WO2006060199A2 - Imidazole derivatives for the treatment of sexual dysfunction - Google Patents

Imidazole derivatives for the treatment of sexual dysfunction Download PDF

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Publication number
WO2006060199A2
WO2006060199A2 PCT/US2005/042001 US2005042001W WO2006060199A2 WO 2006060199 A2 WO2006060199 A2 WO 2006060199A2 US 2005042001 W US2005042001 W US 2005042001W WO 2006060199 A2 WO2006060199 A2 WO 2006060199A2
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chlorophenyl
alkyl
imidazole
phenyl
trifluoromethyl
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PCT/US2005/042001
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French (fr)
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WO2006060199A3 (en
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Bernhard Glombitza
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Bayer Pharmaceuticals Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin

Definitions

  • This invention relates to imidazole derivatives which are useful in treating sexual dysfunction.
  • Erectile dysfunction may result from failure to initiate, fill, or store adequate blood volume within the lacunar network of the penis.
  • ED may be vasculogenic, neurogenic, endocrinologic, diabetic, psychogenic, or medication-related.
  • ED affects 10-25% of middle-aged and elderly men, and has a profound impact on the well-being of affected men. It is currently treated using PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil. Intraurethral alpostadil (prostaglandin El) may be used in patients that fail on oral agents. In addition, vacuum constriction devices (VCD) are a well-established, noninvasive therapy.
  • PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil.
  • Intraurethral alpostadil prostaglandin El
  • VCD vacuum constriction devices
  • FSD Female sexual dysfunction
  • arousal arousal
  • orgasm arousal
  • symptoms include diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieveing orgasm.
  • VIP vasoactive intestinal peptide
  • NO nitic oxide
  • sex hormones such as estrogens and androgens
  • Current treatment approaches include estrogen replacement therapy, methyl testosterone, PDE5 inhibitors such as sildenafil, the NO-donor L-arginine, prostaglandin El, phentolamine, and the dopamine agonists apomorphine.
  • the present invention relates to compounds which are useful in the treatment of sexual dysfunctions such as erectile dysfunction and female sexual dysfunction.
  • the invention relates to substituted imidazole derivatives that have utility in the treatment of sexual dysfunction, said derivatives of the Formula (I), prodrugs thereof, tautomers thereof and salts thereof
  • R 1 and R 2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (Ci-C 6 )alkyl, (Q- Q)alkoxy, trifluoromethyl, cyano, nitro, (Ci-C 6 )alkyl sulfonyl, (Ci-C 6 )alkyl sulfonyl- amino, (Ci-C 6 )alkyl carbonyl-amino, (Q-C 6 )alkyl amino-carbonyl-amino, or phenyl,
  • cyclohexyl optionally substituted with (Ci-C 6 )alkyl, (Q-C 6 )alkoxy, trifluoromethyl, cyano, or with one or more fluorine,
  • 1-naphthyl or 2-naphthyl optionally substituted with halogen, (Q-C 6 )alkyl, (Q- Ce)alkoxy, trifluoromethyl, or cyano, benzyl optionally substituted on the phenyl ring with one or more halogen, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, or cyano,
  • a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, or cyano, and
  • a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, cyano, nitro, or phenyl;
  • R 3 is hydrogen, (Ci-C 6 )alkyl, benzyl, chloro, or bromo;
  • R 4 is hydrogen or (Ci-C 6 )alkyl
  • R 5 is selected from
  • benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Ci-C 6 )alkyl, and optionally substituted on the phenyl ring with one or more halogen, (Ci-Cg)alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro,
  • piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl each of which may optionally be substituted on the nitrogen atom of the piperidine or pyrrolidine ring with (Q- C 6 )alkyl, hydroxy-substituted (Ci-Ce)aUcyl, (Ci-C 3 )alkoxy-substituted (Q- C 3 )alkyl, benzyl, or phenyl optionally substituted with one or more of (C 1 - QOalkyl, (Q-C 6 )alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, nitro, or halogen, -NR 6 R 7 where R 6 is hydrogen or (Ci-C 6 )alkyl;
  • R 7 is (Q-C ⁇ alkyl; or phenyl optionally substituted with one or more of (C 1 -C 6 )alkyl, hydroxy-substituted (Ci-C 6 )alkyl, (Q-C 3 )alkoxy- substituted (Ci-C 3 )alkyl, phenyl, hydroxy, benzyloxy, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, nitro, or a halogen atom, or
  • R 6 and R 7 taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more (Q-C 6 )alkyl, (Q- C 6 )alkoxy, hydroxy-substituted (Ci-C 3 )alkyl, (Q-C 3 )alkoxy-substituted (Ci-C 3 )alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine;
  • R 4 and R 5 taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (Q-Cg)alkyl, (Ci-Cg)alkoxy, (Q- C 6 )alkyl-amino, bis[(Q-C 3 )alkyl]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (Ci-C 6 )alkyl, phenyl-substituted (Q-C 6 )alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (Q-C 6 )alkyl, hydroxy, benzyloxy, (Q- C 6 )alkoxy, trifluoromethyl, cyano, nitro, or halogen;
