WO2003101381A2 - Composes 1,2 diamido cycloalkyle bloqueurs des canaux sodiques - Google Patents

Composes 1,2 diamido cycloalkyle bloqueurs des canaux sodiques Download PDF

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WO2003101381A2
WO2003101381A2 PCT/US2003/016335 US0316335W WO03101381A2 WO 2003101381 A2 WO2003101381 A2 WO 2003101381A2 US 0316335 W US0316335 W US 0316335W WO 03101381 A2 WO03101381 A2 WO 03101381A2
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βalkyl
phenyl
6alkyl
pharmaceutically acceptable
optionally substituted
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PCT/US2003/016335
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WO2003101381A3 (fr
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Michael H. Fisher
Chunshi Li
Jun Liang
Peter T. Meinke
Dong Ok
William H. Parsons
Pengcheng Patrick Shao
Sriram Tyagarajan
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Merck & Co., Inc.
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Priority to AU2003237224A priority Critical patent/AU2003237224A1/en
Publication of WO2003101381A2 publication Critical patent/WO2003101381A2/fr
Publication of WO2003101381A3 publication Critical patent/WO2003101381A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/50—Spiro compounds

Definitions

  • the present invention is directed to cycloalkyl compounds substituted at the 1 and 2 positions with amido moieties.
  • this invention is directed to 1,2 diamido cycloalkyl compounds that are sodium channel blockers useful for the treatment of chronic and neuropathic pain.
  • the compounds of the present invention are also useful for the treatment of other conditions, including, for example, central nervous system (CNS) disorder such as epilepsy, manic depression and bipolar disease.
  • CNS central nervous system
  • Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function.
  • Sodium channels play a special role by mediating the rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels.
  • Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties.
  • All voltage-gated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating [Catterall, W. A. Structure and function of voltage-gated sodium and calcium channels. Current Opinion in Neurobiology 1, 5-13 (1991)].
  • sodium channels are closed. Following membrane depolarization, sodium channels open rapidly and then inactivate. Channels only conduct currents in the open state and, once inactivated, have to return to the resting state, favored by membrane hyperpolarization, before they can reopen.
  • Different sodium channel subtypes vary in the voltage range over which they activate and inactivate as well as in their activation and inactivation kinetics.
  • Sodium channels are the target of a diverse array of pharmacological agents, including neurotoxins, antiarrhythmics, anticonvulsants and local anesthetics [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)].
  • Several regions in the sodium channel secondary structure are involved in interactions with these blockers and most are highly conserved. Indeed, most sodium channel blockers known to date interact with similar potency with all channel subtypes. Nevertheless, it has been possible to produce sodium channel blockers with therapeutic selectivity and a sufficient therapeutic window for the treatment of epilepsy (e.g. lamotrigine, phenytoin and carbamazepine) and certain cardiac arrhythmias (e.g. lignocaine, tocainide and mexiletine).
  • epilepsy e.g. lamotrigine, phenytoin and carbamazepine
  • neuropathic pain include, but are not limited to postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.
  • Lidoderm R lidocaine applied in the form of a dermal patch
  • PHN PHN
  • Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clinical Journal of Pain, 2000. 16(3): p. 205- 208.].
  • sodium channel blockers In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggest that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with MS [Clare, J. J. et. al. And Anger, T. et. al.].
  • U.S. Patent Nos. 5,714,489 and 5,852,017 describe 2,3(lH,4H)quinoxalinedione compounds suitable for treatment of neurodegenerative disorders.
  • International Patent Publications WO92/13838 and WO95/04732 describe oligopeptide antirepreviral agents.
  • International Patent Publication WO94/11339 describes substituted cyclopentane chelating agents.
  • International Patent Publication WO94/11339 describes cyclic amino acid derivatives that are inhibitors of matrix metalloproteases and TNF-alpha.
  • U.S. Patent No. 5,278,311 describes nonionic radiographic contrast agents. L.J. Goldsworthy et al., J.Chem.
  • the present invention is directed to 1,2 diamido cycloalkyl compounds which are sodium channel blockers useful for the treatment of chronic and neuropathic pain and disorders of the CNS including, but not limited to treatment of the symptoms of epilepsy, manic depression and bipolar disease.
  • This invention also provides a pharmaceutical composition that includes an effective amount of the novel
  • 1,2 diamido cycloalkyl compounds 1,2 diamido cycloalkyl compounds, and a pharmaceutically acceptable carrier.
  • This invention further provides a method of treatment of acute pain, chronic pain, visceral pain, inflammatory pain, or neuropathic pain and disorders of the CNS including, but not limited to treatment of the symptoms of epilepsy, manic depression and bipolar disease by the administration of an effective amount of the novel 1,2 diamido cycloalkyl compounds.
