MXPA01006909A - Method of treating sexual disturbances - Google Patents

Abstract

The present invention is a method of treating sexual disturbances in humans and inducing mating in non-human mammals using the compounds of formula (A) in a dosage range where the sexually therapeutic amount is from about 0.2 thru 8 mg/person/dose and where the sexually mating amount is from about 0.003 thru 0.2 mg/kg/dose.

Description

METHOD FOR TREATING SEXUAL ALTERATIONS FIELD OF THE INVENTION The present invention is a method for treating sexual disorders using the compounds of U.S. Patent 5, 273, 975. 2. DESCRIPTION OF THE RELATED TECHNIQUE There are several diseases / conditions that directly affect the sexual lives of humans and animals. These include orgasmic disorders, lack of interest in sex and erectile dysfunction in males or males. In addition, there are several diseases / conditions that indirectly affect the sexual lives of human beings. There are few pharmaceutical agents to treat these diseases / conditions and others in clinical development. U.S. Patent 5,273,975 discloses that the compounds (A) of the present invention are useful for stimulating sexual activity and for alleviating impotence. The useful dose variation set forth in U.S. Patent 5,273,975 is "at least 10 mg to about 1200 mg per day." The dose variation operable in the present invention is considerably less. The compounds of U.S. Patent 5,273,975 have been used in clinical trials to prove their usefulness in the treatment of Parkinson's disease at a dose of 30 mg / person. The compounds (A) of the present invention are used at a dose of less than 8 mg in the treatment of the sexual disorders of the present invention. U.S. Patent 5,273,975 generically discloses compounds wherein the variable substituent "A" can be either a carbonyl group (-CO-) or a thiocarbonyl group (-CS-). U.S. Patent 5,250,534 discloses sildenafil (VIAGRA®). The compounds (A) of the present invention are very different chemically from sildenafil. International Publication O94 / 282902 discloses the use of sildenafil for the treatment of male impotence. U.S. Patent 4,127,118 discloses the int racavernous injection of a vasodilator to intensify an erection of the penis. PGE1 is a vasodilator and is sold as CAVERJECT® to treat male erectile dysfunction. The compounds (A) of the present invention are not prostaglandins and are not injected into the penis. Excerpts # 417 and 419 of the In t erna ti ona l Jo u rna l of Impo t in ce Rese a rch, 10 (Supplement 3), August 1998, state that apomorphine, which is available in several of the countries to treat Parkinson's disease is in the last stage of development as a sublingual formulation for the treatment of male erectile dysfunction. The compounds (A) used in the present invention are not apomorphine analogues. U.S. Patent 5,770,606 discloses the sublingual use of apomorphine to treat erectile dysfunction. U.S. Patent 5,541,211 discloses that yohimbine can be used to treat erectile dysfunction. The compounds of formula (A) are very different chemically as compared to yohimbine. U.S. Patent 4,801,587 discloses that phentolamine (VASO AX®) which is available in several of the countries for treating hypertension is also useful for treating erectile dysfunction. The compounds of formula (A) are very different chemically as compared to phentolamine. In addition, the compounds of the formula (A) do not apply neither topically to the penis nor intra-urethrally. U.S. Patent 5,773,020 teaches that intraurethral PGEl (MUSE) is useful for treating erectile dysfunction. The compounds (A) are not prostaglandins and neither are administered intraurethrally. The reports of Bra in Research, 55, 383-389 (1973) on the stimulating effect of sexuality of L-DOPA administered to male rats and joints that may be the reason that hypersexuality is occasionally observed in patients with Parkinson's syndrome during treatment with L-DOPA.

BRIEF DESCRIPTION OF THE INVENTION A method is described for treating sexual disorders in humans that need this treatment and which comprises administering a therapeutically and sexually effective amount of a compound of the formula (A) wherein Rif R2 and R3 are the same or different and are: -H, alkyl of d-C6, alkenyl of C3-C5, alkynyl of C3-C5, cycloalkyl of C3-C5, cycloalkyl of C4-C? 0, alkyl of C? -C6 substituted with phenyl, -NR1R2 wherein Ri and R2 are cyclized with the attached nitrogen atom to produce pyrrolidyl, piperidinyl, morphoninyl, 4-methyl piperazinyl or imidazolyl; X is: -H, alkyl of C? -C6, -F, -Cl, -Br, -I, -OH, Ci-Ce alkoxy, cyano, carboxamide, carboxyl, (Ci-Cß alkoxy) carbonyl; A is: CH, CH2, CH- (halogen) wherein the halogen is -F, -Cl, -Br, -I, CHCH3, C = 0, C = S, C-SCH3, C = NH, C-NH2 , C-NHCH3, C-NHCOOCH3, C-NHCN, S02, N; B is: CH2, CH, CH- (halogen) wherein the halogen is as defined above, C = 0, N, NH, N-CH3, D is: CH, CH2, CH- (halogen) wherein the halogen is as defined above, C = 0, O, N, NH, N-CH3; and n is 0 or 1, and where t.ttit is a single or double bond, with the conditions: (1) that when n is 0, and A is CH2, CH- (halogen) where the halogen is as defined previously, CHCH3, C = 0, C = S, C = NH, S02; then D is CH2, CH- (halogen) wherein the halogen is as defined above, C = 0, O, NH, N-CH3; (2) that when n is 0, and A is CH, C-SCH3, C-NH2, C-NHCH3, C-NHCOOCH3, C-NHCN, N; then D is CH, N; (3) that when n is 1, and A is CH2, CH- (halogen) wherein the halogen is as defined above, CHCH3, C = 0, C = S, C = NH, S02; and B is CH2, CH- (halogen) wherein the halogen is as defined above, C = 0, NH, N-CH3; then D is CH2, C = 0, O, NH, N-CH3; (4) that when n is 1, and A is CH, C-SCH3, C-NH2, C-NHCH3, C-NHCOOCH3, C-NHCN, N; and B is CH, N; then D is CH2, C = 0, O, NH, N-CH3; (5) that when n is 1, and A is CH2, CHCH3, C = 0, C = S, C = NH, S02, and B is CH, N; then D is CH, N; and pharmaceutically acceptable salts thereof for the human. Also disclosed is a method for inducing mating of a non-human mammal comprising administering a sexually matched amount of a compound of the formula (A) and the pharmaceutically acceptable salts thereof. Furthermore, a method for treating a state of sexual deficiency in a human being having epilepsy, craniopharyngioma, hypogonadism or who has had a hysterectomy or oophorectomy, his trectomy or oophorectomy which comprises administering a therapeutically and sexually effective amount of a compound of the formula (A) and pharmaceutically acceptable salts thereof. Additionally, a method for increasing desire, interest or sexual performance in a human being who desires the same and which comprises administering a sexually useful effective amount of a compound of the formula (A) and pharmaceutically acceptable salts thereof is disclosed. The (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [, 5, l-i j] quinolin-2 (1H) -thione and the pharmaceutically acceptable salts thereof are exposed.

