MXPA00000353A - Aroylpiperazines for modulating sexual activity - Google Patents

Abstract

The present invention discloses that substituted acetic acid derivatives containing a N-alkylpiperazino moiety are useful as pro-libido agents for males and females, and may be used for the treatment of sexual dysfunction including impotence and to enhance sexual performance.

Description

AROILPIPERAZINAS TO MODULATE SEXUAL ACTIVITY FIELD OF THE INVENTION The present invention is generally directed to N-alkylpiperazine derivatives of substituted acetic acids and their pharmaceutical compositions, to the preparation of said compounds and compositions, and to the use of said compounds and compositions for improving sexual functioning, as pro-libido agents and / o for the treatment and / or prevention of sexual malfunction in male and / or female animals.

BACKGROUND OF THE INVENTION At present, there is a wide variety of pharmacological agents used and / or reported to be useful as pro-libido agents and / or for the treatment of sexual malfunction. Some examples include: serotonin receptor agonists and antagonists (see, for example, EP 385,658, WO 94 / 15,920, GB 2,248,449, and GB 2,276,165), dopamine receptor agonists (see, for example, WO 93 / 23,035; 94 / 21,608; Pomerantz SM, Pharmacol. Biochem. Behav., 39: 123-128, 1991 and Ferrari F, et al., Psychopharmacology 113: 172-176, 1993); adrenergic receptor agonists (see, for example, WO 95 / 13,072; EP 611,248; US 5,229,387; and WO 92 / 11,851); Phosphodiesterase inhibitors (see, for t _ «_ M (__« M_ Bgaa___ ^ _a_E__i _____ for example, DE 4,338,948, and WO 94 / 28,902); histamine receptor agonists (see, for example, US 4,013,659, US 4,126,670, US 4,767,778, WO 91 / 17,146, US 5,047,418, and EP 0,458,661); neuropeptide Y antagonists (see, for example, WO 95 / 00,161); angiotensin II receptor antagonists (see, for example, EP 577,025); cholinesterase inhibitors (see, for example, US 5,177,070 and US 4,633,318); combinations of agents with different types of biological activity (see, for example, US 5,145,852 and WO 95 / 05,188); vasoactive intestinal peptide derivative (see, for example, US 5,147,855; EP 540,969; and EP 463,450); prostaglandins (see, for example, WO 93/00894; and EP 459.3770); antidepressants and antipsychotics (see, for example, US 4,931,445; GB 2,448,449; and Naganuma et al., Clin. Exp. Pharm. Physiol. 20: 177-183, 1993); nitric oxide donors (see, for example, WO 92 / 21,346, DE 4,305,881, DE 4,212,585, and WO 94 / 16,729); peptide related to the calcitonin gene (see, for example, Steif, C. G. et al., Urology, 41: 397-400, 1993); and androgens (see, for example, JP 06,211,675, HU 62,473, and WO 94/16,709). Many or all of these pharmacological agents are associated with adverse effects, some examples of which are noted below. Dopamine receptor agonists may aggravate schizophrenia or induce it again in some patients. Serotonin receptor agonists are capable of producing an effect that has been termed as "serotonin syndrome" (Glennon, R.A.J. Med. Chem. 30: 1-9, 1987). The latter effect has been fully investigated in animals (Peroutka, SJ Science 212: 827-829, 1981, Goddwin GM et al., Br. J. Pharmacol.84: 743-753, 1985, and Tricklebank, MD, Eur. J. Pharmac. 117: 15-24, 1985), and manifests in, for example, head shaking, "wet dog shaking", forefoot treading, flat body posture, abduction of the hind limb, tail of Straub and yawns. Histamine receptor agonists can induce malfunctioning of the central nervous system and adverse effects on the endocrine system. Smooth muscle relaxants (such as papaverinas) can induce pain, equitomosis and occasional episodes of priapism. It has been reported that systematically administered α-adrenoceptor blockers induce priapism characterized by a persistent erection that can not be mitigated by sexual intercourse or masturbation (Kaisary, A.V. and others, Br. J. Urol. 68: 227, 1986). Accordingly, there is a need for the technique of identifying new pharmacological agents, compositions and / or treatments that are useful as pro-libido agents and / or are useful in the treatment and / or prevention of sexual malfunction in men or women, and / or can improve a patient's sexual functioning. The present invention satisfies these needs and furthermore provides related advantages.

COMPENDIUM OF THE INVENTION In summary, one aspect of the invention provides compounds of the formula (I): Or Ar- CH2- C-L-R ± -N G? N-R2 (I) including its salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures, and wherein, independently at each occurrence: Ar is selected from a carbocyclic ring of 3 to 13 carbon atoms, and ring systems selected from the formulas (II), (III), (IV), (V), (VI), and (VII): (II) wherein R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 20 7 carbon atoms, alkyl of 1 to 6 carbon atoms, carbon carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, aryl and N (Ri5-Rie) wherein R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (III) (IV) wherein Rio, and Rn independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R16) wherein R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 2 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 -. ?. 'ms s & '!' Misyií carbon atoms, and N (R15, R? 6) where R15 and RI independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (VI) (VII), L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms (such as -CH2- and -CH2CH2-), and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms. Another aspect of the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent in combination with a compound of the formula (I): including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof, having the , ^^^^^ i ... ^ -,. ^ -. P. .., ^ ^.,. ^^^ .., .. ^^ previously established definition. Another aspect of the invention provides a method for treating and / or preventing sexual malfunction in a male or female patient, wherein the method includes the step of administering to the patient with need thereof an amount of a compound of the formula I or a composition of it: including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof, having the definition stated above, and wherein the amount is effective to treat and / or prevent sexual malfunction. The sexual malfunction can be, for example, malfunctioning erectile in men or impotence. Another aspect of the invention provides the use of a compound for the manufacture of a medicament for treating and / or preventing sexual malfunction in a male or female patient, wherein the compound is of the formula (I): including salts, solvates, isolated enantiomers, diesteromers isolates, isolated tautomers and mixtures thereof, having the definition established above. The sexual malfunction can be, for example, an erectile malfunction of man or impotence. Another aspect of the invention provides a method for increasing the lividity of a male or female patient, wherein the method includes the step of administering to a man or woman with the need thereof an effective amount of a compound or composition of the formula ( I): including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof, having the definition stated above, and wherein the amount is effective to increase the lividity of the patient. Another aspect of the invention provides the use of a compound or a composition thereof, to make a medicament for increasing the lividity of a male or female patient, wherein the compound is of the formula (I): (I) including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof, having the definition stated above. Another aspect of the invention provides a method for improving the sexual functioning of a male or female patient, which comprises administering to the patient with the need thereof a therapeutically effective amount of a compound or composition thereof of the formula (I): including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof, having the definition stated above and wherein the amount increases the sexual functioning of the patient. Another aspect of the invention provides the use of a compound or composition thereof for manufacturing a medicament for improving the sexual functioning of a male or female patient, wherein the compound is of the formula (I): including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof, having the _. ,. »» A__íj ______ a_a __ * ._ ^ _ ^^ definition previously established. Another aspect of the invention is a method for the preparation of a compound of the formula (I): Ar- CH, -? Cí- L- R-, N G? N-R, "v_ (I) including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof, having the definition stated above. According to the method of the invention, a substituted acetic acid compound or its activated version having the formula: wherein X is OH or an activated (leaving) group such as chlorine, is reacted with a compound having the formula: The reaction provides a bond between C = O and L as shown in formula (I): ^ Üjj ^^ ¡to ^^^^ íSÉ | §ÉÉfi¡iJ & These and other aspects of the invention will be more readily understood after reference to the detailed description and examples that follow.

DETAILED DESCRIPTION OF THE INVENTION An understanding of the present invention can be obtained by reference to the following definitions and explanations of conventions used herein.