  • R 10 is (Q-C 9 )alkyl optionally substituted with one or more phenyl, hydroxy, benzyloxy, (Q-QOalkoxy, or a fluorine atom, or phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, (Ci-C 6 )alkoxy, or halogen;
  • Examples of compounds of Formula (I) include, but are not limited to:
  • any moiety when any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence.
  • Representative salts of the compounds of the present invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanes
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lauryl
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R, S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active.
  • prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention.
  • Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc.
  • Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility.
  • compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or lipases in vivo. See for example U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
  • subject includes mammals (e.g., humans and animals).
  • treatment includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease condition and/or disorder.
  • administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent.
  • administration encompasses use of each type of therapeutic agent in a sequential manner.
  • terapéuticaally effective means the amount of each agent administered that will achieve the goal of improvement in a disease condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
  • pharmaceutically acceptable means that the subject item is appropriate for use in a pharmaceutical product.
  • the compounds of the present invention are useful in treating sexual dysfunction including erectile dysfunction and female sexual dysfunction.
  • the compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of sexual dysfunction. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy. [031] For example, the compounds of the present invention may be used in combination with other drugs that are used for treating erectile dysfunction (e.g., sildenafil, vardenafil, tadalafil, and alprostadil) and female sexual dysfunction.
  • erectile dysfunction e.g., sildenafil, vardenafil, tadalafil, and alprostadil
  • Such co-therapies may be administered in any combination of two or more drags (e.g., a compound of the invention in combination with a drug useful for treating erectile dysfunction).
  • Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
  • the effective dosage of the compounds of this invention can readily be dete ⁇ nined for treatment of each desired indication.
  • the amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day.
  • a unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day.
  • the daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg.
  • the daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight.
  • the transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds described herein may be administered with a pharmaceutically- acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
  • the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers.
  • the compounds of this invention may be tableted with conventional tablet bases in combination with binders, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • Suitable excipients for use in oral liquid dosage forms include diluents either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
  • compositions of this invention may also be in the form of oil-in-water emulsions.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant or emulsifying agent and other pharmaceutical adjuvants.
  • compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drag.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art ⁇ see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release.
  • Such formulations can be comprised of synthetic polymers or copolymers.
  • Such formulations allow for injection, inhalation, nasal or oral administration.
  • the construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., U.S. Patent No. 6, 706,289, incorporated herein by reference).
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • implantable delivery system used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference.
  • compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
  • Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20 th edition, 2000).
  • Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of a sexual dysfunction, the following assays may be used.
  • Drugs affecting erectile function may be tested by measuring the effect on apomorphine- evoked increases in intracavernous pressure in the awake rat as described by Andersson, et al, (J. Urol. 161 : 1707-1712, 1999).
  • One end of a polyethylene tubing is implanted into the cavernosal space of the penis of male Sprague-Dawley rats. After recovery from the surgery, intracavemous pressure is recorded using a pressure transducer connected to a multichannel pen-recorder. Erections are induced by administration of apomorphine (100-250 ug/kg s.c.) with or without test compound, and the results are compared for the treated group and the non-treated group.
  • Systems to test compounds for the treatment of female sexual dysfunction include in vitro and in situ models using vaginal or clitoral smooth muscle preparations, histological evaluation, and vaginal blood flow assessments.