DETAILED DESCRIPTION OF THE INVENTION The present invention includes four separate methods for treating sexual problems. The first is a method for treating sexual disorders in a human being that needs this treatment and which comprises administering a sexually therapeutic amount of a compound of the formula (A) and its pharmaceutically acceptable salts. Second, there is included a method for inducing mating of a non-human mammal comprising administering a sexually matched amount of a compound of the formula (A) and the pharmaceutically acceptable salts thereof. Third, a method to treat a state of sexual deficiency is included in a human being who has a disease / condition, the primary pathology that is not related to a sexual dysfunction, although it indirectly produces reduced sexual functioning. Diseases / conditions that can cause this type of sexual dysfunction include epilepsy, craniopharyngioma, hypogonadism or who has had a hysterectomy, oophorectomy, historectomy or oophorectomy. Fourth, there are individuals who do not seem to have any sexual disorders or illness / conditions that will have an adverse effect on their sex lives, but nevertheless wish to increase their desire, sexual interest or sexual performance and who will benefit from using the compounds of the formula (A). The compounds of the formula (A), and pharmaceutically acceptable salts, which are useful in the method of treatment of the present invention are known, see U.S. Patent 5,273,975. It is preferred that the pharmaceutically acceptable salt be selected from the group consisting of salts of the following methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH3- (CH2) n, -COOH acids wherein n is from 0 to 4, HOOC- (CH2) N-COOH wherein n is as defined above. It is preferred that the compound of the formula (A) have n to be 0, A to be C = 0 and D to be NH. It is more preferred that the compound of the formula (A) be any of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) - ona or (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2 (1H) -thione. It is more preferred that the compound of the formula (A) be (5R) - (methylamino) -5,6-dihydro-H-imidazo [4, 5, li j] quinolin-2 (1H) -one ( Z) -2-butenedioate (1: 1). A preferred process for producing the preferred compounds within the scope of the compounds of the formula (A) is shown in PREPARATION 1 and the numerical EXAMPLES as well as in the DIAGRAM A. Non-human mammals include commercial animals (horses, goats, pigs, sheep and transgenic mice) and zoo animals (panda bears, elephants, zebras, lions, tigers, monkeys and apes), animals for sport (horses and dogs) ) as well as domestic animals (dogs and cats). The human and non-human mammals will both be either male or female. The sexual alterations in humans treated by the present invention include hypoactive sexual desire disorders, female sexual arousal disorder, male erectile disorder, female orgasmic disorder and male orgasmic disorder. The sexual alterations of the present invention are known to those skilled in the art and are suitably described by a medical professional. In particular, see Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV), American Psychiatric Association, Washington DC, 1994 as well as the DSM-IV Guidebook, American Psychiatric Press, Inc., Washington DC, 1995. When mating is induced in non-human mammals it is desired to treat a mating pair member in some cases. It is more likely to be the situation where previous pair mating attempts have failed and a member of the pair is known to have had previous offspring. In this case, this member would be treated advantageously. In other cases, it would be desirable to treat both male and female before early mating. The latter is more likely to be advantageous when mating is attempted between animals without sexual experience and before attempts at pairing the pair have failed. The compounds of the formula (A) are also useful for treating human beings whose disease, condition or primary situation is not one of sexual dysfunction, but instead the disease or primary condition leads to a secondary clinical situation wherein the experiences of the being human (male or female) decrease desire, interest and / or sexual function. These diseases include epilepsy, craniopharyngioma, hypogonadism, or who have had an erectomy or oophorectomy, hysterectomy, or oophorectomy, and can cause a state of sexual deficiency that is treated in the same way as individuals who have one or more of the five sexual disorders identified above. The sexually effective therapeutic amount is the same and is administered in the same way by the same routes of administration as for those humans who have sexual alterations. The compounds of the formula (A) are also useful for increasing sexual desire, interest or performance in individuals who have not had any of the five sexual disorders or any of the following diseases or conditions, epilepsy, craniopharyngioma, hypogonadism or who have had a hysterectomy, oophorectomy, hysterectomy or oophorectomy. These individuals are treated in the same way as those who have any of the five sexual disorders. The sexually effective amount useful for use herein is the same as the sexually effective therapeutic amount for those with sexual disorders. The therapeutically effective and sexually useful amount is administered in the same way by the same routes of administration as for those humans who have sexual alterations. In (1) the treatment of sexual alterations of humans, (2) induction of mating of non-human mammals, (3) treatment of humans whose disease or primary condition leads to a secondary clinical situation where human experiences decrease the desire, interest and / or sexual function and (4) increase of desire, interest or sexual performance in individuals who do not have any of the above problems, the compounds of the formula (A) in the form of appropriate pharmaceutical dosage known for a route of administration can be administered orally, intra-nasally, buccally, int-pulmonary, parenterally and rectally. For the treatment of humans, it is preferred that the compound of the formula (A) be administered orally, intra-nasally, buccally and intra-pulmonarily; it is more preferred that the compounds of the formula (A) be administered orally. For the treatment of non-human mammals, it is preferred that the compounds of the formula (A) are administered orally, parenterally and rectally; it is more preferred that the compounds of the formula (A) be administered orally.

The sexually therapeutically effective, operable amount, as well as the sexually useful, operable effective amount of the compounds of the formula (A) is between 0.2 and 8 mg / person / dose. It is preferred that the sexually effective therapeutic amount and the sexually useful effective amount be between about 0.5 and 5 mg / person / dose. It is more preferred that the sexually effective therapeutic amount and the sexually useful effective amount be between about 1 and 3 mg / person / dose. If doses lower than this are used, the desired effect will not be obtained. If doses higher than this are used, undesirable side effects occur and the desired effect will not be obtained. The term "therapeutic" is used in the treatment of a disease or condition; the term "useful" is used when the treatment of human beings who do not have one of the above diseases or conditions that cause sexual dysfunction but are considered normal and wish to increase their desire, interest or sexual performance. The amount for operable sexual pairing of the compounds of the formula (A) is between about 0.003 and 0.2 mg / kg / dose. It is preferred that the amount for sexual intercourse be between 0.01 and 0.125 mg / kg / dose. It is preferred that the amount for sexual intercourse be between 0.025 and 0.075 mg / kg / dose. To obtain the desired effect in humans, the sexually effective therapeutic amount or the sexually useful effective amount of the compounds of the formula (A) will be administered between about 10 minutes and 8 hours before sexual activity. It is preferred that the compounds of the formula (A) are administered between about 0.5 hour and 1 hour before sexual activity. It is more preferred that the compounds of the formula (A) are administered at about 0.5 hour before sexual activity. Sexual activity includes sexual intercourse with or without orgasm, ejaculation, masturbation and sexual erotic stimulation. To obtain the desired mating effect in non-human mammals, the compounds of the formula (A) are administered between about 10 minutes and 8 hours before mating. It is preferred that the compounds of the formula (A) are administered between about 10 minutes and 1 hour before mating. It is more preferred that the compounds of formula (A) are administered between about 10 minutes and 0.5 hours before mating. It is preferred that humans do not have Parkinson's disease. It is preferred that the administration in humans of the compounds of the formula (A) does not produce postural hypotension. The present invention is further illustrated by EXAMPLES A-P. The exact dose of the compounds of the formula (A) which are useful in the four methods of this invention depends on the route of administration, the particular compound used, the particular condition to be treated, the severity of the condition to be treated, the age, weight, general physical condition of the patient in particular, another medication that the individual may be ingesting as is known to those skilled in the art and which can be administered with greater precision by measuring the blood level or concentration of the compound and / or metabolite in the patient's blood and / or the patient's response to the particular condition that will be treated. The compounds of the formula (A) can also be used with other agents in (1) the treatment of the five sexual alterations, (2) in inducing the mating of a non-human mammal, (3) in the treatment of a state of sexual deficiency in humans that have one or more of the following diseases / conditions-epilepsy, craniopharyngioma, hypogonadism or who has had a hysterectomy or oophorectomy, hysterectomy or oophorectomy or (4) increase sexual desire, interest or performance in a human being who does not have no sexual alteration or one of the previous diseases / conditions. It is known that relaxation of vascular smooth muscle is necessary for vascular fullness of the penis and clitoris during normal male and female sexual behavior and that agents that promote vascular fullness of the penis and clitoris are useful for intensifying motivation, desire and sexual performance. Agents that affect vascular smooth muscle relaxation include phosphodiesterase type 5 inhibitors such as sildenafil (Viagra) and IC0S-351; the type 3 phosphodiesterase inhibitors, such as milrinone; non-selective phosphodiesterase inhibitors such as papaverine; nitric oxide donor drugs such as linsidomine; Adrenergic receptor antagonists; Type 1 alpha such as phentolamine produce relaxation of the vascular smooth muscle of the human penis in the presence of norepinephine; alpha-2 type adrenergic receptor antagonists such as yohimbine; the prostaglandin receptor agonists such as PGEl (CAVERJECTMR and MUSEMR injection); as well as vasoactive intestinal polypeptide agents (VIP). These agents for vascular smooth muscle relaxation are administered orally, parenterally, buccally, rectally, intranasally, intrapulmonally, intraurethrally or topically. The preferred route of administration will depend on the specific properties of the drugs to be combined with the compounds of the formula (A). The preferred route of administration for a type 3 or 5 phosphodiesterase receptor inhibitor and an alpha 1 or 2 adrenergic receptor inhibitor is oral. The preferred route of administration for a prostaglandin E receptor agonist, non-specific phosphodiesterase inhibitor, nitric oxide donor, and VIP is intravenous injection or intraurethral topical administration in male mammals or topical administration in the vulva of the female.