Definitions and Conventions In the formulas illustrated herein, a link to a substituent and / or a linkage that binds a molecular fragment to the remainder of a compound can be shown as intersecting one or more bonds in a ring structure. This indicates that the bond can be attached to any of the atoms that constitute the ring structure, provided that a hydrogen atom is otherwise present in that atom. When no particular substituent is identified for a particular position in a structure, then hydrogen is present in that position. In those cases where the invention specifies that a non-aromatic ring is substituted with more than one R group, and - * • _ & "- *. those R groups are shown connected to the non-aromatic ring with bonds that cut the ring bonds, then the R groups may be present on different ring atoms, or on the same ring atom, provided that that atom can otherwise be substituted with a hydrogen atom. Also, when the invention specifies compounds containing the group Ar-CH2C (O) -L-, where Ar is equal to group (V): (V) The invention is intended to encompass compounds wherein -CH2C (O) -L- is linked through CH2 to group Ar (V) at any atom forming the group (V) provided that group ( V) otherwise it can be substituted with a hydrogen atom. From this way, there are seven positions (identified with the letters "a" to "g") in the structure (V) where the group -CH2C (O) -L- can be joined, and joins in one of those seven positions. Group R12 could occupy one and only one of the six remaining positions, and hydrogen atoms could be present in each of the five remaining positions. The compounds of the present invention can contain two or more asymmetric carbon atoms and thus exist as enantiomers and diesteromers. Unless otherwise indicated, the present invention includes all enantiomeric and diesteromeric forms of the compounds of the invention. Pure stereoisomers, mixtures of enantiomers and / or diesteromers and mixtures of different compounds of the invention are included in the present invention. In this manner, the compounds of the present invention can occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms included in the present invention. A racemate or racemic mixture does not only involve a 50:50 mixture of stereoisomers. The compounds of the formula (I) can also exist in tautomeric forms and the invention includes individual tautomers both in mixtures and separate. The phrase "independently of each occurrence" means (i) when any variable occurs more than once in a compound of the invention, the definition of that variable in each occurrence is independent of its definition in each other occurrence; (ii) the identity of any of the two different variables (for example, R-t within the group RT and R2) is selected without considering the identity of the other member of the group. However, combinations of substituents and / or variables are allowed only if such combinations result in stable compounds. In accordance with the present invention and as used herein, the following terms are defined to have the following meanings, unless explicitly stated .7; __ a? ^ Fc.aa ^, A ^^ otherwise: "Acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free bases and that are not biologically or otherwise undesirably formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid , fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. "Acyl" refers to branched or unbranched hydrocarbon fragments terminated by a carbonyl group - (C = O) - containing the specific number of carbon atoms. Examples include acetyl [CH3C = O-, an acyl of C2] and propionyl [CH2CH2C = O-, an acyl of C3], "Alkanoyloxy" refers to an ester substituent, wherein the oxygen ether is the point of attachment to the molecule. Examples include propanoyloxy [(CH3CH2C = OO, a C3 alkanoyloxy] and ethanoyloxy [CH3C = OO, C2 alkanoyloxy] "Alkoxy" refers to an O atom substituted by an alkyl group, for example methoxy [OCH3, a C 1 alkoxy "Alkoxyalkyl" refers to an alkylene group substituted with an alkoxy group, for example, methoxyethyl [CH 3 CH 2 CH 2] and ethoxymethyl _ * _ ^ fa __ «__ rf_ & _. i [CH3CH2OCH2] both are C3 alkoxyalkyl groups. "Alkoxycarbonyl" refers to an ester substituent, wherein the carbonyl carbon is the point of attachment to the molecule. Examples include ethoxycarbonyl [CH3CH2OC = O-, a C3 alkoxycarbonyl and methoxycarbonyl [CH3OC = O-, a C2 alkoxycarbonyl]. "Alkyl" refers to a branched or unbranched hydrocarbon fragment containing the specific number of carbon atoms and having a point of attachment. Examples include n-propyl (a C3 alkyl), iso-propyl (also a C3 alkyl), and t-butyl (a C alkyl). "Alkylene" refers to a divalent radical, which is a branched or unbranched hydrocarbon fragment containing the specific number of carbon atoms, and having two attachment points. An example is propylene [-CH2CH2CH2-, an alkylene of C3]. "Alkylcarboxyl" refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl [HOOC-CH2-, a C2 alkylcarboxy] and carboxyethyl [HOOC-CH2CH2-, a C3 alkylcarboxy]. "Aryl" refers to aromatic groups having at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups. Carbocyclic aryl groups are generally preferred in the compounds of the present invention, wherein the phenyl and naphthyl groups are carbocyclic aryl groups : _... a ^ _ _-_ _ _, _. a ^^^ S ^ ñSSL ^? ^^ - aM ^? ^^? m preferred. "Aralkyl" refers to an alkylene group wherein one of the attachment points is to an aryl group. An example of an aralkyl group is the benzyl group [C6H5CH2-, an aralkyl group of C7]. "Cycloalkyl" refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic or tricyclic formed entirely from carbon atoms. An example of a cycloalkyl group is the cyclopentenyl group (C5H7-), is a saturated cycloalkyl group of five carbons (C5). "Carbocyclic" refers to a ring that can be either an aryl ring or a cycloalkyl ring, both as defined above. "Heterogeneous atom" refers to a non-carbon atom, wherein the preferred heterogeneous atoms are chorus, nitrogen, oxygen, sulfur and phosphorus, with heterogeneous nitrogen, oxygen and sulfur atoms being particularly preferred in the compounds of the present invention . "Heteroaryl" refers to aryl groups having from 1 to 9 carbon atoms and the rest of the atoms are heterogeneous atoms, and include those heterocyclic systems described in "Handbook of Chemistry and Physics", 49th edition, 1968, RC Weast , publisher: The Chemical Rubber Co., Cleveland, OH. See in particular, Section C. Rules for Naming Organic Compounds, Fundamental B. Heterocycic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like. "Hydroxyalkyl" refers to a branched or unbranched hydrocarbon fragment substituted with a hydroxy (-OH) group. Examples include hydroxymethyl (-CH2OH, a hydroxyalkyl of C) and 1-hydroxyethyl (-CHOHCH3, a hydroxyalkyl of C2). "Thioalkyl" refers to a sulfur atom substituted by an alkyl group, for example, thiomethyl (CH3S-, thioalkyl of C ^). As used herein, the term "patient" refers to a warm-blooded animal such as a mammal, which can and will be benefited from the previous treatment (curative or prophylactic). It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and humans are examples of male and female patients within the scope of the meaning of the term. "Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical art, and are described in, for example, Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro, ed., 1985). For example, saline sterile and saline regulated in its pH can be used with phosphate at a physiological pH. Preservatives, stabilizers, colorants and even flavoring agents can be provided in the pharmaceutical composition. For example, in sodium benzoate, sorbic acid and p-hydroxybenzoic acid esters can be added as preservatives. kj In 1449. In addition, antioxidants and suspending agents can be used, id ^ ^^^^^^ a ^^^^^^^^ a "Pharmaceutically acceptable salt" refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (addition salts of acid) or an organic or inorganic base (5-base addition salts). The compounds of the present invention can be used either in the free base or salt forms, both being considered within the scope of the present invention. The "therapeutically effective amount" of a compound of the The present invention will depend on the route of administration, the type of warm-blooded animal to be treated, and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determine this amount are well known to those skilled in the medical art. This quantity and the method of administration can be designed to obtain optimal efficacy, but will depend on factors such as weight, diet, concurrent medication and other factors that those skilled in the medical art will recognize. The compositions described herein as "containing a The compound of the formula (I) "encompasses compositions containing more than one compound of the formula (I).

Compounds of the Present Invention As noted above, the present invention is directed to compounds having the formula (I): __ "__ ^ ____ hJ_at__, < _-_ .. - ^ ¡seáSSi ^ * * «¿> s & i ~ ^^ including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers and mixtures thereof. In the compounds, independently in each occurrence: Ar is selected from a C3-C13 carbocyclic ring, and the ring systems selected from formulas (III), (IV), (V), (VI), (VII) and (Vlll), wherein the compounds having each of the ring systems represented by the formulas (II), (III), (IV), 10 (V), (VI), and (VII) independently represent preferred groups of compounds of the invention: (II) Wherein R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms, carbon carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, aryl and N (Ri5, íe) wherein R 5 and R 16 are independently selected of hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 atoms of érti _ - ___ & _ ^^^^ s? ^^ i ^ aaí si ^ Mmi ^^ aíiM í ^ carbon; (III) (IV) wherein R10, and Rn independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R6) where R15 and R6 are independently selected from hydrogen , acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 2 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 -thioalkyl, and N (R 15, R 6) where R 15 and R 6 are independently selected from hydrogen, acetyl , methanesulfonyl and alkyl of 1 to 6 carbon atoms; Y (VI) (VII); L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms (such as -CH2- and -CH2CH2-), and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms. These compounds can be collectively referred to herein as "compounds of the invention" or "the inventive compounds" or "substituted acetic acid derivatives of the invention" or the like. In a preferred plurality, Ar is an aryl group. In general, the compounds of the present invention may be in the form of a solvate or salt, preferably a solvate or pharmaceutically acceptable salt, for example, an acid addition salt. Said salts include, without limitation, hydrochloride salts, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art. The group Ar is preferably, but not necessarily, a hydrophobic portion. Typically, a hydrophobic portion is composed of non-polar chemical groups such as hydrocarbons or hydrocarbons substituted with halogens or ethers or heterocyclic groups, containing nitrogen, oxygen or sulfur atoms. The hydrocarbons are carbocyclic rings of 3 to 13 carbon atoms. Particularly preferred citric hydrocarbons include selected aromatic groups, such as phenyl, 1-naphthyl, 2-naphthyl, indenyl, naphthyl, acenaphthyl and fluorenyl, and are represented by formulas (II), (III), (IV), ( V), (VI), or (Vil) respectively. An Ar group within the compounds of the present invention is a phenyl ring represented by the formula (II): (H) wherein R7, R8 and Rg independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms from £ __ * »__... ^ -:« _ - »« * _ s_as? »I» ^ carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms carbon, and aryl N (R15, R16), wherein R15 and R16 are independently selected from hydrogen, acetyl, methansulfonyl and alkyl of 1 to 6 carbon atoms. Other suitable Ar groups in the compounds of the present invention are 1-naphthyl groups as represented by the formula (III): (III) wherein R10 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and aryl N (Ri5.R? ß) > wherein R 5 and R 16 independently are selected from hydrogen, acetyl, methansulfonyl and alkyl of 1 to 6 carbon atoms. Other suitable Ar groups in the compounds of the present invention are 2-naphthyl groups as represented by the ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (IV) wherein R10 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon , alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and aryl N (Ri5, Ri6), wherein R? 5 and R? 6 independently are selected from hydrogen, acetyl, methansulfonyl and alkyl of 1 to 6 carbon atoms. Other Ar groups suitable for the compounds of the present invention are aromatic groups represented by the formula (V): (V) wherein R 2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to . ^ .S __ «aJJ ^^^^ 6 carbon carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R16), wherein R5 and R6 are independently selected from hydrogen, acetyl, methansulfonyl and alkyl of 1 to 6 carbon atoms. Another suitable group Ar to the compounds of the present invention is the acenaphthyl group as represented by the formula (VI): (SAW) Still another suitable Ar group in the compounds of the present invention is the fluorenyl group represented by the formula (VII): (VII) In the further preferred embodiments, the acenaphthyl group is a 1-acenaphthyl group, and the fluorenyl group is a 9-fluorenyl group. In preferred embodiments of the invention, L is O, or NH, or N (alkalyl of 1 to 6 carbon atoms). N (alkyl of 1 to 6 carbon atom) refers to an alkyl-N-substituted (nitrogen) atom, wherein the alkyl group has at least 1 and not more than 6 carbon atoms. These carbon atoms can be arranged in any linear, branched or cyclic form. Alkyl groups encompassed by alkyl of 1 to 6 carbon atoms include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, sec-butyl, t-butyl, cyclopropyl and cyclobutyl, cyclopentyl , methyl-substituted (all isomers), and cyclohexyl, to name some. A preferred alkyl group that can be bonded to the nitrogen atom is methyl. In other preferred embodiments of the invention, for each of L which is O (oxygen), NH or N (alkyl of 1 to 6 carbon atoms), Ri is a direct bond, or a group of 1 to 6 carbon atoms.

