WO2008064317A1 - Lipophilic opioid receptor active compounds - Google Patents

Lipophilic opioid receptor active compounds Download PDF

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Publication number
WO2008064317A1
WO2008064317A1 PCT/US2007/085394 US2007085394W WO2008064317A1 WO 2008064317 A1 WO2008064317 A1 WO 2008064317A1 US 2007085394 W US2007085394 W US 2007085394W WO 2008064317 A1 WO2008064317 A1 WO 2008064317A1
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compound
group
alkyl
het
aryl
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PCT/US2007/085394
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French (fr)
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William J. Welsh
Sonia Arora
Kaipeen Yang
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University Of Medicine And Dentistry Of New Jersey
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Publication of WO2008064317A1 publication Critical patent/WO2008064317A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the interface between the blood and an organ is mediated by endothelial cells that control the transfer of drugs from the blood stream into the cell and also from the cell to the blood.
  • endothelial cells that control the transfer of drugs from the blood stream into the cell and also from the cell to the blood.
  • Two of these processes, passive and facilitated diffusion, are concentration driven and unidirectional according to the gradient.
  • Facilitative diffusion is relatively uncommon, but glucose is transferred into the central nervous system (CNS) by a non-energy-dependent glucose transporter.
  • the third of these processes, active transfer requires an energy source (ATP) and can transfer molecules via a carrier against a gradient.
  • ATP energy source
  • the CNS being extremely sensitive to many compounds in the blood and also to drugs, is designed to be very selective as to what types of drugs can transport across the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • CNS active drugs to penetrate the blood-brain barrier and exhibit CNS activity are related to their fundamental physiochemical properties.
  • CNS drugs possess values of lipophilicity, polarity, conformational flexibility, and number of hydrogen bond donors and acceptors that, in general, differ from general therapeutics. Optimizing the balance among these physiochemical properties to make the best compromises is critical for designing new drugs likely to penetrate the BBB and affect relevant biological systems.
  • CNS drugs that are able to cross the BBB by passive diffusion possess greater lipophilicity, lower polarity, less conformational flexibility, and fewer hydrogen bonding atoms or groups than their non-CNS active counterparts.
  • CNS drugs that are able to cross the BBB by passive diffusion possess greater lipophilicity, lower polarity, less conformational flexibility, and fewer hydrogen bonding atoms or groups than their non-CNS active counterparts.
  • These classes and sub-classes of compounds were specifically designed such that they possess an optimal combination of high lipophilicity, low polarity, limited conformational flexibility, and few hydrogen bonding atoms or groups. Design strategies for achieving this objective are disclosed here, together with specific examples to illustrate the general principles.
  • the present invention relates to a compound of Formula I(a) or I(b):
  • R1-R5 define cyclopentane, cyclopentene, cyclopentadiene, or a five- membered heteroaromatic ring comprising from 1 to 3 heteroatoms and 2 to 4 carbon atoms
  • Ri, R 3 , and R 4 are N or C
  • R 1 -R 5 is optionally substituted at R 2 , R 5 , or both in formula Ia or R 3 , R 4 , or both in formula Ib with halo
  • X 1 , X 2 , and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group
  • one of R 6 , R7, and Rs is H, (Ci_7)alkyl, (C3_i2)cycloalkyl, aryl, Het, halo, CH
  • R 6 , R 7 , and Rs is (Ci_ 7 )alkyl or a group that includes one or more basic atoms; or a derivative of said compound selected from N-oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.
  • Another embodiment of the present invention is a compound of Formula II(a) or ll(b):
  • X 1 , X 2 , and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group; one of Ri 7 , R 1 S, and R i9 is H, (Ci_ 7 )alkyl, (C 3 -i2)cycloalkyl, aryl, Het,
  • R a and R b are each independently H, (Ci_ 7 )alkyl, (C 3 _i 2 )cycloalkyl, (C 2 _ 7 )alkanoyl, (C 2 _ 7 )alkanoyloxy, alkylene, acetyl, aryl, or -CH 2 -aryl, or R a and R b together with a nitrogen to which they are attached form a Het;
  • R 20 is N or CH
  • X 1 , X 2 , and X 3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group;
  • R 23 is H, (Ci_ 7 )alkyl, (C 3 -i 2 )cycloalkyl, aryl, halo, Het, CH 2 NR a R b , a group that includes one or more basic atoms, or a group that includes one or more halo atoms;
  • (Ci_ 7 )alkyl or (C 3 -i 2 )cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, OR a , halo, NO 2 , NR a R b , cyano, C0NR a R b , CO 2 Ra, SO 1n Ra, S(O) m NR a Rb, or P(K ) )(ORa)(Ra); wherein R a and R b are each independently H, (Ci_ 7 )alkyl, (C 3 _i 2 )cycloalkyl, (C 2 -7)alkanoyl, (C 2 -7)alkanoyloxy, alkylene, acetyl, aryl, or -CH 2 -aryl, or Ra and Rb together with a nitrogen to which they are attached form a Het;
  • Patient means a mammal including a human.
  • Effective amount means an amount of compound of the present invention effective for treating opioid receptor related diseases or conditions, and thus producing the desired therapeutic effect.
  • Treatment or “treatment” or “treating” mean to lessen, eliminate, inhibit, improve, alter, or prevent a disease or condition, for example by administration of compound of the present invention.
  • Porture refers to, for example, a localized or generalized physical suffering associated with bodily disorder, such as a disease or an injury, and can include a basic bodily sensation induced by a noxious stimulus, received by naked nerve endings, characterized by physical discomfort such as pricking, throbbing, or aching, and typically leads to evasive action.
  • neuropathic pain which is a chronic condition associated with diabetes, chronic inflammation, cancer, and herpes virus infection.
  • “Analgesia” or “pain relief includes, for example, inducing or providing insensitivity to pain, and preferably without loss of consciousness.
  • "Diseases or conditions where an opioid receptors are implicated” and “opioid receptor related disease or conditions” include, inflammation (e.g. inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome,
  • Behcet's syndrome polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis), pain, headache, fever, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis), asthma, bronchitis, menstrual cramps, tendinitis, bursitis, skin related conditions (e.g. psoriasis, eczema, burns and dermatitis), gastrointestinal conditions (e.g.
  • inflammatory bowel disease Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis
  • cancer e.g. colorectal cancer
  • ophthalmic diseases e.g. retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and acute injury to the eye tissue
  • pulmonary inflammation such as that associated with viral infections and cystic fibrosis
  • central nervous system disorders such as cortical dementias including Alzheimer's disease
  • central nervous system damage e.g. resulting from stroke, ischemia, or trauma.
  • Compounds of the invention may also be useful for modifying the effects of other biologically active compounds (for example for treating narcotic addiction), and for treating diseases or conditions other than ones associated with receptors, for example, blocking, inhibiting, or promoting, metabolic pathways or enzyme function, and selectively interacting with genetic material.
  • other biologically active compounds for example for treating narcotic addiction
  • diseases or conditions other than ones associated with receptors for example, blocking, inhibiting, or promoting, metabolic pathways or enzyme function, and selectively interacting with genetic material.