The dose of some agents for vascular smooth muscle relaxation is known to those skilled in the art, especially for sildenafil (VIAGRAM® Tablets), PGEl (CAVERJECTMR and MUSEMR Injection). For yohimbine, the dose is between approximately 1 and 10 mg orally and can be administered approximately three to four times a day as a routine. For phentolamine the dose is between 2 and 40 mg orally or by mouth patch or between 0.5 and 5 mg when administered by int racavernosa injection. For papaverine, the dose is between approximately 4 and 20 mg administered by int racavernosa injection. For VIP the dose is between approximately 5 and 60 mg when administered by int racavernosa injection. When the compounds of the formula (A) are used together with the vascular smooth muscle relaxation agents, the compounds of the formula (A) must be administered within the time frame discussed above. The sexually effective time period for the administration of vascular smooth muscle relaxation agents is known for sildenafil (VIAGRAM® Tablets), PGEl (CAVERJECTMR and MUSEMR Injection). The sexually effective time period for the administration of yohimbine is between about 0 and 4 hours before sexual activity; for phentolamine it is between about 0 and 4 hours before sexual activity when administered orally or buccally and between about 0 and 2 hours when administered by intracavernosal injection; for papaverine and VIP is between approximately 0 and 2 hours before sexual activity. When used in combination, the preferred combinations are (5R) (methylamino) -5,6-dihydro-4H-imidazo [4,5, l-ij] quinolin-2 (lH) -one and sildenafil, (5R) (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2 (1H) -one and PGEl, (5R) -5- (methylamino) -5,6-dihydro-4H -imidazo [4, 5, 1-ij] quinolin-2 (1H) -thione and sildenafil or (5R) -5- (methyl amino) -5, β-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -thione and PGEl.

DEFINITIONS AND CONVENTIONS The following definitions and explanations are for the terms as used throughout this document that include both the specification and the claims.

I. CONVENTIONS FOR THE FORMULAS AND DEFINITIONS OF THE VARIABLES The content of carbon atoms of the variable substituents is indicated in one of two ways. The first method uses a prefix for the full name of the variable such as "C1-C4", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C 1 -C 4 alkyl" represents alkyl of 1 to 4 carbon atoms, (including the isomeric forms thereof unless an express indication to the contrary is given). Whenever this simple prefix is provided, the prefix indicates the total content of carbon atoms of the variable being defined. In this way, C2-C4 alkoxycarbonyl describes a group CH3- (CH2) n-0-C0- where n is zero, one or two. By the second method, the content of carbon atoms of only each portion of the definition is indicated separately by enclosing the designation "Ci-Cj" in parentheses and placing it immediately before (without any space) before the definition portion. which is being defined. By the optional convention (C1-C3) alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because "C1-C3" refers only to the content of carbon atoms of the alkoxy group. Similarly, while both C2-C6 alkoxyalkyl and (C1-C3) alkoxy (C1-C3) alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ because the above definition allows any Alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits any of those groups to 3 carbon atoms.

II. DEFINITIONS All temperatures are given in degrees Celsius. TLC refers to thin layer chromatography. HPLC refers to high pressure liquid chromatography. Saline refers to a saturated aqueous solution of sodium chloride. Chromatography (column and flash chromatography) refers to the purification / separation of the compounds expressed as (support, eluent). It should be understood that suitable fractions are pooled and concentrated to provide the desired compounds. NMR refers to nuclear magnetic resonance (proton) spectroscopy; chemical shifts are reported in ppm (d) of the downfield of tetramethylsilane. CMR refers to magnetic resonance spectroscopy C-13 chemical shifts are reported in ppm (d) of the descending field of TMS. Pharmaccally acceptable refers to those properties and / or substances that are acceptable to the patient from a pharmacological / toxicological point of view and to the pharmaccal manufacture of the chemical from a physical / chemical point of view with respect to the composition, formulation, stability, Patient acceptance and bioavailability. Pharmaccally acceptable anionic salts include salts of the following methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic acids, CH3- (CH2) n -COOH wherein n is from 0 to 4, HOOC - (CH2) N-COOH where n is as defined above. (Z) -2-butenedioate refers to maleate.

When solvent pairs are used, the proportions of solvents used will be in volume / volume (v / v). When the solubility of a solid in a solvent is used, the ratio of the solid to the solvent is weight / volume (w / v). Sexual alteration refers to a hypoactive sexual desire disorder, female sexual arousal disorder, male erectile disorder, female orgasmic disorder, and male orgasmic disorder as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) ), American Psychiatric Association, Washington DC, 1994 as well as the DSM-IV Guidebook, American Psychiatric Press, Inc., Washington DC, 1995. These definitions of particular disease states are as defined in 1994 and 1995. All five " Sexual alterations "were still defined on the same day. In the future, the terms of these sexual alterations may change, although one skilled in the art will know and understand that the same disease states are the same. Sexual activity includes sexual intercourse with or without orgasm, ejaculation, masturbation and sexual erotic stimulation.

EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the above description, practice the present invention to its highest degree. The following detailed examples describe how to prepare the various compounds and / or perform the various processes of the invention and are presented simply as illustrative and not as limitations of the above description in any way whatsoever. Those skilled in the art will readily recognize suitable variations of the procedures for the reagents as well as for the reaction conditions and techniques.