  • X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -C ⁇ _6alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C()-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _6alkyl, -OC ⁇ _6alkyl,
  • E is -Ci_6alkyl-;
  • Rl is hydrogen or-C ⁇ _(5alkyl;
  • R2 is -Co-6alkyl-phenyl, -C ⁇ _6alkyl-thienyl, -C ⁇ _6alkyl-thiazolyl,
  • -Ci -6alkyl-pyridyl -C ⁇ _6alkyl-furanyl, -C ⁇ _6alkyl-naphthyl, -C ⁇ _6alkyl-indolyl, -C i _6alkyl-indanyl, -C i -6alkyl-methylenedioxyphenyl, -C i-6alkyl- tetrahydroquinolinyl, -C 1 _6alkyl-benzimidazolyl, -C 1 _6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent hal
  • Rl and R are connected, optionally substituted with 1-3 independent -Ci- ⁇ alkyl or halogen substituents;
  • R3 is -Co-6alkyl
  • A is -C n H2n-; B is -C m H2m-; n and m each is 0, 1, 2, or 3; wherein the sum of n and m is 1, 2, or 3;
  • R6 to R27 are each independently -C ⁇ -6 a lkyl; and any alkyl is optionally substituted with 1-6 independent halogen or
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci -6alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci_6alkyl, -OCi-6alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R10, or -NRllCONRl2Rl3 ; E is -C ⁇ _6alkyl-; Rl is hydrogen or
  • R3 is -Co-6alkyl
  • A is -C n H2n-;
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, optionally substituted with 1-4 independent -Ci- ⁇ alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C ⁇ -6 a lkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _6alkyl, -OC ⁇ _6alkyl, -SO 2 R6, - SO 2 NR7R8, -NR9SO 2 R10, or - RllCOMRl2Rl3
  • Rl is hydrogen or -Ci-6alkyl
  • R2 is -C ⁇ -6alkyl-phenyl, -Ci- ⁇ alkyl-thienyl, -Ci . ⁇ alkyl-thiazolyl, -Ci-6alkyl-pyridyl, -Ci-6alkyl-furanyl, -Ci_6alkyl-napthyl, -Ci _6alkyl-indolyl, -C ⁇ _6alkyl-indanyl, -C i - ⁇ alkyl-methylenedioxyphenyl, -C 1 _6alkyl- tetrahydroquinolinyl, -C ⁇ _6alkyl-benzimidazolyl, -Ci -6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxy
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl optionally substituted with 1-4 independent -C ⁇ _6alkyl, halogen, -NO 2 , or -N(C ⁇ -6alkyl)(C ⁇ -6alkyl) substituents;
  • E is -C ⁇ _6alkyl-
  • Rl is hydrogen or-Ci - ⁇ alkyl
  • R2 is -C ⁇ -6alkyl-phenyl, -Ci-6alkyl-thienyl, -C ⁇ _6alkyl-thiazolyl, -Ci-6alkyl-pyridyl, -C ⁇ _6alkyl-furanyl, -Ci _6alkyl-napthyl, -C ⁇ _6alkyl-indolyl, -C ⁇ _6alkyl-indanyl, -C ⁇ _6alkyl-methylenedioxyphenyl, -Ci - ⁇ alkyl- tetrahydroquinolinyl, -Ci-6alkyl-benzimidazolyl, -C ⁇ _6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl substituted with a phenyl substituent, and further optionally substituted with 1-4 independent -C ⁇ _6alkyl, halogen, -NO 2 , -N(C ⁇ - 6alkyl)(C()-6alkyl) substituents, wherein the phenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci -galkyl, -OC ⁇ - ⁇ alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R10, or -NRllCONRl2Rl3 ;
  • E is -Ci_6alkyl-;
  • Rl is hydrogen or-C ⁇ _6alkyl;
  • R2 is -C ⁇ -6alkyl-phenyl, -C ⁇ _6alkyl-thienyl, -Ci-6alkyl-thiazolyl,
  • R3 is -Co-6alkyl; A is -C n H2n-;
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl substituted with a pyridyl, pyrimidyl, or benzothiophenyl substituent, and further optionally substituted with 1-4 independent -Ci_6alkyl, halogen, -NO 2 , or -N(C()-6alkyl)(C ⁇ -6alkyl) substituents, wherein the pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci-6alkyl, -OCi -6alkyl, -SO 2 R6, -SO 2 NR7R8 ;
  • E is -C ⁇ _6alkyl-;
  • Rl is hydrogen or-Ci_6alkyl;
  • R2 is -Co-6alkyl-phenyl, -Ci- ⁇ alkyl-thienyl, -C ⁇ _6alkyl-thiazolyl,
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is thienyl, optionally substituted with 1-4 independent -Ci_6alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _6alkyl, -OC ⁇ _6alkyl, -SO 2 R6, -
  • E is -C ⁇ _6alkyl-;
  • Rl is hydrogen or -Ci - ⁇ alkyl;
  • R2 is -Ci_6alkyl-thienyl, -C ⁇ _6alkyl-thiazolyl, -C ⁇ _6alkyl-pyridyl, -Ci-6alkyl-furanyl, -Ci _6alkyl-na ⁇ thyl, -C ⁇ _6alkyl-indolyl, -C ⁇ _6alkyl-indanyl, -C l -6alkyl-methylenedioxyphenyl, -C i _6alkyl-tetrahydroquinolinyl, -C i -6alkyl- benzimidazolyl, -Ci -6alkyl-benzothiophenyl, wherein the thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl
  • Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which R and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -C ⁇ -4alkyl-phenyl, -C ⁇ - 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -C ⁇ _6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci - ⁇ alkyl or halogen substituents; R3 is -Co-6alkyl;
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is pyridyl optionally substituted with 1-4 independent -C ⁇ _6alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C()-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _6alkyl, -OC ⁇ _6alkyl, -SO 2 R6,
  • E is -Ci_6alkyl-;
  • Rl is hydrogen or -C ⁇ _6alkyl;
  • R2 is -C ⁇ -6alkyl-phenyl, -C ⁇ _6alkyl-thienyl, -Ci_6alkyl-thiazolyl, -Ci_6alkyl-pyridyl, -Ci_6alkyl-furanyl, -Ci-6alkyl-napthyl, -C ⁇ _6alkyl-indolyl, -C i - ⁇ alkyl-indanyl, -C i - ⁇ alkyl-methylenedioxyphenyl, -C ⁇ _6alkyl- tetrahydroquinolinyl, -C i - ⁇ alkyl-benzimidazolyl, -C 1. ⁇ alkyl
  • R3 is -Co-6alkyl; A is -C n H2n-;
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -C ⁇ _6alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci- ⁇ alkyl, -OC ⁇ _6alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R1 , or -NRl 1CONR12R13 ; E is -C ⁇ _6alkyl-; Rl is hydrogen or