Carbon, or a 1,2-disubstituted carbon atom alkyl cycle (i.e., a 1,2-disubstituted cyclopentyl ring) or a 1,2-disubstituted, 1-carbon carbon alkyl cycle (i.e. a 1,2-disubstituted cyclohexyl ring). In another preferred embodiment, the compounds of the present invention exhibit L and R1 both as direct links. In other preferred embodiments R2 is methyl for each of the compounds having L as O, NH or N (C1-C6alkyl), and R1 being cycloalkylene of 1, 2-disubstituted carbon atoms, or cycloalkylene of 5 carbon atoms 1, 2-disubstituted, or alkylene of 1 to 6 carbon atoms. 25 The alkylene group of 1 to 6 carbon atoms has at ^ feaa = ^^ = ^^. aiá¿-éi _________ ai_8 - ^^ minus 1, as much as 6 carbon atoms. These carbon atoms may be arranged in a linear or branched form, provided that the carbon atoms have 2 open valencies to bind to L and one nitrogen from the piperazino moiety. Exemplary C 1 -C 6 alkylene groups include, without limitation, -CH 2 -, -CH 2 CH 2 -, -CH (CH 3) CH 2 and CH 2 CH 2 CH 2 CH 2 CH (CH 3) -, which illustrate both linear and branched arrangements and the lower end (Ci) and the upper end (C6) of the alkylene chain. In a preferred embodiment, the compounds of the invention have the formula: including salts, solvates, isolated enantiomers, isolated distereomers, isolated tautomers, and mixtures thereof. In this formula, the bond that binds Ar (naphthyl group) to the side chain (-CH2-C (= O) -L-etc.) Is shown between the carbon atoms of the Ar group (rather being connected to any carbon atom). particular ring), to denote so that the side chain can be linked to group Ar in any position thereof. In other preferred embodiments, a compound of the invention has the following formula: including salts, solvates, isolated enantiomers, isolated distereomers, isolated tautomers, and mixtures thereof. According to this embodiment of the invention, a preferred compound has L equal to N (CH3), and is referred to herein as the compound XVa (which encompasses both trans enantiomers). Also according to the invention with this embodiment, another preferred compound has L equal to O, and is referred to herein as the compound XVa, wherein XVc includes both trans enantiomers. In other preferred embodiments, the compound of the invention has the formula: - "3" = "^ - i ^^ including salts, solvates, isolated enantiomers, isolated distereomers, isolated tautomers, and mixtures thereof. According to this embodiment of the invention, a preferred compound has L equal to N (CH 3), and when both enantiomers are present, it is referred to herein as the compound XVb. In another preferred embodiment of the compounds of the invention, when R1 is a direct bond, then L is also a direct bond. In this way, the preferred compounds of the invention have the formula: Including salts, solvates, isolated enantiomers, isolated distereomers, isolated tautomers, and mixtures thereof. According to this embodiment of the invention, a preferred compound has Ar equal to 1 -naphthyl, and is referred to herein as compound XVIa, and has the following structure: including salts, solvates, isolated tautomers and mixtures of same. Also according to this embodiment of the invention, other preferred compounds have Ar equal to 2-naphthyl, and is referred to herein as a compound XVIb, and has the following structure: including salts, solvates and mixtures thereof. In another embodiment, the compound has the following formulas: including salts, solvates, isolated tautomers, and mixtures thereof. Certain compounds of the invention can be prepared by a method wherein a substituted acetic acid compound or activated version thereof, having the formula: wherein X is OH or an activated group (such as chlorine), is reacted with a compound of the formula: The reaction provides a bond between C = O, and L is shown in the formula: Compounds of the formula Ar-CH2-C (= O) -X, wherein X is different from -OH, can be prepared from the acid15 corresponding (where X is -OH). These acid starting materials, such as 1-naphthalene acetic acid, 2-naphthalene acetic acid, phenylacetic acid, bromophenylacetic acid (including the isomers of positions 2,3 and 4), methylphenylacetic acid (also known as tolyl acetic acid) and many others Compounds of the formula Ar-CH2-COOH are commercially available. See, for example, Aldrich Chemical Co., Milwaukee, Wl. A substituted acetic acid can be reacted with, for example, thionyl chloride, to prepare an activated substituted acetic acid compound. Other synthetic protocols for preparing an activated acid can be found in, for example, Szmuszkovicz, J; Von Voigtlander, P.F. (1982) J. Med. Chem. 25: 1125-1126; U.S. Patent 5,506,257 to MacLeod B.A. and others, Patent of E.U.A. 5,637,583 from MacLeod B.A. and others, and Clark. C.R. et al. (1988) J. Med. Chem. 31: 831-836. The activated acetic acid compound is then reacted with an amine or an alcohol compound (depending on the identity of L) of the formula: The preparation of two 1,2-diaminocylhexyl intermediates is described in, for example, Szmuszkovicz, J .; Von Voigtlander, P.F. (1982) J. Med. Chem. 25: 1125-1126; and Patent of E.U.A. 5,506,257 from MacLeod B.A. and others. The preparation of the 1-hydroxy-2-aminocyclohexyl intermediate is described in US Pat. 5,637,583, also by MacLeod B.A. and others. The preparation of reactive carboxylic acid derivatives is described in the above references, as well as in Clark, C.R. et al. (1988) J. Med. Chem. 31: 831-836. The carboxylic acids can be coupled to the amine in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC) or the like. The reaction is carried out in a suitable solvent such as tetrahydrofuran or dioxane at room temperature, but depending on the reactivity of the specific starting materials employed, the reaction time, the solvent employed and the reaction temperature can be varied without undue experimentation. by someone skilled in the art to obtain the desired coupling reaction. Typically, a reaction temperature between about -25 ° C and the boiling point of the solvent is employed. The reaction between activated carboxylic acid (eg, acid chloride) and the amine is generally carried out at room temperature in a suitable solvent such as chloroform or dichloromethane in the presence of an acid acceptor (i.e., a base) such as a tertiary amine or an alkali metal carbonate or bicarbonate. The mixture of amine and acid halide is allowed to react until the reaction is essentially complete.

Compositions of the Present Invention The present invention provides compositions, preferably pharmaceutical compositions, containing at least one compound of the present invention as set forth above, and at least one pharmaceutically acceptable diluent, wherein the compounds of the present invention have the formula I: ,: ¿;;. V -_ .., ..-..- .. ,,:, _- ^^^^^^:, .... J ,,, .. ,, _, _, . ,, ...., .... ", _ ^^^^^^^^^^^^^^^^^^^ including salts, solvates, isolated enantiomers, isolated distereomers, isolated tautomers, and mixtures thereof, wherein independently at each occurrence: Ar is selected from a carbocyclic ring of 3 to 13 carbon atoms and ring systems of the formulas (II ), (III), (IV), (V), (VI) and (VII): wherein R7, R8 and R are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms, carbon carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, aryl and (Ri5, Rie) wherein R15 and R16 are independently selected from hydrogen, acetyl , methanesulfonyl and alkyl of 1 to 6 carbon atoms; wherein R10, and Rn independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, Rie) wherein R15 and R6 are independently selected from hydrogen, acetyl , methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 2 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, C 1-6 alkoxy, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R 15, R 16) wherein R 15 and R 16 are independently selected from hydrogen, acetyl, i ___ ^.: _? j _.-. ^ -_._,; .--. ?? '.%? rv? Ji_J «Ja_a .........:. ^ - ^^^^^^^^^^ m ^ my ^ methanesulfonyl and alkyl of 1 to 6 carbon atoms; Y including its isolated, diastereomeric, tautomeric and geometric enantiomeric isomers and their mixtures. L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms (such as -CH2- and -CH2CH2-), and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms. The composition may include, for example, water. In a preferred embodiment the composition is in the form of a tablet, and particularly a rapid release tablet for oral administration. A rapid release tablet (having a rapid disintegration time) is desired in order to provide the patient with a rapid onset of improved sexual function and / or increased libido and / or alleviation of sexual malfunction. 20 A "quick release" tablet will have a disintegration time of less than about one hour, preferably less than about 20 minutes, and very preferably less than about 2 to 1 minute. A suitable rapid release tablet contains 40 mg of a compound of the present invention, 8 mg of silicon dioxide (NF), 4 mg of stearic acid (NF), 212 mg of lactose (NF), 120 mg of microcrystalline cellulose ( NF) and 16 mg of croscarmellose sodium (NF). A tablet containing these ingredients can be prepared by finely dividing and then mixing each ingredient together and then compressing the mixture to the form of a tablet. The tablet has a weight of approximately 400 mg. Other methods for mixing and formulating the tablet will be readily apparent to those skilled in the art. A tablet prepared by this method will typically have a hardness of 10.7 kp, an average thickness of about 0.508 cm and a disintegration time of about 45 minutes. Disintegration compounds, such as croscarmellose sodium (NF), (available from Ac-Di-Sol-of FMC Corporation), can be used to improve the dissolution time of the present invention. Other disintegrating agents such as potato starch, Explotab ™ sodium starch glycolate, crospovidone NF Polyplasdone ™ XL, NF Starch 1500 ™ pregelatinized starch can be used in the formulations of the present invention. Each of the patents of E.U.A. Nos. 5,731,339, 5,298,261, and 5,079,018 also describe formulas that describe fast disintegration times, which can be employed to prepare a rapid release formulation of the present ? S ^^ ^ XXX ^ iái ^ M? S ^^ '-, ^^^. ^. invention. Disintegration methods and methods to measure the disintegration time of the tablets include Gissinger and others "A Comparative Evaluation of the Properties of some Table Disintegrants "Drug Development and Industrial Pharmacy 6 (5): 511-536 (1980); and European Pharmacopeia 1980. The pharmaceutical compositions of the present invention can be in any form, which allows the composition to be administered to the patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, without limitation, oral, topical, parenteral (eg, sublingually or bocally), sublingual, rectal, vaginal or intranasal. The term "parenteral" as used herein, includes subcutaneous, intravenous, intramuscular, intrasternal, intracavernous, intrameatal, intrauretal injection, or infusion techniques. The pharmaceutical compositions of the invention are formulated in order to allow the active ingredients contained therein to be bioavailable after administration to a patient. The compositions that will be administered to a patient have the form of one or more unit doses, wherein, for example, a tablet can be a single unit dose, and a container of one or more compounds of the invention in the form of an aerosol can maintain a plurality of dose units. For oral administration, an excipient may be present ^^ AMi > ^^ iíém ^ & ^ &^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Examples are sucrose, kaolin, glycerin, starch dextrins, sodium alginate, carboxymethylcellulose and ethylcellulose. Coloring agents and / or flavoring agents may be present. A coating shell may be used. The composition may be in the form of a liquid, for example, an elixir, a syrup, emulsion or suspension. The liquid may be for oral administration or for subministering by injection, as examples. When intended for oral administration, the preferred composition contains, in addition to the compounds of the invention, one or more of a sweetening agent, preservatives, dye-dye and a flavor improver. In a composition that is intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, pH regulator, stabilizer and isotonic agent may be included. The liquid pharmaceutical compositions of the invention, whether as solutions, suspensions or other similar form, may include one or more of the following auxiliaries: sterile diluents such as water for injection, saline, preferably physiological solution, Ringer's solution, sodium chloride isotonic, fixed oils such as mono or synthetic diglycerides, which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; - ^. AÉgés_i_ a_ ^^ chelating agents such as ethylenediaminetetraacetic acid; pH regulators such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is the preferred auxiliary. A pharmaceutical composition is preferably sterile. A liquid composition intended for either parenteral or oral administration must contain an amount of the compound of the invention, so that an adequate dose will be obtained. Typically this amount is at least 0.01% of the compound of the invention in the composition. When intended for oral administration, this amount may be varied between 0.1 and about 70% of the weight of the composition. Preferred oral compositions contain between 4% and about 50% of the compound of the invention. Preferred compositions and preparations according to the present invention are prepared such that a parenteral dosage unit contains between 0.01 and 1% by weight of the active compound. The pharmaceutical composition may be intended for topical administration in which case the vehicle may conveniently comprise a solution, an emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol and emulsifiers and stabilizers. Thickening agents may be present in the pharmaceutical composition for topical administration. If it is intended for transdermal administration the composition may include a transdermal patch iontophoresis device. The formulations may contain a concentration of the active compound of about 0.1 about 10% w / v (weight per unit volume). The composition can be intended for rectal administration, in the form of, for example, a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable non-irritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. The compounds of the invention can be administered through the use of inserts, beads, release formulations over time, patches or rapid release formulations. It will be apparent to those skilled in the art that the optimum dose of the substituted acetic acid derivatives of the present invention may depend on the weight and physical condition of the patient.; of the severity and duration of sexual malfunction (when the goal is to treat a sexual malfunction); in the particular form of the active ingredient, the manner of administration and the composition employed. It should be understood that the use of a substituted acetic compound of the invention in a chemotherapy may involve said compound bound to an agent, for example, a antipolimonoclonal or polyclonal, a protein or a liposome, which helps the release of said compound. Therefore, the invention further relates to a pharmaceutical or veterinary composition comprising an effective amount of a substituted acetic acid derivative of the formula I provided above, in association with a carrier. In a further embodiment, the present invention is directed to the use of a substituted acetic acid derivative of the formula provided above (including physiologically acceptable salts and hydrates) for the manufacture of a medicament, for the treatment, alleviation or prevention of the effects of sexual malfunction. In this manner, the substituted acetic acid derivatives of the formula I provided above, can be used for the manufacture of a medicament to help treat or prevent the effects of male sexual malfunction, preferably erectile malfunction and male orgasm inhibited, especially Erectile malfunction. The substituted acetic acid derivatives of the formula provided above can also be used for the manufacture of a medicament for treating, alleviating or preventing the effects of female sexual malfunction, preferably a sexual arousal disorder and female orgasm inhibited especially an arousal disorder sexual. In a further embodiment, the present invention provides a method for the treatment of a male or female patient suffering from a sexual malfunction, or a method of preventing sexual malfunction in a patient (having, for example, a history of a sexual malfunction) comprising administering a therapeutically or prophylactically effective amount of a compound of formula I, or a composition including the same, as specified above. Sexual malfunction can be, for example, male erectile malfunction or impotence. A patient who can not obtain an erection can be treated according to the present invention, while a patient who can not maintain an erection can receive a prophylactic dose of a compound of the invention in order to avoid premature loss of an erection. erection. In a further embodiment, the present invention provides a method for increasing the libido of a male or female patient comprising administering thereto a therapeutically effective amount of a compound of formula I or a composition including the same, as was provided previously. In yet another embodiment, the present invention provides a method for improving the sexual functioning of a male or female patient who does not necessarily exhibit symptoms of sexual malfunction, which comprises administering to the patient with the need thereof, a therapeutically or prophylactically effective amount. of a compound of formula I, a composition including the same as provided above. He ^ Mtt ^^^^ É ^^^^^^^^^^^^^ & ^ g ^^^ is ^^^^ s ^^ >; ^ «J ^^ s ^^^^^ Improved sexual functioning occurs when there is an increase in the type of behavior that is typically associated with the patient's sexual activity or interest in sexual activities. The increased tone in the patient's genitals is an indication of an improvement in sexual functioning. The improvement of sexual functioning can result, for example, in a pro-erectile response in the patient, or an improvement in erectile function such as any increase in the patient's ability to maintain an erection, induce or improve ejaculation (for example, have multiple ejaculations within a short period), or induce or improve orgasm. Specific examples in sexual functioning are described in relation to the pharmacological test of the compounds and compositions of the present invention, as set forth herein. The term "therapeutically effective amount" refers to an amount that is effective, after the administration of single or multiple doses to the patient, to improve the libido and / or sexual functioning of the patient receiving the compound or a composition containing the compound as provided above. Said amount can serve a sexual malfunction, for example, impotence in men, and / or to improve the sexual desire and / or the sexual functioning of a patient without a sexual malfunction. For example, the therapeutically effective amount may be administered to, for example, a bull, for promote increased ejaculation of semen, where the semen ejaculate is collected and stored for use as needed to pregnant cows in the promotion of a breeding program. Increased sexual ejaculation is an example of improved sexual functioning according to the present invention. A therapeutically or prophylactically effective amount of a substituted acetic acid derivative of the invention is expected to range from 0.01 milligrams per kilogram of body weight per day (mg / kg / day) to approximately 200 mg / kg / day.