PREPARATION 1 (R) -Naproxen Chloride R-naproxen (260 g), methylene chloride (3.33 kg) and DMF (8.2 ml) are added to a reactor. The oxalyl chloride (191.8 g) is added slowly to this mixture. After adding the oxalyl chloride, the suspension is stirred at 5 to 10 ° and then heated slowly from 20 to 25 °. The resulting mixture is concentrated to remove methylene chloride, branched octane is added to the concentrate and the mixture is concentrated again. More branched octane is added to the concentrate and the mixture is cooled to 0 ° and stirred to crystallize. The crystal suspension is filtered, the crystalline cake is washed with octane and dried at 20-25 ° to obtain the title compound. The filtrate from the first crop is concentrated, branched octane is added and the mixture is cooled and stirred to obtain a second crop of the title compound. The suspension is filtered, the crystalline cake is washed with branched octane and dried at 20-25 °.

EXAMPLE 1 1 -Benzyl-4H-imidazo [4, 5, l-ij] quinolin-2 (lH) -one (II) A mixture of 4H-imidazo [4, 5, li j] quinolin-2 (lH) - Ona (I, J. He t erocycl ic Ch em., 1 9, 837-49 (1982), l.Og, 5.8 mmol) in DMT (lOml) is cooled to 0 ° and treated with potassium t-butoxide. in THF (1.98 M, 3.2 ml, 6.3 mmol) maintaining the reaction temperature at 0 °. The resulting mixture is stirred at 0 ° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is then added while maintaining the reaction temperature at 0 °. After 1 hour, the mixture is divided with methyl t-butyl ether (MTBE) from the water followed by various washes with water. The MTBE phase is concentrated under reduced pressure. The concentrate is cooled to 0 °, filtered and washed twice with MTBE at 0 °. The product is dried at 50 ° under reduced pressure with a nitrogen purge to provide the title compound, CMR (CDC13, 100 MHz) L 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37.

EXAMPLE 2 (5R *, 6R *) -l-benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo [4, 5, l-ij] quinolin-2 (1H) -one (III) l-Benzyl-4H-imidazo [4, 5, li j] quinolin-2 (1H) -one (II, EXAMPLE 1,240 g), acetonitrile (1086 kg), water (227 ml) and fluoboric acid (48.5) %, 13.4 g) are mixed and cooled from 0 to 5 °. Dibromantine (163.5 g) is suspended in acetonitrile and added to the reaction mixture. The reaction is carried out for about 3 hours from 0 to 5 °. After the reaction is complete, methyl t-butyl ether is added for about 45 minutes keeping the reaction temperature in the cell below 10 °. The suspension is cooled from -10 to -15 °, stirred for one hour and then filtered. The product is washed with pre-cooled methyl t-butyl ether, dried under nitrogen at 40 ° to provide the title compound, CMR (CDCl 3) d 156.0, 137.8, 130.5, 129.6, 129.3, 129.1, 126.6, 123. 6, 122.5, 119.6, 110.4, 69.9, 49.6, 47.7, 46.9 and 43.8.

EXAMPLE 3 (2R) -2- (6-methoxy-2-naphthyl) propanoate of (5S, 6S) -1-Benzyl-5-bromo-2-oxo-1, 2,5,6-tetrahydro-4H-imidazo [4, 5, l-ij] quinolin-6-yl (IVA) and ( 2R) -2- (6-methoxy-2-naphthyl) propanoate of (5R, 6R) -l-benzyl-5-bromo-2-oxo-1, 2,5,6-tetrahydro-4H-imidazo [4, 5,1-ij] quinolin-6-yl (IVB) To the reactor (5R, 6R) -1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (III, EXAMPLE 2, 143 g), methylene chloride (3.136 g), N-methyl morpholine (100.2 g) and -dimet ilaminopyridine (497 mg) and the mixture is cooled from 0 to 5 °. The (R) -Naproxen chloride (PREPARATION 1, 118.5 g) dissolved in methylene chloride (694 ml) is added to the reactor for about 1 hour and the mixture is stirred at 0 to 5 ° to complete the reaction. If necessary, additional naproxen chloride is added to complete the reaction. The potassium carbonate solution diluted with water is added to the mixture.

The aqueous phase is extracted with methylene chloride and the combined methylene phase is washed with water. The washed mixture is concentrated by vacuum distillation and solvent exchange is carried out with ethyl acetate. The concentrate is cooled to -10 ° and stirred. The crystalline suspension is filtered and the crystalline cake is washed with pre-cooled methyl t-butyl ether and dried at 50 ° to give the title compound in solid form, (2R) -2- (6-methoxy-2-naphthyl) (5S, 6S) -l-benzyl-5-bromo-2-oxo-l, 2, 5, 6-tetrahydro-4H-imidazo [4, 5, 1-ij] quinolin-6-yl propanoate (VAT) , CMR (CDC13) d 173.2, 157.8, 153.4, 136.1, 134.6, 133.7, 129.2, 128.8, 127.8, 127.8, 127.6, 127.2, 125.9, 125.9, 125.6, 121.5, 121.4, 119.1, 113.2, 109.0, 105, 105.6, 69.2, 55.3, 45.4, 45.2, 42.5, 41.7 and 18.3. The unwanted isomer, (2R) -2- (6-methoxy-2-naphthyl) propanoate of (5R, 6R) -l-benzyl-5-bromo-2-oxo-1, 2, 5, 6-tetrahydro- 4H-imidazo [4, 5, li j] quinolin-6-yl (IVB) is in the filtrate and can be recovered by means well known to those skilled in the art, (5R, 6R) -l-benzyl-5- hydroxy-6- (methylamino) -5,6-dihydro-4 H -imide zo [4,5, l-ij] quinolin-2 (lH) -one, CMR 173.2, 157.9, 153.4, 136.1, 135.0, 133.8, 129.2, 128.9, 128.8, 127.8, 127.6, 127.4, 125.8, 125.8, 125.7, 121.6, 121.5, 119.3, 113.1, 109.1, 105.7, 68.7, 55.3, 45.3, 45.2, 42.2, 41.3 and 18.1 d.

EXAMPLE 4 (5R, 6R) -l-benzyl-5-hydroxy-6- (methylamino) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -one (V ) The (2S) -2- (6-methoxy-2-naphthyl) propanoate of (5S, 6S) -1-Benzyl-5-bromo-2-oxo-1, 2,5,6-tetrahydro-4H- Imidazo [A, 5, 1-ij] quinolin-6-yl (IVA, EXAMPLE 3, 110 g) is suspended in acetonitrile (1.297 g). After adding aqueous methylamine (40% by weight, 327 g), the reaction is carried out for about 12 hours at about 30 °. After the reaction is complete, the mixture is concentrated and ethyl acetate is added. Dilute hydrochloric acid is added to provide the water soluble salt of the title compound. The by-product (acetamide impurity R-naproxen) is insoluble in water and remains in the ethyl acetate phase. The extractions and extra washes are carried out for a greater separation of the impurity (acetamide of naproxen) with a minimum loss of the desired product. The sodium hydroxide solution is then added to the aqueous phase and the hydrochloride salt of the title compound is converted to the free base.