  • R2 is -C ⁇ -6alkyl-phenyl, -Ci-6alkyl-thienyl, -C ⁇ _6alkyl-thiazolyl, -C ⁇ _6alkyl-pyridyl, -C ⁇ _6alkyl-furanyl, -Ci-6alkyl-napthyl, -Ci-6alkyl-indolyl, -Ci_6alkyl-indanyl, -Ci- ⁇ alkyl-methylenedioxyphenyl, -Ci_6alkyl- tetrahydroquinolinyl, -C ⁇ _6alkyl-benzimidazolyl, -C ⁇ _6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, te
  • R3 is -Co-6alkyl; A is -C n H2n-;
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci- ⁇ alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _6alkyl, -OCi- ⁇ alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R10, or-
  • R3 is -Co-6alkyl
  • A is -C n H2n-;
  • B is -C m H2m-;
  • n and m each is 0, 1 , or 2; wherein the sum of n and m is 2;
  • R4 and R5 together form -CH 2 CH 2 -;
  • R6 to R27 are each independently -C ⁇ -6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -C ⁇ _ ⁇ alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _ ⁇ alkyl, -OCi- ⁇ alkyl,
  • E is -Ci_6alkyl-
  • Rl is hydrogen or -Ci . ⁇ alkyl
  • R2 is -C ⁇ -6alkyl-phenyl, -C ⁇ _ ⁇ alkyl-thienyl, -Ci - ⁇ alkyl-thiazolyl, -Ci- ⁇ alkyl-pyridyl, -Ci- ⁇ alkyl-furanyl, -C ⁇ _ ⁇ alkyl-napthyl, -Ci- ⁇ alkyl-indolyl, -C i - ⁇ alkyl-indanyl, -C i . ⁇ alkyl-methylenedioxyphenyl, -C 1 - ⁇ alkyl- tetrahydroquinolinyl, -Ci - ⁇ alkyl-benzimidazolyl, -Ci- ⁇ alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl,
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci- ⁇ alkyl, halogen, -NO 2 , -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci - ⁇ alkyl, -OC ⁇ - ⁇ alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R1°, or
  • R2 is -C ⁇ - ⁇ alkyl-phenyl, -Cj . - ⁇ alkyl-thienyl, -Ci - ⁇ alkyl-thiazolyl, -Ci- ⁇ alkyl-pyridyl, -Ci- ⁇ alkyl-furanyl, -Ci- ⁇ alkyl-napthyl, -Ci_ ⁇ alkyl-indolyl, -Ci - ⁇ alkyl-indanyl, -Ci- ⁇ alkyl-methylenedioxyphenyl, -Ci- ⁇ alkyl- tetrahydroquinolinyl, -Ci - ⁇ alkyl-benzimidazolyl, -C ⁇ _ ⁇ alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl,
  • R3 is -Co-6alkyl
  • A is -C n H2n-;
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, optionally substituted with 1-4 independent -Ci- ⁇ alkyl, halogen, -N0 2 , -N(C ⁇ - ⁇ alkyl)(C ⁇ - ⁇ alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci- ⁇ alkyl, -OCi- ⁇ alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R10, or -NRHCONRl2Rl3 ;
  • R2 is -C ⁇ - ⁇ alkyl-phenyl, -Ci - ⁇ alkyl-thienyl, -Ci - ⁇ alkyl-thiazolyl, -Ci - ⁇ alkyl-pyridyl, -Ci - ⁇ alkyl-furanyl, -Ci - ⁇ alkyl-napthyl, -C ⁇ _ ⁇ alkyl-indolyl, -Ci - ⁇ alkyl-indanyl, -Ci - ⁇ alkyl-methylenedioxyphenyl, -Ci - ⁇ alkyl- tetrahydroquinolinyl, -C - ⁇ alkyl-benzimidazolyl, -Ci- ⁇ alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl,
  • R3 is -Co-6alkyl; A is -C n H2n-;
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl substituted with a phenyl substituent, further optionally substituted with 1-4 independent -Ci - ⁇ alkyl, halogen, -N0 2 , or -N(C ⁇ - ⁇ alkyl)(C ⁇ - ⁇ alkyl) substituent, wherein the phenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci - ⁇ alkyl, -OCi- ⁇ alkyl, -SO 2 R6, -S0 2 NR7R8, -NR9S0 2 R10, or -NRllCONRl2Rl3 ;
  • E is -Ci - ⁇ alkyl-;
  • Rl is hydrogen or -Ci - ⁇ alkyl;
  • R2 is -C ⁇ - ⁇ alkyl-phenyl, -Ci - ⁇ alkyl-thienyl, -C ⁇ _ ⁇ alkyl-thiazolyl, -Ci- ⁇ alkyl-pyridyl, -C ⁇ _ ⁇ alkyl-furanyl, -Ci- ⁇ alkyl-napthyl, -Ci - ⁇ alkyl-indolyl, -Ci - ⁇ alkyl-indanyl, -Ci - ⁇ alkyl-methylenedi oxyphenyl, -Cj .
  • Rl and R2 are connected, optionally substituted with 1-3 independent -Ci- ⁇ alkyl or halogen substituents;
  • R3 is -Co- ⁇ alkyl
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci - ⁇ alkyl, halogen, -NO 2 , -N(C ⁇ - ⁇ alkyl)(C ⁇ - ⁇ alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci - ⁇ alkyl, -OC ⁇ _ ⁇ alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R10,
  • E is -C ⁇ _ ⁇ alkyl-
  • Rl is hydrogen or -Ci - ⁇ alkyl
  • R2 is -C ⁇ - ⁇ alkyl-phenyl, -Ci- ⁇ alkyl-thienyl, -Ci - ⁇ alkyl-thiazolyl, -Ci- ⁇ alkyl-pyridyl, -Ci- ⁇ alkyl-furanyl, -Ci- ⁇ alkyl-napthyl, -Ci . ⁇ alkyl-indolyl, -Ci - ⁇ alkyl-indanyl, -Ci - ⁇ alkyl-methylenedioxyphenyl, -Ci- ⁇ alkyl- tetrahydroquinolinyl, -Ci_ ⁇ alkyl-benzimidazolyl, -Ci- ⁇ alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedi
  • R3 is -Co- ⁇ alkyl
  • A is -C n H2n-;
  • B is -C m H2m-;
  • n and m each is 0, or 1 ; wherein the sum of n and m is 1 ;
  • R6 to R27 are each independently -C ⁇ -6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl, optionally substituted with 1-4 independent -C ⁇ _ ⁇ alkyl, halogen, -NO 2 , -N(C ⁇ - ⁇ alkyl)(C ⁇ -6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _ ⁇ alkyl, -OC ⁇ - ⁇ alkyl, -SO R6, -SO 2 NR7R8, -NR9SO 2 R10, or -NRHCONR12R13 ; E is -C ⁇ _ ⁇ alkyl-;
  • Rl is hydrogen or -Ci - ⁇ alkyl
  • R2 is -C ⁇ - ⁇ alkyl-phenyl, -Ci - ⁇ alkyl-thienyl, -Ci - ⁇ alkyl-thiazolyl, -Ci- ⁇ alkyl-pyridyl, -C ⁇ _ ⁇ alkyl-furanyl, -Ci. ⁇ alkyl-napthyl, -C ⁇ _ ⁇ alkyl-indolyl, -Ci- ⁇ alkyl-indanyl, -Ci- ⁇ alkyl-methylenedioxyphenyl, -Ci. ⁇ alkyl- tetrahydroquinolinyl, -C 1 - ⁇ alkyl-benzimidazolyl, -C i_ ⁇ alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylened
  • R3 is -Co- ⁇ alkyl
  • A is -C n H2n-; B is -C m H2m-; n and m each is 0, or 1 ; wherein the sum of n and m is 1 ;
  • R6 to R27 are each independently -C ⁇ -6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -C ⁇ _4alkyl.
