WO2008064318A2 - Composés actifs de récepteurs opioïdes périphériques - Google Patents

Composés actifs de récepteurs opioïdes périphériques Download PDF

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WO2008064318A2
WO2008064318A2 PCT/US2007/085396 US2007085396W WO2008064318A2 WO 2008064318 A2 WO2008064318 A2 WO 2008064318A2 US 2007085396 W US2007085396 W US 2007085396W WO 2008064318 A2 WO2008064318 A2 WO 2008064318A2
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group
aryl
alkyl
compound
halo
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PCT/US2007/085396
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WO2008064318A3 (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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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms

Definitions

  • Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction.
  • Mediation of antinociception via opioid receptors located in the periphery is a viable strategy to produce analgesia without the occurrence of side effects associated with stimulation of opioid receptors located in the central nervous system.
  • Peripheral opioid receptors are particularly important in inflammatory pain states and in the responses to pruritogenic stimuli, and have been implicated in the transmission of visceral pain.
  • Medicinal chemistry approaches to achieve peripheralization of opioid receptor active agents have often started with a centrally acting opioid agonist or antagonist as a template, and introduced various alterations in charge, lipophilicity, hydrophilicity, or combinations thereof to achieve preferential or exclusive peripheral activity.
  • the present invention describes selective, peripheral, opioid-receptor agonists and antagonist that are designed to elicit their pharmacological effects through the peripheral opioid receptors.
  • the subject compounds compete with opioid analgesics for binding sites on opioid receptors and particularly the delta and/or mu opioid receptors, but are unable to cross the blood-brain barrier.
  • These compounds and their compositions offer methods of treatment for numerous clinically relevant conditions, including cytoprotection (e.g., cardioprotection) and other peripherally acting beneficial effects.
  • examples of the delta and mu opioid receptor active agents described in the subject disclosure would be expected to function as antagonists to ameliorate certain adverse side effects (e.g., constipation, nausea, respiratory depression) associated with the mu agonists such as morphine.
  • the present invention relates to a compound of Formula I(a) or I(b):
  • Xi, X 2 , and X 3 are independently a bond, an alkyl group, a halogenated alkylene group, or a saturated or unsaturated alkylene group; one of R 6 , R7, and Rg is H, (Ci_7)alkyl, (C3-i 2 )cycloalkyl, aryl, Het, halo, CH 2 NRaRb, a group that includes one or more basic atoms, or a group that includes one or more halo atoms; two of Re, R 7 , 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, CH 2 NRaRb, NO 2 , NRaRb, cyano, CONR a R b , CO 2 R a , SO m R
  • 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 Rn, Ri8, and Ri9 is H, (Ci_7)alkyl, (C3_i 2 )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 Ra and Rb together with a nitrogen to which they are attached form a Het;
  • Zi, Z 2 , and Z 3 are independently selected from the group consisting of O, N,
  • Another embodiment of the present invention is a compound of Formula III:
  • 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;
  • the present invention relates to a compound of Formula IV:
  • Xi, X 2 , and X3 are independently a bond or a saturated or unsaturated alkylene group;
  • Z is ORioa, H, or CONR a R b ;
  • R 9 is H, (Ci_ 7 )alkyl, (C 3-12 )cycloalkyl, aryl, Het, CONRaR b , or a group that includes one or more basic atoms;
  • Rioa is H, (Ci_ 7 )alkyl, or aryl;
  • 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, aryl, -CH 2 -aryl, or Ra and Rb together with a nitrogen to which they are attached form a Het;
  • X 1 , X 2 , and X3 are independently a bond or a saturated or unsaturated alkylene group;
  • one of Ri7, Ri8, andRi9 is H, (C 1-7 )alkyl, (C 3-12 )cycloalkyl, aryl, -CH 2 -aryl, Het, CONR a Rb, CH 2 NR a Rb, a group that includes one or more basic atoms, or a group that includes one or more halo atoms;
  • two Of R 17 , Ri8, andRw are 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, NO 2 , NR a Rb, cyano, CONR a Rb, CO 2 R a , SO m Ra, S(O) 1n NRaRb, P(K)
  • 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, acetyl, or aryl, or R ⁇ and R b 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
  • inflammation
  • 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, sulf ⁇ nyl, 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, ReRfN- (wherein R ⁇ 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 NRaRb, 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.
  • 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 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.
  • ReRfN- means a substituted or unsubstituted amino group, wherein Rg and Rf 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 Re and Rf 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.
  • 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 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 - V can contain chiral centers, for example, in any of the Ra - Rb, R 6 - Rio, and Rn - R19 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
  • R represents R 9 -X 3 - in formula IV as defined above.
  • the compounds of formulas I-V 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.
  • the compounds of the present invention can act as selective agonists or antagonists of these receptors.
  • the compounds can also function as mixed agonist/antagonist opioid receptor agents, which exhibit the desired therapeutic effect of an opioid with a reduction in undesirable, unacceptable, or toxic side effects, such as physical addiction, physical dependence, narcotic addiction, and the like.
  • the compounds of the present invention can be largely excluded from the brain and will exert primarily peripheral actions.
  • 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 e.g. resulting from stroke, ischemia, or trauma
  • 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, IV, V, or a combination thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further includes a ⁇ - agonist.
  • the ⁇ -agonist is morphine or fentanyl. Also provided is a method for preventing, diagnosing, or treating a condition mediated by a peripheral opioid receptor, said method comprising administering an effective amount of the compound of formula I, II, III, IV, V, or a combination thereof to a patient in need thereof.
  • a composition containing a compound of formula I, II, III, IV, or V 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, III, IV, or V 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, III, IV, or V which is suitable for use as a medicament in a patient.
  • 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, III, IV, or V 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, III, IV, or V 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, III, IV, or V 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, III, IV, or V 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, III, IV, or V may be used.
  • the compound of formula I, II, III, IV, or V 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, III, IV, or V 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 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.
  • biocompatible or non-cytotoxic (homo or hetero) polymer such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • 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.
  • a hydrophilic film for example a hydrogel
  • 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.
  • 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
  • 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 percentage of compound of formula I, II, III, IV, or V 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, III, IV, or V 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.
  • 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.
  • the compound of formula I, II, III, IV, or V may be administered 1 to 4 times per day.
  • it will be necessary to prescribe not more than one or two doses per day.

Abstract

L'invention concerne des pyrazoles, des imidazoles, des triazoles, d'autres composés de cycle hétéroaromatiques à 5 éléments, des composés de cycle hétéroaromatiques à 6 éléments, et des composés de fluorène et de carbazole substitués, et des pyrazoles, des imidazoles, des triazoles, d'autres composés de cycle hétéroaromatiques à 5 éléments substitués par deux groupes phényle, pouvant être utilisés comme agonistes périphériques sélectifs de récepteurs d'opioïdes conçus pour obtenir des effets pharmacologiques par l'intermédiaire desdits récepteurs opioïdes périphériques. Lesdits composés font concurrence à des analgésiques opioïdes pour des sites de liaison sur des récepteurs opioïdes et, en particulier les récepteurs opioïdes delta et mu, mais ne peuvent pas traverser la barrière hémato-encéphalique. Les composés et les compositions pharmaceutiques comprenant lesdits composés offrent des méthodes de traitement d'états induits par des récepteurs opioïdes, notamment les douleurs postopératoires et chroniques, et la cytoprotection.
PCT/US2007/085396 2006-11-22 2007-11-21 Composés actifs de récepteurs opioïdes périphériques WO2008064318A2 (fr)

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