WO2008063625A2 - Composés pyridiniques et procédés relatifs à leur utilisation - Google Patents

Composés pyridiniques et procédés relatifs à leur utilisation Download PDF

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WO2008063625A2
WO2008063625A2 PCT/US2007/024220 US2007024220W WO2008063625A2 WO 2008063625 A2 WO2008063625 A2 WO 2008063625A2 US 2007024220 W US2007024220 W US 2007024220W WO 2008063625 A2 WO2008063625 A2 WO 2008063625A2
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pyridin
methyl
morpholinomethyl
compound according
dimethyl
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PCT/US2007/024220
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WO2008063625A3 (fr
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Roland E. Dolle
Karin Worm
Allan J. Goodman
Guo-Hua Chu
Bertrand Lebourdonnec
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Adolor Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to novel pyridine compounds, pharmaceutical compositions containing such compounds, and uses thereof. More particularly, the present invention relates to novel pyridine compounds that may affect the cannabinoid receptor system and thus may be useful, inter alia, as agonists or antagonists of cannabinoid receptors.
  • Cannabis sativa preparations have long been known as therapeutic agents to treat various diseases (Mechoulam, R., "Cannabinoids as Therapeutic Agents” CRC Press, Boca Raton, FIa. 1-19, 1986).
  • the native active constituent, delta 9-tetrahydrocannabinol ( ⁇ 9 -THC) is prescribed today, under the generic name dronabinol, as an anti-emetic and for enhancement of appetite, mainly in AIDS patients.
  • ⁇ 9 -THC delta 9-tetrahydrocannabinol
  • dronabinol an anti-emetic and for enhancement of appetite, mainly in AIDS patients.
  • separation between the clinically undesirable psychotropic effects and the therapeutically desirable effects on the peripheral nervous systems, the cardiovascular system, the immune and endocrine system is problematic.
  • the discovery of two cannabinoid receptors, CB1 and CB2 has helped to elucidate the diverse cannabinoid effects.
  • the CB1 receptor has been cloned from rat, mouse, and human tissues and exhibits 97- 99% amino acid sequence identity across species.
  • the CB2 receptor exhibits 48% homology with the CB1 receptor (A.C. Howlett et al. Pharmacological Reviews 2002, 54, 161-202).
  • the structures of both receptors are consistent with seven transmembrane G-protein coupled receptors.
  • both receptors exert their effect by negative regulation of adenylyl cyclase activity through pertussis toxin-sensitive GTP-binding proteins. They have been shown to activate the mitogen activated protein kinase (MAPK) in certain cell types (Parolaro, D., Life Sci. 1999, 65, 637-44).
  • MAPK mitogen activated protein kinase
  • the CB1 receptor is expressed mainly in the central nervous systems (CNS) and to a lesser extent in other tissues including, for example, gastrointestinal tissues, immune cells, reproductive organs, heart, lung, urinary bladder, and adrenal gland.
  • the CB2 receptor is expressed mostly in peripheral tissue associated with immune functions including, for example, macrophages, B cells, T cells and mast cells, as well as in peripheral nerve terminals (Perrwee, R.G., Prog. Neurobiol. 2001, 63, 569-611).
  • the central distribution pattern of CB1 receptors accounts for several unwanted pharmacological properties of cannabinoids, such as impaired cognition and memory, altered control of motor function, and psychotropic and other neurobehavioral effects.
  • CB1 receptors are also found on pain pathways in brain, spinal cord and at the peripheral terminals of primary sensory neurons (A. S. Rice, Curr. Opin. Investig. Drugs 2001 2(3), 399-414).
  • CB1 knockout mice have been shown to be unresponsive to cannabinoids in behavioral assays providing molecular evidence that the psychotropic effects, including sedation, hallucinations, and antinociception are manifested through the activation of the CB1 receptor, present primarily in the CNS.
  • Analysis of the CB2 knockout mouse has corroborated the evidence for the function of CB2 receptors in modulating the immune system.
  • the CB2 receptor does not affect immune cell development and differentiation as determined by FACS analysis of cells from the spleen, lymph node and thymus from CB2 knockout mice. Further studies in these mice have shown that the immunosuppressive effects of ⁇ 9 -THC are mediated by the CB2 receptor.
  • cannabinoid receptor agonists have been shown to produce potent antinociception with equivalent efficacy to morphine in animal models of acute pain, persistent inflammatory pain, and neuropathic pain. They have also been reported to induce a number of unwanted CNS side effects. Furthermore, the known cannabinoid receptor agonists are in general highly lipophilic and insoluble in water. There is thus a need for cannabinoid receptor agonists with improved properties for uses as therapeutic agents.
  • CB1 cannabinoid receptor agonists produce a characteristic profile of in vivo effects in mice, including suppression of spontaneous activity, antinociception, hypothermia, and catalepsy. Measurement of these four properties, commonly referred to as the tetrad test, has played a key role in establishing the structure-activity relationship of cannabinoids and cannabimimetics acting at CB1 receptors. Catalepsy in mice is indicative of CB1 activation and predictive of cannabinoid psychoactivity. Pertwee showed a correlation between catalepsy in the ring test in mice and the previously validated dog static ataxia model (R.G. Pertwee, Br. J. Pharmacology 1972, 46, 753-763).
  • catalepsy in mice is viewed as an excellent predictor of CNS effects in humans (D.R. Compton, Marijuana: An International Research Report 7, 213-218, 1987; E.W. Gill and G. Jones, Biochem. Pharmacol. 21, 2237-2248, 1972; E.W. Gill et al. Nature 228, 134-136, 1970).
  • CB2 receptor-selective inverse agonists are capable of altering cellular chemotaxis mediated by either cannabinoids or chemokines, both in vivo and in vitro. They have reported that administration of these compounds can decrease allergic eosinophilia in animal models for asthma.
  • the present invention is directed, in part, to novel pyridine compounds which may be modulators, agonists, and/or antagonists of cannabinoid receptors and which thus may be useful, inter alia, for the treatment of diseases or disorders which are associated with the cannabinoid receptor system.
  • the present invention relates to compounds of formula I:
  • A is a ring atom or a bond
  • D is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, Or -NR 2 R 3 ;
  • E is N or CR 12 ;
  • Y is N or CR 6 ;
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR x , -SR x , -NR y R z , F, Cl, or Br, or R 1 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring substituted with -[C(R 8 )(R 9 )] n -D; provided that: when R 1 or D independently includes a cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring moiety, then the included ring moiety is a monocyclic 3- to 7-membered ring having 0 or 1 heteroatom ring members, and when R 1 and
  • R 4 is:
  • each R a and each R are independently H or alkyl
  • R 5 and R 5a are each independently H or alkyl
  • R c is H, alkyl, or aryl
  • R and R e are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a carbocyclic ring;
  • R 6 and R 12 are each independently H, F, Cl, or alkyl, or R 6 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring substituted with -[C(R 8 )(R 9 )] n -D;
  • R 7 is H, F, or alkyl, or R 1 and R 7 taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, or R 7 and R 12 taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring;
  • R 1 , R 6 , and R 7 are other than F;
  • R 7 when R 7 is F, then at least one of R 1 and R 6 is other than F, Cl, or Br;
  • R 7 and R 12 , R 1 and R 7 , R 1 and A, and R 6 and A form a monocyclic cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring; or a pharmaceutically acceptable salt thereof.
  • the invention is directed to compounds according to formula Ia:
  • E is N or CR 12 ;
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR X , -SR x , -NR y R z , F, Cl, or Br; provided that when R 1 includes a cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring moiety, then the included ring moiety is a monocyclic 3- to 7- membered ring having 0 or 1 heteroatom ring members,
  • R v is C 1-3 unsubstituted alkyl
  • R 4 is:
  • each R a and each R are independently H or alkyl;
  • R 5 and R 5a are each independently H or alkyl;
  • R c is H, alkyl, or aryl;
  • R d and R e are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a carbocyclic ring;
  • R 6 and R 12 are each independently H, F, Cl, or alkyl
  • R 7 is H, F, or alkyl, or R 1 and R 7 taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, or R 7 and R 12 taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring;
  • R 7 and R 12 no more than one pair of R 7 and R 12 , and R 1 and R 7 form a monocyclic cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring; or a pharmaceutically acceptable salt thereof.
  • the present invention is directed, in part, to pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a compound of formula I or Ia.