  • the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • X is phenyl substituted with a phenyl substituent, further optionally substituted with 1-4 independent -Ci - ⁇ alkyl, halogen, -NO 2 , or -N(C ⁇ - ⁇ alkyl)(C ⁇ - ⁇ alkyl) substituent, wherein the phenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -C ⁇ _ ⁇ alkyl, -OCi- ⁇ alkyl, -SO 2 R6, -SO 2 NR7R8, -NR9SO 2 R10, or -NRHCONRl2Rl3;
  • E is -C ⁇ _ ⁇ alkyl-;
  • Rl is hydrogen or -C ⁇ _ ⁇ alkyl;
  • R2 is -C ⁇ - ⁇ alkyl-phenyl, -Ci - ⁇ alkyl-thienyl, -C ⁇ _ ⁇ alkyl-thiazolyl, -Ci- ⁇ alkyl-pyridyl, -Ci- ⁇ alkyl-furanyl, -Ci- ⁇ alkyl-napthyl, -Ci_ ⁇ alkyl-indolyl, -Ci - ⁇ alkyl-indanyl, -Ci_ ⁇ alkyl-methylenedioxyphenyl, -Ci. ⁇ alkyl- tetrahydroquinolinyl, -Ci- ⁇ alkyl-benzimidazolyl, -Ci- ⁇ alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphen
  • alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like.
  • alkenyl alkynyl and other like terms include carbon chains containing at least one unsaturated C-C bond.
  • cycloalkyl means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems.
  • fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles.
  • Cycloalkyl includes such fused ring systems as spirofused ring systems.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- tetrahydronaphalene and the like.
  • cycloalkenyl means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes.
  • Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
  • aryl means an aromatic substituent which is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic. The preferred aryl substituents are phenyl and naphthyl groups.
  • cycloalkyloxy unless specifically stated otherwise includes a cycloalkyl group connected by a short Ci _2alkyl length to the oxy connecting atom.
  • C ⁇ - ⁇ alkyl includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms.
  • An alkyl with no carbon atoms is a hydrogen atom substituent when the alkyl is a terminal group and is a direct bond when the alkyl is a bridging group.
  • hetero unless specifically stated otherwise includes one or more O, S, or N atoms.
  • heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms.
  • the hetero atoms replace ring carbon atoms.
  • a heterocycloCsalkyl is a five-member ring containing from 4 to no carbon atoms.
  • heteroaryls include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl.
  • heterocycloalkyls examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
  • heteroC ⁇ -4alkyl means a heteroalkyl containing 3, 2, 1, or no carbon atoms. However, at least one heteroatom must be present. Thus, as an example, a heteroC ⁇ -4alkyl having no carbon atoms but one N atom would be a -NH- if a bridging group and a -NH-2 if a terminal group. Analogous bridging or terminal groups are clear for an O or S heteroatom.
  • amine unless specifically stated otherwise includes primary, secondary and tertiary amines substituted with C ⁇ -6alkyl.
  • carbonyl unless specifically stated otherwise includes a C ⁇ - ⁇ alkyl substituent group when the carbonyl is terminal.
  • halogen includes fluorine, chlorine, bromine and iodine atoms.
  • optionally substituted is intended to include both substituted and unsubstituted.
  • optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
  • optionally substituted multiple moieties such as, for example, alkylaryl are intended to mean that the aryl and the aryl groups are optionally substituted. If only one of the multiple moieties is optionally substituted then it will be specifically recited such as "an alkylaryl, the aryl optionally substituted with halogen or hydroxyl.”
  • Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above chemical Formulas are shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of the chemical Formulas and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine,
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • additional therapeutic ingredients include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID”), ix) selective serotonin reuptake inhibitors ("SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontin (gabapent
  • compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compositions are useful in the treatment of chronic, visceral, inflammatory and neuropathic pain syndromes.
  • compositions of the present invention have clinical uses in the treatment of epilepsy and partial and generalized tonic seizures. They are also useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis.
  • compositions of the present invention have clinical uses in the treatment of bipolar disease.
  • compositions of the present invention have clinical uses in the treatment of tachy-arrhythmias.
  • compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
  • compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
  • Dosage levels from about O.Olmg/kg to about 140mg/kg of body weight per day are useful in the treatment of inflammatory and neuropathic pain, or alternatively about 0.5mg to about 7g per patient per day.
  • inflammatory pain may be effectively treated by the administration of from about O.Olmg to 75mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • Neuropathic pain may be effectively treated by the administration of from about O.Olmg to 125mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5g per patient per day. Further, it is understood that the compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about lmg to about lOOOmg of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg.
  • the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound represented by Formula I, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy.
  • such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical media may be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about O.lmg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about O.lmg to about 500mg of the active ingredient.
  • a tablet, cachet, or capsule conveniently contains O.lmg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, or 500mg of the active ingredient taken one or two tablets, cachets, or capsules, once, twice, or three times daily.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • the compounds and pharmaceutical compositions of this invention have been found to block sodium channels. Accordingly, another aspect of the invention is the treatment in mammals of, for example, acute pain, chronic pain, visceral pain, inflammatory pain, or neuropathic pain, as well as tinnitus and noise induced hearing loss - maladies that are amenable to amelioration through blockage of neuronal sodium channels - by the administration of an effective amount of the compounds of this invention.