The free base is less soluble in water and extracted in ethyl acetate. The product mixture is concentrated and the solvent is exchanged with ethyl acetate to remove the water. The crystallization is carried out by adding branched chain octane and cooling the mixture. The resulting suspension is filtered, washed and dried at 50 ° to provide the title compound, CMR (CDC13) d 153.7, 136.3, 128.7, 127.8, 127.7, 125.7, 121.3, 119.9, 118.6, 107.5, 66.2, 60.1, 45.1, 42.6 and 34.0.

EXAMPLE 5 (7aS, 8aR) -4 -benzyl-8-methi -7, 7a, 8, 8a-tetrahydroacirene [2,3c] imidazo [4,5,1-ij] quinolin-5 (4H) -one (VI ) (5R, 6R) -l-benzyl-5-hydroxy-6- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (V, EXAMPLE 4, 70 g) and THF (1.389 g) are concentrated to remove any moisture with the distillate as a precaution due to the reactivity of n-butyl lithium with respect to water. The mixture is cooled to -10 ° and n-butyl lithium is added to produce the lithium salt of the starting material with the formation of the n-butane by-product in an exothermic reaction. Benzene sulfonyl chloride is added slowly to produce the benzene sulfonate in an exothermic reaction. The reaction mixture is heated to 20-25 ° to complete the reaction. Aqueous potassium carbonate solution is added to purify the benzene sulfonic acid and the mixture is stirred to allow crystallization. Water is added to complete the crystallization, the suspension is stirred, cooled and filtered. The crystalline cake is washed with water followed by branched chain octane and dried at 40 to 50 ° to provide the title compound, CMR (CDC13) d 154.1, 136.3, 128.6, 127.9, 127.6, 124.3, 120.7, 119.7, 107.4 , 46.7, 44.9, 40.7, 38.1 and 37.6.

EXAMPLE 6 (SR) - (methylamino) -5,6-dihydro-4H-imidazo [4,5, l-ij] quinolin-2 (1 H) -one (VII) A mixture of (7aS, 8aR) -4- benzyl-8-met-il-7, 7a, 8, 8a-tetrahydroazirene [2, 3-c] imidazo [4, 5, 1-ij] quinolin-5 (4H) -one (VI, EXAMPLE 5, 40 g) , t-amyl alcohol (42.4 g) and anhydrous ammonia (1,200 g) is treated with lithium at -33 °. After the addition of lithium is complete, the reaction mixture changes from a yellow suspension to a dark blue mixture. This dark blue mixture is stirred for 30-60 minutes and then stopped with the addition of water. The cooling is removed from the condenser and the ammonia is allowed to evaporate. The residue is dissolved in methanol. This mixture is then concentrated to dryness to provide the title compound, which is carried out directly to the next step without isolation.

EXAMPLE 7 (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, l-ij] quinolin-2 (1H) -one (1: 1) ( VIII) The (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (VII, EXAMPLE 6, 28.0 g) is dissolved in water and the pH is adjusted to 10 with the addition of hydrochloric acid. The mixture is applied in portions to a column of XAD-16 resin that is eluted first with water and then with ethanol. The inorganic salts are eluted from the first column with the desired product eluted with ethanol. The ethanol eluted from the column is treated with maleic acid and the water level is decreased until the ethanol acetalic distillation. The precipitated product is isolated by filtration, rinsed with ethyl acetate and dried to give the title compound, CMR (DMSO-d6) d 167.6, 153.9, 136.4, 127.1, 121.5, 119.6, 114.1, 107.5, 51.9, 31.3 and 26.5.

EXAMPLE 8 (5R) -5- (Methylamino) -5,6-dihydro-4H-imidazo [4, 5, l-ij] quinolin-2 (1H) -thione A mixture of (5R) - (methylamino) - 5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (VII, EXAMPLE 6, 15.0 g, 73.8 mmol) and tetraphosphorus decasulfide (36.1 g, 81.2 mmol) in pyridine (300 mL) is heated in a 125 ° oil bath under nitrogen. The reaction is stirred for 5 hours. The mixture is cooled to 20-25 ° and the pyridine is removed under reduced pressure. Sodium hydroxide (2.2 N, 200 mL) is added. Sodium hydroxide (1 N) is then added. The mixture is saturated with sodium chloride and extracted with methylene chloride (2.5 L, in portions). The organic phase is taken up in silica gel (40 g) and purified by column chromatography (silica gel, 225 g, methanol / methylene chloride, 3.5-5.0 / 96.5-95) to give a solid. Recrystallization of this material from methanol / ethyl acetate / hexanes gives the title compound, m.p. = 210-213 °; IR (variation) 2940, 2907, 2884, 1483, 1458, 1391, 1366, 1354, 1254, 1239, 1229, 895, 762, 734, 630 cirT1; NMR (300 MHz, CDC13) 7.12, 7.03, 7.00, 4.30, 3.96, 3.30-3.50, 3.15, 2.88 and 2.57 d; MS (El, m / z) 219 (M +), 190, 189, 187, 186, 164, 163, 155, 145; HRMS (FAB) calculated for CnH? 3N3S (MH +) = 220.0908, found 220.0904.

EXAMPLE 9 (5R) -5- (Methylamino) -5,6-dihydro-4H-imidazo [4,5, l-ij] quinoline-2 (1 H) -thione malate A mixture of maleic acid (0.317 g) is added , 2.36 mmol) in a minimum amount of methanol (~1 mL) to a mixture of (5R) -5- (meth i lamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin -2 (1H) -thione (EXAMPLE 8, 0.493 g, 2.25 mmol) in methylene chloride. The resulting solid is collected by filtration to provide the title compound, m.p. = 195-196 °; [α] 25 D = -60 ° C 0.93, methanol); GO (variation) 3140, 3112, 3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389.1361, 1220, 868 and 747 cm "1; NMR (300 MHz, CD3OD) 7.20-7.30, 7.10-7.20 , 6.26, 4.49, 4.31, 4.05-4.20, 3.47, 3.28 and 2.83 d; CMR (100 MHz, DMSO-d6 + CD3OD) 170.4, 169.4, 136.6, 131.1, 130.9, 125.1, 122.1, 116.2, 109.6, 53.9, 43.1 , 31.9 and 27.2 d; MS (ESI, m / z) 220.1 (MH +).