  • Alkyl means aliphatic hydrocarbon group which may be branched or straight-chained having about 1 to about 10 carbon atoms. Preferred alkyl is "lower alkyl” having about 1 to about 3 carbon atoms; more preferred is methyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain.
  • the alkyl group is also optionally substituted by alkoxy, halo, carboxy, hydroxy or R 6 R f N- (wherein R 6 and R f are independently hydrogen or alkyl, or R e and R f taken together with the nitrogen atom to which R ⁇ and Rf are attached form azaheterocyclyl); and preferably optionally substituted by fluoro.
  • alkyl include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl.
  • Cycloalkyl means a non-aromatic monocyclic ring system of about 3 to about 7 carbon atoms.
  • Preferred monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl; more preferred are cyclohexyl and cyclopentyl.
  • Aryl means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms.
  • exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent” includes hydrogen, hydroxy, halo, alkyl, alkoxy, methoxy, carboxy, alkoxycarbonyl, YiY 2 NCO-, wherein Yi and Y 2 are independently hydrogen or alkyl, diethyl carboxamide, a group that contains one or more halo atoms, CH 2 NR a Rb, as defined below, or a group that includes one or more basic atoms.
  • Het is a three-(3), four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from the group consisting of oxy, thio, sulfmyl, sulfonyl, and nitrogen, which ring is optionally fused to a benzene ring.
  • Het includes "heteroaryl,” which encompasses about a 5- to about a 10- membered aromatic monocyclic or bicyclic hydrocarbon ring system in which one to three of the atoms in a monocyclic ring system, and one to four of the atoms in a bicyclic ring system, is/are elements(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Het may also be substituted by one or more of the following: alkoxy, halo, carboxy, hydroxyl, RgRfN- (wherein Rg and Rf are independently hydrogen or alkyl, or R e and R f taken together with the nitrogen atom to which R e and Rf are attached form azaheterocyclyl), hydrogen, hydroxy, alkyl, methoxy, alkoxycarbonyl, YiY 2 NCO-, wherein Yi and Y 2 are independently hydrogen or alkyl, diethyl carboxamide, a group that contains one or more halo atoms, CH 2 NR a R b , as defined below, or a group that includes one or more basic atoms.
  • heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazoly, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,l-b]thiazolyl, benzofurzanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, and isoquinolinyl.
  • "Acyl” means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described.
  • acyls contain a lower alkyl.
  • exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and caproyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • Preferred alkoxy is "lower alkoxy” having about 1 to about 3 carbon atoms; more preferred is methoxy.
  • the alkoxy may be optionally substituted by one or more alkoxy, carboxy, alkoxycarbonyl, carboxyaryl or R e R f N- (wherein R 6 and R f are as defined above).
  • Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy, 2-(morpholin-4-yl)ethoxy and 2-(ethoxy)ethoxy.
  • Aryloxy means aryl-O- group in which the aryl group is as previously described.
  • acyloxy means and acyl-O- group in which the acyl group is as previously described.
  • Carboxy means a HO(O)C- (carboxylic acid) group.
  • RgR f N- means a substituted or unsubstituted amino group, wherein R 6 and R f are as previously described. Exemplary groups include amino (H 2 N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.
  • ReRfNCO- means a substituted or unsubstituted carbomoyl group, wherein
  • R e and R f are as previously described.
  • Exemplary groups are carbamoyl (H 2 NCO-) are dimethylaminocarbamoyl (Me 2 NCO-).
  • AcylRgN- means an acylamino group wherein Rg and acyl are as defined herein.
  • Halo means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
  • Prodrug means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use. A prodrug is transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood.
  • Solvate means a physical association of a compound of this invention with one or more solvent molecules.
  • solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule(s) is/are H 2 O.
  • Substituent of a ring structure means any atom or group of atoms bonded to a ring in a molecule.
  • opioid receptor activity for example, delta, mu, or kappa, or related receptor activity using the standard tests described herein, or using other similar tests.
  • compounds of formulas I, II, and III can contain chiral centers, for example, in any of the Ra - Rb, R 6 - Rio, and Rn - Rig substituents.
  • R1-R5 is a f ⁇ ve-membered heteroaromatic ring selected from 1,3-dioxolane; pyrazolidine; imidazoline; 2-pyrazoline with one chiral center; 2-imidazoline; pyrazole (1,2-diazole); lH-imidazole; 1,2,3-triazole; 1,2,4-triazole; 2-thiazole; 3H- 1 ,2-dithiole; 2H-l,3-dithiole; 3H-l,2-oxathiole; isoxazole (1,2-oxazole); oxazole(l,3- oxazole); thioazole(l,3-thiazole); isothiazole(l, 2-thiazole); 1,2,3-oxadiazole; 1,2,4- oxadiazole; l,2,5-oxadiazole(furazan); 1,3,4
  • Another embodiment of the present invention is a compound of formula I, II, or III, wherein one of R 6 -s, one of Ri 7 _i 9 , or R 23 , respectively, is selected from: -CH 2 N(CH 3 ) 2 , substituted Het, unsubstituted Het, -CH 2 N(CF 3 ) 2 , morpholinyl, pyrrolidinyl, and CH 2 NR a Rb as defined above.
  • Another embodiment of the present invention includes the following compounds: (CH 3 3)/3 (Idi) (CH 3 ) 3
  • Ra and Rb are independently selected from methyl, ethyl, ethylene, -CH 2 -benzyl, or a combination thereof. More preferably, Ra and Rb are both methyl, both ethyl, or both ethylene.
  • R and Rl are Het substituents as defined above.
  • R and Rl are independently selected from (Ci_7)alkyl, halo, and a group that includes one or more halo atoms. More preferably, R and Rl are independently selected from methyl, ethyl, halo, and halogenated alkyl.
  • n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2;
  • Ph represents phenyl, unsubstituted or substituted with one or more aryl group substituents as defined above, preferably alkyl, methoxy, halo, a group that includes one or more halo atoms, or diethyl carboxamide;
  • R' represents an aryl group substituent as defined above;
  • R represents Rs-X 3 - as defined above.
  • X 3 is a bond and R and R' are independently selected from methyl, ethyl, halo, isopropyl, and t-butyl.
  • R represents a Het group substituent as defined above.
  • Another embodiment of the present invention is a compound of formula I, II, or III wherein the compound has 0 to 2 chiral centers.
  • the compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates. Exemplary general procedures follow.
  • the compounds of formulas I, II, and III can be included in pharmaceutical compositions to treat, for example, a condition mediated by an opioid receptor in a patient.
  • targeted opioid receptors include delta ( ⁇ ), mu ( ⁇ ), and kappa (K) opioid receptors.
  • Conditions mediated by an opioid receptor include, but are not limited to, those disclosed in U.S. Publication No. 2003-0225072 Al, the contents of which are incorporated herein by reference in their entirety, inflammation (e.g. inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis), pain, headache, fever, depression, stress, anxiety, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus
  • psoriasis eczema
  • burns and dermatitis e.g. gastrointestinal conditions (e.g. inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis), cancer (e.g. colorectal cancer), ophthalmic diseases (e.g.