Preferred amounts vary from about 0.5 to about 80 mg / kg / day. A pharmaceutical composition containing the substituted acetic acid derivative of the invention may contain between 001 and 1% by weight of substituted acetic acid, and between about 5 and 10% by weight of glucose in order to increase the osmorality of the solution. Two illustrative compositions are (1) 5 mg / ml of a substituted acetic acid derivative of the invention and distilled water in a total volume of 100 ml, and (2) 5 mg / ml of a substituted acetic acid derivative of the invention, 25 mg / ml of glucose and distilled water in a total volume of 100 ml To effect the treatment of a patient in need of an agent for the treatment of sexual malfunction and / or to improve sexual functioning and / or a pro-libido agent, a compound of the invention may be administered in any way or way that makes the compound bioavailable in effective amounts, including oral, aerosol and parenteral routes. For example, the compounds of the invention can be administered orally, via aerosolisation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like. The compounds of the invention can be administered via direct injection to, for example, the corpus cavernosum (intracavernosely). The compounds of the invention can be administered intraurethrally (for example, through an intraurethral catheter). The compounds of the invention can be administered topically, for example, directly to the penis. The compounds can be administered intrameatally. Generally, oral or aerosol administration is preferred. One skilled in the art to prepare formulations can easily select the appropriate form and modes of administration depending on the particular characteristics of the selected compound, the condition to be treated, the condition stage and other relevant circumstances. See, for example, Remington's Pharmaceutical Sciences, 18th edition. Mack Publishing Co. (1990).

The compounds can be administered alone or in the form of a pharmaceutical composition in combination with subsequent pharmaceutically acceptable carriers, the proportion and nature of which is determined through the solubility and chemical properties of the selected compound, the chosen route of administration and the standard pharmaceutical practice. In another embodiment, the present invention provides ta_a_l.? i__ ai?? iftf & amp; compositions comprising an acetic acid derivative of the invention in admixture or otherwise in association with one or more inert carriers. These compositions are useful, for example, as assay standards, as convenient means for making bulk shipments or as pharmaceutical compositions. An analyzable amount of a compound of the invention is an amount that is easily measurable through standard assay methods and techniques as is known and appreciated by those skilled in the art. The analyzable amounts of a compound of the invention generally vary from about 0.001% to about 75% of the composition by weight. Inert carriers can be any material that does not degrade or otherwise covalently react as a compound of the invention. Examples of inertly suitable vehicles are water; pH regulators in slurries, such as those that are generally useful in high performance liquid chromatography (HPLC) analysis; organic solvents such as acetonitrile, ethyl acetate, hexane and the like; pharmaceutically acceptable excipient vehicles. More particularly, the present invention provides pharmaceutical compositions containing a therapeutically effective amount of a substituted acetic acid derivative as described above, in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions are prepared in a manner known in the pharmaceutical art. The excipient vehicle can be a solid, semi-solid or liquid material, which can serve as a medium vehicle for the active ingredient. Suitable excipient carriers are well known in the art. The pharmaceutical composition can be adapted for oral, parenteral, or topical use and can be administered to a patient in the form of tablets, capsules, solution, suspensions or the like. The compounds of the present invention can be administered orally, for example, in an inert diluent or with an edible vehicle. These can be enclosed in gelatin capsules or compressed into tablets. For the purposes of therapeutic oral administration, the compounds can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should preferably contain at least 4% of the compound of the invention as an active ingredient, but this amount may vary depending on the particular form and conveniently may be between 4% a approximately 70% of the unit's weight. The amount of the compound present in the compositions is such that an adequate dose will be obtained. Tablets, pills, capsules and the like may also contain one or more of the auxiliary ingredients: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, agents of '^ ts ^ É ^^ ¿? ^^ ^^ l ^ li ^? bÁj ^^^ s ^ teJM- = ¿- ^ - __i _ ^ __ h_a «_ ^^^ disintegration such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; slip agents such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin, can be either aggregates or a flavoring agent such as peppermint, methyl salicylate or orange flavor. When the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a carrier such as polyethylene glycol or a fatty oil. Other forms of dose unit may contain several other materials that modify the physical form of the dose unit, for example, as coatings. A syrup may contain, in addition to the compounds of the present invention, sucrose as a sweetening agent and certain preservatives, dyes and dyes and flavors. The materials used to prepare these various compositions must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the compounds of the present invention can be incorporated into a solution or suspension. These preparations must contain at least 0.1% of a compound of the invention, but this amount may vary to be between 0.1 and about 50% of its weight. The amount of the compound of the invention present in such compositions is such that an adequate dose will be obtained. The compositions and preferred preparations according to The present invention is prepared so that one unit dose __-_ «B__? > _-. J. _rt «_? __._ H« __ «_ < -l_lÍM > _ ^^ parenteral contains between 0.01 to 1% of the active compound. The compounds of the present invention can also be administered through an aerosol. The term aerosol is used to denote a variety of systems that vary from those of 5 colloidal nature to systems consisting of pressurized packages. The supply can be through a pressurized or compressed gas or through a suitable pump system that delivers the active ingredients. The aerosols of the compounds of the invention can be supplied in single phase systems, of two phases or of three phases in order to supply the active ingredient. The aerosol supply includes container, activators, valves, subcontainers, necessary separators, and the like, which together can form a team. Preferred aerosols are capable of being determined by one skilled in the art. The compounds of this invention can also be administered topically, and when done so the vehicle can conveniently comprise a solution, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol and emulsifiers and stabilizers. Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w / v (weight per unit volume). Solutions or suspensions may also include one or more of the following auxiliaries: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; pH regulators such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred diluent or vehicle. The substituted acetic acid derivatives of the invention can be combined with one or more pharmacological agents used in the treatment and / or prevention of sexual malfunction and / or that are known to improve libido and / or sexual functioning of a patient receiving the pharmacological agents. The following examples are offered by way of illustration and not by way of limitation.

EXAMPLES In the following examples, unless otherwise indicated, the reagents, and solvents were of standard commercial grade, and were obtained from Aldrich Chemical Co. Milwaukee, Wl, or from a similar chemical supplier house.