EXAMPLE A Hypoactive sexual desire disorder in a female patient A 24-year-old female patient weighing 44 kg is referred by her psychologist for evaluation and for medical treatment of a hypoactive sexual desire disorder. The patient recently began cohabiting with a 28-year-old man. She consulted a clinical psychologist due to anguish over frequent arguments with her partner. These arguments related to her frustration are because her partner is not willing to marry her and her partner's accusations that she is sexually irresponsible and "bored in bed." The patient reports that although she wishes to continue the relationship, she has little or no interest in sexual activity with her partner. The partner initiates all the sexual activity in the relationship and she fulfills it in such a way that the relationship will continue. She states that her partner wants a sexual intercourse approximately once a day. Occasionally, the frequency of the couple's sexual intercourse is at most twice a day. She reports that she has no sexual fantasies since the present relationship began. The patient had an earlier relationship with a man that lasted 3 years and involved sexual activity that she found sexually exciting and satisfying. The patient had recently had a physical examination by her family physician, the findings of which were not considerable. She currently does not take prescription drugs other than low-dose birth control pills. She does not routinely use medications without a prescription or alcohol and refuses to take toxic drugs. The patient was diagnosed as having a Hypoactive Sexual Desire Disorder of acquired fit due to a situation factor (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 1994). He was prescribed (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (1: 1) at 1 mg / dose to be taken 0.5 hours before the patient intends to participate in a sexual activity. The patient is instructed to use the drug on a daily basis, if she and her partner want sexual activity at this frequency. She is also instructed that she can sometimes use the drug twice in a single day if this is the attempted frequency of intercourse. The patient is examined after one month. She reports that she uses the drug once and occasionally twice a day. She reports that she has sexual fantasies 3 to 4 times a week, occasionally initiates sexual activity with her partner, and enjoys an improved sexual relationship with her partner. She reports that she and her partner argue less often and that her partner does not accuse her of being uninterested in sexual relationships. The patient is instructed to continue using the drug.EXAMPLE B Disorder of female sexual arousal in a female patient A 22-year-old female patient weighing 64 kg complains of vaginal dryness and mild discomfort during sexual intercourse. The patient recently started a relationship with a 35-year-old man. His partner complained of vaginal dryness and poor vaginal expansion during sexual intercourse. Her partner has made several comments regarding this during the previous two months and the patient is concerned that her partner is dissatisfied with her lack of sexual response and can end the relationship. The patient reports that she wants to continue the relationship. The patient has had several previous sexual relations. She reports that vaginal dryness and some discomfort with vaginal intercourse has occurred during her past sexual intercourse. When questioned, it indicates that she has little or no feeling of sexual arousal during intercourse. The patient indicates that she has sexual fantasies several times a week. She finds her current partner attractive and sexually desirable. She indicates that she masturbates approximately once a week. During these episodes she usually has an orgasm. Lubrication is not a problem when she masturbates. The patient has recently had a physical examination by her family doctor, the findings of which are not considerable. She currently does not take prescription drugs other than low-dose birth control pills. She does not routinely use medications without a prescription or alcohol and refuses to take toxic drugs. The patient is diagnosed as having a female sexual arousal disorder that is situationally due to psychological factors (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 1994). He was prescribed (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2 (1H) -one (1: 1) at 3 mg / dose to be taken 0.5-1 hour before the patient intends to participate in sexual activity. The patient is instructed that she can use the drug on a daily basis, if this is the frequency of sexual activity intended. The patient is examined after one month. She reports that she uses the drug before copulation. She reports that vaginal dryness is no longer a problem and that she has no pain during the initiation of vaginal penetration by her partner. She enjoys an improved sexual relationship with her partner. The patient is instructed to continue using the drug.

EXAMPLE C Male erectile disorder A 56-year-old male patient of 56 years of age has been married for 20 years. He complains that during the past six months he has had difficulty getting an erection until sexual intercourse is complete. He develops an adequate erection at the beginning of sexual activity but detumescence occurs when he tries to penetrate. His wife is his only current sexual partner. He reports that his wife is patient and understanding of his problem but that he is worried, feels he is a failure and his anger grows progressively and he feels bad about his inability to maintain an erection. He masturbates approximately twice a month. During masturbation, he is usually able to maintain an erection until he ejaculates. The patient recently had a physical examination by his family doctor. The significant findings were a supine diastolic blood pressure of 94 mm of mercury and a total plasma cholesterol level of 230 mg / dl. He was instructed to follow the dietary recommendations of the American Heart Association and reduce his body weight by 5 kg. Currently he does not take prescription drugs. He does not routinely use medications without prescription or alcohol and denies taking toxic drugs. It was diagnosed that the patient has Male Erectile Disorder that is acquired and situational. It is more likely that the etiology is due to psychological factors, although combined factors, for example, mild hypertension or atherosclerosis, can contribute (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 1994). He was prescribed (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, l-ij] quinolin-2 (1H) -one (1: 1) to 3 mg / dose to be taken 0.5 hours before the patient intends to participate in the sexual relationship. The patient is instructed that he or she can use the drug on a daily basis, if this is the intended frequency of sexual activity. The patient is examined after one month. He reports that he uses the drug before copulation. He reports that he maintains an erection during a satisfactory period after vaginal penetration in almost every attempt at intercourse. He usually experiences intra-vaginal ejaculation. The patient and his wife consider that the quality of their sexual relationship was considerably improved. The patient is instructed to continue using the drug.

EXAMPLE D Female Orgasmic Disorder A 22-year-old female patient weighing 50 kg who was married three months before presenting for treatment. She complains of not having an orgasm during sexual activity with her husband even when she enjoys the experience and becomes sexually aroused during intercourse. She was not sexually active before getting married. She reports that her husband had multiple premarital partners and that he reports that all of her past partners had orgasms. The patient is upset by her inability to have orgasms and believes she is a bad wife. In the interrogation she says that she is "too fat" although her weight is adequate for her height. She does not masturbate. The patient recently had a physical examination by her family doctor, the findings of the same were not considerable. Currently, he does not take prescription drugs other than low birth control pills. She does not use drugs without a prescription or alcohol and denies taking toxic drugs. It was diagnosed that the patient had a Female Orgasmic Disorder that is situational due to psychological factors (Diagnostic and Statistical Manual of Mental Desorders, Fourth Edition, 1994). (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [, 5, li j] quinolin-2 (1H) -one (1: 1) to 1 was prescribed. mg / dose to be taken approximately 0.5 hours before the patient intends to participate in sexual activity. The patient is instructed that she can use the drug on a daily basis, if this is the intended frequency of sexual activity. The patient was examined after two months. She says she uses the drug before copulation. She says she has an orgasm during sexual intercourse most of the time. Enjoy an improved sexual relationship with your partner. She is advised to continue using the drug for about six more months, then stop taking the drug for a period of two months to determine if she now believes she is capable of having orgasms in the absence of drug therapy.

EXAMPLE E Male Orgasmic Disorder A 40-year-old man weighing 80 kg has been married for 15 years. He complains that he has begun to have difficulty in achieving an orgasm during vaginal intercourse with his wife. In most cases he is unable to ejaculate during sexual intercourse. Infrequently, he is able to ejaculate during sexual intercourse, but only after a prolonged vaginal intercourse. He indicates that this has been happening for at least three months and that he is frustrated and upset about the situation. He also comments that his wife finds the prolonged intercourse he requires to ejaculate uncomfortable and has begun to avoid sexual intercourse. He comments that he ejaculates normally when he masturbates. The patient recently had a physical examination by his family doctor, the findings of which were not considerable. Currently he does not take prescription drugs. He does not use drugs without a prescription or alcohol and denies taking toxic drugs. It was diagnosed that the patient had Male Orgasmic Disorder that is acquired and situational due to psychological factors (Diagnostic and Statistical Manual of Mental Desorders, Fourth Edition, 1994). He was prescribed (Z) -2-butenedioate of (5R) (methylamino) -5,6-dihydro-4H-imidazo [, 5, li j] quinolin-2 (1H) -one (1: 1) at 3 mg / dose to be taken 0.5-1 hours before the patient intends to participate in a sexual activity. The patient was instructed that he can use the drug on a daily basis, if this is the intended frequency of sexual activity. The patient was examined after one month. On this visit he comments that he now ejaculates during vaginal intercourse on all occasions. The patient and his wife feel that the quality of their sexual relationship has improved markedly. The patient is instructed to continue using the drug.