  • mammals includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited examples that are human afflictions.
  • the compound of this invention can be utilized in combination with other therapeutic compounds.
  • the sodium channel blocking compound of this invention can be advantageously used in combination with i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID”), ix) selective serotonin reuptake inhibitors ("SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontin (gabapentin).
  • NSAID non-steroidal anti-inflammatory drugs
  • SSNRI selective serot
  • the identification of inhibitors of the sodium channel can be accomplished using Aurora Biosciences technology, and is based on the ability of sodium channels to cause cell depolarization when sodium ions permeate through agonist-modified channels. In the absence of inhibitors, exposure of agonist-modified channel to sodium ions will cause cell depolarization. Sodium channel inhibitors will prevent cell depolarization caused by sodium ion movement through agonist-modified sodium channel. Changes in membrane potential can be determined with voltage- sensitive fluorescence resonance energy transfer (FRET) dye pairs that use two components, a donor coumarin (CC 2 DMPE) and an acceptor oxanol (DiSBAC 2 (3)). Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential.
  • FRET voltage- sensitive fluorescence resonance energy transfer
  • HEK-PN1 PN1 sodium channel
  • Electrophysiological Assays Cell preparation: A HEK-293 cell line stably expressing the PN1 sodium channel subtype was established in-house. The cells were cultured in MEM growth media (Gibco) with 0.5mg/mL G418, 50 units/mL Pen/Strep and lmL heat- inactivated fetal bovine serum at 37°C and 10% CO 2 . For electrophysiological recordings, cells were plated on 35mm dishes coated with poly-D-lysine. Whole-cell recordings: HEK-293 cells stably expressing the PN1 sodium channel subtype were examined by whole cell voltage clamp (Hamill et. al.
  • the bath solution consisted of 40 mM NaCl, 120 mM NMDG CI, 1 mM KC1, 2.7 mM CaCl 2 , 0.5 mM MgCl 2 , 10 mM NMDG HEPES, pH 7.4, and the internal (pipet) solution contained 110 mM Cs-methanesulf ⁇ nate, 5 mM NaCl, 20mM CsCl, lOmM CsF, 10 mM BAPTA (tetra Cs salt), 10 mM Cs HEPES, pH 7.4.
  • compounds were prepared in a 1:4:5 vehicle of ethanol, PEG400 and saline (EPEGS) and injected subcutaneously into the dorsal surface of the left hind paw 5min prior to formalin.
  • EPEGS ethanol, PEG400 and saline
  • compounds were prepared in either a EPEGS vehicle or a Tween80 (10%)/sterile water (90%) vehicle and were injected i.v. (via the lateral tail vein 15min after formalin) or p.o. (60min before formalin).
  • the number of flinches was counted continuously for 60min using an automated nociception analyzer (UCSD Anesthesiology ReseaiOh, San Diego, CA). Statistical significance was determined by comparing the total flinches detected in the early (0-10min) and late (ll-60min) phase with an unpaired t-test.
  • CFA Mycobacterium tuberculosis, Sigma; suspended in an oil/saline (1:1) emulsion; 0.5mg Mycobacterium/ml) in the plantar surface of the left hindpaw.
  • This dose of CFA produced significant hind paw swelling but the animals exhibited normal grooming behavior and weight gain over the course of the experiment.
  • Mechanical hyperalgesia was assessed 3 days after tissue injury using a Randall-Selitto test (S. G. Khasar, F. J. Miao, J. D. Levine, Neuroscience 69, 685-90. (1995). Repeated Measures ANOVA, followed by Dunnett's Post Hoc test.
  • the von Frey filaments (over a range of intensities from 0.4 to 28.8g) were applied to the mid- plantar surface for 8s or until a withdrawal response occurred. Following a positive response, an incrementally weaker stimulus was tested. If there was no response to a stimulus, then an incrementally stronger stimulus was presented. After the initial threshold crossing, this procedure was repeated for four stimulus presentations per animal per test session. Mechanical sensitivity was assessed 1 and 2 hour post oral administration of the test compound.
  • the compounds described in this invention displayed sodium channel blocking activity of ⁇ 50 ⁇ M in the in vitro assays. It is preferred that the compounds display sodium channel blocking activity of ⁇ 5 ⁇ M in the in vitro assays. It is more advantageous that the compounds display sodium channel blocking activity of ⁇ l ⁇ M in the in vitro assays. It is even more advantageous that the compounds display sodium channel blocking activity of ⁇ 0.5 ⁇ M in the in vitro assays. It is still more preferred that the compounds display sodium channel blocking activity of ⁇ 0.1 ⁇ M in the in vitro assays.
  • the compositions of this invention are useful in the treatment of chronic, visceral, inflammatory and neuropathic pain syndromes. They are also useful for the treatment of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, HIV and HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and related neuralgias. Further, they are useful as local anesthetics. Compounds of this invention are useful in the treatment of irritable bowel syndrome and related disorders, as well as Crohns disease, tinnitus and noise induced hearing loss.
  • compositions of the present invention have clinical uses in the treatment of epilepsy and partial and generalized tonic seizures.
  • compositions of the present invention have clinical uses in the treatment of bipolar disease.
  • compositions of the present invention have clinical uses in the treatment of tachy-arrhythmias. Further, it is understood that compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
  • Polymorphism may result in isolation of materials with different melting points in some preparations.
  • the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data.
  • yields are for illustration only.
  • NMR data is in the form of delta ( ⁇ ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300MHz, 400MHz or 500MHz using the indicated solvent.
  • TMS tetramethylsilane
  • Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.
  • the compounds of the present invention are prepared by sequential amide formation.
  • a cyclic dicarboxylic acid 1 (in this case, cyclopentane-l,2-dicarboxylic acid) is activated by reaction with CDI (carbonyldiimidazole) in an aprotic solvent such as THF (tetrahydrofuran) or CH 2 C1 (dichloromethane) or a combination of the two.
  • CDI carbonyldiimidazole
  • aprotic solvent such as THF (tetrahydrofuran) or CH 2 C1 (dichloromethane) or a combination of the two.