  • the present invention is also directed, in part, to methods of binding cannabinoid receptors in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound according to formula I or Ia.
  • the present invention is generally directed to pyridine compounds, pharmaceutical compositions containing these compounds, and methods of their pharmaceutical use.
  • alkyl refers to an optionally substituted, saturated, straight or branched hydrocarbon having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), preferably with from about 1 to about 8 carbon atoms, more preferably with from about 1 to about 6 carbon atoms, yet more preferably with from about 1 to about 4 carbon atoms, still more preferably with from about 1 to about 3 carbon atoms, with 1 carbon being even more preferred.
  • 1 or more of the hydrogen atoms on the alkyl group are substituted with fluorine atoms.
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • cycloalkyl or “carbocyclic ring” each refers to an optionally substituted, mono-, di-, tri-, or other multicyclic alicyclic ring system having from about 3 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein).
  • the cycloalkyl groups have from about 3 to about 8 carbon atoms, more preferably from about 3 to about 6 carbon atoms.
  • Multi-ring structures may be bridged or fused ring structures, wherein the additional groups fused or bridged to the cycloalkyl ring may include optionally substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl rings.
  • exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, adamantyl, 2-[4-isopropyl-1- methyl-7-oxa-bicyclo[2.2.1]heptanyl], and 2-[1,2,3,4-tetrahydro-naphthalenyl].
  • bicycloalkyl refers to an optionally substituted, alicyclic group having two bridged rings in its structure and having from about 7 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 7 to about 15 carbon atoms being preferred.
  • Exemplary bicycloalkyl-ring structures include, but are not limited to, norbornyl, bornyl, [2.2.2]-bicyclooctyl, cis-pinanyl, trans-pinanyl, camphanyl, iso-bornyl, and fenchyl.
  • tricycloalkyl refers to an optionally substituted, alicyclic group having three bridged rings in its structure and having from about 7 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 7 to about 15 carbon atoms being preferred.
  • Exemplary tricycloalkyl-ring structures include, but are not limited to, tricyclo[5.1.2.0 2,6 ]decane, 1,7,7-trimethyl tricyclo[2.2.1.0 2,6 ]heptane, alpha-santalol, patchouli alcohol, alpha-cedrene, and longifolene.
  • cycloalkylalkyl refers to an optionally substituted ring system comprising an alkyl radical bearing one or more cycloalkyl substituents, and having from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 10 carbon atoms being preferred, wherein alkyl and cycloalkyl are as previously defined.
  • Non-limiting examples include, for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylpropyl, cyclohexylmethyl, 2-cyclooctyl-1-methylethyl, 2-[4-isopropyl-1-methyl-7-oxa-bicyclo[2.2.1]heptanyl]methyl, 2-[1,2,3,4-tetrahydro-naphthalenyl]ethyl, and adamantylpropyl.
  • alkylcycloalkyl refers to an optionally substituted ring system comprising a cycloalkyl group having one or more alkyl substituents, wherein cycloalkyl and alkyl are each as previously defined.
  • exemplary alkylcycloalkyl groups include 2-methylcyclohexyl, 3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and 4-methyldecahydronaphthalenyl.
  • heterocycloalkyl and “heterocyclic ring” each refers to an optionally substituted ring system composed of a cycloalkyl radical wherein in at least one of the rings, one or more of the carbon atom ring members is independently replaced by a heteroatom group selected from the group consisting of O, S, N, and NH, wherein cycloalkyl is as previously defined.
  • Heterocycloalkyl ring systems having a total of from about 5 to about 14 carbon atom ring members and heteroatom ring members (and all combinations and subcombinations of ranges and specific numbers of carbon and heteroatom ring members) are preferred.
  • heterocyclic groups may be fused to one or more aromatic rings.
  • heterocycloalkyl moieties are attached via a ring carbon atom to the rest of the molecule.
  • Exemplary heterocycloalkyl groups include, but are not limited to, azepanyl, tetrahydrofuranyl, hexahydropyrimidinyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl, 2-oxo-morpholinyl, morpholinyl, 2-oxo-piperidinyl, piperadinyl, decahydroquinolyl, octahydrochromenyl, octahydro-cyclopenta[c]pyranyl, 1,2,3 ,4,-t
  • two moieties attached to a heteroatom may be taken together to form a heterocycloalkyl ring, such as when R and R , taken together with the nitrogen atom to which they are attached, form a heterocycloalkyl ring.
  • the resultant ring when a moiety containing one ring replacement atom replaces a ring carbon atom, the resultant ring, after replacement of a ring atom by the moiety, will contain the same number of ring atoms as the ring before ring atom replacement.
  • the resultant ring after replacement will contain one more ring atom than the ring prior to replacement by the moiety.
  • the resultant ring is a 7-membered ring containing 2 ring nitrogen atoms and the carbon of a carbonyl group in addition to 4 other carbon ring atoms (CH 2 groups) from the original piperidine ring.
  • heterocycloalkylalkyl refers to an optionally substituted ring system composed of an alkyl radical having one or more heterocycloalkyl substituents, wherein heterocycloalkyl and alkyl are as previously defined.
  • the alkyl moieties of the heterocycloalkylalkyl groups have from about 1 to about 3 carbon atoms.
  • heterocycloalkyl groups include, but are not limited to, azepanylmethyl, tetrahydrofuranylethyl, hexahydropyrimidinylisobutyl, tetrahydrothienylpropyl, piperidinyl-2,2- dimethylethyl, pyrrolidinylmethyl , isoxazolidinylethyl, isothiazolidinylpropyl, pyrazolidinylmethyl, oxazolidinylbutyl, thiazolidinylisopropyl, piperazinylmethyl, 2-oxo-morpholinylmethyl, morpholinylethyl, 2-oxo-piperidinylethyl, piperadinylmethyl, decahydroquinolylethyl, octahydrochromenylpropyl, octahydro-cyclopenta[c]pyranylbutyl, 1,2,3,4,-te
  • alkenyl refers to an optionally substituted alkyl group having from about 2 to about 10 carbon atoms and one or more double bonds (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), wherein alkyl is as previously defined.
  • alkynyl refers to an optionally substituted alkyl group having from about 2 to about 10 carbon atoms and one or more triple bonds (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), wherein alkyl is as previously defined.
  • aryl refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system having from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), preferably with from about 6 to about 10 carbons, with about 6 carbon atoms being preferred.
  • Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.
  • aryl is phenyl, optionally substituted, more preferably substituted with at least one halo or haloalkyl group.
  • aralkyl refers to an optionally substituted ring system comprising an alkyl radical bearing an aryl substituent and having from about 7 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), preferably with from about 7 to about 11 carbon atoms, with about 7 carbon atoms being preferred.
  • Non-limiting examples include, for example, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
  • alkylaralkyl refers to an optionally substituted ring system comprising an alkyl radical bearing an aralkyl substituent and having from about 8 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 8 to about 12 carbon atoms being preferred, wherein alkyl and aralkyl are as previously defined.
  • Non-limiting examples include, for example, to lylm ethyl, bis(isopropylphenyl)methyl, 1-tolyl-1-ethylphenylmethyl, tert-butylphenylethyl, and ort ⁇ o-methyl-jp ⁇ ra-butylphenylethyl.
  • alkoxyl refers to an optionally substituted alkyl-O- group wherein alkyl is as previously defined.
  • the alkyl moieties of the alkoxy groups have from about 1 to about 4 carbon atoms.
  • Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxy.
  • aryloxyl refers to an optionally substituted aryl-O- group wherein aryl is as previously defined.
  • Exemplary aryloxy groups include, but are not limited to, phenoxy and naphthoxy.
  • aralkoxyl refers to an optionally substituted aralkyl-O- group wherein aralkyl is as previously defined.
  • exemplary aralkoxy groups include, but are not limited to, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, and 3-naphthytheptoxy.
  • 1,1-dioxo-thio refers to a diradical having the structure:
  • a 1 , 1 -dioxo-thio is a ring member of a heterocyclic ring.
  • exemplary ring member 1,1-dioxo-groups such as 1,1-dioxo-thiirane, 1,1-dioxo-thietane, 1,1-dioxo- tetrahydrothiophene, 1,1-dioxo-thiopyran, 1,1-dioxo-thiepane, and the like, more preferably 1,1- dioxo-thiopyran.
  • one or more ring carbon atoms of a 1,1-dioxo-thio ring is optionally replaced by -O-, -S-, or -N(R 9a )-.