  • retinitis retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and acute injury to the eye tissue
  • pulmonary inflammation such as that associated with viral infections and cystic fibrosis
  • cardiovascular diseases such as stroke
  • acute pulmonary edema central nervous system disorders
  • central nervous system disorders such as cortical dementias including Alzheimer's disease
  • peripheral nervous system damage such as peripheral neuropathy
  • central nervous system damage e.g. resulting from stroke, ischemia, or trauma
  • organ transplantation organ transplantation.
  • the compounds can also provide cytoprotective effects.
  • composition comprising a pharmaceutically effective amount of the compound of formula I, II, III, or a combination thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further includes a ⁇ - agonist.
  • the ⁇ -agonist is morphine or fentanyl.
  • compositions containing a compound of formula I, II, or III may be administered in any variety of suitable forms, for example, by inhalation, topically, parenterally, rectally, or orally. More specific routes of administration include intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, colonical, peritoneal, transepithelial including transdermal, ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation via insufflation, and aerosol.
  • compositions containing a compound of formula I, II, or III may be presented in forms permitting administration by the most suitable route.
  • the invention also relates to administering compositions containing a compound of formula I, II, or III which is suitable for use as a medicament in a patient.
  • These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
  • the compositions may be presented in the form of oral dosage forms, or injectable solutions, or suspensions.
  • vehicle and the compound of formula I, II, or III in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
  • aqueous suspensions When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used.
  • the compound of formula I, II, or III may be incorporated into sustained-release preparations and formulations.
  • emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
  • the injectable forms must be fluid to the extent that it can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • Solutions of the compound of formula I, II, or III as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl- cellulose.
  • Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
  • aqueous solutions also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation, microfiltration, and/or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of formula I, II, or III in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze drying technique, which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile- filtered solution thereof.
  • Topical administration gels (water or alcohol based), creams or ointments containing the compound of formula I, II, or III may be used.
  • the compound of formula I, II, or III may be also incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier.
  • the compound of formula I, II, or III may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • compositions according to the invention may also be formulated in a manner which resists rapid clearance from the vascular (arterial or venous) wall by convection and/or diffusion, thereby increasing the residence time of the particles at the desired site of action.
  • a periadventitial depot comprising a compound according to the invention may be used for sustained release.
  • One such useful depot for administering a compound according to the invention may be a copolymer matrix, such as ethylene- vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic shell.
  • a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia.
  • microparticles may be comprised of a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Such microparticles enable strategic manipulation of variables including total dose of drug and kinetics of its release. Microparticles can be injected efficiently into the arterial or venous wall through a porous balloon catheter or a balloon over stent, and are retained in the vascular wall and the periadventitial tissue for at least about two weeks. Formulations and methodologies for local, intravascular site-specific delivery of therapeutic agents are discussed in Reissen et al. (Am. Coll. Cardial. 1994; 23: 1234-1244), the entire contents of which are hereby incorporated by reference.
  • a composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • a biocompatible or non-cytotoxic (homo or hetero) polymer such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • Such polymers have been described, for example, in application W093/08845, the entire contents of which are hereby incorporated by reference. Certain of them, such as, in particular, those obtained from ethylene and/or propylene oxide are commercially available.
  • the compounds according to the invention can be administered in different ways.
  • the compounds of the invention are administered directly to the blood vessel wall by means of an angioplasty balloon, which is coated with a hydrophilic film (for example a hydrogel) which is saturated with the compound, or by means of any other catheter containing an infusion chamber for the compound, which can thus be applied in a precise manner to the site to be treated and allow-the compound to be liberated locally and efficiently at the location of the cells to be treated.
  • This method of administration advantageously makes it possible for the compound to contact quickly the cells in need of treatment.
  • the hydrogel is introduced at the desired intravascular site by coating a catheter, for example a balloon catheter, and delivery to the vascular wall, preferably at the time of angioplasty.
  • a catheter for example a balloon catheter
  • the saturated hydrogel is introduced at the site to be treated by means of a balloon catheter.
  • the balloon may be chaperoned by a protective sheath as the catheter is advanced toward the target vessel, in order to minimize drug washoff after the catheter is introduced into the bloodstream.
  • Another embodiment of the invention provides for a compound according to the invention to be administered by means of perfusion balloons.
  • perfusion balloons which make it possible to maintain a blood flow and thus to decrease the risks of ischaemia of the myocardium, on inflation of the balloon, also enable the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes, which may be necessary for its optimal action.
  • a channeled balloon catheter (“channeled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Corp., Watertown, MA) may be used.
  • the latter consists of a conventional balloon covered with a layer of 24 perforated channels, which perfuse via an independent lumen through an additional infusion orifice.
  • balloon catheters such as double balloon, porous balloon, microporous balloon, channel balloon, balloon over stent and hydrogel catheter, all of which may be used to practice the invention, are disclosed in Reissen et al. (1994), the entire contents of which are hereby incorporated by reference.
  • a perfusion balloon catheter is especially advantageous, as it has the advantages of both keeping the balloon inflated for a longer period of time by retaining the properties of facilitated sliding and of site-specificity of the hydrogel are gained simultaneously.
  • Poloxamer 407 is a non-toxic, biocompatible polyol, commercially available (BASF, Parsippany, NJ).
  • a poloxamer impregnated with a compound according to the invention may be deposited directly on the surface of the tissue to be treated, for example during a surgical intervention.
  • Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity.
  • the percentage of compound of formula I or II in the compositions used in the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. A dose employed may be determined by a physician or qualified medical professional, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient.
  • the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 10, mg/kg body weight per day by intravenous administration.
  • the doses are determined in accordance with the factors distinctive to the patient to be treated, such as age, weight, general state of health and other characteristics, which can influence the efficacy of the compound according to the invention.
  • the compound of formula I, II, or III used in the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the compound of formula I, II, or III may be administered 1 to 4 times per day. Of course, for other patients, it will be necessary to prescribe not more than one or two doses per day.

Abstract

Substituted pyrazoles, imidazoles, triazoles, other 5-membered heteroaromatic ring compounds, substituted 6-membered heteroaromatic ring compounds, and fluorene and carbazole compounds, may be included in pharmaceutical central nervous system drug compositions to treat a condition mediated by an opioid receptor in a patient. Such compounds are designed to possess improved transport across the blood-brain barrier. These compounds possess an optimal combination of high lipophilicity, low polarity, limited conformational flexibility, and few hydrogen bonding groups. Such lipophilic opioid receptor active compounds are useful for treating pain, inflammation, arthritis, central nervous system disorders, and other diseases.