EXAMPLE F Mating of commercially valuable animals A male giant Giant Panda, on temporary loan from a foreign zoo, is desired to have offspring with an adult female Giant Panda, who normally resides at the zoo. Due to the commercial value of a potential offspring it is desirable that the animals mate during the time the adult is on loan. Both animals are sexually inexperienced and do not participate in intercourse for a period of two weeks. As an alternative the animals were anesthetized for a facilitated transfer of semen between the animals, on one occasion it was added to the diet of the male and female Giant Pandas (Z) -2-(5R) - (methylamino) -butenedioate -5 , 6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (1: 1). The concentration of the drug in the diet was calculated to provide 0.05 mg of free base equivalents of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1- ij] quinolin-2 (1H) -one (1: 1) per kilogram of body weight. One hour after ingesting the diet that contains the drug, the animals participated in a sexual intercourse. A pregnancy and the subsequent birth of a descendant were the results of this copulation.

EXAMPLE G Reduced sexual function in a male person with idiopathic epilepsy A male patient weighing 75 kg and 40 years of age had idiopathic epilepsy. He first presented with primary generalized attacks at the age of 15 years and was diagnosed with idiopathic epilepsy. He has been treated with carbamazepine since the age of 20 years. Currently receives 500 mg / day of the drug. He has had two tonic-clonic seizures during the previous year. The patient complains of a diminished sexual interest in his wife of 8 [sic] years. On the occasions when he tries a sexual intercourse, he is able to maintain a sufficient erection during copulation a third of time. It indicates that this problem has had a gradual appearance during the previous 5 years. He says he rarely has sexual fantasies and rarely masturbates. The patient recently had a physical examination by his family physician, the findings of which were not considerable. Currently, he does not take prescription drugs other than carbamazepine. He does not use drugs without a prescription or alcohol and denies taking toxic drugs.

A test with penile injection with a Caverject ™ injection resulted in a normal erection and duplex Doppler ultrasonography indicated an intact vascular system. Plasma testosterone and globulin assays were performed for the sex hormone binding. The plasma testosterone level is 25 nM, which is considered normal. The level of globulin for plasma sex hormone binding is 55 nM, which is considered high compared to the normal range. The patient was diagnosed with hypogonadism, secondary to chronic, carbamazepine treatment (Epilepsy 36: 366-370, 1995). It was prescribed (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, l-i j] quinolin-2 (1H) -one (1: 1) to 3 mg / dose to be taken 0.5 hours before the patient intends to participate in sexual activity. The patient was instructed that he can use the drug on a daily basis, if this is the intended frequency of sexual activity. The patient was examined after one month. He says he took the drug 2 to 3 times a week. After taking the drug, he felt more interest in sex and usually he initiates sexual activity with his wife. He says he enjoys a normal sexual relationship. The patient is instructed to continue with the treatment.

EXAMPLE H Reduced sexual function in a male patient with erectile dysfunction and a hypoactive sexual desire disorder A male patient of 70 kg of weight and 55 years of age appears to be in good health. He complains of a loss of sexual desire and frequent erectile dysfunction because he is occupying an executive position in his company, six weeks before. He says he works long hours and feels a high degree of pressure associated with his work. He is frustrated and annoyed because when he has a break from work he is unable to have an intimate relationship with his wife. He says that although he is interested periodically in initiating sexual relations, in most cases he is unable to maintain a large enough level of interest to initiate or respond adequately to sexual activity that begins with his wife. It also indicates that during the past six months, he has had difficulty maintaining an erection until the end of sexual intercourse. He develops a semi-rigid erection at the beginning of sexual activity but detumescence occurs when he tries to penetrate. He says that he has few erotic fantasies. He has not masturbated in the last months. He attributes this to a lack of motivation and interest. The patient recently had a physical examination by his family doctor, the findings of which were not considerable. He does not use drugs without a prescription or alcohol and denies taking toxic drugs. Both (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (1: 1) were prescribed. , 3 mg / dose, such as sildenafil (Viagra Tablets), 50 mg / dose. Each of which is taken orally approximately 0.5 hours before the patient intends to participate in a sexual activity. The patient is instructed that he can use the combination of the drug on a daily basis, if this is the intended frequency of sexual activity. The patient was examined after one month. He says he takes the drug combination 2 to 3 times a week. After taking the combination of the drug he feels motivated to initiate a sexual activity, he easily has sexual fantasies that are maintained during sexual intercourse and he has no difficulty in maintaining an erection until sexual intercourse is complete. Report that you enjoy an improved sexual relationship with your partner. The patient is advised to continue taking the (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 (1H) -one ( 1: 1) for another six months as it adapts to the situational stress associated with their new job. After this time, it is recommended that you stop taking the drug for a period of two weeks to determine if your motivation and sexual desire have returned to the level he enjoyed before changing jobs.

EXAMPLE I Hypoactive sexual desire disorder in a female patient Following the general treatment method of EXAMPLE A and making noncritical variations but using (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4 , 5, l-ij] quinolin-2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [, 5, 1- ij] quinolin-2 (1H) -one (1: 1) the same positive treatment effect was obtained.

EXAMPLE J Female sexual arousal disorder in a female patient Following the general treatment method of EXAMPLE B and making non-critical variations but using (5R) -5- (methylamino) -5,6-dihydro-4H-i idazo [ 4, 5, li j] quinolin-2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [, 5, li j ] quinolin-2 (1H) -one (1: 1) the same positive treatment effect was obtained.

EXAMPLE K Male erectile disorder Following the general method of treatment of EXAMPLE C and making non-critical variations but using (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin- 2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2 (1H) -one (1: 1), the same effect of the positive treatment is obtained.

EXAMPLE L Female orgasmic disorder Following the general method of treatment of EXAMPLE D and making non-critical variations but using (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin- 2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2 (1H) - ona (1: 1), the same effect of the positive treatment is obtained.

EXAMPLE M Male orgasmic disorder Following the general treatment method of EXAMPLE E and making non-critical variations, but using (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [, 5, li j] quinolin- 2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [, 5, li j] quinolin-2 (1H) -one (1: 1), the same effect of the positive treatment is obtained.

EXAMPLE N Mating of animals of commercial value Following the general method of treatment of EXAMPLE F and making non-critical variations but using (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j ] quinolin-2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2 ( 1 H) -one (1: 1), the same effect of the positive treatment is obtained.

EXAMPLE O Reduced sexual function in a male person with idiopathic epilepsy Following the general treatment method of EXAMPLE G and making non-critical variations, but using (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2 (1H) -one (1: 1), the same effect of the positive treatment is obtained.

EXAMPLE P Reduced sexual function in a male patient with erectile dysfunction and hypoactive sexual desire disorder Following the general treatment method of EXAMPLE H and making non-critical variations, but using (5R) -5- (methylamino) -5, 6-dihydro-4H-i idazo [4, 5, li j] quinolin-2 (1H) -thione in place of (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H -imidazo [4, 5, 1-ij] quinolin-2 (1H) -one (1: 1), the same effect of the positive treatment is obtained.

