WO2011071996A1 - Inhibiteurs de faah - Google Patents

Inhibiteurs de faah Download PDF

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Publication number
WO2011071996A1
WO2011071996A1 PCT/US2010/059428 US2010059428W WO2011071996A1 WO 2011071996 A1 WO2011071996 A1 WO 2011071996A1 US 2010059428 W US2010059428 W US 2010059428W WO 2011071996 A1 WO2011071996 A1 WO 2011071996A1
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Prior art keywords
pain
disease
pharmaceutically acceptable
acceptable salt
ring
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PCT/US2010/059428
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English (en)
Inventor
Kevin Sprott
John Jeffrey Talley
Jane Yang
Bo Peng
Original Assignee
Ironwood Pharmaceuticals, Inc.
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Priority to US13/514,343 priority Critical patent/US20130109721A1/en
Publication of WO2011071996A1 publication Critical patent/WO2011071996A1/fr

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    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to N-benzyl pyrrole compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH).
  • Fatty Acid Amide Hydrolase Fatty Acid Amide Hydrolase
  • the disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders.
  • the endocannabinoid (eCB) system has been implicated in a variety of processes including cell signaling, memory encoding, compensatory mechanisms, and immunosuppressant and anti-inflammatory responses.
  • the eCB system comprises at least two receptors: the CB 1 cannabinoid receptor, widely distributed in the brain and present in some peripheral organs, and the CB2 receptor, found principally in the periphery and immune systems and in some regions of the brain.
  • the endogenous agonists of these receptors are the endogenous cannabinoids (eCBs), a family of lipids comprising the fatty acid Anandamide (AEA) as well as other fatty acids.
  • eCBs cannabinoids
  • AEA fatty acid Anandamide
  • Endocannabinoid-degrading enzymes including fatty acid amide hydrolase
  • FAAH inhibitors may also be useful agents for treating glaucoma.
  • ring B is selected from the group consisting of phenyl and a 5-6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
  • each J is independently selected from the group consisting of halogen, -N0 2 , -CN, Ci. 6 aliphatic, C3.6 cycloaliphatic, C
  • p is an integer selected from the group consisting of 0, 1, 2 and 3;
  • R is selected from the group consisting of halogen, -N0 2 , -CN, C ⁇ * aliphatic, phenyl, a 5-6- membered heteroaryl ring and a C 3 . 7 cycloalkyl, wherein said Ci_ 6 aliphatic, phenyl, 5-6-membered heteroaryl ring and C 3 . 7 cycloalkyl is optionally substituted by up to three instances of halogen;
  • R 5 is selected from the group consisting of hydrogen, halogen, -CN, C
  • Ci -6 aliphatic, C 3-7 cycloaliphatic ring, 5-6-membered heteroaryl ring, and phenyl is optionally substituted with up to three instances of halogen, Ci- 4 alkyl, C haloalkyl, Ci -4 alkoxy or C haloalkoxy; or
  • cycloaliphatic ring a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring
  • said heterocyclic and heteroaryl ring formed by R 4 and R 5 contain up to three heteroatoms selected from the group consisting of N, O and S, and wherein said cycloaliphatic, heterocyclic and heteroaryl ring formed by R 4 and R 5 is optionally substituted by up to 3 instances of halogen, C
  • each R is independently selected from the group consisting of Ci -6 aliphatic, C 3-7
  • each R Y is optionally substituted by up to six instances of halogen, C
  • the invention also relates to pharmaceutical compositions comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. Also within the scope of the invention are pharmaceutical compositions further comprising at least one additional therapeutic agent.
  • compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase "optionally substituted” is used interchangeably with the phrase "substituted or
  • the phrase "up to”, as used herein, refers to zero or any integer number that is equal to or less than the number following the phrase.
  • optionally substituted with "up to 3" means substituted with 0, 1, 2, or 3 substituents.
  • a specified number range of atoms includes any integer therein.
  • a group having from 1-4 atoms could have 1, 2, 3 or 4 atoms. It will be understood by one of ordinary skill in the art that when a group is characterized as substituted (as opposed to optionally substituted) with, e.g., "up to 3" substituents, it can only be substituted with 1, 2 or 3 substituents.