EXAMPLE 1 PREPARATION OF MONOCLORHYDRATE (±) -TRANS-N-METHYL-, 2- (1-4-METHYL) PIPERAZINIDCICLOHEXIL.NAFTALEN 1-ACETAMIDE (XVA) 5 Formation of acid chloride: 1-naphthylacetic acid was refluxed ( 2.35 g, 12.6 mmol) in 10 ml of thionyl chloride under nitrogen for 1 hour After stirring at room temperature for a further 2 hours, the thionyl chloride was removed under vacuum to leave an oil, which was dissolved in 10 ml. ml of dichloromethane Formation of diamine: (±) -2- (1- (4-methyl) piperazino) cyclohexanol (15.0 g, 75.8 mmol) was added to triethylamine (11.4 ml, 81.8 mmol) and 100 ml of methylene chloride low nitrogen. The solution was cooled in an ice water bath to provide a cold aminoalcohol solution. Methanesulfonyl chloride (6.4 ml, 82.7 mmol) and 40 ml of methylene chloride were added to the cold aminoalcohol solution under nitrogen. The ice water was stirred and the mixture was stirred at room temperature for 2 hours. The GC analysis showed that the reaction was essentially complete. The reaction mixture was divided between 100 ml of methylene chloride and 100 ml of water. The aqueous phase was extracted with 50 ml of additional methylene chloride. The methylene chloride layers were combined, dried over sodium sulfate and the solvent was removed under vacuum.

The isolated product (20.73 g) was dissolved in 50 ml (645 mmol) of a methylamine solution (40 p / v in water) and heated to reflux at 2.5 hours. GC analysis of the reaction mixture showed that the displacement reaction was complete. The reaction mixture was partitioned between a solution of sodium dioxide (140 ml 10%) and methylene chloride. The aqueous phase was extracted with 85 ml of additional methylene chloride. The methylene chlorides were combined and dried over sodium sulfate and the solvent was removed in vacuo. The crude diamine (14.07 g) was a yellow oil. Vacuum distillation gave 12.08 g of a colorless liquid which was (±) -2- (1- (4-methyl) piperazino) cyclohexanol-N-methylamine. Amide formation: the chloride solution was added through a cannula to a cooled solution (ice bath) of (±) -2- (1- (4-methyl) piperazino) cyclohexanol-N-methylamine (2.53 g, 123.0 mmoles) in 10 ml of dichloromethane under nitrogen. The mixture was stirred at 0 ° C for 15 min., then at room temperature for 2 hours. 40 ml of ether were slowly added to the solution. A thin white liquid was precipitated. The mixture is stirred for 45 min, and then the solid product is filtered. The solid was rinsed with ether and dried in vacuo. The crude product (5.38 g) was recrystallized from 300 ml of hot methanol. The solution was cooled slowly to room temperature. 3 harvests of the recrystallized product were collected, rinsed with ether and dried in vacuo. The weight of the first harvest was 3.5 g, the second was 0.49 g and the third was 0.56 g. The three were combined and dissolved in 275 ml of hot methanol. The product was recrystallized twice and rinsed in ether and dried in vacuo. Microanalysis: C 61.78, H 7.82, N 9.35, Cl 15.83% (theoretical for) C24H35N3OCI2: C 63.71, H 7.80.N 9.29, CI 15.67%).

EXAMPLE 2 PREPARATION OF MONOCLORHYDRATE (+, -TRANS-N-, 2- (1 -4- METHLYPIPERAZINLL.CYCLOHEXILlNAFTALEN-2-ACETAMIDE (XVB) Acid chloride formation: naphthylacetic acid (2.23 g, 12.0 mmol) in thionyl chloride (10 ml, 12.0 mmol) was brought to reflux under nitrogen for 1 hour. The thionyl chloride was removed in vacuo (using 1 x 10 ml, 2 x 5 ml CCI) to leave a tan solid, which was dissolved in 10 ml of dichloromethane. Azide formation: a 2-neck round bottom flask dried with flames was charged with sodium azide (14.8 g, 227 mmol) and 50 ml of DMF. The (±) -trans-2- (1- (4-methyl) piperazino) cyclohexanol mesylate (15.17 g, prepared as in Example 1) was dissolved in 100 ml of dry DMF and added to the suspension of sodium through a cannula. 20 ml of DMF was added to the reaction mixture. The flask was fitted with a reflux condenser and the mixture was heated at 50 ° C for 1.5 hours. The product mixture was divided between ether and water. The ether extract was analyzed through GC and found not to be »" ^ '- *' "H. go * riliif ^ ntrt.a ^ - '^^. ^^^^^ ugly contained nothing of mesylate. The reaction mixture was stirred overnight at room temperature under nitrogen. Then 250 ml of diethyl ether was added and the combination was washed with 100 ml of water. The aqueous DMF phase had a red-brown color while the ether base was yellow. The ether layer was washed with additional water (2 x 20 ml) and then dried over sodium sulfate. After removal of the solvent in vacuo, the residue (±) -2- (1- (4-methyl) piperazino) cyclohexylazide weighed 12.37 g. Diamine Formation: (±) -trans-2- (1- (4-methyl) piperazino) cyclohexylazide (12.37 g, 55.5 mmol) was dissolved in a 4: 1 solution of glacial acetic methanohacid (55 ml). 2.1 g of palladium on carbon was added to the solution and the mixture was heated. The mixture was placed in a high pressure pump and the pump was placed in a liquid nitrogen bath until the contents were frozen. The pump was evaluated, then charged with hydrogen gas and sealed, while maintaining the contents of the pump in a frozen state. The reaction mixture was removed from the liquid nitrogen bath and warmed to room temperature, stirred for 4 days, dried and filtered. GC analysis showed that the content of the mixture was 60:40 of a starting material aminocyclohexylpiperazine: azide the reaction mixture was again placed under a hydrogen atmosphere, according to the procedure described above, and then heated at room temperature and stirred for 2 days. The CG analysis failed to identify any azide in the reaction mixture. The The reaction mixture was filtered and rinsed with a 4: 1 solution of methanol: glacial acetic acid and dried under vacuum. 100 ml, 10% concentrated acetic acid were added, and the pH was reduced to 1 by adding 6N HCl. The aqueous acidic cap was extracted with methylene chloride (3 x 50 ml), and the methylene chloride extracts were discarded. The aqueous layer was basified to a pH of 12 through the addition of a 50% sodium dioxide solution and then extracted with methylene chloride (4 x 50 ml). The methylene chloride extracts were combined and dried over sodium sulfate and the solvent was then removed in vacuo. The weight of the crude product was 10.65 g. Vacuum distillation afforded a colorless solid distillate, 8.48 g, m.p. 78-79 ° C, which is (±) -trans-2- (1- (4-methyl) piperazino) cyclohexyllamina. Amide formation: the acid chloride solution was added through a cannula to a room temperature solution of (±) -trans-2- (1- (4-methyl) piperazino) cyclohexylamine (2.25 g, 11.4 mmol) in 10 ml of dichloromethane under nitrogen. The mixture was stirred at room temperature for 1 hour. A fine precipitate formed. 50 ml of ether was slowly added to the mixture to complete the precipitation of a solid, which was filtered and rinsed with ether (3 x 15 ml). The crude product (4.63 g) was recrystallized from 60 ml of hot ethyl acetate / 20 ml of hot methanol. The solution was cooled slowly to room temperature to give 3 crops of crystalline product, which were collected, rinsed with ether and dried in vacuum. The weight of the first harvest was 3 g, the j ^^ m second crop of 0.6 g, and the third harvest of 1.15 g. Microanalysis: C 68.97, H 7.94, N 10.81% (theoretical for C22H32N3OCI: C 68.72, H 8.02, N 10.45%).

EXAMPLE 3 PREPARATION OF 1-ACETATE MONOCLORHYDRATE (±) - TRANS-.2- (1 - (4-M ETI DPI PE RAZINO? CIC HEXIL1 NAFTALENE (XVC) Acid chloride formation: 1-naphthylacetic acid (2.47 g, 13.3 mmol) in 10 ml of thionyl chloride was refluxed under nitrogen for 1 hour. The mixture was stirred at room temperature for a further 3 hours before removing the thionyl chloride in vacuo (using 1 x 10 ml, 2 x 5 ml CCI4). The residue was dissolved in 10 ml of chloroform. Ester formation: the acid chloride solution was added through a cannula to a room temperature solution of (±) -trans-2- [1- (4-methyl) piperazino] cyclohexanol (2.51 g, 12.6 mmol, " starting aminoalcohol ") in 10 ml of chloroform under nitrogen. The reaction was refluxed for 2.5 hours at that time, the GC analysis showed a mixture (2: 1 of ester: starting aminoalcohol) of products. Accordingly, the reaction mixture was refluxed for a further 16 hours before the solvent was removed in vacuo, the solvent was dissolved in a solution of HCl (100 ml, 1M) and 60 ml of ether. The aqueous phase was extracted with additional ether ^ J ^ a_a__a_a ^^^^ í.M ^ "^ _ Bfc¿a_ (2 x 30 ml). The aqueous layer was basified to a pH of 12 through the addition of a 50% solution of NaOH. The aqueous phase was basified with ether (1 x 60 ml, 2 x 40 ml) and the ether extracts were washed and combined with water (2 x 100 ml, 2 x 75 ml, 2 x 50 ml, 16 x 25 ml 5 to remove any aminoalcohol. The GC analysis showed that the ether extract contained 1.5% starting aminoalcohol impurity. The ether extract was dried over sodium sulfate and the solvent was removed in vacuo. The isolated product (3.24 g) was dissolved in 20 ml of ether and treated with a solution of HCl in ether. A fine precipitate formed. The solid was filtered and rinsed with ether (3 x 10 ml). The salt was dried under vacuum. The crude HCl salt was recrystallized from 10 ml hot methanol. Two small crops of recrystallized product were collected. The weight of the first harvest was 0.59 g, the second crop of 0.14g. The mother liquor was evaporated and the residue was dissolved in 40 ml of hot ethyl acetate / 3 ml of hot ethanol. A third crop of this was collected and combined with the first two crops. The first, second and third combined crops were pumped into a vacuum line for 3 hours. A fourth crop of product was collected as was done previously. The micro-analysis indicated that the salt contained 1.6 equivalents of HCl. The four crops of salt were combined and dissolved in 30 ml of hot methanol and a solution of HCl was added to it. in methanol to produce a fine white precipitate. They were collected two crops of the dihydrochloride salt were rinsed with ether (3 x 10 ml) and dried in vacuo. These two crops were recrystallized from 40 ml of ethyl acetate / 60 ml of hot methanol. The recrystallized dihydrochloride salt (1.78 g) was filtered, rinsed with ether 5 (3 x 10 ml) and dried in vacuo. The dihydrochloride salt (di-HCl) did not dissolve in D2O. The mother liquor from the recrystallization from ethyl acetate / methanol was evaporated and the residue was mixed with the isolated dihydrochloride salt. This mixture was divided between a 1M NaOH solution (80 ml) and 80 ml of dichloromethane. The aqueous phase was further extracted from dichloromethane (1 x 50 ml, 1 x 30 ml). The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The residual free ester (2.20 g) is pumped into a vacuum line. The free ester was dissolved in dichloromethane: ether (1.6, 80 ml).