  • In vivo studies of sexual responses focus on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method (see, e.g., Hale, et al., Int. J. Impot. Res. 15 Suppl 5:S75-79, 2003).

Abstract

This invention relates to imidazole derivatives which are useful in treating sexual dysfunction.

Description

IMIDAZOLE DERIVATIVES FOR THE TREATMENT OF SEXUAL DYSFUNCTION
[001] This application claims benefit of U.S. Provisional Application Serial No. 60/632,001 ; filed on November 30, 2004, the contents of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[002] This invention relates to imidazole derivatives which are useful in treating sexual dysfunction.
BACKGROUND OF THE INVENTION
[003] Normal sexual function requires, among others, the ability to achieve and maintain penile erection. Major anatomic structures of the penis that are involved in erectile function include the corpus cavernosum, corpus spinosum, and the tunica albuginea (a collagenous sheath that surrounds each corpus). Thecorpora are composed of a mass of smooth muscle (trabecula) which contains a network of endothelial-lined vessels (lacunar spaces). Penile tumescence and erection is caused by relaxation of the arteries and corporal smooth muscles, while closing emissary veins, leading to increased blood flow into the lacunar network. Central and peripheral innervation contributes to regulation of the erectile response.
[004] Erectile dysfunction (ED) may result from failure to initiate, fill, or store adequate blood volume within the lacunar network of the penis. Depending on the underlying dysfunction, ED may be vasculogenic, neurogenic, endocrinologic, diabetic, psychogenic, or medication-related.
[005] ED affects 10-25% of middle-aged and elderly men, and has a profound impact on the well-being of affected men. It is currently treated using PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil. Intraurethral alpostadil (prostaglandin El) may be used in patients that fail on oral agents. In addition, vacuum constriction devices (VCD) are a well-established, noninvasive therapy.
[006] Female sexual dysfunction (FSD) is highly prevalent, age-related, and progressive. It affects 30 to 50% of women (Berman, et al., Urology 54:385-391, 1999). FSD denotes a range of medical problems and is categorized according to disorders of (1) desire, (2) arousal, (3) orgasm and (4) sexual pain, and symptoms include diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieveing orgasm. On a molecular level, vasoactive intestinal peptide (VIP), nitic oxide (NO), and sex hormones such as estrogens and androgens have been suggested to be important in female sexual function. Current treatment approaches include estrogen replacement therapy, methyl testosterone, PDE5 inhibitors such as sildenafil, the NO-donor L-arginine, prostaglandin El, phentolamine, and the dopamine agonists apomorphine.
[007] Accordingly, despite the presence of some pharmaceuticals that are used to treat these disorders, there still remains a need for new pharmaceuticals that are both safe and effective agents for the treatment of sexual dysfunction.
[008] The present invention relates to compounds which are useful in the treatment of sexual dysfunctions such as erectile dysfunction and female sexual dysfunction.
DETAILED DESCRIPTION OF THE INVENTION
[009] The invention relates to substituted imidazole derivatives that have utility in the treatment of sexual dysfunction, said derivatives of the Formula (I), prodrugs thereof, tautomers thereof and salts thereof
Figure imgf000003_0001
( I )
wherein
R1 and R2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (Ci-C6)alkyl, (Q- Q)alkoxy, trifluoromethyl, cyano, nitro, (Ci-C6)alkyl sulfonyl, (Ci-C6)alkyl sulfonyl- amino, (Ci-C6)alkyl carbonyl-amino, (Q-C6)alkyl amino-carbonyl-amino, or phenyl,
(C2-C6)aBcyl,
cyclohexyl optionally substituted with (Ci-C6)alkyl, (Q-C6)alkoxy, trifluoromethyl, cyano, or with one or more fluorine,
1-naphthyl or 2-naphthyl optionally substituted with halogen, (Q-C6)alkyl, (Q- Ce)alkoxy, trifluoromethyl, or cyano, benzyl optionally substituted on the phenyl ring with one or more halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, trifluoromethyl, or cyano,
a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine, (Ci-C6)alkyl, (Ci-C6)alkoxy, trifluoromethyl, or cyano, and
a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, trifluoromethyl, cyano, nitro, or phenyl;
R3 is hydrogen, (Ci-C6)alkyl, benzyl, chloro, or bromo;
Figure imgf000004_0001
where R4 is hydrogen or (Ci-C6)alkyl;
R5 is selected from
(C2-C9)alkyl or (C7-Cn)bicycloalkyl, each of which may optionally be substituted with one or more phenyl, hydroxy, benzyloxy, (Ci-C6)alkoxy, (C1-C6)alkyl- amino, bis[(Ci-C3)alkyl]-amino, 1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-l,4- benzodioxin-2-yl, hydroxy-substituted (Ci-C6)alkyl, or fluorine,
benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Ci-C6)alkyl, and optionally substituted on the phenyl ring with one or more halogen, (Ci-Cg)alkyl, (Ci-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro,
piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, each of which may optionally be substituted on the nitrogen atom of the piperidine or pyrrolidine ring with (Q- C6)alkyl, hydroxy-substituted (Ci-Ce)aUcyl, (Ci-C3)alkoxy-substituted (Q- C3)alkyl, benzyl, or phenyl optionally substituted with one or more of (C1- QOalkyl, (Q-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, nitro, or halogen, -NR6R7 where R6 is hydrogen or (Ci-C6)alkyl;
R7 is (Q-C^alkyl; or phenyl optionally substituted with one or more of (C1-C6)alkyl, hydroxy-substituted (Ci-C6)alkyl, (Q-C3)alkoxy- substituted (Ci-C3)alkyl, phenyl, hydroxy, benzyloxy, (C1-C6)alkoxy, trifluoromethyl, cyano, nitro, or a halogen atom, or
R6 and R7, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more (Q-C6)alkyl, (Q- C6)alkoxy, hydroxy-substituted (Ci-C3)alkyl, (Q-C3)alkoxy-substituted (Ci-C3)alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine;
or
R4 and R5, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (Q-Cg)alkyl, (Ci-Cg)alkoxy, (Q- C6)alkyl-amino, bis[(Q-C3)alkyl]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (Ci-C6)alkyl, phenyl-substituted (Q-C6)alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (Q-C6)alkyl, hydroxy, benzyloxy, (Q- C6)alkoxy, trifluoromethyl, cyano, nitro, or halogen;
or
Figure imgf000005_0001
where R10 is (Q-C9)alkyl optionally substituted with one or more phenyl, hydroxy, benzyloxy, (Q-QOalkoxy, or a fluorine atom, or phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, (Ci-C6)alkoxy, or halogen;
and pharmaceutical salts and esters thereof.
[010] Methods of synthesizing compounds of Formula (I) are described in WO 03/040107 (PCT/EPOl/03247), which is incorporated herein in its entirety.
[011] Examples of compounds of Formula (I) include, but are not limited to:
1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl] carbonyl } -4-(4- fluorophenyl)-4-piperidinol;
1 - { [2-(2-chloropheny I)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl]carbonyl } -4-(4- chlorophenyl)-4-piperidinol; l-{ [2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-[3-
(trifluromethyl)phenyl]-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(4- trifluoromethoxyphenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(3- fluorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-lH-imidazol-4- yl]carbonyl}-4-(3-chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(3- fluoro-4-chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-[3-
(trifluoromethoxy)phenyl]-4-piperidinol;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[l-(2-pyridinyl)-4-piperidinyl]-lH- imidazole-4-carboxamide;
[2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4- yl](cyclohexyl)methanone;
2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-(4-pyridinyl)- 1 H-imidazole-4- carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[2-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[3-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide; N'-[2-chloro-4-(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4- chlorophenyl)- 1 H-imidazole-4-carbohydrazide ;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-chloro-2-
(trifluoromethyl)phenyl]-lH-imidazole-4-carbohydrazide;
N'-(4-chloro-2-methylphenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carboliydrazide;
N'-(2,4-dichlorophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;
N'-[2,4-bis(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4-chlorophenyl)- lH-imidazole-4-carbohydrazide;
N'-(2-chloro-4-cyanophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-(2,4-dichlorophenyl)-5-methyl-
1 H-imidazole-4-carbohydrazide ;
1 -(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-( 1 -piperidinyl)- 1 H-imidazole-
4-carboxamide;
1 -(4-chlorophenyl)-2-(2-chlorophenyl)-N-( 1 -piperidinyl)- 1 H-imidazole-4- carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-butyl-lH- imidazole-4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-methyl-lH- imidazole-4-carboxamide;
1 -(4-isopropylphenyl)-2-(2-chlorophenyl)-N-( 1 -piperidinyl)-5-ethyl- 1 H- imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-hexahydrocycloρenta[c]pyrrol-
2(lH)-yl-lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclohexyl]- lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]- 1 H-imidazole-4-carboxamide ;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-5-propyl-N-[( 1 S,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexylHH-imidazole^-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lR,2R)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l~(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(cis)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;
4-(4-{[l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-lH-imidazol-4- yl]carbonyl } - 1 -piperazinyl)benzonitrile; and
4-(4- { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl] carbonyl } - 1 - piperazinyl)benzonitrile.