  • Exemplary rings include 1,1-dioxo- thiomorpholine and [1,4]oxathiane 4,4-dioxide.
  • halo refers to a fluoro, chloro, bromo, or iodo moiety, with fluoro, chloro, or bromo moieties being preferred. In certain embodiments, fluoro or chloro moieties are more preferred.
  • heteroaryl refers to an optionally substituted aryl ring system wherein in at least one of the rings, one or more of the carbon atom ring members is independently replaced by a heteroatom group selected from the group consisting of S, O, N, and NH, wherein aryl is as previously defined.
  • Heteroaryl groups having a total of from about 5 to about 14 carbon atom ring members and heteroatom ring members(and all combinations and subcombinations of ranges and specific numbers of carbon and heteroatom ring members) are preferred.
  • heteroaryl groups include, but are not limited to, pyrryl, furyl, pyridyl, pyridine-N-oxide, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
  • Heteroaryl may be attached via a carbon or a heteroatom to the rest of the molecule.
  • heteroarylalkyl refers to an optionally substituted ring system comprising an alkyl radical bearing a heteroaryl substituent, having from about 2 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 25 carbon atoms being preferred.
  • Non- limiting examples include 2-(1H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and 3 -(pyrimidin-2-yl)-2-methylcyclopentanyl.
  • spiroalkyl refers to an optionally substituted alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group.
  • the spirocyclic group as herein defined, has 3 to 20 ring atoms, preferably with 3 to 10 ring atoms.
  • Exemplary spiroalkyl groups taken together with its parent group include, but are not limited to, 1-(1-methyl-cyclopropyl)-propan-2-one, 2-(1-phenoxy- cyclopropyl)-ethylamine, and 1-methyl-spiro[4.7]dodecane.
  • substituted chemical moieties include one or more substituents that replace hydrogen.
  • each moiety R" can be, independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, or when (R"(R")) is attached to a nitrogen atom, R" and R" can be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered nitrogen heterocycle, wherein the heterocycloalkyl ring is optionally interrupted by one or more additional -O-, -S-, -SO, -SO 2 -, -NH-, -N(alkyl)-, or -N(aryl)- groups, for example,
  • chemical moieties are substituted by at least one optional substituent, such as those provided hereinabove.
  • the optional substituents are not further substituted.
  • R 1 is an alkyl moiety, it is optionally substituted, based on the definiton of "alkyl" as set forth herein.
  • R 1 is alkyl substituted with optional aryl, the optional aryl substituent is not further substituted.
  • 2-(alpha-naphthyl)ethyl is within the scope of optionally substituted alkyl.
  • 2-(3-chlorophenyl)ethyl (wherein ethyl is the alkyl moiety and 3-chlorophenyl is the optional substituent) is not within the scope of optionally substituted alkyl because the optional aryl substiuent cannot be further substituted by a further chemical group.
  • cannabinoid refers to any one of a group of naturally occurring compounds of related structure that may be isolable from Cannabis sativa, more commonly known as marijuana, and structurally modified derivatives thereof.
  • Cannabinoids include for example, compounds such as ⁇ 9 -tetrahydrocannabinol, ⁇ 8 -tetrahydrocannabinol, cannabichromene, cannabicyclol, cannabidiol, cannabielsoin, cannabigerol, cannabinol, cannabitriol, nabilone, and nantradol, and numerous structural variants.
  • cannabinoids are lipophilic and have low solubility in water.
  • cannabinoids refers to any of a group of endogenous or exogenous receptor ligands that bind one or more of the receptors bound by cannabinoids and mimic one or more behaviors of cannabinoids while so bound.
  • Examples of endogenous cannabimimetics (also referred to as “endocannabinoids”) produced in mammalian tissues include, for example, arachidonoylethanolamide (anandamide), 2-arachidonoyl glycerol, 1(3)- arachidonoyl glycerol, and palmitoylethanolamide.
  • exogenous cannabimimetics examples include, for example WIN 55,212-2, CP 55,940, HU-210, and the like.
  • exogenous cannbimimetics may be found in publications such as R.B. Pertwee, "Pharmacology of Cannabinoid Receptor Ligands", Current Medicinal Chemistry, 1999, 6, 635-664, and A.C. Howlett, et al. "International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors", Pharmacological Reviews, 2002, 54(2), 161-202, the disclosures of which are each hereby incorporated herein by reference in their entireties.
  • the term "antagonist” refers to a compound that binds to a receptor to form a complex that preferably does not elicit any response, in the same manner as an unoccupied receptor, and does not alter the equilibrium between inactive and active receptor.
  • agonist refers to a ligand that produces a conformational change in the receptor and alters the equilibrium of the receptor's active and inactive states, which in turn induces a series of events, resulting in a measurable biological response.
  • Agonists include, for example, conventional agonists, which exhibit positive receptor activity, and inverse agonists, which exhibit a negative intrinsic activity.
  • prodrug refers to compounds that may serve to maximize the amount of active species that reaches the desired site of reaction that are themselves typically inactive or minimally active for the activity desired, but through biotransformation are converted into biologically active metabolites.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ as regards the arrangement of the atoms or groups in space.
  • partial stereoisomers refers to stereoisomers having two or more chiral centers wherein at least one of the chiral centers has defined stereochemistry (i.e., R or S) and at least one has undefined stereochemistry (i.e., R or S).
  • R or S defined stereochemistry
  • R or S undefined stereochemistry
  • stereoisomer has three chiral centers and the stereochemical configuration of the first center is defined as having "S" stereochemistry
  • the term "or partial stereoisomer thereof refers to stereoisomers having SRR, SRS, SSR, or SSS configurations at the three chiral centers, and mixtures thereof.
  • Asymmetric carbon atoms may be introduced into the molecule depending on the structure of the moiety R 4 when R a and R b are non-identical or when R c , R d , and R e are non- identical.
  • R 4 when R a is hydrogen and R b is other than H, the carbon atom to which R a is attached is asymmetric.
  • asymmetric centers are contemplated in the present invention.
  • Asymmetric centers are, by convention, present in R 4 moieties structure such as those shown below at the ring carbon atoms identified with an asterisk (*). As such, these classes of compounds can exist as
  • N-oxide refers to compounds wherein the basic nitrogen atom of either a heteroaromatic ring or tertiary amine is oxidized to give a quaternary nitrogen bearing a positive formal charge and an attached oxygen atom bearing a negative formal charge.
  • hydrate refers to a compound of the present invention which is associated with water in the molecular form, i.e., in which the H-OH bond is not split, and may be represented, for example, by the formula R ⁇ 2 O, where R is a compound of the invention.
  • R is a compound of the invention.
  • a given compound may form more than one hydrate including, for example, monohydrates (R . H 2 O) or polyhydrates (R . nH 2 O wherein n is an integer > 1) including, for example,
  • solvate refers to a compound of the present invention which is associated with solvent in the molecular form, i.e., in which the solvent is coordinatively bound, and may be represented, for example, by the formula Resolvent), where R is a compound of the invention.
  • a given compound may form more than one solvate including, for example, monosolvates (R . (solvent)) or polysolvates (R . n(solvent)) wherein n is an integer > 1) including,
  • Solvents herein include mixed solvents, for example, methanol/water, and as such, the solvates may incorporate one or more solvents within the solvate.
  • the term "acid hydrate” refers to a complex that may be formed through association of a compound having one or more base moieties with at least one compound having one or more acid moieties or through association of a compound having one or more acid moieties with at least one compound having one or more base moieties, said complex being further associated with water molecules so as to form a hydrate, wherein said hydrate is as previously defined and R represents the complex herein described above.
  • the term "pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
  • the term "effective amount” refers to an amount of a compound as described herein that may be therapeutically effective to inhibit, prevent or treat the symptoms of particular disease, disorder or side effect.
  • diseases, disorders and side effects include, but are not limited to, those pathological conditions associated with the binding of cannabinoid receptors (for example, in connection with the treatment and/or prevention of pain), wherein the treatment or prevention comprises, for example, agonizing the activity thereof by contacting cells, tissues or receptors with compounds of the present invention.
  • the term "effective amount,” when used in connection with cannabinoids, for example, for the treatment of pain refers to the treatment and/or prevention of the painful condition.