One equivalent of HCl in dichloromethane: ether (1: 6) was added dropwise, with stirring, to the solution thereof for a period of 6/8 hours. A fine white solid precipitated from the solution. The solid was filtered and washed with ether (3 x 10 ml). The monohydrochloride salt (2.09 g) was dissolved in 30 ml of hot ethyl acetate / 10 ml of methanol hot. The solution was cooled slowly to room temperature. Two crops of the recrystallized monohydrochloride salt were collected and recombined. This product was rinsed with ether and rinsed in vacuo. Microanalysis: C 67.33, H 7.52, N 6.91% (theoretical for C 23 H 31 N 2 O 2 CI: C 68.56, H 7.75, N 6.95%).

^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ EXAMPLE 4A PREPARATION OF MONOCLORHYDRATE OF 1- MET1L-4M NAFTALENACETIL) PIPERAZINE (XVIA) Acid chloride formation: 1-naphthylacetic acid (5.00 g, 26.8 mmol) in 10 ml of thionyl chloride was brought to reflux under nitrogen for 1 hour. The mixture was stirred at room temperature for an additional hour, and the thionyl chloride was removed in vacuo (using 1 x 10 ml, 2 x 5 ml CCL4) to leave an oil, which was dissolved in 50 ml of dichloromethane. Amide formation: the acid chloride solution was added through a cannula to a cold solution (-78 ° C) of 1-methylpiperazine (2.69 g, 26.8 mmol) in 50 ml of dichloromethane under nitrogen. The resulting thick white suspension was filtered and washed with ether (3 x 10 ml) and dried to provide 3.06 g of a first crop. A second crop of 1.05 g was collected from the filtrate. Microanalysis: C 66.30, H 6.96, N 9.13% (theoretical for C? 7H21N2OCI: C 66.99, H 6.94, N 9.19%).

EXAMPLE 4B PREPARATION OF 1-ETHYL-4,2-NAPHTHALENACEHYL MONOCLORHYDRATE PIPERAZINE (XVIB) Formation of acid chloride: it was brought to acid reflux 2- ? > > ^ aa ___ ^ M__B »* a_B ___ ¿____ ^^ naphthylacetic (3.90 g, 21.0 mmoles) in 10 ml of thionyl chloride under nitrogen for 1 hour. The mixture was stirred at room temperature for an additional 1.5 hours before removing the thionyl chloride in vacuo (using 1 x 10 ml, 2 x 5 ml CCL4). The residue, an orange solid, was dissolved in 7 ml of dichloromethane. Amide Formation: The acid chloride solution was added through a cannula to a cold solution (ice bath) of 1-methylpiperazine (2.0 g, 20 mmol) in 10 ml of dichloromethane under nitrogen. An additional 25 ml of dichloromethane was added with the In order to reduce the viscosity of the reaction medium, a large amount of white solid was precipitated from the solution almost immediately. The mixture was stirred at room temperature for 30 min. The crude product (5.44 g) was filtered and washed with ether (3 x 15 ml). The product is pumped into a vacuum line, and then dissolved in hot methanol. Additional cooling (slowly) provided a solid precipitate of 3.19 g. The product was filtered, washed with ether and dried under vacuum.

Microanalysis: C 66.60, H 7.27, N 9.12% (theoretical for 20 C17H21N2OCI (0.5 H2O): C 65.06, H 7.07, N 8.93%). _fi ^ astírWa? i ^ aaa £ | iai ^ "J? faM - * '- **» «. ^ ateÁa ^ iM_.

EXAMPLE 5A PREPARATION OF MONOCLORHYDRATE OF 1 -METIL-4Í2-.3.4 DICLOROFENIL) PIPERAZINE (XVIIA) Acid chloride formation: 3,4-Dichlorophenyl acetic acid (5.13 g, 25.0 mmol) in 13 ml of thionyl chloride was brought to reflux under argon for 1 hour. After stirring at room temperature for 30 min. Further, excess thionyl chloride was removed in vacuo (using 3 x 5 ml CCL4). The residue, an orange oil, was dissolved in 25 ml of dichloromethane. Amide Formation: A solution of 1-methylpiperazine (2.66 ml, 24.0 mmoles) in 15 ml of dichloromethane in argon was added via syringe to the solution of acid chloride used with an ice-water bath. The mixture was then made a slurry, which was stirred at 0 ° C for 10 min and at room temperature for 1 hour. The crude product (7.56 g) was filtered and washed with 10 ml of dichloromethane and 2 x 20 ml of ether, and dried in a high vacuum line for 30 min. The crude product was recrystallized from 15 ml of hot methanol / 30 ml of acetone / 25 ml of ether. Harvest # 1 (4.99 g, white glass) was collected, washed with acetone / ether (1: 3 v / v, 2 x 15 ml) and dried under vacuum. Harvest # 2 (1.26 g, pale yellow powder) was collected from the concentrated mother liquor. 3C harvest NMR # 1 (75 MHz, D2O) d: 171.56 (CO); 135.23, 131.89, 131.51, 130.75, 130.66, 129.61 (aromatic); 53.07 (CH2NCH3); 43.21 (NCH3); 43.0, 39.31 (CH2NCO); 38.51 (CH2CO) EXAMPLE 5B Preparation of 1 -methyl-monohydrochloride 4-, 3.4- DIMETOXIACETIL) piperazine (XVIIB) .HCl Acid Chloride Formation: 3,4-Dimethoxyphenyl acetic acid (5.0 g, 25.5 mmol) in 14.7 ml of thionyl chloride was brought to reflux under argon for 1 hour. After stirring at room temperature for a further 30 min, the thionyl chloride was removed in vacuo (using 1 x 10, 2 x 5 ml CCL4). The residue, a dark red oil, was dissolved in 7 ml of dichloromethane. Amide Formation: The acid chloride solution was added to a cooled solution (ice bath) of 1-methylpiperazine (2.42 g, 24.2 mmol) in 10 mL of dichloromethane under argon. Added 25 The additional dichloromethane was added to allow the agitation to stir (a large amount of white solid was precipitated from the solution almost immediately). The mixture was stirred at room temperature for 30 min. The crude product was filtered and washed with ether (3 x 15 ml). The product was pumped into a vacuum line, and then recrystallized from toluene / ethanol. The flaky crystal was filtered and washed with ether and dried in vacuo to yield a white solid (5.0 g). 13C NMR (75 MHz, D2O) d: 172.93 (CO); 148.4, 147.4, 127.4, 121.8, 112.8, 112.1 (aromatic); 55.8 (OCH2); 53.0 (NCH3), 43.1 (NHCj), 39.2 (CONCH2); 39.0 (COCH2).

PHARMACOLOGICAL TEST EXAMPLE 6 EFFECT OF N-METHYLPIPERAZIN ACETIC ACID COMPOUNDS IN THE SEXUAL BEHAVIOR OF PRIMATES MALE (STUDY OF OBSERVATION IN PAIRS) Primates macaca fascilaris adults (3.8-8kg; n = 6) were given by injection (1.0 mg / kg; ip; 0.5 ml / kg of body weight) saline and / or solutions of XVa compounds. XVb. XVc. XVIa and XVIb, and their behavioral responses were observed for 1 hour after a delay of 10 min for the distribution of the drug. The monkeys used for the test were separated ,? A.? I? R? Mi? ¡Tm »ñ." M. -J ___ ^ ta * ___ JtM__h ____- ^ ... J ^ __> g> M?> _ > _fl¿_ of the group of cages and tested and observed in pairs in the middle of the housing environment The test compounds were randomized so that one monkey received the test compound and the other received saline in each pair, although the observers did not know which was the animal treated with the drug The results are given in Table N = 3 for all animals treated with drug, while N = 18 for animals treated with saline Table 1 indicates the sexual response of test animals exhibiting erection The data are expressed as the number of test animals having a particular degree of penile response.Penile responses were classified every 10 seconds for 1 hour according to the following scale: Grade 0 = glanders were not observed Grade 1 = glanders were clearly visible Grade 2 = extended penis Grade 3 = ere Full version Grade 4 = erection with masturbation Grade 5 = erection with masturbation and ejaculation TABLE I EFFECT OF N-METHYLPIPERAZINES OF ACETIC COMPOUNDS EXAMPLE 7 DIRECT ACTION OF PENIS ERECTION Cavernous body (CC) vehicle strips of 10 penises obtained from rabbit (N = 6) were prepared. The CC strips were dissected free of tunica albungia and were mounted in 10 or 25 ml of organ baths containing the Tyrode solution saturated with a mixture of 95% O2 / 5% CO2. Compound XVIb and 1-methyl-4-trifluoromethylphenylpiperazine (concentration variation of 104 M to 15 104 M) failed to reduce the tone in the pre-contracted rabbit CC of noradrenaline, while Trazodone reduced the rabbit CC tone in a dose-dependent manner. twenty ^ Ll ^ Ug ^^^^^^^ ggggg ^ ^ EXAMPLE 8A XVKA effects of compounds. B.) IN THE SEXUAL BEHAVIOR OF RAT (PROERÉCTILE ACTIONS) Male SD rats (350-450 g, n = 10 per group) were injected with increasing doses of XVIb (4.0-64.0 mg / kg), XVIa (1.0, 4.0 or 16 mg / kg) or saline and observed for 5 minutes after, in groups of 5, for the number of erections and the time of the first erection, during an observation period of 60 minutes. Compound XVIb produced erections in rats in a bell-shaped dose response form (Table 2). The maximum effect of compound XVIb was observed at 16 mg / kg. The duration of the first erection was carried out in a dose-response form with a "U" shape with a minimum time to the first erection also occurring at a dose of 16 mg / kg. At doses greater than 16 mg / kg, the number of erections / rat was decreased, while the number of responses was not reduced. The duration of the first erection was also increased to doses greater than 16 mg / kg. Compound XVIa also increased penile erections, although to a much lesser degree than XVIb. In Table 2, the effects of XVIb, XVIa and saline on erection in male rats are indicated. The data are expressed as the mean + _ sem for 10 test animals. The data marked with an "*" indicate the significant difference from saline (a <; 0.05) as determined by ANOVA with the turkey test for multiple comparisons.