  • THF tetrahydrofuran
  • CH 2 C1 diichloromethane
  • An effective method is by reacting compounds 1 or 2 with pyr-BOP (benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate) or the BOP-Reagent (benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate) in a solvent such as DMF (dimethylformamide) followed by the appropriate amine in the presence of a base such as diisopropylethylamine.
  • pyr-BOP benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate
  • BOP-Reagent benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate
  • dicarboxylic acid compound 4 wherein one of the acids is protected as a t-butyl ester, for instance, is converted to amide 5 as described in SCHEME 1.
  • Compound 5 is then converted to its free acid by reaction with TFA (trifluoroacetic acid) or HCl in solvents such as THF.
  • TFA trifluoroacetic acid
  • HCl in solvents such as THF.
  • the free acid is then converted to compound 3 as described in SCHEME 1.
  • Bromobenzyl amide derivative 6 is prepared as described in SCHEME 1.
  • One of the more useful is the Suzuki reaction where aryltriflates or aryl bromides such as compound 6 are coupled with arylboronic acids (ArB(OH) 2 in the presence of palladium catalysts to give derivatives 7 (see March J. "Advanced Organic Chemistry", 5th ed., John Wiley & Sons, New York, pp. 868 (2001).
  • boronic acid 8 is reacted under Suzuki-type conditions with aryltriflates or aryl bromides in the presence of palladium catalysts to give derivatives 7.
  • Unsymmetrical biarylmethylamine intermediates can be prepared by an approach exemplified in SCHEME 5.
  • 4-bromotoluene 9 is converted to the corresponding boronic acid by reaction with t-butyl lithium at low temperatures.
  • the lithium salt of compound 9 is then reacted with a boronate ester such as tri- isopropyl borate which upon workup with an acid such as HCl gives compound 10.
  • Compound 10 can be converted to biaryl 11 according to procedures described in SCHEME 3.
  • the aryltoluene intermediate 11 can be converted to arylbenzylamine intermediate 14 by a three step sequence using methods that are commonly practiced.
  • N-substituted aryl and biarylmethylamine intermediates 16 can be prepared by an approach exemplified in SCHEME 6. Reaction of compound 12 with the appropriate substituted amine R 3 NH 2 in a solvent such as THF gives 16.
  • Cyclopentane diacid intermediates containing an exo-methylene group at position 4 can be prepared by a 3+2 cycloaddition reaction of a trimethylenemethane - Pd[0] complex with olefins as described in SCHEME 7. Reaction of dimethyl fumarate 17 with (2-(acetoxymethyl)-3-allyl)trimethylsilane (Aldrich) 17 and a Pd [0] reagent such as [Ph 3 P] 4 Pd in THF gives almost exclusively trans diester 18. (see Trost, B. M. J. Am. Chem. Soc, 105, 2315-2325 (1983). If dimethyl maleate is used in this reaction, the cis diester is produced as a 1:1 mix with the trans diester. Compound 18 can be converted to the corresponding diacid by standard hydrolysis methodology and elaborated as described in previous reaction schemes.
  • Compound 19 prepared as described in SCHEME 7 can be converted to methyl derivative 20 by hydrogenation in a solvent such as EtOH and a catalyst such as 10% Pd/C typically at a pressure of hydrogen of 40 psi.
  • Compound 19 is also converted to cyclopropane derivative 21 by variations of the Simmons - Smith reaction (see March J. "Advanced Organic Chemistry", 5th ed., John Wiley & Sons, New York, pp. 1088 (2001).
  • a solvent such as CH 2 C1 2
  • diethyl zinc and trifluoroacetic acid followed by di-iodomethane resulting in compound 21.
  • Compound 21 can be converted to compound 22 by hydrogenaolysis in a solvent such as acetic acid and a catalyst such as platinum oxide.
  • Compound 19 prepared as described in SCHEME 7 can be converted to ketone 26 by a variety of oxidative conditions including ozonolysis.
  • a mild sequence involves reaction of compound 19 with catalytic amounts of osmium tetroxide (OsO 4 ) and sodium metaperiodate (NaI0 ) typically in a solvent mixture of t-butanol, H 2 O and EtOAc.
  • OsO 4 osmium tetroxide
  • NaI0 sodium metaperiodate
  • Ketone 26 is reduced to alcohol 27 with sodium borohydride in CH 2 C1 and methanol.
  • Various chiral reducing agents can be used to achieve chiral reductions of ketone 26.
  • Alcohol 26 can then be converted to a variety of compounds (ethers, carbamates, esters etc. using commonly practiced procedures.
  • Step A 4-(2-aminosulfonylphenyl)benzylamine: Step A-l: 4-methylphenylboronic acid To a stirred solution of 84g (0.49mol) of 4-bromotoluene in 800mL of diethyl ether at -60°C, was carefully added a solution of 462mL of a 1.7M solution of t-butyl lithium in pentane (0.78mol) and the reaction mixture was stirred at -60°C for lh. To this reaction mixture at -60°C was added a solution of 97g (0.52mol) of tri- isopropyl borate in lOOmL of diethyl ether and the mixture was stirred at -60°C for lh.
  • Step A-2 T-butyl-2-bromophenylsulfonamide
  • Step A-3 4-(2-T-butylaminosulfonylphenyl)toluene.
  • Step A-4 4-(2-T-butylaminosulfonylphenyl)benzyl bromide
  • Step A-7 4-(2-aminosulfonylphenyl)benzylamine
  • Step B trans-l-(RS)-[4-(2-Aminosulfonylphenyl)1-benzylaminocarbonyl-2-
  • Step C trans- 1 -(RS)-[4-(2-Aminosulfonylphenyl)l -benzylaminocarbonyl-2-
  • Step A-l r4-(Thien-2-yl)-thien-2-vnmethanol
  • Step B Trans-l-(SR)-[4-(thien-2-yl -thien-2-vnmethylamino- carbonylcyclopentane-2-(RS)-carboxylic acid
  • O.lg (0.63mmol) of trans-l,2-cyclopentane carboxylic acid
  • a solution of 0.107g (0.63mmol) of carbonyldiimidazole (CDI) in 2mL of THF and 2mL of CH 2 C1 2 was added to a stirred solution of O.lg (0.63mmol) of trans-l,2-cyclopentane carboxylic acid in 2mL of THF at rt.