Description

LIPOPHILIC OPIOID RECEPTOR ACTIVE COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application Serial No. 60/867,096, which was filed on November 22, 2006, the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The interface between the blood and an organ is mediated by endothelial cells that control the transfer of drugs from the blood stream into the cell and also from the cell to the blood. Basically, there are three mechanisms of transfer for small molecules that can be classified according to whether there is an energy-requiring step. Two of these processes, passive and facilitated diffusion, are concentration driven and unidirectional according to the gradient. Facilitative diffusion is relatively uncommon, but glucose is transferred into the central nervous system (CNS) by a non-energy-dependent glucose transporter. The third of these processes, active transfer, requires an energy source (ATP) and can transfer molecules via a carrier against a gradient. The CNS, being exquisitely sensitive to many compounds in the blood and also to drugs, is designed to be very selective as to what types of drugs can transport across the blood-brain barrier (BBB). Most, if not all, known opioid receptor active agents in the clinic must exercise the mechanism of passive diffusion to cross the BBB.
The ability of CNS active drugs to penetrate the blood-brain barrier and exhibit CNS activity are related to their fundamental physiochemical properties. CNS drugs possess values of lipophilicity, polarity, conformational flexibility, and number of hydrogen bond donors and acceptors that, in general, differ from general therapeutics. Optimizing the balance among these physiochemical properties to make the best compromises is critical for designing new drugs likely to penetrate the BBB and affect relevant biological systems.
DETAILED DESCRIPTION OF THE INVENTION
In general, CNS drugs that are able to cross the BBB by passive diffusion possess greater lipophilicity, lower polarity, less conformational flexibility, and fewer hydrogen bonding atoms or groups than their non-CNS active counterparts. We now recognize that certain classes of chemical compounds within this genus distinguish themselves as possessing improved likelihood for BBB transport. These classes and sub-classes of compounds were specifically designed such that they possess an optimal combination of high lipophilicity, low polarity, limited conformational flexibility, and few hydrogen bonding atoms or groups. Design strategies for achieving this objective are disclosed here, together with specific examples to illustrate the general principles.
The present invention relates to a compound of Formula I(a) or I(b):
Figure imgf000003_0001
wherein R1-R5 define cyclopentane, cyclopentene, cyclopentadiene, or a five- membered heteroaromatic ring comprising from 1 to 3 heteroatoms and 2 to 4 carbon atoms, wherein R2 and R5 of formula Ia and R3 and R4 of formula Ib are selected from the group consisting of O, N, C=O, NRa, S, and CH; Ri, R3, and R4 are N or C; and R1-R5 is optionally substituted at R2, R5, or both in formula Ia or R3, R4, or both in formula Ib with halo; X1, X2, and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group; one of R6, R7, and Rs is H, (Ci_7)alkyl, (C3_i2)cycloalkyl, aryl, Het, halo, CH2NRaRb, a group that includes one or more basic atoms, or a group that includes one or more halo atoms; two of R6, R7, and Rs are phenyl rings meta- or para-substituted with from one to three substituents each selected independently from aryl, halo, a group that includes one or more halo atoms, ORa, trifluoromethoxy, trifluoromethyl, CH2NRaRb, NO2, NRaRb, cyano, CONRaRb, CO2Ra, SOmRa, S(O)mNRaRb, P(K))(ORa)(Ra), (Ci_7)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, (C3-12)cycloalkyl, (C1- 7)acyl, Het, a naphthyl group having a structure selected from
Figure imgf000004_0001
or fused-ring structure selected from
(I)
Figure imgf000004_0002
wherein (C1-7)alkyl or (C3-i2)cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, ORa, halo, NO2, NRaRb, cyano, C0NRaRb, CO2Ra, SO1nRa, S(O)mNRaRb, or P(=O)(ORa)(Ra); wherein Ra and Rb are each independently H, (C1-7)alkyl, (C3-12)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or Ra and Rb together with a nitrogen to which they are attached form a Het;
Z1, Z2, and Z3 are independently selected from O, N, C=O, NRa, S, and CH; m is O, 1, or 2; n is O, 1, 2, 3, or 4; wherein when Formula Ia is:
Figure imgf000005_0001
one of R6, R7, and Rs is (Ci_7)alkyl or a group that includes one or more basic atoms; or a derivative of said compound selected from N-oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.
Another embodiment of the present invention is a compound of Formula II(a) or ll(b):
Figure imgf000005_0002
wherein
R11-16 define phenyl or a six-membered heteroaromatic ring comprising from 1 to 3 heteroatoms and 3 to 5 carbon atoms, wherein Rn, R13, and R15 of formula Ha and Ri3, R14, and R15 of formula lib are selected from the group consisting of O, N, C=O, NRa, S, and CH; Ri2, Ri4, and Ri6 of formula Ha and Rn, Ri2, Ri6 are N or C; and R11-16 is optionally substituted at Rn, R13, Ris, or a combination thereof in formula Ha and R13, R14, R15, or a combination thereof in formula lib with halo;
X1, X2, and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group; one of Ri7, R1S, and Ri9 is H, (Ci_7)alkyl, (C3-i2)cycloalkyl, aryl, Het,
CH2NRaRb, halo, a group that includes one or more basic atoms, or a group that includes one or more halo atoms; two of Ri7, Ri8, andRw are phenyl rings ortho-, meta-, or para-substituted with from one to three substituents each selected ORa, aryl, a group that includes one or more halo atoms, halo, trifluoromethoxy, trifluoromethyl, CH2NRaRb, NO2, NR3Rb, cyano, CONRaRb, CO2Ra, SOmRa, S(O)mNRaRb, P(=O)(ORa)(Ra), (C1.7)alkyl, (C2. 6)alkenyl, (C2_6)alkynyl, (C2_7)alkanoyl, (C2_7)alkanoyloxy, (C3_i2)cycloalkyl, (Ci_ 7)acyl, Het, a naphthyl group having a structure selected from
Figure imgf000006_0001
or a fused-ring structure selected from
(ID
Figure imgf000006_0002
wherein (Ci_7)alkyl or (C3_i2)cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, ORa, halo, NO2, NRaRb, cyano, CONRaRb, CO2Ra, SOmRa, S(O)mNRaRb, or P(=0)(0Ra)(Ra);
Ra and Rb are each independently H, (Ci_7)alkyl, (C3_i2)cycloalkyl, (C2_7)alkanoyl, (C2_7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or Ra and Rb together with a nitrogen to which they are attached form a Het;
Zi, Z2, and Z3 are independently selected from the group consisting of O, N, C=O, NRa, S, and CH; m is O, 1, or 2; n is 0, 1, 2, 3, or 4; or a derivative of said compound selected from the group consisting of N- oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.
Another embodiment of the present invention is a compound of Formula III:
Figure imgf000007_0001
wherein
R20 is N or CH;
X1, X2, and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group;
R23 is H, (Ci_7)alkyl, (C3-i2)cycloalkyl, aryl, halo, Het, CH2NRaRb, a group that includes one or more basic atoms, or a group that includes one or more halo atoms;
R2i and R22 are each selected independently from aryl, halo, a group that includes one or more halo atoms, ORa, trifluoromethoxy, trifluoromethyl, CH2NRaRb, NO2, NRaRb, cyano, CONRaRb, CO2Ra, SOmRa, S(O)mNRaRb, P(=O)(ORa)(Ra), (Ci. v)alkyl, (C2_6)alkenyl, (C2_6)alkynyl, (C2_7)alkanoyl, (C2_7)alkanoyloxy, (C3. i2)cycloalkyl, (Ci_7)acyl, Het, a naphthyl group having a structure selected from
Figure imgf000007_0002
or fused-ring structure selected from
Figure imgf000007_0003
wherein (Ci_7)alkyl or (C3-i2)cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, ORa, halo, NO2, NRaRb, cyano, C0NRaRb, CO2Ra, SO1nRa, S(O)mNRaRb, or P(K))(ORa)(Ra); wherein Raand Rb are each independently H, (Ci_7)alkyl, (C3_i2)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or Ra and Rb together with a nitrogen to which they are attached form a Het;
Z1, Z2, and Z3 are independently selected from O, N, C=O, NRa, S, and CH; m is O, 1, or 2; n is 0, 1, 2, 3, or 4; or a derivative of said compound selected from N-oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" means a mammal including a human.