  • a compound such as the compounds of the invention or other compounds herein disclosed, may be present in its free form (e.g., an amorphous form or polymorphs). Under certain conditions, compounds may also form salts, and/or other multi-component crystalline forms (e.g., solvates (i.e., hydrates), and co-crystals). As used herein, the term co- form is synonymous with the term multi-component crystalline form. When one of the components in the co-form has clearly transferred a proton to the other component, the resulting co-form is referred to as a "salt".
  • solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein (or its salts or co-crystals).
  • a "hydrate” is a particular type of solvate in which the solvent is water.
  • diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the disclosure.
  • the present disclosure also embraces isotopically labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., I4 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron-emitting isotopes such as 15 0, 13 N, n C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • aliphatic or "aliphatic group”, as used herein, mean a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms and in yet other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec- butyl, terr-butyl, butenyl, propargyl, acetylene and the like.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1 ⁇ 1 carbon atoms or 1-3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms,
  • cycloaliphatic refers to a cyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In one embodiment, the term “cycloaliphatic” refers to a monocyclic C3-C12 hydrocarbon or a bicyclic C 7 -Ci 2 hydrocarbon.
  • any individual ring in a bicyclic or tricyclic ring system has 3-7 members.
  • Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
  • cyclohexenyl cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • cycloaliphatic also includes polycyclic ring systems in which the non-aromatic carbocyclic ring can be "fused” to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, as long as the radical or point of attachment is on the non-aromatic carbocyclic ring.
  • a heterocycle may be monocyclic, bicyclic or tricyclic.
  • the heterocycle has 3-18 ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur or nitrogen, and each ring in the system contains 3 to 7 ring members.
  • a heterocycle may be a monocycle having 3-7 ring members (2-6 carbon atoms and ⁇ heteroatoms) or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6 heteroatoms).
  • Examples of bicyclic heterocyclic ring systems include, but are not limited to: adamantanyl, 2-oxa- bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl.
  • heterocycle also includes polycyclic ring systems wherein the heterocyclic ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the heterocyclic ring.
  • heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3- thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1- tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 2-thiazolid
  • the term also includes polycyclic ring systems where the aryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the aryl ring.
  • aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl, and anthracenyl.
  • An optionally substituted "aralkyl” can be substituted on both the alkyl and the aryl portion.
  • an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion.
  • the same principle applies, for example, to a substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion.
  • a substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom.
  • a bicyclic 6,5 heteroaromatic system as used herein, for example, is a six-membered heteroaromatic ring fused to a second five-membered ring wherein the radical or point of attachment is on the six-membered ring.
  • Heteroaryl rings include, but are not limited to the following monocycles: 2- furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5- tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-
  • cyclo encompasses mono-, bi- and tri-cyclic ring systems including cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which has been previously defined.
  • “Fused” bicyclic ring systems comprise two rings which share two adjoining ring atoms.
  • “Bridged” bicyclic ring systems comprise two rings which share three or four adjacent ring atoms.
  • the term “bridge” refers to a bond or an atom or a chain of atoms connecting two different parts of a molecule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are referred to as "bridgeheads".
  • bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
  • ring atom refers to an atom such as C, N, O or S that is part of the ring of an aromatic group, a cycloaliphatic group or a heteroaryl ring.
  • a “substitutable ring atom” is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group.
  • substituted ring atom does not include ring nitrogen or carbon atoms which are shared when two rings are fused.
  • substituted does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to one or more moiety other than hydrogen and no hydrogens are available for substitution.
  • Heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • Exemplary rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the molecule.
  • a phenyl group is substituted with two occurrences of R 0 as in Formula Dl:
  • an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain can optionally be replaced with said other atom or group.
  • the optional replacements form a chemically stable compound.
  • Optional interruptions can occur both within the chain and/or at either end of the chain; i.e. both at the point of attachment(s) to the rest of the molecule and/or at the terminal end.
  • Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound.