  • CDI carbonyldiimidazole
  • Step A 4-(2-aminophenyl)benzylamine: The title compound was prepared as described in Example 1, Step A with the exception that 2-nitrobromobenzene is used in Step A-3 of Example 1. The nitro group is subsequently hydrogenated to give the title compound. Step B.
  • Step A-l 4-(2-methylmercaptophenyl)toluene
  • the title compound was prepared according to procedures described in
  • Step A-2 4-(2-methylsulfonylphenyl toluene
  • Step A-3 4-(2-methylsulfonylphenyl)benzylamine
  • Step A-l 4-Trifluoromethylphenylboronic acid To a solution of lmL (7.1mmol) of 4-trifluoromethylphenyl bromide (JRD Fluoro Chemical LTD) in 20mL of THF at -78°C in a nitrogen atmosphere was added 7.1mL (8.5mmol) of nBuLi (1.6M in THF). After stirring for30 min, 2.5mL (10.65mmol) of triisopropyl borate (Aldrich) was slowly added and the reaction mixture was slowly warmed to rt.
  • the reaction mixture was concentrated and dissolved in lOmL of a mixture of acetic acid and H2O (2: 1). After stirring for 3h, the reaction mixture was concentrated and dissolved in lOOmL of ethyl acetate. The solution was washed with sat'd NaCl solution, and the organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound.
  • Step A-2 1 -t-Butoxycarbonyl-4-trifluoromethylsulfonyloxy- 1,2,3,6- tetrahydropyridine
  • Step A-3 1 -t-Butoxycarbonyl-4-(4-trifluoromethylphenyl)- 1 ,2,3 ,6- tetrahydropyridine
  • Step A-4 4-(4-Trifluoromethylphenyl)- 1 ,2,3 ,6-tetrahydropyridine
  • Step A-l N-methyl-4-(2-T-butylaminosulfonylphenyDbenzylamine
  • a solution of lg (2.6mmol) of 4-(2-t-butylaminosulfonylphenyl)benzyl bromide [Example 1] in 25mL of THF was saturated with methylamine gas and the reaction mixture was stirred at rt for 3h.
  • the reaction mixture was partitioned between EtOAc and Na C0 3 solution.
  • the aqueous fraction was extracted twice with EtOAc and the combined organic fractions were dried (K 2 C0 3 ), filtered and the filtrate was concentrated.
  • Step A-2 N-methyl-4-(2-aminosulfonylphenyDbenzylamine:
  • Step A-l 2-trimethylstannylthiophene
  • a stirred solution of 200mL (0.2 mol) of a IM solution of 2- thienyllithium in THF (Aldrich) in 400mL of THF at -40°C was added 40g (0.2mol) of trimethyltin chloride over lOmin.
  • the reaction was mixture was allowed to warm to rt and was stirred for 2h.
  • the reaction was quenched with a sat'd solution of NH- 4 CI and the reaction mixture was concentrated. The residue was partitioned between H 2 0 and ether.
  • Step A-2 4-[(thien-2-yl)-thien-2-yl1carboxaldehvde
  • Step A-3 N-methyl-[4-(thien-2-vD-thien-2-yllmethylamine
  • Step A-l 4-(2-T-butylaminosulfonylphenyDacetophenone
  • Step A-2 4-(2-T-butylaminosulfonylphenvDacetophenone hydroxamate
  • Step A-3 l-[4-(2-T-butylaminosulfonylphenyDphenylleth-l-ylamine
  • Step A-4 1 - [4-(2-aminosulf onylphenvDphenyll eth- 1 -ylamine
  • the title compound was obtained from l-[4-(2-t-butylaminosulfonyl phenyl)phenyl] eth- 1 -ylamine according to procedures described in Example 1, Step A-7.
  • the product was purified by chromatography (silica, 1: 20, (2M NH 3 in CH 3 OH: CH 2 C1 2 ).
  • Step A-2 l-[4-(thien-2-vD-thien-2-ylleth-l-ylamine
  • Example 86 The individual enantiomers of Example 86 (dl mixture) were separated by HPLC (ChiralCel OJ column, eluent: 20% ethanol in heptane); enantiomer A (fast-moving isomer); enantiomer B (slow-moving isomer) Mass Spectrum (ESI) of each isomer m/e 590.1 M+l.
  • Step A-l trans-l-(RS)-[4-(2-trifluoromethylpenyDl-benzylaminocarbonyl-2- (SR)-carboxycyclopentane
  • Step A-2 trans- 1 -(RS )- [4-(2-trifluoromethylphenvD1 -benzylaminocarbonyl-2- (SRV[4-(thien-2-yD-thien-2-yllmethylaminocarbonyl cyclopentane
  • the title compound was prepared from 1 trans-l-(RS)-[4-(2- trifluoromethylpenyl)]-benzylaminocarbonyl-2-(SR)-carboxycyclopentane and [4-
  • Examples 104 - 120 were prepared according to procedures described in Example 103.
  • Examples 121-124 were prepared according to procedures that were previously described, with the exception that trans- 1,2- cyclohexane dicarboxylic acid (Aldrich) was used.
  • Examples 146 - 153 were prepared from trans-N- methyl- 1 -(RS)-(4-bromo)-benzylaminocarbonyl-2-(SR)-(4- trifluoromethoxy)benzylaminocarbonyl cyclopentane according to procedures described in Example 104.
  • Examples 154 - 159 were prepared from trans-N- methyl-l-(RS)-(6-bromo)-pyrid-3-ylmethylaminocarbonyl-2-(SR)-(4- trifluoromethoxy) benzylaminocarbonylcyclopentane or trans-N-methyl-l-(RS)-(5- bromo)-pyrid-2-ylmethylaminocarbonyl-2-(SR)-(4- trifluoromethoxy)benzylaminocarbonylcyclopentane according to procedures described in Example 104.
  • the title compound was prepared from trans-N-methyl-l-(RS)-(4- bromo)-benzylaminocarbonyl-2-(SR)-(4-trifluoromethoxy)benzylaminocarbonyl cyclopentane according to procedures described in Example 104.