"Effective amount" means an amount of compound of the present invention effective for treating opioid receptor related diseases or conditions, and thus producing the desired therapeutic effect.
"Treat" or "treatment" or "treating" mean to lessen, eliminate, inhibit, improve, alter, or prevent a disease or condition, for example by administration of compound of the present invention.
"Pain" refers to, for example, a localized or generalized physical suffering associated with bodily disorder, such as a disease or an injury, and can include a basic bodily sensation induced by a noxious stimulus, received by naked nerve endings, characterized by physical discomfort such as pricking, throbbing, or aching, and typically leads to evasive action. A specific example is neuropathic pain which is a chronic condition associated with diabetes, chronic inflammation, cancer, and herpes virus infection.
"Analgesia" or "pain relief includes, for example, inducing or providing insensitivity to pain, and preferably without loss of consciousness. "Diseases or conditions where an opioid receptors are implicated" and "opioid receptor related disease or conditions" include, inflammation (e.g. inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis), pain, headache, fever, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis), asthma, bronchitis, menstrual cramps, tendinitis, bursitis, skin related conditions (e.g. psoriasis, eczema, burns and dermatitis), gastrointestinal conditions (e.g. inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis), cancer (e.g. colorectal cancer), ophthalmic diseases (e.g. retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and acute injury to the eye tissue), pulmonary inflammation (such as that associated with viral infections and cystic fibrosis), central nervous system disorders (such as cortical dementias including Alzheimer's disease), and central nervous system damage (e.g. resulting from stroke, ischemia, or trauma). Compounds of the invention may also be useful for modifying the effects of other biologically active compounds (for example for treating narcotic addiction), and for treating diseases or conditions other than ones associated with receptors, for example, blocking, inhibiting, or promoting, metabolic pathways or enzyme function, and selectively interacting with genetic material.
"Alkyl" means aliphatic hydrocarbon group which may be branched or straight-chained having about 1 to about 10 carbon atoms. Preferred alkyl is "lower alkyl" having about 1 to about 3 carbon atoms; more preferred is methyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halo, carboxy, hydroxy or R6RfN- (wherein R6 and Rf are independently hydrogen or alkyl, or Re and Rf taken together with the nitrogen atom to which R^ and Rf are attached form azaheterocyclyl); and preferably optionally substituted by fluoro. Examples of alkyl include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl. "Cycloalkyl" means a non-aromatic monocyclic ring system of about 3 to about 7 carbon atoms. Preferred monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl; more preferred are cyclohexyl and cyclopentyl.
"Aryl" means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes hydrogen, hydroxy, halo, alkyl, alkoxy, methoxy, carboxy, alkoxycarbonyl, YiY2NCO-, wherein Yi and Y2 are independently hydrogen or alkyl, diethyl carboxamide, a group that contains one or more halo atoms, CH2NRaRb, as defined below, or a group that includes one or more basic atoms.
"Het" is a three-(3), four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from the group consisting of oxy, thio, sulfmyl, sulfonyl, and nitrogen, which ring is optionally fused to a benzene ring. Het includes "heteroaryl," which encompasses about a 5- to about a 10- membered aromatic monocyclic or bicyclic hydrocarbon ring system in which one to three of the atoms in a monocyclic ring system, and one to four of the atoms in a bicyclic ring system, is/are elements(s) other than carbon, for example nitrogen, oxygen or sulfur. "Het" may also be substituted by one or more of the following: alkoxy, halo, carboxy, hydroxyl, RgRfN- (wherein Rg and Rf are independently hydrogen or alkyl, or Re and Rf taken together with the nitrogen atom to which Re and Rf are attached form azaheterocyclyl), hydrogen, hydroxy, alkyl, methoxy, alkoxycarbonyl, YiY2NCO-, wherein Yi and Y2 are independently hydrogen or alkyl, diethyl carboxamide, a group that contains one or more halo atoms, CH2NRaRb, as defined below, or a group that includes one or more basic atoms.
Exemplary heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazoly, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,l-b]thiazolyl, benzofurzanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, and isoquinolinyl. "Acyl" means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and caproyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Preferred alkoxy is "lower alkoxy" having about 1 to about 3 carbon atoms; more preferred is methoxy. The alkoxy may be optionally substituted by one or more alkoxy, carboxy, alkoxycarbonyl, carboxyaryl or ReRfN- (wherein R6 and Rf are as defined above). Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy, 2-(morpholin-4-yl)ethoxy and 2-(ethoxy)ethoxy.
"Aryloxy" means aryl-O- group in which the aryl group is as previously described.
"Acyloxy" means and acyl-O- group in which the acyl group is as previously described.
"Carboxy" means a HO(O)C- (carboxylic acid) group.
"RgRfN-" means a substituted or unsubstituted amino group, wherein R6 and Rf are as previously described. Exemplary groups include amino (H2N-), methylamino, ethylmethylamino, dimethylamino and diethylamino. "ReRfNCO-" means a substituted or unsubstituted carbomoyl group, wherein
Re and Rf are as previously described. Exemplary groups are carbamoyl (H2NCO-) are dimethylaminocarbamoyl (Me2NCO-).
"AcylRgN-" means an acylamino group wherein Rg and acyl are as defined herein. "Halo" means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
"Prodrug" means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use. A prodrug is transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, et., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule(s) is/are H2O.
"Substituent of a ring structure" means any atom or group of atoms bonded to a ring in a molecule.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). It is also well known in the art and, for example, as illustrated hereinbelow how to determine opioid receptor activity, for example, delta, mu, or kappa, or related receptor activity using the standard tests described herein, or using other similar tests. In particular, it is understood that compounds of formulas I, II, and III can contain chiral centers, for example, in any of the Ra - Rb, R6 - Rio, and Rn - Rig substituents.