TABLE 2 EXAMPLE OF XVIA COMPOUNDS. XVIB AND SALINA IN ERECTILE RESPONSES IN MALE RATS ^^^ jfci ^ ammkmá EXAMPLE 8B EFFECTS OF COMPOUND XVIb ORALALLY ADMINISTERED ON RAT SEXUAL BEHAVIOR (PROERÉCTILE ACTIONS) 5 Male SD rats (250-300 g) were given increasing doses of XVIb (30-100 mg / kg) in distilled water, by os) or distilled water only through a feeding tube, and were observed 5 minutes later for the number of erections (it will be characterized by penis growth) during an observation period of 60 minutes. Six rats at the same time, housed individually, were observed by two observers. The treatments were administered in a standard randomized and double blind manner. Compound XVIb produced erections in rats after oral administration. The effect of compound XVIb was dose dependent. At a dose of 30 mg / kg p.o., the maximum number of erections / rat was 3 / hour, while at 100 mg / kg p.o., the maximum number of erections / rat was 5 / hour, with 100% responses in both drug groups. In the control rats, the maximum number of rat erections was 1 / hour only with 50% responses.

EXAMPLE 8C EFFECTS OF COMPOUNDS XVIIa AND XVIIb ON SEXUAL BEHAVIOR OF RAT (PROTRACT ACTIONS) Male SD rats (250-300 g) were injected with compound XVIIa (16 mg / kg, ip), XVIIb (16 mg / kg, ip), or distilled water (ip), and were observed 5 minutes later for number of erections (as characterized by penis growth) and time for the first erection, during a 60-minute observation period. Six rats at the same time, housed individually, were observed by two observers. The treatments were administered in a standard randomized and double blind manner. At the dose used (16 mg / kg), the maximum number of erections / rat was 3 / hour and the duration of the first erection was 6 minutes of compound XVIIa with 67% responses; while for compound XVIIb the maximum number of erections / rat was 5 / hour and the duration of the first erection was 16 minutes with 100% response. In the control rats, the maximum number of erections per rat was 1 / hour and the duration of the first erection was 21 minutes with only 50% responses.

. ^ ^ ^^^^^ Mj ^^^ teab ^ EXAMPLE 9 EFFECTS OF THE XVIB COMPOUND ON THE BEHAVIOR OF RAT. CHEMICAL BLOOD AND TEMPERATURE OF THE BODY Male SD rats (350-450 g, n = 15 per group) were injected with a single dose of compound XVIb (16 mg / kg, ip) and saline and observed 5 minutes later, in pairs, for choices, ejaculation , movement and growth during a 60-minute observation period. The rectal temperature was recorded before of the administration of the drug and one hour after the administration of the drug. At the end of the experiments, the rats were decapitated and blood was collected from the trunk through RIA analysis of serum levels of cortisol and prolactin. At a dose of 16 mg / kg of compound XVIb, erections and ejaculations were significantly increased compared to the control output (XVIb 5.6 + 0.7 erections / 60 minutes against output, 1.3 + 0.3 erections / 60 minutes, XVIb, 1.8 + 0.1 ejaculations against saline, 0.2 +.0.1 ejaculations, p <0.001 ). At this dose, compound XVIb significantly increased the penis growth (XVIb, 12.1 ± 3.3 growths / 60 minutes against saline, 7.4 ± 2X growths / 60 minutes, p <0.01) but there was no effect on non-penile growth (XVIb, 22 +. 4.8 growths / 60 minutes against saline, 21.3 ± 3.4 growths / 60 minutes, p> 0.5). Elevation (XVIb 77 + ^ 5.9 elevations / minutes; 25 p> 0.3) and locomotion (XVIb, 20.7 +.3.3 movements against saline, 28. 4 + _ 4.6 movements; p > 0.4) were not significantly affected at this dose. The prolactin and cortisol levels in the serum were not significantly altered. The rectal temperature was not significantly altered by compound XVIb at 16 mg / kg.

EXAMPLE 10 EFFECTS OF COMPOUND XVIb AGAINST COMPARATIVE COMPOUNDS IN RAT BEHAVIOR SD rats were injected in male (300-500 g, n = 6 per group) with (+ _) - Pindolol scopolamine, haloperidol or ketanserin, 30 minutes before the injection of a single dose of compound XVIb / 16 mg / kg, ip) or saline. The animals were observed 5 minutes later for the occurrence of erection during a 60 minute observation period. The (+ _) - Pindolol (0.1-3 mg / kg) and scopolamine (0.1-3.0 mg / kg), but not haloperidol (0.01-0.3 mg / kg) and ketanserin (0.1-3.0 mg / kg), antagonized the erection promoting actions of an optimal dose of compound XVIb (16 mg / kg). At the highest dose tested, (+ _) - pindolol reduced the erection from 7.8 +.1.4 erections / 60 minutes to 2.0 + _0.4 erections / 60 minutes (p <0.05). Scopolamine reduced erections from 1.7 erections / 60 minutes to 1.2 + _ 0.3 erections / 60 minutes (p <0.05). r ~ ^^^ Ér ?? jtr_ff_ffi_1M _-_ - _ EXAMPLE 11 EFFECTS OF XVIB COMPOUND IN PROCOPULATION ACTIONS IN RAT Male Long-Evans rats (300-600 g, n = 15 per group) were injected with saline or compound XVIb (1.5-30.5 mg / kg; ip) 5 minutes before being placed in pairs with a sexually receptive female rat. through the administration of estradiol benzoate (25 μg, 48 hours before the test) and progesterone (1 mg / kg, 4 hours before the test). Mounting duration, duration of intrusion, duration of ejaculation, mounts, intrusions, ejaculations and the subsequent ejaculation interval were recorded during an observation period of 30 minutes. Mounting duration and intrusion were not significantly affected at the dose of 15 mg / kg, despite an obvious tendency for a reduction in both durations. The duration of ejaculation, the number of ejaculations and the number of intromissions were all significantly affected at a dose of 15 mg / kg (Table 3). The posterior ejaculation interval was not affected at any of the doses tested. At the previous and below 15 mg / kg, compound XVIb did not show significant effects on ejaculation behaviors other than reducing the number of intrusions (7.5 mg / kg and 30.5 mg / kg only, data not shown). In Table 3, the effect of compound XVIb in the »Rja3« «a__ < _ ^ ^ Copulation behavior in male rats. The data are expressed as a mean (sem for 15 test animals). Duration is the time in seconds for the appearance of that behavior. The ejaculations are the number of such events during 30 minutes of observation. Intrusions are the number of such events before ejaculation. The posterior ejaculation interval is the time in seconds from the ejaculation in the meddling to the first montage of the next copulation sequence. The P values derived from the double-ended T test for importance between the mean values (a < 0.05).

TABLE 3 EFFECTS OF THE XVIB COMPOUND ON THE BEHAVIOR OF MACHO RAT COPULATION ¡A ^^^^ »^ ¿___ ¡¡¡¡¡te_ ¿^ ^ ^ ^ ^ a ^ EXAMPLE 12 EFFECTS OF THE XVIB COMPOUND ON BEHAVIOR SEXUAL OF PRIMATES (STUDY OF OBSERVATION ISOLATED) Male Macaca fascilaris primates, adults (3.8-8 kg, n = 6) (0.1-10.0 mg / kg, or 0.5 ml / kg of body weight) were injected either with saline or compound XVIb and observed 10 minutes then for behavior and locomotion responses for 1 hour. The monkeys used for the test were injected and observed at separate sites away from the housing environment. Each monkey received a dose of compound XVIb at 72 hour intervals. The dose of compound XVIb (0.1-10 mg / kg) reliably increased grade 1 penile erections in primates observed in the isolate. However, this effect reached importance only at the highest dose tested. Advanced degrees of penile erection (grades 2-5) were not significantly affected by any dose (Table 4). At the highest dose tested, lip gesture indicators but not yawning were significantly increased (Table 4). In Table 4, the effect of compound XVIb on erectile responses was reported for male primates observed in isolation. Data are expressed as a mean aspect (sem, standard error of measurements) for 6 test animals. The penis responses were classified every 10 seconds for 1 hour according to . _ __fc __ &S: tan. , ... ^^ aaata ^ aa ^ aaaJBaa ^^ ü ^ ,, ^ ^ ¿saÜÉ -A ~ ^^^ ffjm? ff-f]? the following scale: Grade 0 = glanders not seen, Grade 1 = clearly visible glands, Grade 2 = extended penis, Grade 3 = full erection, Grade 4 = erection with masturbation, Grade 5 = erection with masturbation and ejaculation. In Table 4, the data marked with an "*" indicate a significant difference from saline as determined by repeated measures of ANOVA and the Dunnetts test for multiple comparisons (< 0.05). The data in Table 4 are reported as a percentage of genital observations.

TABLE 4 EFFECT OF THE XVIB COMPOUND IN ERECTION REPLIES w_ »ai_.fc_aÉ ^^^ EXAMPLE 13 TOXICITY STUDIES A compound of the present invention was orally administered to the rat, and the rat showed no obvious sign of adverse toxicity at a dose of up to 100 mg / kg (p.o.). When tested in mice, the following LD50 values were obtained for the compound: 318 mg / kg (subcutaneous); 194 mg / kg (intraperitoneal); 87 mg / kg (intravenous), and 400 mg / kg (oral). All publications and patent applications mentioned in this specification are incorporated herein by reference to the same degree as if each individual publication or patent application was specifically or individually incorporated by reference. From the foregoing, it will be appreciated that, while specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except that through the appended claims. £ _ & & - «« _ < ._. ^^^^^^^ ^ ^ ^^^^

Claims (41)

1. - The use of a compound for the manufacture of a medicament for the treatment or prevention of sexual malfunction in a patient, the compound having the formula: including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence: Ar is selected from a C3-C? 3 carbocyclic ring, and ring systems selected from the formulas (II), (III), (IV), (V), (VI), and (VII): (II) wherein R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7-alkanoyloxy, C6-alkyl, C6-C6 alkoxy , C2-C7 alkoxycarbonyl, C6-C6 thioalkyl, aryl selected from carbocyclic aryl, aryl x? ^? MU? t? ^^? ^^ S? A? t ^ heterocyclic and biaryl, and N (R15, R16) where R15 and R independently are selected from hydrogen, acetyl, methanesulfonyl and Ci-Cd alkyl; (III) (IV) wherein R 10, and R n independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 2 alkoxycarbonyl alkoxy -C7, Ci-Ce thioalkyl, and N (R15, R16) wherein R15 and R independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 12 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R16) wherein Ri5 and R16 , ^ _ »* A _" _ ^ _____ E___ > ___ LMt__5 _ ^^ independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (VI) (VII), L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms, and cycloalkyl of 5 to 6 carbon atoms of 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms; wherein the amount is effective to treat or prevent the sexual malfunction of the patient.