  • the replacement or interruption occurs at a terminal end of the chain, the replacement atom is bound to an H on the terminal end. For example, if
  • a C3 aliphatic can be optionally replaced by -N(R S )-, -C(O)-, and -N(R $ )- to form -N(R $ )C(0)N(R s )- (a urea).
  • the term "vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
  • terminal refers to the location of a group within a substituent.
  • a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
  • Carboxyalkyl i.e., R x O(0)C-alkyl is an example of a carboxy group used terminally.
  • a group is internal when the group is present in the middle of a substituent at the end of the substituent bound to the rest of the chemical structure.
  • Alkylcarboxy e.g., alkyl-C(0)0- or alkyl-O(CO)-
  • alkylcarboxyaryl e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-
  • carboxy groups used internally are examples of carboxy groups used internally.
  • alkoxy or “alkylthio” refer to an alkyl group, as previously defined, attached to the molecule, or to another chain or ring, through an oxygen (“alkoxy,” e.g., -O-alkyl) or a sulfur (“alkylthio,” e.g., -S-alkyl) atom.
  • alkoxy e.g., -O-alkyl
  • sulfur e.g., -S-alkyl
  • C n-m alkoxyalkyl
  • C n-m alkoxyalkenyl
  • C n . m alkoxyaliphatic
  • alkoxyalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups, wherein the total number of carbons between the alky and alkoxy, alkenyl and alkoxy, aliphatic and alkoxy or alkoxy and alkoxy, as the case may be, is between the values of n and m.
  • these moieties are optionally substituted they can be substituted in either of the portions on both sides of the oxygen or sulfur.
  • an optionally substituted C 4 alkoxyalkyl could be, for instance, -CH 2 CH 2 OCH 2 (Me)CH 3 or -CH 2 (OH)0 CH 2 CH 2 CH 3 ;
  • aryloxy refers to an aryl or benzyl group attached to the molecule, or to another chain or ring, through an oxygen (“aryloxy” “benzyloxy,” e.g., -O-Ph, -OCH 2 Ph) or sulfur (“arylthio,” e.g., -S-Ph, -S- CH 2 Ph) atom.
  • aryloxyalkyl means alkyl, alkenyl or aliphatic, as the case may be, substituted with one or more aryloxy or benzyloxy groups, as the case may be.
  • the number of atoms for each aryl, aryloxy, alkyl, alkenyl or aliphatic will be indicated separately.
  • a 5-6-membered is a 5-6 membered aryl ring, attached via an oxygen atom to a C alkyl chain, which, in turn, is attached to the rest of the molecule via the terminal carbon of the C
  • an optionally substituted "aralkyl” can potentially be substituted on both the alkyl and the aryl portion. Unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies to, for example, substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom. For example, an optionally substituted 6-membered aryloxy(C3alkyl) group could be, for instance,
  • an optionally substituted 6-membered heteroaryloxy(C 4 alkyl) could, for instance, be -CH 2 CH 2 CH 2 -0-(3-F-2-pyrydyl) or -CH(CH 3 )-0-CH 2 CH 2 -(5,6- dimethyl-l,3-pyrimidine). If the alkyl chain on the "aralkyl" group is also substituted that will be specifically indicated. For instance, an optionally substituted 6-membered
  • heteroaryloxy(C 4 alkyl) that is also optionally substituted on the alkyl, would be referred to as "an optionally substituted 6-membered heteroaryloxy(C 4 alkyl), wherein said C 4 alkyl chain is optionally substituted".
  • An example of this latter group could be 5, 6-dimethyl-l,3- pyrimidine-0-CF(CH 3 )-CH(OH)CH 2 -, wherein the alkyl chain is substituted with F and with -OH.
  • haloalkyl means alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • a Ci -3 haloalkyl could be -CFHCH 2 CHF 2 and a Q -2 haloalkoxy could be -OC(Br)HCHF 2 .
  • This term includes perfluorinated alkyl groups, such as -CF 3 and -CF 2 CF 3 .
  • cyano refers to -CN or -C ⁇ N.
  • cyanoalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups.
  • . cyanoalkyl could be -C(CN) 2 CH 2 CH 3 and a C
  • -2 cyanoalkenyl could be CHC(CN)H 2 .