One embodiment of the present invention is a compound of formula I, wherein R1-R5 is a fϊve-membered heteroaromatic ring selected from 1,3-dioxolane; pyrazolidine; imidazoline; 2-pyrazoline with one chiral center; 2-imidazoline; pyrazole (1,2-diazole); lH-imidazole; 1,2,3-triazole; 1,2,4-triazole; 2-thiazole; 3H- 1 ,2-dithiole; 2H-l,3-dithiole; 3H-l,2-oxathiole; isoxazole (1,2-oxazole); oxazole(l,3- oxazole); thioazole(l,3-thiazole); isothiazole(l, 2-thiazole); 1,2,3-oxadiazole; 1,2,4- oxadiazole; l,2,5-oxadiazole(furazan); 1,3,4-oxatriazole; 1,2,3,4-oxatriazole; 1,2,3,5- oxatriazole; 3H-l,2,3-dioxazole; and 1,2,4-dioxazole. One embodiment of the present invention is a compound of formula I, II, or III, wherein one of R6-S, one of R17-19, or R23, respectively, is selected from substituted or unsubstituted:
Figure imgf000013_0001
Another embodiment of the present invention is a compound of formula I, II, or III, wherein one of R6-s, one of Ri7_i9, or R23, respectively, is selected from: -CH2N(CH3)2, substituted Het, unsubstituted Het, -CH2N(CF3)2, morpholinyl, pyrrolidinyl, and CH2NRaRb as defined above.
Another embodiment of the present invention includes the following compounds:
(CH '33)/:3 (Id)
Figure imgf000013_0002
'33)/:3 (Ie) (CH '33)/:3 (if)
Another embodiment of the present invention includes the following compounds:
Figure imgf000014_0001
Figure imgf000014_0002
(Ij) (Ik)
Figure imgf000014_0003
Figure imgf000014_0004
Figure imgf000015_0001
(ip) (Iq)
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000015_0004
(Iv) (Iw) Another embodiment of the present invention includes the following compounds:
Figure imgf000016_0001
Figure imgf000016_0002
(CH33)/3 (Idi)
Figure imgf000016_0003
(CH3)3
(lei)
Figure imgf000016_0004
Figure imgf000017_0001
)':3 C
Figure imgf000017_0002
(THIii)
Figure imgf000017_0003
Another embodiment of the present invention includes the following compound:
Figure imgf000017_0004
wherein R2 represents Ra and Rb, as described above. Preferably, Ra and Rb are independently selected from methyl, ethyl, ethylene, -CH2-benzyl, or a combination thereof. More preferably, Ra and Rb are both methyl, both ethyl, or both ethylene. Once past the BBB, compound Ipi is converted to:
Figure imgf000018_0001
Another embodiment of the present invention includes the following compounds:
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000019_0001
wherein R and Rl are Het substituents as defined above. Preferably, R and Rl are independently selected from (Ci_7)alkyl, halo, and a group that includes one or more halo atoms. More preferably, R and Rl are independently selected from methyl, ethyl, halo, and halogenated alkyl.
Another embodiment of the present invention includes the following compounds:
Figure imgf000020_0001
wherein n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2; "Ph" represents phenyl, unsubstituted or substituted with one or more aryl group substituents as defined above, preferably alkyl, methoxy, halo, a group that includes one or more halo atoms, or diethyl carboxamide; R' represents an aryl group substituent as defined above; and R represents Rs-X3- as defined above. Preferably, X3 is a bond and R and R' are independently selected from methyl, ethyl, halo, isopropyl, and t-butyl.
Another embodiment of the present invention includes the following compounds:
Figure imgf000020_0002
Figure imgf000021_0001
wherein R represents a Het group substituent as defined above. Preferably, R is selected from -H, -CH3, and -CH2CH=CH2.
Another embodiment of the present invention is a compound of formula I, II, or III wherein the compound has 0 to 2 chiral centers.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein. The compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates.
The compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates. Exemplary general procedures follow.
Compounds of formula I can be prepared according to the following exemplary schemes, wherein the variables are as described above, excepting those variables which one skilled in the art would appreciate would be incongruent with the method described. It is noted that Rc and Rd in the following schemes designate the substituents OfR7 and Rg respectively.
Scheme I
Figure imgf000021_0003
Figure imgf000021_0002
Figure imgf000021_0004
Acetic acid
Figure imgf000021_0005
Scheme II.
CH,COCHCICOOEt
Figure imgf000022_0001
Figure imgf000022_0002
The compounds of formulas I, II, and III can be included in pharmaceutical compositions to treat, for example, a condition mediated by an opioid receptor in a patient. Examples of targeted opioid receptors include delta (δ), mu (μ), and kappa (K) opioid receptors.
Conditions mediated by an opioid receptor include, but are not limited to, those disclosed in U.S. Publication No. 2003-0225072 Al, the contents of which are incorporated herein by reference in their entirety, inflammation (e.g. inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis), pain, headache, fever, depression, stress, anxiety, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis), asthma, bronchitis, cough, menstrual cramps, tendinitis, bursitis, skin related conditions (e.g. psoriasis, eczema, burns and dermatitis), gastrointestinal conditions (e.g. inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis), cancer (e.g. colorectal cancer), ophthalmic diseases (e.g. retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and acute injury to the eye tissue), pulmonary inflammation (such as that associated with viral infections and cystic fibrosis), cardiovascular diseases (such as stroke), acute pulmonary edema, central nervous system disorders (such as cortical dementias including Alzheimer's disease), peripheral nervous system damage (such as peripheral neuropathy), central nervous system damage (e.g. resulting from stroke, ischemia, or trauma), and organ transplantation. The compounds can also provide cytoprotective effects.
Therefore, also provided is a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula I, II, III, or a combination thereof and a pharmaceutically acceptable carrier.
In one embodiment, the pharmaceutical composition further includes a μ- agonist. In another embodiment, the μ-agonist is morphine or fentanyl.
Also provided is a method for preventing, diagnosing, or treating a condition mediated by a central opioid receptor, said method comprising administering an effective amount of the compound of formula I, II, III, or a combination thereof to a patient in need thereof.
In practice, a composition containing a compound of formula I, II, or III may be administered in any variety of suitable forms, for example, by inhalation, topically, parenterally, rectally, or orally. More specific routes of administration include intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, colonical, peritoneal, transepithelial including transdermal, ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation via insufflation, and aerosol.
A composition containing a compound of formula I, II, or III may be presented in forms permitting administration by the most suitable route. The invention also relates to administering compositions containing a compound of formula I, II, or III which is suitable for use as a medicament in a patient. These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of oral dosage forms, or injectable solutions, or suspensions. The choice of vehicle and the compound of formula I, II, or III in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to be observed in pharmaceutical practice. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used. In addition, the compound of formula I, II, or III may be incorporated into sustained-release preparations and formulations.
For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The injectable forms must be fluid to the extent that it can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. Solutions of the compound of formula I, II, or III as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl- cellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation, microfiltration, and/or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
Sterile injectable solutions are prepared by incorporating the compound of formula I, II, or III in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying technique, which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile- filtered solution thereof.
Topical administration, gels (water or alcohol based), creams or ointments containing the compound of formula I, II, or III may be used. The compound of formula I, II, or III may be also incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier.
For administration by inhalation, the compound of formula I, II, or III may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Compositions according to the invention may also be formulated in a manner which resists rapid clearance from the vascular (arterial or venous) wall by convection and/or diffusion, thereby increasing the residence time of the particles at the desired site of action. A periadventitial depot comprising a compound according to the invention may be used for sustained release. One such useful depot for administering a compound according to the invention may be a copolymer matrix, such as ethylene- vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic shell. Alternatively, a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia.