  • the term "effective amount”, when used in connection with the present cannabinoid receptor agonist compounds refers to the treatment, reduction and/or prevention of side effects typically associated with cannabinoids including, for example, such side effects as those hereinabove mentioned.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the term “in combination with”, “combination therapy” and “combination products” refer, in certain embodiments, to the concurrent administration to a patient of cannabinoids and the compounds of the Formula I, II, III, or IV.
  • each component When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • the term “dosage unit” refers to physically discrete units suited as unitary dosages for the particular individual to be treated. Each unit may contain a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect(s) in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention may be dictated by (a) the unique characteristics of the active compound(s) and the particular therapeutic effect(s) to be achieved, and (b) the limitations inherent in the art of compounding such active compound(s).
  • treatment includes preventative (e.g., prophylactic), curative or palliative treatment and “treating” as used herein also includes preventative, curative and palliative treatment.
  • pain refers to the perception or condition of unpleasant sensory or emotional experience, which may or may not be associated with actual or potential tissue damage or described in terms of such damage.
  • Pain includes, but is not limited to, two broad categories of pain: acute and chronic pain (Buschmann, H.; Christoph, T; Friderichs, E.; Maul, C; Sundermann, B; eds.; Analgesics, Wiley- VCH, Verlag GMbH & Co. KgaA, Weinheim; 2002; Jain, K. K. "A Guide to Drug Evaluation for Chronic Pain”; Emerging Drugs, 5(2), 241-257(2000)).
  • Non-limiting examples of pain include nociceptive pain, inflammatory pain, visceral pain, somatic pain, neuropathic pain, AIDS pain, cancer pain, phantom pain, and psychogenic pain, and pain resulting from hyperalgesia, pain caused by rheumatoid arthritis, migraine, allodynia, and the like.
  • the term "patient” refers to animals, including mammals, preferably humans.
  • side effect refers to a consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other then the one sought to be benefited by its administration.
  • the term “side effect” may refer to such conditions as, for example, psychotropic effects, such as confusion, anxiety, panic, distortion of perception, pretendizing, sedation, inner unrest, irritability and insomnia, sweating, rhinorrhoea, loose stools, hiccups, dry mouth, tachycardia, ataxia, dizziness, orthostatic hypotension, and anorexia.
  • any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the present invention is directed, in part, to a new class of cannabinoid receptor modulator compounds, preferably pyridine compounds, which may be highly useful in connection with the binding of cannabinoid receptors.
  • Compounds binding cannabinoid receptors may agonize and/or antagonize the receptors.
  • a cannabimimetic compound or ligand agonizes one or more cannabinoid receptors the resultant binding is believed to trigger an event or series of events in the cell that results in a change in the cell's activity, its gene regulation, or the signals that it sends to neighboring cells, similar to that of a cannabinoid.
  • compounds of the invention may serve to prevent or treat diseases or disorders in which cannabinoid receptors are implicated.
  • a cannabimimetic compound or ligand antagonizes one or more cannabinoid receptors
  • the resultant binding typically occurs comparatively to a greater extent relative to that of the cannabinoid, but does not trigger one or more of the events of signal transduction.
  • Compounds with these properties are highly useful, for example, in connection with the study of functions of cannabinoid receptors, which may result, for example, in the development of new cannabimimetic agonist compounds, such as those, for example, reported in Rinaldi-Carmona, M. et al., Journal of Pharmacology and Experimental Therapeutics, 1998, 284(2), 644-650, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • the present invention provides compounds of formula I: wherein:
  • A is a ring atom or a bond
  • D is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, Or -NR 2 R 3 ;
  • E is N or CR 12 ;
  • Y is N or CR 6 ;
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR x , -SR X , -NR y R z , F, Cl, or Br, or R 1 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring substituted with -[C(R 8 )(R 9 )] n -D; provided that: when R 1 or D independently includes a cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring moiety, then the included ring moiety is a monocyclic 3- to 7-membered ring having 0 or 1 heteroatom ring members, and when R 1 and
  • R 4 is:
  • each R a and each R D are independently H or alkyl
  • R 5 and R 5a are each independently H or alkyl
  • R c is H, alkyl, or aryl
  • R d and R e are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a carbocyclic ring;
  • R 6 and R 12 are each independently H, F, Cl, or alkyl, or R 6 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring substituted with -[C(R 8 )(R 9 )] n -D;
  • R 7 is H, F, or alkyl, or R 1 and R 7 taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, or R 7 and R 12 taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring;
  • R 1 , R 6 , and R 7 are other than F;
  • R 7 when R 7 is F, then at least one of R 1 and R 6 is other than F, Cl, or Br;
  • R 7 and R 12 , R 1 and R 7 , R 1 and A, and R 6 and A form a monocyclic cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of formula Ia:
  • E is N or CR 1 1 2.
  • Y is N or CR 6 ;
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR X , -SR X , -NR y R z , F, Cl, or Br; provided that when R 1 includes a cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring moiety, then the included ring moiety is a monocyclic 3- to 7- membered ring having 0 or 1 heteroatom ring members,
  • R v is C 1-3 unsubstituted alkyl
  • R 4 is:
  • each R a and each R are independently H or alkyl
  • R 5 and R 5a are each independently H or alkyl
  • R c is H, alkyl, or aryl
  • R and R e are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a carbocyclic ring;
  • R 6 and R 12 are each independently H, F, Cl, or alkyl
  • R 7 is H, F, or alkyl, or R 1 and R 7 taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, or R 7 and R 12 taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring;
  • R 7 and R 12 no more than one pair of R 7 and R 12 , and R 1 and R 7 form a monocyclic cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring; or a pharmaceutically acceptable salt thereof.
  • the compound of formula I or Ia has the structure of formula II:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, D, and n are as defined above.
  • the compound of formula I or Ia has the structure of formula III: wherein R 1 , R 4 , R 7 , R 8 , R 9 , A, D, and n are as defined above.
  • the compound of formula I has the structure of formula IV:
  • R 4 , R 7 , R 8 , R 9 , D, E, Y, Z, and n are as defined above.
  • A is a bond.
  • D is -NR 2 R 3 .
  • D is heterocycloalkyl containing at least one nitrogen atom or dioxo-thio group; more preferably heterocycloalkyl containing at least one nitrogen atom.
  • D is preferably morpholinyl, piperidinyl, or 1,1-dioxo-thiomorpholinyl, each optionally substituted.
  • D is N(H)-aralkyl or -N(CH 3 )-aralkyl.
  • E is N.
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, hetero aralkyl, -OR X , -SR X , -NR y R z , F, Cl, or Br, more preferably H, alkyl, cycloalkyl, aryl, heteroaryl, -OR X , or Br, with alkyl, -OR X , or Br being even more preferred.
  • R 1 is H.
  • R 1 is -OR X , more preferably alkoxy. In still other preferred embodiments, R 1 is alkyl. In certain other preferred embodiments, when R 1 includes a cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring moiety, then the included ring moiety is a monocyclic 3- to 7- membered ring having 0 or 1 heteroatom ring members.
  • the term "included ring moiety" refers to when any element independently, for example, R 1 , is a group having a ring moiety within the group.
  • R 1 is the group cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl.
  • These groups respectively comprise the ring moiety cycloalkyl, cycloalkyl, aryl, aryl, heterocycloalkyl, heterocycloalkyl, heteroaryl, or heteroaryl.
  • groups such as aralkyl, heterocycloalkylalkyl, and heteroaralkyl which are alkyl moieties substituted with an aryl, heterocycloalkyl, and heteroaryl ring moieties respectively, have an included ring moiety.
  • R 1 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, more preferably a monocyclic 4- to 7-membered cycloalkyl ring, wherein the monocyclic ring group is substituted at any available position with -[C(R )(R )] n -D, and may be further optionally substituted.
  • R 1 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring group
  • the result is a monocyclic ring group which is fused to the core pyridine ring to provide a fused bicyclic ring system, wherein the monocyclic ring group is substituted with -[C(R 8 )(R 9 )] n -D.
  • the -[C(R 8 )(R 9 )] n -D moiety is attached to the monocyclic ring carbon atom which is both adjacent to, and closer in proximity to the Y moiety in the core pyridine ring in the compound of formula I, II, or III.
  • R 1 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 6-membered aryl ring
  • the resulting fused bicyclic ring system which is formed will be a quinoline group or isoquinoline group, depending upon which of E and Y is N.
  • Y is N
  • the resulting fused bicyclic ring system is a substituted quinoline group.
  • the resulting fused bicyclic ring system is a substituted isoquinoline group.