[012] When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence.
[013] Representative salts of the compounds of the present invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
[014] Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
[015] It will be appreciated that diastereomers and enantiomers of the exemplified structures will often be possible, and that pure isomers represent preferred embodiments. It is intended that pure stereoisomers, and mixtures thereof, are within the scope of the invention.
[016] The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R, S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active.
[017] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.
[018] Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (= Z-) or trans (= E-) form, and both isomeric forms are encompassed within the scope of this invention.
[019] The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.
[020] For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.
[021 ] It is anticipated that prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention. Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc. Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility. For example, compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or lipases in vivo. See for example U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
Methods of Use
[022] As used herein, various terms are defined below.
[023] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.
[024] The term "subject" as used herein includes mammals (e.g., humans and animals).
[025] The term "treatment" includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
[026] The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat a disease condition and/or disorder. Such administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner.
[027] The phrase "therapeutically effective" means the amount of each agent administered that will achieve the goal of improvement in a disease condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
[028] The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product.
[029] The compounds of the present invention are useful in treating sexual dysfunction including erectile dysfunction and female sexual dysfunction.
[030] The compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of sexual dysfunction. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy. [031] For example, the compounds of the present invention may be used in combination with other drugs that are used for treating erectile dysfunction (e.g., sildenafil, vardenafil, tadalafil, and alprostadil) and female sexual dysfunction.
[032] Such co-therapies may be administered in any combination of two or more drags (e.g., a compound of the invention in combination with a drug useful for treating erectile dysfunction). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
[033] Based on well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be deteπnined for treatment of each desired indication. The amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
[034] The total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
[035] Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
[036] The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds described herein may be administered with a pharmaceutically- acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
[037] For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers.
[038] In another embodiment, the compounds of this invention may be tableted with conventional tablet bases in combination with binders, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
[039] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
[040] The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The emulsions may also contain sweetening and flavoring agents.
[041] Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents. [042] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant or emulsifying agent and other pharmaceutical adjuvants.
[043] The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant.
[044] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
[045] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
[046] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drag.
[047] Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art {see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[048] Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release. Such formulations can be comprised of synthetic polymers or copolymers. Such formulations allow for injection, inhalation, nasal or oral administration. The construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., U.S. Patent No. 6, 706,289, incorporated herein by reference). [049] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference.
[050] The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
[051] Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20th edition, 2000).
[052] It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.
Evaluation of Biological Activity
[053] In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.
[054] Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of a sexual dysfunction, the following assays may be used.
Erectile Dysfunction
[055] Drugs affecting erectile function may be tested by measuring the effect on apomorphine- evoked increases in intracavernous pressure in the awake rat as described by Andersson, et al, (J. Urol. 161 : 1707-1712, 1999). One end of a polyethylene tubing is implanted into the cavernosal space of the penis of male Sprague-Dawley rats. After recovery from the surgery, intracavemous pressure is recorded using a pressure transducer connected to a multichannel pen-recorder. Erections are induced by administration of apomorphine (100-250 ug/kg s.c.) with or without test compound, and the results are compared for the treated group and the non-treated group.