An alternative approach for minimizing washout of a compound according to the invention during percutaneous, transvascular delivery comprises the use of nondiffusible, drug-eluting microparticles. The microparticles may be comprised of a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Such microparticles enable strategic manipulation of variables including total dose of drug and kinetics of its release. Microparticles can be injected efficiently into the arterial or venous wall through a porous balloon catheter or a balloon over stent, and are retained in the vascular wall and the periadventitial tissue for at least about two weeks. Formulations and methodologies for local, intravascular site-specific delivery of therapeutic agents are discussed in Reissen et al. (Am. Coll. Cardial. 1994; 23: 1234-1244), the entire contents of which are hereby incorporated by reference.
A composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge. Such polymers have been described, for example, in application W093/08845, the entire contents of which are hereby incorporated by reference. Certain of them, such as, in particular, those obtained from ethylene and/or propylene oxide are commercially available.
In the use of compounds according to the invention for treating atherosclerosis, or a condition related thereto, the compounds according to the invention can be administered in different ways. For the treatment of atherosclerosis, the compounds of the invention are administered directly to the blood vessel wall by means of an angioplasty balloon, which is coated with a hydrophilic film (for example a hydrogel) which is saturated with the compound, or by means of any other catheter containing an infusion chamber for the compound, which can thus be applied in a precise manner to the site to be treated and allow-the compound to be liberated locally and efficiently at the location of the cells to be treated. This method of administration advantageously makes it possible for the compound to contact quickly the cells in need of treatment.
Advantageously, the hydrogel is introduced at the desired intravascular site by coating a catheter, for example a balloon catheter, and delivery to the vascular wall, preferably at the time of angioplasty. In a particularly advantageous manner, the saturated hydrogel is introduced at the site to be treated by means of a balloon catheter. The balloon may be chaperoned by a protective sheath as the catheter is advanced toward the target vessel, in order to minimize drug washoff after the catheter is introduced into the bloodstream.
Another embodiment of the invention provides for a compound according to the invention to be administered by means of perfusion balloons. These perfusion balloons, which make it possible to maintain a blood flow and thus to decrease the risks of ischaemia of the myocardium, on inflation of the balloon, also enable the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes, which may be necessary for its optimal action. Alternatively, a channeled balloon catheter ("channeled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Corp., Watertown, MA) may be used. The latter consists of a conventional balloon covered with a layer of 24 perforated channels, which perfuse via an independent lumen through an additional infusion orifice.
Various types of balloon catheters, such as double balloon, porous balloon, microporous balloon, channel balloon, balloon over stent and hydrogel catheter, all of which may be used to practice the invention, are disclosed in Reissen et al. (1994), the entire contents of which are hereby incorporated by reference.
The use of a perfusion balloon catheter is especially advantageous, as it has the advantages of both keeping the balloon inflated for a longer period of time by retaining the properties of facilitated sliding and of site-specificity of the hydrogel are gained simultaneously.
Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the invention and poloxamer, such as Poloxamer 407 is a non-toxic, biocompatible polyol, commercially available (BASF, Parsippany, NJ). A poloxamer impregnated with a compound according to the invention may be deposited directly on the surface of the tissue to be treated, for example during a surgical intervention. Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity.
The use of a channel balloon catheter with a poloxamer impregnated with a compound according to the invention is especially advantageous. In this case, the advantages of both keeping the balloon inflated for a longer period of time while retaining the properties of facilitated sliding, and of site specificity of the poloxamer, are gained simultaneously.
The percentage of compound of formula I or II in the compositions used in the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. A dose employed may be determined by a physician or qualified medical professional, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 10, mg/kg body weight per day by intravenous administration. In each particular case, the doses are determined in accordance with the factors distinctive to the patient to be treated, such as age, weight, general state of health and other characteristics, which can influence the efficacy of the compound according to the invention.
The compound of formula I, II, or III used in the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the compound of formula I, II, or III may be administered 1 to 4 times per day. Of course, for other patients, it will be necessary to prescribe not more than one or two doses per day.
The following non-limiting examples set forth hereinbelow illustrate certain aspects of the invention.
EXAMPLES Representative compounds were prepared by reaction schemes described herein. IC50 and selectivity of the representative compounds as measured by radioligand binding assay are set forth in Table I: Table I.
Compound
Structure IC50 (nM)±S.E.M. Selectivity μ K μ/δ κ/δ
DOP112 28.8 245 46.3 8.5 1.6
DOP114 121 >10000 760 >80 6.1
Figure imgf000029_0001
The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the present invention. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention. Such variations are not regarded as a departure from the spirit and script of the invention.

Claims

What is claimed is:
1. A compound of Formula I(a) or I(b):
Figure imgf000030_0001
wherein R1-R5 define cyclopentane, cyclopentene, cyclopentadiene, or a five- membered heteroaromatic ring comprising from 1 to 3 heteroatoms and 2 to 4 carbon atoms, wherein R2 and R5 of formula Ia and R3 and R4 of formula Ib are selected from the group consisting of O, N, C=O, NRa, S, and CH; R1, R3, and R4 are N or C; and R1-R5 is optionally substituted at R2, R5, or both in formula Ia or R3, R4, or both in formula Ib with halo;
X1, X2, and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group; one OfR61 R7, and R8 is H, (Ci_7)alkyl, (C3_i2)cycloalkyl, aryl, Het, halo, CH2NRaRb, a group that includes one or more basic atoms, or a group that includes one or more halo atoms; two of R6, R7, and R8 are phenyl rings meta- or para-substituted with from one to three substituents each selected independently from aryl, halo, a group that includes one or more halo atoms, ORa, trifluoromethoxy, trifluoromethyl, CH2NRaRb, NO2, NRaRb, cyano, C0NRaRb, CO2Ra, SOmRa, S(O)mNRaRb, P(K))(ORa)(Ra), (Ci_7)alkyl, (C2_6)alkenyl, (C2_6)alkynyl, (C2_7)alkanoyl, (C2_7)alkanoyloxy, (C3_i2)cycloalkyl, (Ci_7)acyl, Het, a naphthyl group having a structure selected from
Figure imgf000030_0002
or fused-ring structure selected from
Figure imgf000031_0001
wherein (Ci_7)alkyl or (C3-i2)cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, ORa, halo, NO2, NRaRb, cyano, CONRaRb, CO2Ra, SOmRa, S(O)mNRaRb, or P(=O)(ORa)(Ra); wherein Ra and Rb are each independently H, (Ci_7)alkyl, (C3-i2)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or RΆ and Rb together with a nitrogen to which they are attached form a Het;
Z1, Z2, and Z3 are independently selected from O, N, C=O, NRa, S, and CH; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; wherein when Formula Ia is:
Figure imgf000031_0002
one of R6, R7, and Rg is (Ci_7)alkyl or a group that includes one or more basic atoms; or a derivative of said compound selected from N-oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.