  • the formed monocyclic ring group has 0 or 1 heteroatom ring members.
  • R x , R y , and R z are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl.
  • R x is alkyl.
  • R 2 and R 3 are each independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, more preferably when at least one of R 2 and R 3 is aralkyl or cycloalkyl; still more preferably when at least one of R 2 and R 3 is aralkyl, with when one of R 2 and R 3 is aralkyl and the other is alkyl being even more preferred.
  • R 3 is H or alkyl.
  • R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring, the ring is fused to a C 6 -aryl ring. In certain other embodiments wherein R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring, the heterocycloalkyl ring is substituted with at least one hydroxy, alkyl, dialkylamino, halo, heteroarylcarbonyl, or alkylcarbonyl group. In still other alternative embodiments, R 2 and R 3 are each independently alkyl.
  • R 4 is :
  • R 4 is:
  • R 5 is H. In other preferred embodiments of the compounds of formula I or IV, R 5a is H.
  • each R a and each R b are independently H or alkyl.
  • each R a is H.
  • each R b is H.
  • R a and R b are each H.
  • R 6 is H.
  • R 6 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, more preferably a monocyclic 4- to 8-membered cycloalkyl ring, wherein the monocyclic ring group is substituted at any available position with -[C(R 8 )(R 9 )] n -D, and may be further optionally substituted .
  • R 6 and the ring atom A taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring group
  • the result is a monocyclic ring group which is fused to the core pyridine ring to provide a fused bicyclic bicyclic ring system, wherein the monocyclic ring group is substituted with -[C(R 8 )(R 9 )] n -D.
  • the -[C(R 8 )(R 9 )] n -D moiety is attached to the monocyclic ring carbon atom which is either on a ring carbon alpha or beta to the core pyridine ring, and closer in proximity to the R 1 moiety in the compound of formula I or II.
  • the resulting fused bicyclic ring system which is formed will be an isoquinoline group.
  • the formed monocyclic ring group has 0 or 1 heteroatom ring members.
  • R c is H, alkyl, or aryl, preferably H or alkyl, with alkyl being more preferred. In some preferred embodiments where R c is substituted alkyl, R c is preferably alkoxy substituted alkyl. In other preferred embodiments where R c is substituted aryl, R c is preferably alkoxy substituted aryl.
  • R d and R e are each independently H or alkyl, more preferably alkyl.
  • R c , R d , and R e are each independently alkyl.
  • R d or R e is substituted alkyl, it is more preferably alkoxy substituted alkyl.
  • R d and R e taken together with the carbon atom to which they are attached form a carbocyclic ring, preferably a monocyclic carbocyclic ring.
  • the carbocyclic ring is further substituted, preferably with at least one alkyl or alkoxy group, or any combination thereof.
  • R d and R e taken together with the carbon atom to which they are attached, form a 3- to 12-membered carbocyclic ring, wherein the carbocyclic ring is substituted with 0-5 groups each independently selected from d.C 4 alkyl and C 1 .C 4 alkoxyl. More preferably, the carbocyclic ring is bicycloalkyl or tricycloalkyl, still more preferably bicycloalkyl; with bicycloalkyl ring is substituted with 1-3 alkyl, preferably groups.
  • R 7 is H or alkyl. In other preferred embodiments, R 7 is F.
  • R 1 and R 7 taken together with the atoms through which they are connected form a monocyclic 4- to 7- membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, more preferably a monocyclic 4- to 7-membered cycloalkyl ring, wherein the monocyclic ring group is substituted at any available position with -[C(R 8 )(R 9 )] n -D, and may be further optionally substituted .
  • R 1 and R 7 taken together with the atoms through which they are connected form a monocyclic 4- to 7-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring group
  • the result is a monocyclic ring group which is fused to the core pyridine ring to provide a fused bicyclic ring system.
  • R 1 and R 7 taken together with the atoms through which they are connected form a monocyclic 6-membered aryl ring
  • the resulting fused bicyclic ring system which is formed will be a quinoline group or isoquinoline group, depending upon which of E and Y is N.
  • the resulting fused bicyclic ring system is an isoquinoline group.
  • E is N
  • the resulting fused bicyclic ring system is a quinoline group.
  • R 1 and R 7 taken together with the atoms through which they are connected form a ring
  • the formed monocyclic ring group has 0 or 1 heteroatom ring members.
  • R 1 and R 7 taken together with the atoms through which they are attached form an aryl ring, even more preferably a C 6 aryl ring.
  • R 7 and R 12 taken together with the atoms through which they are connected form a monocyclic 4- to 8- membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, more preferably a monocyclic 4- to 8-membered cycloalkyl ring, wherein the monocyclic ring group is substituted at any available position with -[C(R 8 )(R 9 )] n -D, and may be further optionally substituted .
  • R 7 and R 12 taken together with the atoms through which they are connected form a monocyclic 4- to 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring group
  • the result is a monocyclic ring group which is fused to the core pyridine ring to provide a fused bicyclic ring system.
  • the resulting fused bicyclic ring system which is formed will be an isoquinoline group.
  • the formed monocyclic ring group has 0 or 1 heteroatom ring members.
  • R and R are each H. Alternatively, they are each independently alkyl.
  • R 12 is H.
  • n and r are each independently 0, 1, 2, or 3, preferably 0, 1, or 2, more preferably 0 or 1. In certain even more preferred embodiments r is 0. In other even more preferred embodiments, n is 1.
  • the compound of formula I is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of: N-((l/?,2i?,4S)-bicyclo-[2.2.1]heptan-2-yl)-4-(morpholinomethyl)-6,7-dihydro-5H- cyclopenta[b]-pyridin-2-amine;
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula Ia is selected from the group consisting of: N-[4-(l , 1 -Dioxo- 1 -lambda *6*-thiomorpholin-4-yl-methyl)-5-methylpyridin-2-yl]-2,2- dimethylbutyr amide;
  • the compound of formula Ia is selected from the group consisting of:
  • prodrug is intended to include any covalently bonded carriers which release the active parent drug, for example, as according to Formula I, Ia, II, III, or IV, or other formulas or compounds employed in the methods of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds employed in the present methods may, if desired, be delivered in prodrug form. Thus, the present invention contemplates methods of delivering prodrugs.
  • Prodrugs of the compounds employed in the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively.
  • Examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.
  • the compounds employed in the methods of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by the methods described below, or variations thereon as appreciated by the skilled artisan. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.
  • compounds employed in the present methods may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms.
  • optically active or racemic forms all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
  • protecting groups present may contain protecting groups during the course of synthesis.
  • Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxy groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed.
  • Any of a variety of protecting groups may be employed with the present invention.
  • Preferred protecting groups include the benzyloxycarbonyl group and the tert-butyloxycarbonyl groups.
  • Preferred hydroxyl protecting groups include the benzyl and the tertiary-butyldimethylsilyl groups.
  • Other preferred protecting groups that may be employed in accordance with the present invention may be described in Greene, T.W.
  • the compounds of the present invention are preferably combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington 's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980), the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington 's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980), the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • the compounds of the present invention may be administered as the pure chemicals, it is preferable to present the active ingredient as a pharmaceutical composition.
  • the invention thus further provides pharmaceutical compositions comprising one or more of the cannabinoid receptor modulator compounds of the present invention, for example, compounds of Formula I, Ia, II, III, or IV, together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • compositions and methods of the invention may further comprise at least one cannabinoid.
  • cannabinoids are available that may be suitable for use in the present methods and compositions.
  • the cannabinoid provide the desired effect (for example, pain alleviation), and be capable of being incorporated into the present combination products and methods (discussed in detail below).
  • the present methods and compositions may involve a cannabinoid that is selected from ⁇ -tetrahydrocannabinol and cannabidiol, and mixtures thereof, more preferably, ⁇ 9 -tetrahydrocannabinol.
  • compositions and methods of the invention may further comprise at least one opioid.
  • opioids are available that may be suitable for use in the present methods and compositions. Generally speaking, it is only necessary that the opioid provide the desired effect (for example, pain alleviation), and be capable of being incorporated into the present combination products and methods (discussed in detail below).
  • the present methods and compositions may involve an opioid that is selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil and/or tramadol.
  • an opioid that is selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentan
  • the opioid is selected from morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, tramadol, and mixtures thereof.