  • amino refers to -NH 2 .
  • aminoalkyl aminoalkenyl
  • aminoaliphatic aminoalkyl
  • aminoalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups.
  • a Ci -3 aminoalkyl could be -CH(NH 2 )CH 2 CH 2 NH 2 and a Ci. 2 aminoalkoxy could be -OCH 2 CH 2 NH 2 .
  • hydroxyl or "hydroxy” refers to -OH.
  • hydroxyalkyl means alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.
  • -3 hydroxyalkyl could be
  • -CH 2 (CH 2 OH)CH 3 and a C 4 hydroxyalkoxy could be -OCH 2 C(CH 3 )(OH)CH 3 .
  • an “aroyl” or “heteroaroyl” refers to a -C(0)-aryl or a -C(O)- heteroaryl.
  • the aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
  • An aliphatic chain can be optionally interrupted by a carbonyl group or can optionally be substituted by an oxo group, and both expressions refer to the same: e.g., -CH 2 - C(0)-CH 3 .
  • linker refers to a bifunctional chemical moiety attaching a compound to a solid support or soluble support.
  • a linker can be a C
  • An alternative way to define the same -CH 2 -NH-CH 2 -C(0)-CH 2 - and - CH 2 -NH-C(0)-CH 2 - groups is as a C 3 alkyl chain optionally interrupted by up to two -C(O)- or -NH- moieties.
  • Cyclic groups can also form linkers: e.g., a 1,6-cyclohexanediyl R
  • protecting group refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound.
  • a protecting group has one or more, or preferably all, of the following characteristics: a) reacts selectively in good yield to give a protected substrate that is stable to the reactions occurring at one or more of the other reactive sites; and b) is selectively removable in good yield by reagents that do not attack the regenerated functional group.
  • Exemplary protecting groups are detailed in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • nitrogen protecting group refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound.
  • Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • amide coupling agent or "amide coupling reagent” means a compound that reacts with the hydroxyl moiety of a carboxy moiety thereby rendering it susceptible to nucleophilic attack.
  • exemplary amide coupling agents include DIC
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • ring B is selected from the group consisting of phenyl and a 5-6-membered monocyclic
  • heteroaryl ring wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
  • n is an integer selected from the group consisting of 0, 1, 2 and 3;
  • each J is independently selected from the group consisting of halogen, -N0 2 , -CN, C
  • each J C1 is independently selected from the group consisting of halogen, -N0 2 , -CN, C
  • p is an integer selected from the group consisting of 0, 1, 2 and 3;
  • R 2 is selected from the group consisting of halogen, -N0 2 , -CN, C ⁇ aliphatic, phenyl, a 5-6- membered heteroaryl ring and a C 3-7 cycloalkyl, wherein said Ci -6 aliphatic, phenyl, 5-6-membered heteroaryl ring and C 3-7 cycloalkyl is optionally substituted by up to three instances of halogen;
  • R 4 is selected from the group consisting of hydrogen, halogen, -CN, C )-6 aliphatic, a C 3- cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -OR Y and -SR Y ;
  • R 5 is selected from the group consisting of hydrogen, halogen, -CN, Ci -6 aliphatic, a C 3-7 cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -OR Y and -SR Y ;
  • Ci -6 aliphatic, C 3 . 7 cycloaliphatic ring, 5-6-membered heteroaryl ring, and phenyl is optionally substituted with up to three instances of halogen, Ci -4 alkyl, CM alkoxy or Ci -4 haloalkoxy; or
  • cycloaliphatic ring a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring
  • said heterocyclic and heteroaryl ring formed by R 4 and R 5 contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said cycloaliphatic, heterocyclic and heteroaryl rings formed by R 4 and R 5 is optionally substituted by up to 3 instances of halogen, C alkyl, Q -4 haloalkyl, Q -4 alkoxy or CM haloalkoxy; and
  • each R is independently selected from the group consisting of C
  • each R is optionally substituted by up to six instances of halogen, C alkyl, Ci -4 haloalkyl, C alkoxy or CM haloalkoxy;
  • ring B is an optionally substituted ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, imidazole, pyrazole, furan, thiophene, triazole, tetrazole, thiazole, oxathiazole and oxazole.