2. The compound of claim 1, wherein R1-R5 is a fϊve-membered heteroaromatic ring selected from 1,3-dioxolane; pyrazolidine; imidazoline; 2-pyrazoline with one chiral center; 2-imidazoline; pyrazole (1,2-diazole); lH-imidazole; 1,2,3-triazole; 1,2,4-triazole; 2-thiazole; 3H-l,2-dithiole; 2H-l,3-dithiole; 3H-l,2-oxathiole; isoxazole (1,2-oxazole); oxazole(l,3-oxazole); thioazole(l,3-thiazole); isothiazole(l,2-thiazole); 1,2,3-oxadiazole; 1,2,4-oxadiazole; 1,2,5- oxadiazole(furazan); 1,3,4-oxatriazole; 1,2,3,4-oxatriazole; 1,2,3,5-oxatriazole; 3H- 1,2,3-dioxazole; and 1,2,4-dioxazole.
3. The compound of claim 1, wherein one of R6, R7, and Rs, respectively, is selected from substituted or unsubstituted:
Figure imgf000032_0001
4. The compound of Claim 1, wherein one of R6, R7, and Rs, respectively, is selected from: -CH2N(CH3)2, substituted Het, unsubstituted Het, -CH2N(CF3)2, morpholinyl, pyrrolidinyl, and CH2NRaRt,.
A compound selected from a group consisting of:
Figure imgf000032_0002
Figure imgf000033_0001
Figure imgf000033_0002
(Ij), (Ik),
Figure imgf000033_0003
Figure imgf000033_0004
Figure imgf000034_0001
(ip), (iq),
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000034_0004
(Iv), (Iw),
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
wherein R and Rl are Het substituents; and wherein R3 and Rb are each independently H, (Ci_7)alkyl, (C3_i2)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or R3 and Rb together with a nitrogen to which they are attached form a Het.
6. The compound of Claim 5, wherein R and Rl are independently selected from (Ci_7)alkyl, halo, and a group that includes one or more halo atoms.
7. The compound of Claim 6, wherein R and Rl are independently selected from methyl, ethyl, halo, and halogenated alkyl.
8. A compound of Formula II(a) or II (b):
Figure imgf000039_0001
wherein
R11-16 define phenyl or a six-membered heteroaromatic ring comprising from 1 to 3 heteroatoms and 3 to 5 carbon atoms, wherein Rn, R13, and R15 of formula Ha and Ri3, R14, and R15 of formula lib are selected from the group consisting of O, N, C=O, NRa, S, and CH; Ri2, R14, and Ri6 of formula Ha and Rn, R12, Ri6 are N or C; and R11-16 is optionally substituted at Rn, R13, Ris, or a combination thereof in formula Ha and R13, R14, R15, or a combination thereof in formula lib with halo;
X1, X2, and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group; one of Ri7, Ri8, andRi9 is H, (C1-7)alkyl, (C3-12)cycloalkyl, aryl, Het, CH2NRaRb, halo, a group that includes one or more basic atoms, or a group that includes one or more halo atoms; two of R17j Rig, andRig are phenyl rings ortho-, meta-, or para-substituted with from one to three substituents each selected ORa, aryl, a group that includes one or more halo atoms, halo, trifluoromethoxy, trifluoromethyl, CH2NRaRb, NO2, NR3Rb, cyano, CONR1Rb, CO2Ra, SOmRa, S(O)mNRaRb, P(=O)(ORa)(Ra), (Ci_7)alkyl, (C2_6)alkenyl, (C2_6)alkynyl, (C2-7)alkanoyl, (C2_7)alkanoyloxy, (C3-12)cycloalkyl, (Ci_7)acyl, Het, a naphthyl group having a structure selected from
Figure imgf000039_0002
or a fused-ring structure selected from
Figure imgf000040_0001
wherein (Ci_7)alkyl or (C3_i2)cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, ORa, halo, NO2, NRaRb, cyano, CONRaRb, CO2Ra, SOmRa, S(O)mNRaRb, or P(=O)(ORa)(Ra);
Ra and Rb are each independently H, (Ci_7)alkyl, (C3_i2)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or R3 and Rb together with a nitrogen to which they are attached form a Het;
Zi, Z2, and Z3 are independently selected from the group consisting of O, N, C=O, NRa, S, and CH; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; or a derivative of said compound selected from the group consisting of N- oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.
9. The compound of Claim 8, wherein one of Rn1 Rig and R19 is selected from substituted or unsubstituted:
Figure imgf000040_0002
10. The compound of Claim 8, wherein one of Rn1 Rig and R19 is selected from: CH2N(CHs)2, substituted Het, unsubstituted Het, -CH2N(CF3)2, morpholinyl, pyrrolidinyl, and CH2NRaRb wherein Ra and Rb are each independently H, (Ci_7)alkyl, (C3-i2)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or RΆ and Rb together with a nitrogen to which they are attached form a Het.
11. The compound of Formula III :
Figure imgf000041_0001
wherein
R20 is N or CH;
X1, X2, and X3 are independently a bond, an alkyl group, or a saturated or unsaturated alkylene group;
R23 is H, (Ci_7)alkyl, (C3-i2)cycloalkyl, aryl, halo, Het, CH2NRaRb, a group that includes one or more basic atoms, or a group that includes one or more halo atoms;
R2i and R22 are each selected independently from aryl, halo, a group that includes one or more halo atoms, ORa, trifluoromethoxy, trifluoromethyl, CH2NRaRb, NO2, NRaRb, cyano, CONR3Rb, CO2Ra, SOmRa, S(O)mNRaRb, P(=O)(ORa)(Ra), (Ci_7)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, (C3_i2)cycloalkyl, (d_7)acyl, Het, a naphthyl group having a structure selected from
Figure imgf000041_0002
or fused-ring structure selected from
Figure imgf000042_0001
wherein (Ci_7)alkyl or (C3-i2)cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, ORa, halo, NO2, NRaRb, cyano, CONRaRb, CO2Ra, SOmRa, S(O)mNRaRb, or P(=O)(ORa)(Ra); wherein Ra and Rb are each independently H, (Ci_7)alkyl, (C3-i2)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or RΆ and Rb together with a nitrogen to which they are attached form a Het;
Z1, Z2, and Z3 are independently selected from O, N, C=O, NRa, S, and CH; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; or a derivative of said compound selected from N-oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.
12. A compound of Claim 11, wherein R23 is selected from substituted or unsubstituted:
Figure imgf000042_0002
13. A compound of Claim 11 , wherein R23 is selected from: -CH2N(CH3)2, substituted Het, unsubstituted Het, -CH2N(CF3)2, morpholinyl, pyrrolidinyl, and CH2NRaRb wherein Ra and Rb are each independently H, (Ci_7)alkyl, (C3-i2)cycloalkyl, (C2-7)alkanoyl, (C2-7)alkanoyloxy, alkylene, acetyl, aryl, or -CH2-aryl, or RΆ and Rb together with a nitrogen to which they are attached form a Het.
14. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of Claim 1, 8, or 11 and a pharmaceutically acceptable carrier.
15. A method for preventing, diagnosing, or treating a condition mediated by a central opioid receptor, said method comprising administering an effective amount of the compound of Claim 1 , 8, or 11 to a patient in need thereof.
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