Female Sexual Dysfunction
[056] Systems to test compounds for the treatment of female sexual dysfunction include in vitro and in situ models using vaginal or clitoral smooth muscle preparations, histological evaluation, and vaginal blood flow assessments. In vivo studies of sexual responses focus on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method (see, e.g., Hale, et al., Int. J. Impot. Res. 15 Suppl 5:S75-79, 2003).
[057] The structures, materials, compositions, and methods described herein are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.

Claims

ClaimsWhat is claimed:
1. A method for treating sexual dysfunction comprising administering to a subject in need thereof an effective amount of a compound of Formula (I)
Figure imgf000016_0001
( D
wherein
R1 and R2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (Ci-Cβ)alkyl, (Ci- Cβ)alkoxy, trifluoromethyl, cyano, nitro, (Ci-C6)alkyl sulfonyl, (Q-C^alkyl sulfonyl- amino, (Ci-C6)alkyl carbonyl-amino, (Ci-C6)alkyl amino-carbonyl-amino, or phenyl,
(C2-C6)alkyl,
cyclohexyl optionally substituted with (Ci-Ce)alkyl, (Ci-Q)alkoxy, trifluoromethyl, cyano, or with one or more fluorine,
1-naphthyl or 2-naphthyl optionally substituted with halogen, (C1-C6)alkyl, (Q- C6)alkoxy, trifluoromethyl, or cyano,
benzyl optionally substituted on the phenyl ring with one or more halogen, (Ci-C6)alkyl, (Ci-C6)ahcoxy, trifluoromethyl, or cyano,
a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine, (Q-C6)alkyl, (Ci-Ce)alkoxy, trifluoromethyl, or cyano, and
a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, trifluoromethyl, cyano, nitro, or phenyl;
R3 is hydrogen, (Ci-C6)alkyl, benzyl, chloro, or bromo;
Figure imgf000017_0001
where R4 is hydrogen or (Ci-Q)alkyl;
R5 is selected from
(C2-C9)alkyl or (C7-Cn)bicycloalkyl, each of which may optionally be substituted with one or more phenyl, hydroxy, benzyloxy, (Ci-C6)alkoxy, (Q-C6)alkyl- amino, bis[(C1-C3)alkyl]-amino, 1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-l,4- benzodioxin-2-yl, hydroxy-substituted (C1-C6)alkyl, or fluorine,
benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Q-C6)alkyl, and optionally substituted on the phenyl ring with one or more halogen, (Ci-C6)alkyl, (Q-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro,
piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, each of which may optionally be substituted on the nitrogen atom of the piperidine or pyrrolidine ring with (Q- C6)alkyl, hydroxy-substituted (C1-C6)alkyl, (Ci-C3)aucoxy-substituted (Q- C3)alkyl, benzyl, or phenyl optionally substituted with one or more of (C1- Ce)alkyl, (Ci-Cg)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, nitro, or halogen,
-NR6R7 where R6 is hydrogen or (Q-C6)alkyl;
R7 is (Q-C^alkyl; or phenyl optionally substituted with one or more of (C1-C6)alkyl, hydroxy-substituted (Ci-C6)alkyl, (Q-C3)alkoxy- substituted (Q-C3)alkyl, phenyl, hydroxy, benzyloxy, (Ci-C6)alkoxy, trifluoromethyl, cyano, nitro, or a halogen atom, or
R6 and R7, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more (Ci-C6)alkyl, (Q- C6)alkoxy, hydroxy-substituted (Q-C3)alkyl, (Q-C3)alkoxy-substituted
(Q-C3)alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine; or
R4 and R5, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (Q-C6)alkyl, (Q-Ce)alkoxy, (Q- C6)alkyl-amino, bis[(C1-C3)alkyl]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (Q-Ce)alkyl, phenyl-substituted (Q-C6)alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (Ci-C6)alkyl, hydroxy, benzyloxy, (Q- Ce)alkoxy, trifluoromethyl, cyano, nitro, or halogen;
or
Figure imgf000018_0001
where R10 is (Q-Cc>)alkyl optionally substituted with one or more phenyl, hydroxy, benzyloxy, (Q-C6)alkoxy, or a fluorine atom, or
phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, (Q-C6)alkoxy, or halogen;
and pharmaceutical salts and esters thereof.