  • Tetrazol-5- ylphenylboronic acid was prepared as described by Larsen, Robert D., J. Org. Chem. (1994), 59, 6391.
  • the title compound was prepared from trans-l-(RS)-N-methyl-l-[4-(2- aminosulfonyl phenyl)]benzylaminocarbonyl-2-(SR)-(4- trifluoromethyl)benzylaminocarbonyl-4-methylenylcyclopentane (Example 161) by hydrogenation at 40psi in an ethanol solution using 10% Pd/C as a catalyst.
  • Step A trans-Diethyl-4-cyclopropyl-l ,2-cvclopentane dicarboxylate
  • 1,2-cyclopentane dicarboxylate and O.lg of Pt0 2 in 8mL of EtOH and 2mL of HOAc was hydrogenated for 1 week at 50psi.
  • the reaction mixture was filtered and the filtrate was concentrated.
  • the residue was purified by chromatography (silica, 15% EtOAc: hexanes) to give the title compound.
  • Step C trans- 1 -(RS)-N-methyl- 1 - r4-(2-aminosulfonylphenvDl benzylaminocarbonyl -2-(SR)-(4-trifluoromethvD benzylaminocarbonyl-4,4-dimethylcyclopentane
  • the title compound was prepared from trans-diethyl-4,4-dimethyl- 1,2- cyclopentane dicarboxylate according to procedures previously described.
  • Mass Spectrum (ESI) m/e 617 M+l .
  • Step C trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenvDl benzylaminocarbonyl -2-(SR)-(4-trifluoromethvD benzylaminocarbonyl-4-benzyloxycyclopentane
  • the title compound was prepared from trans-dimethyl-4-benzyloxy- 1,2-cyclopentane dicarboxylate according to procedures previously described.
  • Mass Spectrum (ESI) m/e 695 M+l.
  • Step A trans-Diethyl-4-(2,2,2-trifluoroethoxy)- 1 ,2-cvclopentane dicarboxylate
  • Step B trans- 1 -(RS)-N-methyl- 1 -r4-(2-aminosulf onylphenv l benzylaminocarbonyl -2-(SR)-(4-trifluoromethyD benzylaminocarbonyl-4-(2,2,2-trifluoroethoxy)cyclopentane
  • the title compound was prepared from trans-diethyl-4-(2,2,2- trifluoroethoxy)- 1,2-cyclopentane dicarboxylate according to procedures previously described.
  • Mass Spectrum (ESI) m/e 687 M+l.

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  • Organic Chemistry (AREA)
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  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés 1,2 Diamido cycloalkyle qui sont des bloqueurs des canaux sodiques; des compositions pharmaceutiques comprenant une quantité efficace de composés aryle-liaison-aryle thiazolidine-dione et aryle-liaison-aryle oxazolodine-dione et un excipient pharmaceutiquement acceptable; et une méthode permettant de traiter la douleur aiguë, la douleur chronique, la douleur viscérale, la douleur inflammatoire, ou la douleur neuropathique, ainsi que le syndrome du côlon irritable, la maladie de Crohn, l'épilepsie, les crises toniques partielles et généralisées, la sclérose en plaques, les maladies bipolaires, et les tachyarythmies par administration des composés aryle-liaison-aryle thiazolidine-dione et aryle-liaison-aryle oxazolodine-dione seuls ou en combinaison avec un ou plusieurs composés thérapeutiquement actifs.
PCT/US2003/016335 2002-05-29 2003-05-23 Composes 1,2 diamido cycloalkyle bloqueurs des canaux sodiques WO2003101381A2 (fr)

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WO2009156889A1 (fr) * 2008-06-25 2009-12-30 Pfizer Inc. Composés diaryle et leurs utilisations
US7795275B2 (en) 2004-12-24 2010-09-14 Uniquest Pty Limited Method of treatment or prophylaxis
US8551950B2 (en) 2006-03-20 2013-10-08 Spinifex Pharmaceuticals Pty Ltd Method of treatment or prophylaxis of inflammatory pain
US8609630B2 (en) 2005-09-07 2013-12-17 Bebaas, Inc. Vitamin B12 compositions

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CR20220316A (es) * 2019-12-06 2022-10-07 Vertex Pharma Tetrahidrofuranos sustituidos como moduladores de canales de sodio

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US6469036B1 (en) * 1999-01-27 2002-10-22 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors

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US5114953A (en) * 1990-11-21 1992-05-19 University Of Florida Treatment for tissue ulceration
US5541344A (en) * 1994-06-30 1996-07-30 G. D. Searle & Co. Intermediates useful in a process for the preparation of azanoradamantane benzamides
US5639746A (en) * 1994-12-29 1997-06-17 The Procter & Gamble Company Hydroxamic acid-containing inhibitors of matrix metalloproteases
US5820881A (en) * 1995-04-28 1998-10-13 Emisphere Technologies, Inc. Microspheres of diamide-dicarboxylic acids
US6469036B1 (en) * 1999-01-27 2002-10-22 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors

Cited By (8)

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Publication number Priority date Publication date Assignee Title
US7795275B2 (en) 2004-12-24 2010-09-14 Uniquest Pty Limited Method of treatment or prophylaxis
US8404686B2 (en) 2004-12-24 2013-03-26 Spinifex Pharmaceuticals Pty Ltd Method of treatment or prophylaxis
US8492382B2 (en) 2004-12-24 2013-07-23 Spinifex Pharmaceuticals Pty Ltd Method of treatment or prophylaxis
US8722675B2 (en) 2004-12-24 2014-05-13 Spinifex Pharmaceuticals Pty Ltd Method of treatment or prophylaxis
US8609630B2 (en) 2005-09-07 2013-12-17 Bebaas, Inc. Vitamin B12 compositions
US8551950B2 (en) 2006-03-20 2013-10-08 Spinifex Pharmaceuticals Pty Ltd Method of treatment or prophylaxis of inflammatory pain
US9227968B2 (en) 2006-03-20 2016-01-05 Novartis Ag Method of treatment or prophylaxis of inflammatory pain
WO2009156889A1 (fr) * 2008-06-25 2009-12-30 Pfizer Inc. Composés diaryle et leurs utilisations

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