2. The use according to claim 1, wherein the sexual malfunction is erectile malfunction in males.

3. The use according to claim 1, wherein the sexual malfunction is impotence.

4. The use of a compound for the manufacture of a medicament for increasing the male or female patient libido, the compound having the formula: including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence: Ar is selected from a C3-C13 carbocyclic ring, and ring systems selected from the formulas (II ), (III), (IV), (V), (VI), and (VII): (II) wherein R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C ^ Ce alkyl, d-Cd alkoxy , C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, aryl selected from carbocyclic aryl, heterocyclic aryl and biaryl, and N (R 15, R 16) wherein R 5 and R independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl from Awíia¿ ^^ (III) (IV) wherein Rio, and Rn independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C6-C6alkyl, C6Calkoxy , C2-C7 alkoxycarbonyl, Ci-Ce thioalkyl, and N (R15, R16) wherein R15 and Ri6 independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 2 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, C 1-6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1-6 -thioalkyl, and N (R 5, R 16) wherein R 15 and R independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (VI) (VII), L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms, and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms; wherein the amount is effective to treat or prevent the libido of the patient.

5. The use of a compound for the manufacture of a medicament for improving the sexual functioning of a male or female patient, the compound having the formula: Ar- CH, - C-L-RÍ- -N G? N-R, 2 (i) including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence: Ar is selected from a C3-C13 carbocyclic ring, and ring systems selected from the formulas (II ), (III), (IV), (V), (VI), and (Vile): (II) wherein R7, R8 and Rg independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C6-C6 alkyl, C-alkoxy; -C6, C2-C7 alkoxycarbonyl, aryl thioalkyl selected from carbocyclic aryl, aryl Heterocyclic and biaryl, and N (R15, R16) wherein R15 and R6 are independently selected from hydrogen, acetyl, methanesulfonyl and dC6 alkyl; (III) (IV) wherein R? 0, and Rn independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, Ci alkyl -Ce, C? -C6 alkoxy, C2-C7 alkoxycarbonyl, 20 thioalkyl of C? -C6, and N (R15, R16) wherein Ri5 and Rie independently they are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 12 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R16) wherein R15 and R independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (VI) (VII), L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms, and cycloalkyl of 5 to 6 atoms v ^ * ^ - ^ * at ^ m *? É Mt & carbon 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms; wherein the amount is effective to treat or prevent the sexual functioning of the patient.

6. The use according to claim 5, wherein the compound provides a pro-erectile response in the patient.

7. The use according to claim 1, 2, 3, 4, 5, or 6 wherein R1 is a direct link.

8. The use according to claim 1, 2, 3, 4, 5, or 6 wherein L is a direct link.

9. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound has the formula: including its salts, solvates, isolated tautomers and mixtures thereof.

10. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound has the formula: including its salts, solvates, isolated tautomers and mixtures thereof.

11. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound has one of the formulas: including its salts, solvates, isolated tautomers and mixtures thereof.

12. The use according to claim 1, 2, 3, 4, 5, or 6 wherein L is O or NH.

13. The use according to claim 1, 2, 3, 4, 5, or 6 wherein R1 is 1,2-disubstituted cyclohexane.

14. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound has the formula: including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers and mixtures thereof, wherein L is not a direct bond.

15. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound has the formula: including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers and mixtures thereof, wherein L is not a direct bond.

16. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound is formulated for oral administration.

17. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound is formulated for topical administration.

18. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound is formulated for direct injection.

19. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound is formulated for one of intrameatal, intracavernosal or intra urethral administration.

20. The use according to claim 1, 2, 3, 4, 5, or 6 wherein the compound is formulated as a tablet with a disintegration time of less than one hour.

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of the formula: O Ar-CH, -C-L-Ri-N G? N-R2 (I) 15 including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence: Ar is selected from a C3-C13 carbocyclic ring, and ring systems selected from the formulas ( II), (III), (IV), (V), (VI), and 20 (Vil): (II) & ^^ S & amp; amp; M ^ te ^^ m & ^ AL ^ ^ bísÍ! í. It is characterized in that R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, alkyl of d-C6, C? -C6 alkoxy, C2-C7 alkoxycarbonyl, d-C6 thioalkyl, aryl selected from carbocyclic aryl, heterocyclic aryl and biaryl, and N (R15, R16) wherein R15 and R16 are independently selected of hydrogen, acetyl, methanesulfonyl and d-C6 alkyl; (III) (IV) wherein R? 0, and Rn independently are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C? -C6 alkyl, d-alkoxy -C6, C2-C7 alkoxycarbonyl, d-C6 thioalkyl, and N (R15, R16) wherein R5 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) ^. ,.,. fa_i-tififtl __ ^ wherein R12 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R 5, R 16) wherein R 15 and R 6 are independently selected from hydrogen , acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; 10 (VI) (VII), L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms, and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms; wherein the composition is in the form of a tablet for oral administration, and the tablet has a disintegration time of less than one hour. 22.- A method to treat or prevent malfunction sexual in a patient, comprising administering to the patient with the need thereof a quantity of a compound of the formula: including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence: Ar is selected from a C3-C13 carbocyclic ring, and 10 of selected rings of formulas (II), (III), (IV), (V), (VI), and (VII): (II) 15 wherein R7, R8 and Rg are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, metansulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, alkyl d-C6 alkoxy, d- C6, C2-C7 alkoxycarbonyl, d-C6 thioalkyl, aryl selected from carbocyclic aryl, aryl Heterocyclic and biaryl, and N (R15, R16) wherein R15 and R independently are selected from hydrogen, acetyl, methanesulfonyl and d-C6 alkyl; sii ^^ í & Mímís ^ ^ é ^ ff ^^, - ^, ^ (III) (IV) where Rio, Rn and are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, metansulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, alkyl of C? C6 alkoxy, d-C6 , C2-C7 alkoxycarbonyl, d-C6 thioalkyl, and N (R15, R16) wherein R15 and R6 independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; 10 (V) wherein R 2 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, Trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R16) wherein R15 and R6 are independently selected from hydrogen, acetyl, 20 methanesulfonyl and alkyl of 1 to 6 carbon atoms; (VI) (VII), L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms, and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms; wherein the amount is effective to treat or prevent the sexual malfunction of the patient. 23. The method according to claim 22, wherein the sexual malfunction is erectile malfunction in males. 24. The method according to claim 22, wherein the sexual malfunction is impotence. 25. A method for increasing the libido of a male or female patient, comprising administering to the patient with the need thereof a quantity of a compound of the formula: ** ^ «j¿á» «** * ¿^^ including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence: Ar is selected from a carbocyclic ring of C3-C13, and ring systems selected from formulas (II), (III), (IV), (V), (VI), and (VII): (II) wherein R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, metansulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy C2-C7, alkyl d-C6 alkoxy, d-C6 , C2-C7 alkoxycarbonyl, thioalkyl of d-C6alkyl, aryl selected carbocyclic aryl, heterocyclic aryl and biaryl, and N (R15, R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and alkyl d- C6; (III) (IV) ^ I éim? ^ ^^ mááii ASSTI ^^^^^ wherein R10 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, metansulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, alkyl C? -C6, d-C6 alkoxy, C2-C7 alkoxycarbonyl, thioalkyl of d-C6 alkyl, and N (R15, R16) where R15 and Ríe independently selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 12 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R16) wherein R15 and R6 independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (VI) (VII), = - ^^^^^^ -? ^ ¿I¡ ^? * If »- * ¿z *** t > * ~ L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms, and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms; wherein the amount is effective to increase the libido of the patient. 26. A method for improving the sexual functioning of a male or female patient, comprising administering to the patient with the need thereof a quantity of a compound of the formula: including salts, solvates, isolated enantiomers, isolated diesteromers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence: Ar is selected from a C3-C13 carbocyclic ring, and ring systems selected from the formulas (II ), (III), (IV), (V), (VI), and (VII): ^^^ a ^ ai ^ gj f ^^ (II) wherein R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, d-C6 alkyl, d-C6 alkoxy , C2-C7 alkoxycarbonyl, d-C6 thioalkyl, aryl selected from carbocyclic aryl, heterocyclic aryl and biaryl, and N (R5, R16) wherein R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and d-C6; (III) (IV) wherein R, and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, d-C6 alkyl, d-C6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, and N (R 15, R 16) wherein R 15 and R independently are selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (V) wherein R 12 are selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, alkanoyloxy of 2 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms of carbon, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, thioalkyl of 1 to 6 carbon atoms, and N (R15, R16) wherein R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and alkyl of 1 to 6 carbon atoms; (VI) (VII), L is selected from the group of a direct bond, O, NH, and N (alkyl of 1 to 6 carbon atoms); R1 is selected from the group of a direct bond, an alkylene group of 1 to 6 carbon atoms, and cycloalkyl of 5 to 6 carbon atoms 1, 2-disubstituted; and R2 is alkyl of 1 to 6 carbon atoms; where the amount is effective to increase the ..., ^ _ ^: -_ te._fa »_J -._ ,,, ... ^ * * * h *? II * ml * tíi Au * sexual functioning of the patient. 27. The method according to claim 26, wherein the compound provides a pro-erectile response in the patient. 28. The method according to claim 22, 25 or 26, wherein R1 is a direct link. 29. The method according to claim 22, 25 or 26, wherein L is a direct link. 30. The method according to claim 22, 25 or 26, wherein the compound has the formula: including salts, solvates, isolated tautomers and mixtures thereof. 31. The method according to claim 22, 25 or 26, wherein the compound has the formula: _ ^ á ^ ._ ». s ^ ._ * -_._ ^.« j __ ^ a ^^ ¡¡¡¡¡¡Aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaah - - * including salts, solvates, isolated tautomers and mixtures thereof. 32. The method according to claim 22, 25 or 26, wherein the compound has the formula: including salts, solvates, isolated tautomers and mixtures thereof. 33. The method according to claim 22, 25 or 26, wherein L is O or NH. 34. The method according to claim 22, 25 or 26, wherein R1 is 1,2-disubstituted cyclohexane. 35.- The method according to claim 22, 25 or 26, wherein the compound has the formula: including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, wherein L is not a direct link. 36.- The method according to claim 22, 25 or 26, wherein the compound has the formula: including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, wherein L 10 is not a direct bond. 37. The method according to claim 22, 25 or 26, wherein the administration is through oral administration. 38. The method according to claim 22, 25 or 26, wherein the administration is through topical administration. 39. The method according to claim 22, 25 or 26, wherein the administration is through direct injection. 40. The method according to claim 22, 25 or 26, wherein the administration is through one of intrameatal, intracavernous, or intraurethral administration. 41. The method according to claim 22, 25 or 26, wherein the compound is formulated as a tablet with a time More than one hour of disintegration. , _. ~ * ~ * le¿ »* ~ t? * ?? -