  • the opioid component of the present methods and compositions may further include one or more other active ingredients that may be conventionally employed in analgesic and/or cough-cold-antitussive combination products.
  • Such conventional ingredients include, for example, aspirin, acetaminophen, phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and/or guaifenesin.
  • Typical or conventional ingredients that may be included in the opioid component are described, for example, in the Physicians ' Desk Reference, 1999, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • the opioid component may further include one or more compounds that may be designed to enhance the analgesic potency of the opioid and/or to reduce analgesic tolerance development.
  • compounds include, for example, dextromethorphan or other NMDA antagonists (Mao, M. J., et al, Pain, 1996, 67, 361), L-364,718 and other CCK antagonists (Dourish, C.T., et al, Eur. J. Pharmacol, 1988, 147, 469), NOS inhibitors (Bhargava, H. N., et al., Neuropeptides, 1996, 30, 219), PKC inhibitors (Bilsky, E. J., et al, J. Pharmacol.
  • compositions of the invention may further comprise at least one analgesic, such as for example, COX2 inhibitors, aspirin, acetaminophen, ibuprophen, naproxen, and the like, and mixtures thereof.
  • analgesic such as for example, COX2 inhibitors, aspirin, acetaminophen, ibuprophen, naproxen, and the like, and mixtures thereof.
  • COX2 inhibitors such as for example, COX2 inhibitors, aspirin, acetaminophen, ibuprophen, naproxen, and the like, and mixtures thereof.
  • analgesic such as for example, COX2 inhibitors, aspirin, acetaminophen, ibuprophen, naproxen, and the like, and mixtures thereof.
  • the analgesic provide the desired effect (for example, pain alleviation), and be capable of being incorporated into the present combination products and methods (discussed in detail below).
  • compositions of the invention may further comprise at least one therapeutic agent selected from the group consisting of anti-seizure agents, such as, for example, carbamazepine, gabapentin, lamotrigine, and phenytoin, anti-depressants such as, for example, amitryptiline, NMDA receptor antagonists, ion channel antagonists, nicotinic receptor agonists, and anti -Parkinson's agents, such as, for example, deprenyl, amantadine, levodopa, and carbidopa.
  • anti-seizure agents such as, for example, carbamazepine, gabapentin, lamotrigine, and phenytoin
  • anti-depressants such as, for example, amitryptiline, NMDA receptor antagonists, ion channel antagonists, nicotinic receptor agonists
  • anti -Parkinson's agents such as, for example, deprenyl
  • the anti seizure agent, anti-depressant, NMDA receptor antagonist, ion channel antagonist, nicotinic receptor agonist, or antiParkinson's agent provide the desired effect (for example, inhibition of seizures, alleviation of depression, and the like), and be capable of being incorporated into the present combination products and methods (discussed in detail below).
  • the compounds of the invention may be administered in an effective amount by any of the conventional techniques well-established in the medical field.
  • the compounds employed in the methods of the present invention including, for example, the compounds of Formula I, Ia, II, III, or IV, may be administered by any means that results in the contact of the active agents with the agents' site or site(s)of action in the body of a patient.
  • the compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. For example, they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.
  • Compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally.
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic.
  • the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the amount of active compound(s) in such therapeutically useful compositions is preferably such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention may be prepared so that an oral dosage unit form contains from about 0.1 to about 1000 mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain one or more of the following: a binder, such as gum tragacanth, acacia, corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent, such as peppermint, oil of wintergreen or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such
  • any material used in preparing any dosage unit form is preferably pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • the active compound may also be administered parenterally or intraperitoneally.
  • Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • a dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form is preferably sterile and fluid to provide easy syringability. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils.
  • the 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 a dispersion, and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium stearate, sodium stearate, and gelatin.
  • Sterile injectable solutions may be prepared by incorporating the active compounds in the required amounts, in the appropriate solvent, with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions may be prepared by incorporating the 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 may include vacuum drying and the freeze drying technique that yields a powder of the active ingredient, plus any additional desired ingredient from the previously sterile- filtered solution thereof.
  • the therapeutic compounds of this invention may be administered to a patient alone or in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.
  • the dosage of the compounds of the present invention that will be most suitable for prophylaxis or treatment will vary with the form of administration, the particular compound chosen and the physiological characteristics of the particular patient under treatment. Generally, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached. Generally speaking, oral administration may require higher dosages.
  • a daily dosage of the compound of the invention may range from about 0.001 to about 100 milligrams of the compound of the invention, preferably a compound as described herein, (and all combinations and subcombinations of ranges and specific dosage amounts therein), per kilogram of patient body weight.
  • the daily dosage may be about 0.01 to about 10 milligrams of the compound of the invention, preferably a compound as described herein per kilogram of patient body weight.
  • the daily dosage may be about 0.1 milligrams of the compound of the invention, preferably a compound as described herein per kilogram of patient body weight.
  • the compounds of the invention preferably a compound as described herein, generally may be present in an amount of about 0.1 to about 4 milligrams.
  • the combination products of this invention such as pharmaceutical compositions comprising cannabinoids and/or opioids in combination with the compounds of Formula I, Ia, II, III, or rv, may be in any dosage form, such as those described herein, and can also be administered in various ways, as described herein.
  • the combination products of the invention are formulated together, in a single dosage form (that is, combined together in one capsule, tablet, powder, or liquid, etc.).
  • the cannabinoid and/or opioid compounds and the compounds of Formula I, Ia, II, III, or IV may be administered at the same time (that is, together), or in any order.
  • the administration of a cannabinoid and/or opioid and the compounds of Formula I, Ia, II, III, or IV occurs less than about one hour apart, more preferably less than about 30 minutes apart, even more preferably less than about 15 minutes apart, and still more preferably less than about 5 minutes apart.
  • administration of the combination products of the invention is oral, although other routes of administration, as described above, are contemplated to be within the scope of the present invention.
  • the cannabinoids and/or opioids and the compounds of Formula I, Ia, II, III, or IV are both administered in the same fashion (that is, for example, both orally), if desired, they may each be administered in different fashions (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously).
  • the dosage of the combination products of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired.
  • a daily dosage may range from about 0.01 to about 100 milligrams of the cannabinoid and/or opioid (and all combinations and subcombinations of ranges therein) and about 0.001 to about 100 milligrams of the compounds of Formula I, Ia, II, III, or IV (and all combinations and subcombinations of ranges therein), per kilogram of patient body weight.
  • the a daily dosage may be about 0.1 to about 10 milligrams of the cannabinoid and/or opioid and about 0.01 to about 10 milligrams of the compounds of Formula I, Ia, II, III, or IV per kilogram of patient body weight. Even more preferably, the daily dosage may be about 1.0 milligrams of the cannabinoid and/or opioid and about 0.1 milligrams of the compounds of Formula I, Ia, II, III, or IV per kilogram of patient body weight.
  • a typical dosage form of this type of combination product such as a tablet
  • the cannabinoid compounds e.g.
  • ⁇ 9 -tetrahydrocannabinol or cannabidiol and/or the opioid compounds (e.g., morphine) and generally may be present in an amount of about 15 to about 200 milligrams, and the compounds of Formula I, Ia, II, III, or IV in an amount of about 0.1 to about 4 milligrams.
  • the preferred dosage forms of the combination products of this invention are formulated such that although the active ingredients are combined in a single dosage form, the physical contact between the active ingredients is minimized (that is, reduced).
  • one embodiment of this invention where the product is orally administered provides for a combination product wherein one active ingredient is enteric coated.
  • enteric coating one or more of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
  • Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material that effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low- viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
  • HPMC hydroxypropyl methylcellulose
  • the polymer coating serves to form an additional barrier to interaction with the other component.
  • Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer.
  • one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients.
  • dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the dose may also be provided by controlled release of the compound, by techniques well known to those in the art.
  • kits useful in, for example, the treatment of pain which comprise a therapeutically effective amount of a cannabinoid and/or opioid along with a therapeutically effective amount of a pyridine compound of the invention, in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art.
  • the sterile containers of materials may comprise separate containers, or one or more multi-part containers, as exemplified by the UNIVIALTM two-part container (available from Abbott Labs, Chicago, Illinois), as desired.
  • the opioid or cannabinoid compound and the compound of Formula I, II, III, or IV may be separate, or combined into a single dosage form as described above.
  • kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art.
  • kit components such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.
  • the compounds, pharmaceutical compositions and methods of the present invention may involve a peripheral cannabinoid receptor agonist compound.