DIAGRAM TO OH DIAGRAM A - continued DIAGRAM A - continued

Claims (46)

1. CLAIMS 1. One (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [, 5, l-i j] quinolin-2- (1H) -thione and the pharmaceutically acceptable salts thereof.
2. 2. The compound according to claim 1, which is malate of (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2- (1H) -thione.
3. 3. The use of a compound selected from the group consisting of: (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2- (1H) -one and (5R) ) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2- (1H) -thione and the pharmaceutically acceptable salts thereof, for the manufacture of a medicament which contains between about 0.5 and 5 mg of the above compound for use in the treatment of sexual disorders in a human being in need of this treatment.
4. 4. The use of a compound selected from the group consisting of: (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2- (1H) -one and (5R) ) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2- (1H) -thione and the pharmaceutically acceptable salts thereof, for the manufacture of a medicament which contains between about 0.5 and 5 mg of the above compound for use in the treatment of a state of sexual deficiency in a human being who has epilepsy, craniopharyngioma, hypogonadism or who has had a hysterectomy, oophorectomy, hysterectomy or oophorectomy and who needs this treatment.
5. 5. The use of a compound selected from the group consisting of: (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2- (1H) -one and (5R) ) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2- (1H) -thione and the pharmaceutically acceptable salts thereof, for the manufacture of a medicament which contains between 0.5 and 5 mg of the above compound to be used in the increase of sexual desire, interest or performance in a human being who desires the same.
6. 6. The use of a compound selected from the group consisting of: (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2- (1H) -one and (5R) ) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, li j] quinolin-2- (1H) -thione and the pharmaceutically acceptable salts thereof, for the manufacture of the medicament for inducing the mating of a non-human mammal.
7. 7. The use of a compound according to claims 3, 4, 5 and 6, wherein the compound is (Z) -2-butenedioate of (5R) - (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-ij] quinolin-2- (1H) -one (1: 1) -
8. 8. The use of a compound according to claims 3, 4, 5 and 6, wherein the compound is (5R) -5- (methylamino) -5,6-dihydro-4H-imidazo [4, 5, 1-] malate. ij] quinolin-2- (1H) -thione.
9. 9. The use of a compound according to claims 3, 4, 5 and 6, wherein the pharmaceutically acceptable salt is selected from the group consisting of salts of the following acids: methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric , tartaric, fumaric, maleic, CH3- (CH2) n -COOH where n is from 0 to 4, HOOC- (CH2) N-COOH where n is as defined above.
10. 10. The use of a compound according to claims 3, 4, 5 and 6, wherein the medicament is used in combination with a sexually effective amount of one or more vascular smooth muscle relaxation agents, wherein both medicaments are administered within the 8 hours before sexual activity and the vascular smooth muscle relaxation agent is administered within a sexually effective time period before sexual activity.
11. 11. The use of a compound according to claim 10, wherein the vascular smooth muscle relaxation agent is selected from the group consisting of type 5 phosphodiesterase inhibitors, type 3 phosphodiesterase inhibitors, non-selective phosphodiesterase inhibitors, oxide donor drugs. Nitric acid, alpha-adrenergic receptor-type 1 antagonists, alpha-2 adrenergic receptor antagonists, prostaglandin-receptor agonists (PGEI) and vasoactive intestinal polypeptide (VIP) agents.
12. 12. The use of a compound according to claim 11, wherein the agent for vascular smooth muscle relaxation is selected from the group consisting of sildenafil, ICOS-351, milrinone, papaverine, linsidomine, phentolamine, yohimbine, prostaglandin El (PGEl) and VIP.
13. 13. The use of a compound according to claims 2, 3 and 4, wherein the mammal is a male person.
14. 14. The use of a compound according to claims 2, 3 and 4, wherein the mammal is a female person.
15. 15. The use of a compound according to claim 6, wherein the non-human mammal is selected from the group consisting of horses, cattle, pigs, sheep, transgenic mice, panda bears, elephants, zebras, lions, tigers, monkeys, apes, Dogs and cats.
16. 16. The use of a compound according to claim 15, wherein the non-human mammal is a male.
17. 17. The use of a compound according to claim 15, wherein the non-human mammal is a female.
18. 18. The use of a compound according to claims 3, 4 and 5, wherein the medicament is administered orally, intra-nasally, buccally, int-pulmonary, parenterally and rectally.
19. 19. The use of a compound according to claim 18, wherein the medicament is administered orally, intra-nasally, buccally and intra-pulmonarily.
20. 20. The use of a compound according to claim 19, wherein the medicament is administered orally.
21. 21. The use of a compound according to claim 6, wherein the medicament is administered orally, parenterally and rectally.
22. 22. The use of a compound according to claim 21, wherein the medicament is administered orally.
23. 23. The use of a compound according to claims 3, 4 and 5, wherein the medicament is administered between about 10 minutes and 8 hours before sexual activity.
24. 24. The use of a compound according to claim 23, wherein the medicament is administered between about 0.5 hour and 1 hour before sexual activity.
25. 25. The use of a compound according to claim 24, wherein the medicament is administered approximately 0.5 hours before sexual activity.
26. 26. The use of a compound according to claim 6, wherein the medicament is administered between about 10 minutes and 8 hours before mating.
27. 27. The use of a compound according to claim 26, wherein the medicament is administered between about 10 minutes and 1 hour before mating.
28. 28. The use of a compound according to claim 27, wherein the medicament is administered between about 10 minutes and 0.5 hours before mating.
29. 29. The use of a compound according to claims 3, 4 and 5, wherein the medicament is administered to a human being who does not have Parkinson's disease.
30. 30. The use of a compound according to claims 3, 4 and 5, wherein the medicament is administered to a human being who does not suffer from postural hypotension.
31. 31. The use of a compound according to claim 3, wherein the sexual alteration is selected from the group consisting of hypoactive sexual desire disorder, female sexual arousal disorder, male erectile disorder, female orgasmic disorder and male orgasmic disorder.
32. 32. The use of a compound according to claim 31, wherein the sexual alteration is hypoactive sexual desire disorder.
33. 33. The use of a compound according to claim 31, wherein the sexual alteration is female sexual arousal disorder.
34. 34. The use of a compound according to claim 31, wherein the sexual alteration is male erectile disorder.
35. 35. The use of a compound according to claim 31, wherein the sexual alteration is female orgasmic disorder.
36. 36. The use of a compound according to claim 31, wherein the sexual alteration is male orgasmic disorder.
37. 37. The use of a compound according to claims 3, 4 and 5, wherein the medicament contains between about 1 and 3 mg of the compounds.
38. 38. The use of a compound according to claim 4, wherein the human being has epilepsy.
39. 39. The use of a compound according to claim 4, wherein the human has craniopharyngioma.
40. 40. The use of a compound according to claim 4, wherein the human being has hypogonadism.
41. 41. The use of a compound according to claim 4, wherein the human has had a hysterectomy or oophorectomy.
42. 42. The use of a compound according to claim 4, wherein the human has had a hysterectomy.
43. 43. The use of a compound according to claim 4, wherein the human had an oophorectomy.
44. 44. The use of a compound according to claim 6, wherein the medicament delivers between about 0.003 and 0.2 mg / kg / dose.
45. 45. The use of a compound according to claim 44, wherein the medicament supplies between about 0.01 and 0.125 mg / kg / dose.
46. 46. The use of a compound according to claim 45, wherein the medicament delivers between about 0.025 and 0.075 mg / kg / dose.