2. The method of claim 1, wherein said compound of Formula (T) is selected from
1 -{ [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4-yl] carbonyl } -4-(4- fluorophenyl)-4-piperidinol;
1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4-yl] carbonyl } -4-(4- chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-[3-
(trifluromethyl)phenyl]-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(4- trifluoromethoxyphenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(3- fluorophenyl)-4-piperidinol;
1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-5-ethyl- 1 H-imidazol-4- yl]carbonyl}-4-(3-chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(3- fluoro-4-chlorophenyl)-4-piperidinol;
1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl]carbonyl } -4- [3-
(trifluoromethoxy)phenyl]-4-piperidinol;
2-(2-chlorophenyl)- 1 -(4-chloropheny I)-N- [ 1 -(2-pyiidinyl)-4-piperidinyl]- 1 H- imidazole-4-carboxamide;
[2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4- yl] (cyclohexyl)methanone;
2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-(4-pyridinyl)- 1 H-imidazole-4- carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[2-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[3-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
N'-[2-chloro-4-(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4- chlorophenyl)-lH-imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-chloro-2-
(trifluoromethyl)phenyl]-lH-imidazole-4-carbohydrazide;
N'-(4-chloro-2-methylphenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;
N'-(2,4-dichlorophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;
N'-[2,4-bis(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4-chlorophenyl)- lH-imidazole-4-carbohydrazide;
N'-(2-chloro-4-cyanoρhenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-(2,4-dichlorophenyl)-5-methyl- lH-imidazole-4-carbohydrazide; l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(l-piperidinyl)-lH-imidazole-
4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-lH-imidazole-4- carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-butyl-lH- imidazole-4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide ; l-(4-bromophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide;
1 -(4-chlorophenyl)-2-(2-chlorophenyl)-N-( 1 -piperidinyl)-5-methyl- 1 H- imidazole-4-carboxamide ; l-(4-isopropylphenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-hexahydrocyclopenta[c]pyrrol-
2(lH)-yl-lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclohexyl]- lH-irnidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]- lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-propyl-N-[(lS,2S)-2- hydroxycyclohexylj-lH-imidazole^-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lR,2R)-2- hydroxycyclohexyl]-lH~imidazole-4-carboxarnide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(cis)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;
4-(4-{[l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-lH-imidazol-4- yl]carbonyl}-l-piperazinyl)benzonitrile; and
4-(4-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-l- piperazinyl)benzonitrile.
3. The method of claim 1 or 2, wherein said sexual dysfunction is erectile dysfunction.
4. The method of claim 3, further comprising administering a pharmaceutical agent for erectile dysfunction in combination with said compound of Formula (T).
5. The method of claim 4, wherein said pharmaceutical agent is selected from sildenafil, vardenafil, tadalafil, and alprostadil.
6. The method of claim 1 or 2, wherein said sexual dysfunction is female sexual dysfunction.
7. The method of claim 6, further comprising administering a pharmaceutical agent for female sexual dysfunction in combination with said compound of Formula (I).
8. The method of claim 7, wherein said pharmaceutical agent is selected from estrogen replacement therapy, methyl testosterone, sildenafil, vardenafil, tadalafil, alprostadil, L- arginine, prostaglandin El, phentolamine, and apomorphine
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Fonnula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for erectile dysfunction.
10. The pharmaceutical composition of claim 9, wherein said pharmaceutical agent is selected from sildenafil, vardenafil, tadalafil, and alprostadil.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for female sexual dysfunction.
12. The pharmaceutical composition of claim 11, wherein said pharmaceutical agent is selected from estrogen replacement therapy, methyl testosterone, sildenafil, vardenafil, tadalafil, alprostadil, L-arginine, prostaglandin El, phentolamine, and apomorphine.
PCT/US2005/042001 2004-11-30 2005-11-18 Imidazole derivatives for the treatment of sexual dysfunction WO2006060199A2 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040107A1 (en) * 2001-09-24 2003-05-15 Bayer Pharmaceuticals Corporation Imidazole-4-carboxamide derivatives, preparation and use thereof for treatment of obesity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040107A1 (en) * 2001-09-24 2003-05-15 Bayer Pharmaceuticals Corporation Imidazole-4-carboxamide derivatives, preparation and use thereof for treatment of obesity

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