  • peripheral designates that the compound acts primarily on physiological systems and components external to the central nervous system.
  • the peripheral receptor agonist compounds employed in the methods of the present invention exhibit high levels of activity with respect to peripheral tissue, such as, gastrointestinal tissue, while exhibiting reduced, and preferably substantially no CNS activity.
  • substantially no CNS activity means that less than about 20% of the pharmacological activity of the compounds employed in the present methods is exhibited in the CNS, preferably less than about 15%, more preferably less than about 10%, even more preferably less than about 5%, and most preferably 0%, of the pharmacological activity of the compounds employed in the present methods is exhibited in the CNS.
  • the compounds of the present invention may be used in methods to bind cannabinoid receptors, more preferably CB1 or CB2 cannabinoid receptors. Such binding may be accomplished by contacting the receptor with an effective amount of a compound of Formula I, II, III, or IV.
  • the cannabinoid receptors may be located in the central nervous system or located peripherally to the central nervous system or in both locations.
  • the contacting step conducted in an aqueous medium, preferably at physiologically relevant ionic strength, pH, and the like.
  • the compound of the invention administered does not substantially cross the blood-brain barrier and thereby reduces the classical central side effects as observed for blood-brain penetrating cannabinoid agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC).
  • blood-brain penetrating cannabinoid agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC).
  • ⁇ 9 -THC blood-brain penetrating cannabinoid agonists
  • the central side effects of blood brain penetrating cannabinoid agonists limits their clinical utility, such as their use in the relief of pain.
  • does not substantially cross means that less than about 30% by weight of the compound employed in the present methods crosses the blood-brain barrier, preferably less than about 15% by weight, more preferably less than about 10% by weight, even more preferable less than about 5% by weight and most preferably 0% by weight of the compound crosses the blood-brain barrier.
  • Selected compounds can be evaluated for CNS penetration by determining plasma and brain levels following i.v. administration.
  • the invention is directed to methods of binding cannabinoid receptors, preferably CB1 and/or CB2 receptors, comprising the step of administering to a patient in need thereof, an effective amount of a compound of the invention including, for example, a compound of Formula I, Ia, II, III, or IV, or any combination thereof.
  • the methods comprise the step of administering to said patient an effective amount of a compound of Formula I, Ia, II, III, or IV, or any combination thereof.
  • the cannabinoid receptors are CB1 and/or CB2 cannabinoid receptors.
  • the compound selectively binds CB2 cannabinoid receptors relative to CB1 receptors, even more preferably peripheral CB2 receptors.
  • the cannabinoid receptors are located in the central nervous system. In other preferred embodiments, the cannabinoid receptors are located peripherally to the central nervous system. In some other preferred embodiments, the compound exhibits activity toward the cannabinoid receptors. In certain preferred embodiments, the binding agonizes the activity of the cannabinoid receptors.
  • the binding antagonizes the activity of the cannabinoid receptors. In still other preferred embodiments, the binding inversely agonizes the activity of the cannabinoid receptors. [0152] In certain embodiments, the present invention is directed to methods of treating a gastrointestinal disorder, comprising the step of administering to a patient in need thereof, an effective amount of a compound of Formula I, Ia, II, III, or FV, or any combination thereof.
  • the gastrointestinal disorders which may be treated with the present compounds and methods include, for example, nausea, vomiting, loss of appetite, cachexia, diarrhoea, inflammatory bowel disease, or irritable bowel syndrome, or any combination thereof.
  • the present invention is directed to methods of treating inflammation, comprising the step of administering to a patient in need thereof, an effective amount of a compound of Formula I, Ia, II, III, or IV, or any combination thereof.
  • the present invention is directed to methods of treating autoimmune diseases, comprising the step of administering to a patient in need thereof, an effective amount of a compound of Formula I, Ia, II, III, or FV, or any combination thereof.
  • the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, myasthenia gravis, diabetes mellitus type I, osteoporosis, or any combination thereof.
  • the present invention is directed to methods of treating an immune related disorder, comprising the step of administering to a patient in need thereof, an effective amount of a compound of formula I, Ia, II, III, or IV, or any combination thereof.
  • the immune related disorder is asthma, chronic pulmonary obstructive disorder, emphysema, bronchitis, allergy, tissue rejection in organ transplants, celiac disease, or Sjogren's syndrome, or any combination thereof.
  • the present invention is directed to methods of treating pain, comprising the step of administering to a patient in need thereof, an effective amount of a compound of formula I, Ia, II, III, or FV, or any combination thereof.
  • the pain may be inflammatory pain, neuropathic pain, visceral pain, surgical pain, including pain which occurs during surgery or pain which occurs after surgery (i.e., postsurgical pain), or cancer related pain.
  • the present pain ameliorating methods may further comprise the administration to the patient of at least one opioid in the form of combination products and/or combination therapy.
  • Suitable opioids include, for example, alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil or tramadol, and mixtures thereof.
  • the present methods may further comprise administering to a patient codeine, carbamazepine, gabapentin, lamotrigine, phenytoin, amitryptiline, an NMDA receptor antagonist, an ion channel antagonist, or a nicotinic receptor agonist, or a mixture thereof, in the form of combination products and/or combination therapy.
  • the methods for treating pain may further comprise the administration to the patient of at least one cannabinoid.
  • the present invention is directed to methods of treating hypertension, comprising the step of administering to a patient in need thereof, an effective amount of a compound of formula I, Ia, II, III, or IV, or any combination thereof.
  • the present invention is directed to methods of treating neurodegenerative diseases, comprising the step of administering to a patient in need thereof, an effective amount of a compound of formula I, Ia, II, III, or IV, or any combination thereof.
  • the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis.
  • these methods may further comprise the administration to the patient of deprenyl, amantadine, levodopa, or carbidopa, in the form of combination products and/or combination therapy.
  • the present invention is directed to methods of treating neurological disorders, comprising the step of administering to a patient in need thereof, an effective amount of a compound of formula I, Ia, II, III, or FV, or any combination thereof.
  • the neurological disorder is stroke, migraine, or cluster headache, or any combination thereof.
  • the present invention is directed to methods of providing cardioprotection against ischemic and reperfusion effects, comprising the step of administering to a patient in need thereof, an effective amount of a compound of formula I, Ia, II, III, or IV, or any combination thereof.
  • the ischemic or reperfusion effect is arrhythmia or hypertension, or a combination thereof.
  • the present invention is directed to methods of inhibiting mechanical hyperalgesia associated with nerve injury, comprising the step of administering to a patient in need thereof, an effective amount of a compound of Formula I, Ia, II, III, or IV, or any combination thereof.
  • the present invention is directed to methods of inducing apoptosis in malignant cells, comprising the step of contacting said cells with an effective amount of a compound of Formula I, Ia, II, III, or FV, or any combination thereof.
  • the apoptosis occurs in vitro, In other preferred embodiments, the apoptosis occurs in vivo.
  • the present invention is directed to methods for modulating appetite, comprising the step of administering to a patient in need thereof, an effective amount of a compound of Formula I, Ia, II, III, or IV, or any combination thereof.
  • the modulating decreases appetite.
  • the modulating enhances appetite.
  • pyridine compounds of Formula I, Ia, II, III, or IV can be readily prepared.
  • the invention is further described in the following examples.
  • the actual examples, herein provided, are for illustrative purposes only, and are not to be construed as limiting the appended claims. They provide a series of pyridine derivatives (IA-I ID) of Formula I, Ia, II, III, or IV, prepared according to Schemes 1-25, shown below in Examples 1 A-25G.
  • the prophetic examples 12, 13, and any intermediates thereto, herein provided in Schemes 12 and 13, are for illustrative purposes only, and are not to be construed as limiting the appended claims.
  • Schemes 12 and 13 are prophetic.
  • Commercially available 5,6,7,8- tetrahydroisoquinoline 12.1 is oxidized with hydrogen peroxide (Gribble et al., Tetrahedron 1988, 44(11), 3195-3202) and chlorinated with phosphorous oxychloride (Yamanaka et al., Chemical & Pharmaceutical Bulletin 1988, 36(6), 2244-7) to yield 12.2.
  • Conversion to 12.3 is accomplished following a procedure described by Mac Bride et al., Synthetic Commun. 1996, 2(5(12), 2309-2316.
  • a Wittig reaction followed by hydroboration applicable to the synthesis of 12.5 is described in WO20040052851.
