, allyl, propynyl or phenyl-lower alkyl in which the phenyl ring is optionally substituted by 1 or 2 C╬╣_₄ alkoxy groups;

30

R₂ is hydrogen or lower alkyl;

R₃ is (X)_m-S (0)_nR₄, C0R₅, SR₆, or S(OH) (0)NR₇, wherein m is 0 or 1, n is 0, 1, or 2 , X is oxygen or lower alkylene, R₄ is

35 C₁-₄ alkyl, R₅ is hydroxyl, lower alkyl carbonyl , amino, or lower alkyl amino, and Rg and R₇ are lower alkyl; and

ring A represents an optionally substituted phenyl ring of formula

40

wherein Rg , Rg and Rio, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, lower alkylsulphinyl, loweralkylsulphonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano, phenyl, or phenyl substituted by 1 to 3 groups independently selected from lower alkyl, lower alkoxy and trifluoromethyl; or

ring A represents an optionally substituted thiophene ring of formula

wherein R_u is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, phenyl, or phenyl substituted by halogen, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable diluent or carrier.

64. The process of claim 63, wherein the compound has formula II:

65. The process of claim 63, wherein the compound has formula III:

6. The process of claim 64, wherein the compound has formula IIA:

wherein R₃ is (X)_m-S (0) _nR₄, COR₅, SRg, or S(0H)(0)NR₇; and

(a) Rio is hydrogen and R₉ is 6-lower alkoxy, 8-lower alkoxy, 5-halo or 6-halo;

(c) Rio is halo, lower alkoxy or lower alkyl and Rg is 6-lower alkyl, 6-lower alkoxy or 6-halo of a different value from

(d) Rg and R_i0 are hydrogen .