  • Compounds 14AE - 14AG were prepared using methane thiolate c10, ethane thiolate ell and acid chlorides a3, al4 or a2 respectively.
  • Compound 15A was prepared as outlined in Scheme 15. Commercially available methyl 2-amino-6-methylisonicotinate 15.1 was brominated, converted to amide 15.3 and reduced to 15.4 with borane dimethyl sulfide complex. The 4-bromo substituent in 15.4 was replaced through a reaction with sodium methoxide and copper bromide to give 15.5, followed by amide formation with acid chloride a2 to yield compound 15 A.
  • Compound 21 A - 21D were prepared as outlined in Scheme 21.
  • Intermediate 2.3a2 was reacted with triethyl phosphate.
  • the phosphonate 21.1 was reacted under Horner Wadsworth Emmons conditions with 1-acetylpiperidin-4-one or dihydro-2H-pyran-4(3H)-one.
  • Intermediate 21.2a or 21.2c was reacted with methyl zinc chloride and reduced to compounds 21 A or 21C.
  • Intermediate 20.4 was reacted with triethyl phosphate, coupled with 1- acetylpiperidin-4-one and reduced to compound 21B.
  • the aqueous layer was basified with aqueous NaOH, and extracted with DCM. The organic layers were combined, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography using acetone-hexane (1:2) as eluent.
  • N,7V-diiso-propylethylamine (260 ⁇ L, 0.0015 mol) was added at once to the ice cooled reaction and after 1 hour morpholine (320 ⁇ L, 0.0037 mol) was added at once and the reaction was allowed to slowly warm to room temperature and stir overnight.
  • the reaction was diluted with 35 mL of ethyl acetate and washed with 25 mL of water. The aqueous phase was back extracted with 25 mL of ethyl acetate and the combined extracts were dried with sodium sulfate and concentrated under vacuum.
  • the material was chromatographed on a 12 gram silica gel column with a gradient of 15 to 50 % ethyl acetate/hexanes.
  • the oil obtained was dissolved in 4 mL of methanol and 1.5 mL of HCl in dioxane was added. After ten minutes the solvents were removed under vacuum and the sample dried overnight. The yield was 123 mg (32%).
  • N-(5-bromo-4-(morpholinomethyl)pyridin-2-yl)-2,2-dimethylbutanamide 2A was prepared from 2.3 and morpholine bl following general method C in 36% yield.
  • Example 2C was prepared from 2 A following general method E in 20% yield.
  • Examples 2D - 2E were prepared from 2A using 4-pyridine boronic acid c3 and ethyl boronic acid c4 respectively following general method E.
  • Examples 2F - 21 were prepared from the appropriate starting materials and following general methods as described in examples 2A and 2B.
  • the vial was swept with nitrogen for ten minutes and sodium-tert-butoxide (0.070 g, 0.73 mmol) and 2-methoxy-ethylamine (c6, 1.5 mL, 0.017 mol) were added.
  • the reaction was heated in the microwave for 60 minutes at 100 °C. LC/MS indicated the desired product was formed as the major product and starting material was still present.
  • the reaction was heated at 115 °C for 70 minutes.
  • the reaction was partitioned in 30 mL of water and 50 mL of ethyl acetate.
  • the aqueous phase was extracted with an additonal 50 mL of ethyl acetate.
  • the combined organic extracts were dried with sodium sulfate and concentrated under vacuum.
  • Examples 2L - 2R were prepared from the appropriate starting materials and following general methods as described in examples 2A and 2B.
  • Examples 2T - 2V were prepared from the appropriate starting materials and following general methods as described in example 2A.
  • Example 3B was prepared from 3.1 and acid chloride a4 following general method A.
  • Examples 3C - 3H were prepared from 3.1 and the appropriate acid chloride following general method A.
  • Examples 31 - 3O were prepared from 3.1 and acids el- e9 utilizing the coupling reagent Bop-Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride).
  • N-(5-bromo-4-(bromomethyl)-6-methylpyridin-2-yl)-2,2-dimethyl-butanamide 5.3 and N-(5-bromo-6-(bromomethyl)-4-methylpyridin-2-yl)-2,2-dimethylbutanamide 5.4 were obtained as a mixture when N-(5-bromo-4,6-dimethylpyridin-2-yl)-2,2-dimethyl-butanamide 5.2 was reacted with NBS/AIBN following general procedure B. A separation at this stage was not possible.
  • Example 5B was also obtained from this reaction (2.0 g, 61% yield).
  • Example 5D 2,2-dimethyl-N-(6-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide, was obtained as a minor product (28% yield) from the same reaction.
  • N-(4,5-dimethyl-6-(morpholinomethyl)pyridin-2-yl)-2,2-dimethyl-butanamide 5E was obtained from 5B according to general method D in 85% yield.
  • N-(5-bromo-6-(morpholinomethyl)pyridin-2-yl)-2,2-dimethylbutanamide 6 A was prepared from 6.2 according to general method B, followed by general method C in 65% overall yield.
  • Example 6B was obtained from 6A in 76% yield following general method D.
  • Example 8B was obtained from 8.4 and 2-methylcyclohexanecarbonyl chloride al following general method A in 76% yield.
  • Example 10C was prepared in a similar fashion to 10A using 2-butanone d3 and acid chloride al .
  • Examples 10D - 10L were prepared in a similar fashion to 10A using 10.7dl or 10.7dx and the appropriate acid chloride.
  • Examples 10N - 10O were prepared in a similar fashion to 10M using 10.6dl and 1- methoxypropan-2-amine or (1R,2R,4S)-bicyclo[2.2.1]heptan-2-amine respectively.
  • Examples 11C and 11D were prepared from 2B and 10C following the procedure described for example 11B.
  • Example 14B was prepared from 2A and c7 following the procedure described for example 14 A.
  • Example 14 was prepared from 14B and a4 following e procedures described for example 3A.
  • Example 14D - 14K were prepared from 2A and the appropriate acid chlorides following the procedures described for example 3A.
  • Examples 14M - 14S were prepared from 14.2a and the appropriate acids following the procedure described for example 14L.
  • Compound 14T was prepared from 14.2b and acid chloride a2 following general method A. MS analysis m/z - 335+1.
  • Examples 14U - 14AD were prepared from 14.2b and the appropriate acid chlorides or acids following the procedure described for example 14T or 14L respectively.
  • Example 14AF was prepared from 14AE following the procedures described for example 14C.
  • Example 14AG was prepared from 2A and sodium ethane thiolate and acid chloride a2 following the procedures described for example 14T.
  • a 5 mL microwave vial was charged with the t-butyl carbamate (141 mg, 1.21 mmol), xantphos (30 mg, 0.06 mmol) , cesium carbonate (441 mg, 1.35 mmol) and tris(dibenzylideneacetone)dipalladium (0) Pd 2 (dba) 3 (20 mg, 0.02 mmol) and the vial was flushed with nitrogen for ten minutes.
  • the 2-iodo-4-(morpholinomethyl)-5-propoxypyridine (16.6, 350 mg, 0.97 mmol) was dissolved in 1,4-dioxane (1.5 mL) and added as a solution.
  • the reaction was flushed with nitrogen for an additional ten minutes and then heated at 70 °C overnight.
  • the reaction was diluted with 30 mL of water and extracted with two 60 mL portions of ethyl acetate.
  • the organic phase was dried with sodium sulfate and concentrated under vacuum.

Abstract

La présente invention concerne de nouveaux composés pyridiniques, des compositions pharmaceutiques contenant les composés pyridiniques, et des procédés relatifs à leur utilisation pharmaceutique. Dans certains modes de réalisation, les composés pyridiniques sont des agonistes et/ou des ligands des récepteurs cannabinoïdes et peuvent servir, entre autres, à traiter et/ou prévenir une douleur, des troubles gastro-intestinaux, une inflammation, des maladies auto-immunes, des états ischémiques, des troubles immunitaires, une hypertension, des troubles neurologiques, et des maladies neurodégénératives. Il est possible ainsi d'assurer une protection cardiaque contre les effets ischémiques et de reperfusion, d'induire une apoptose des cellules cancéreuses, d'inhiber l'hyperalgésie mécanique associée aux lésions nerveuses, et de stimuler l'appétit.
PCT/US2007/024220 2006-11-20 2007-11-19 Composés pyridiniques et procédés relatifs à leur utilisation WO2008063625A2 (fr)

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