  • ring B is an optionally substituted pyridine or an optionally substituted phenyl. In still further embodiments, ring B is an optionally substituted pyridine. In other embodiments, ring B is an optionally substituted phenyl. [00169] In some embodiments, n is selected from the group consisting of 0 and 1.
  • the invention relates to a compound of Formula III or a pharmaceutically acceptable salt thereof,
  • a method for the treatment or prevention of autoimmune disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of the pharmaceutical composition.
  • the autoimmune disorder is selected from the group consisting of alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune
  • vascular dementia including multi-infarct dementia and dementia associated with intracranial space-occupying lesions, infections and related conditions such as HIV infection
  • Guillain-Barre syndrome myasthenia gravis
  • stroke and various forms of seizures (such as nodding spasms)
  • blood diseases such as acquired hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenia
  • tumor diseases such as acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, extensive metastases and other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration); endocrine diseases such as endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de
  • endocrine diseases such as endocrine opthalmopathy, endocrine orbito
  • a method for the treatment or prevention of pruritus comprises administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above.
  • the pruritus is dermal pruritus, neuropathic pruritus, neurogenic pruritus or psychogenic pruritus.
  • a method is provided for the treatment or prevention of substance abuse-related syndromes, disorders, diseases or withdrawal symptoms comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above.
  • the method of treating substance abuse-related syndromes, disorders,, diseases or withdrawal symptoms are chosen from the group consisting of drug abuse and drug withdrawal, wherein the abused substances include alcohol, amphetamines,
  • amphetamitte-1 ike substances caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or
  • dementia dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders
  • manic-depressive psychoses bipolar disorders
  • extreme psychotic states such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired
  • post-traumatic stress disorder panic disorder
  • obsessive compulsive disorder psychiatric tremors such as dyskinesias, dystonia, and spasticity
  • attention disorders such as ADHD (attention deficit hyperactivity disorders), autism, anxiety states, generalized anxiety, agoraphobia, as well as those behavioral states characterized by social withdrawal
  • a method for the treatment or prevention of appetite-related disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a
  • the methods above are provided for the treatment of a human patient.
  • the patient is a companion animal, exotic animal or a farm animal such as a dog, cat, mouse, rat, hamster, gerbil, guinea pig, rabbit, horse, pig or cow.
  • a method for inhibiting FAAH in a biological sample comprising contacting said biological sample with a composition discussed herein.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound of Formula I.
  • the salts of the compounds of Formula I will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of Formula I or of their pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions.
  • a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as 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 tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine
  • Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
  • benzenesulfonate p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.
  • the term "pharmaceutically acceptable solvate,” is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds described herein.
  • the term “hydrate” means a compound described herein or a salt thereof that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • compositions to treat or prevent the disorders identified herein.
  • pro-drug encompasses a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound described herein.
  • pro-drugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • pro-drugs include derivatives of compounds described herein that comprise -NO, -N0 2 , -ONO, or -ON0 2 moieties.
  • Pro-drugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.).
  • compositions and methods of administration are provided.
  • a typical formulation is prepared by mixing a compound of Formula I, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of Formula I is being formulated.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (e.g., GRAS-Generally Regarded as Safe) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc., and mixtures thereof.
  • the formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of Formula I or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of Formula I, a
  • compositions such as a complex with a cyclodextrin derivative or other known complexation agent
  • a compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution.
  • Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
  • the compound of Formula I or a pharmaceutically acceptable salt, solvate, co- crystal or pro-drug thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • Pharmaceutical formulations of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof may be prepared for various routes and types of administration. Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration.
  • the amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration.
  • the initial pharmaceutically effective amount of the inhibitor administered will be in the range of about 0.01-100 mg/kg per dose, namely about 0.1 to 20 mg kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutically or pharmaceutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms.
  • compositions of Formula I will be formulated, dosed, and administered in a fashion, i.e., the amounts, concentrations, schedules, courses, vehicles, and route(s) of administration, consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular human or other mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.
  • Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride;
  • hexamethonium chloride benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;
  • proteins such as serum albumin, gelatin, or immunoglobulins
  • hydrophilic polymers such as polyvinylpyrrolidone
  • amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine
  • chelating agents such as EDTA
  • sugars such as sucrose, mannitol, trehalose or sorbitol
  • salt-forming counter-ions such as sodium
  • metal complexes e.g., Zn-protein complexes
  • non-ionic surfactants such as TWEENTM, PLURONICSTM or polyethylene glycol (PEG).
  • Remington's The Science and Practice of Pharmacy, 21 st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's”).
  • Controlled drug delivery systems supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated.
  • the primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time.
  • controlled release is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release”, “delayed release”, “modified release” or “sustained release”.
  • sustained-release preparations are the most common applications of controlled release. Suitable examples of sustained-release preparations include
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.
  • immediate-release preparations may also be prepared.
  • the objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • the compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
  • implantable medical devices such as beads, or co-formulated with a polymer or other molecule
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • the formulations include those suitable for the administration routes detailed herein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • administer in reference to a compound, composition or formulation of the invention mean introducing the compound into the system of the animal in need of treatment.
  • administration and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.
  • compositions described herein may be administered systemically or locally, e.g.: orally (e.g., using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like), by inhalation (e.g., with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g., using ear drops), topically (e.g., using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), ophthalmically (e.g., with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g., using enemas or suppositories), nasally, buccally, vaginally (e.g., using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), via an implanted reservoir or the like, or parenterally depending on the severity and
  • parenteral includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time-delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • a water soluble taste-masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.
  • compositions may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs.
  • Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • aqueous suspensions When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.
  • Oily suspensions may be formulated by suspending the compound of Formula I in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha- tocopherol.
  • Aqueous suspensions of compounds of Formula I contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose,
  • croscarmellose povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a naturally occurring phosphatide e.g., lecithin
  • a condensation product of an alkylene oxide with a fatty acid e.g., polyoxyethylene stearate
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • the injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • the injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Other formulations suitable for vaginal administration may be presented as pes
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
  • Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated in an ointment such as petrolatum.
  • an ointment such as petrolatum
  • the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w.
  • the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil- in-water cream base.
  • the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • the oily phase of emulsions prepared using compounds of Formula I may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of compounds of Formula I include Tween -60, Span -80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • Formulations suitable for intrapulmonary or nasal administration have a mean particle size, for example, in the range of 0.1 to 500 microns (including particles with a mean particle size in a range between 0.1 and 500 microns in micron increments such as 0.5, 1, 30, 35 microns, etc.), and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • the pharmaceutical composition may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited herein above, or an appropriate fraction thereof of the active ingredient.
  • a compound of Formula I or a pharmaceutically acceptable salt, co-crystal, solvate or pro-drug thereof may be formulated in a veterinary composition comprising a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit).
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • the subject is a "human”.
  • biological sample includes, without limitation, in vivo or ex vivo cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous humor or other body fluids or extracts thereof.
  • Neuralgia is also involved in disorders such as sciatica and brachial plexopathy with neuropathia. Neuralgias that do not involve the trigeminal nerve are occipital neuralgia and glossopharyngeal neuralgia. Neuropathic pain also includes referred pain.
  • alopecia areata also known as systemic sclerosis (SS)
  • amyloses amyotrophic lateral sclerosis
  • ankylosing spondylarthritis ankylosing spondylitis
  • neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt-Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Age-Associated Memory Impairment.
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt-Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins;
  • Compounds and compositions of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.
  • the terms “in combination” or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents).
  • the use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound described herein
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to a subject.
  • a second therapy e.g., a prophylactic or therapeutic agent such as an anticancer agent
  • Additional therapeutic agents that can be combined with compounds described herein include, without limitation:
  • fenamic acid derivatives meclofenamic acid, mefe-namic acid, and tolfenamic acid
  • oxicams isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican
  • salicylates acetyl salicylic acid, sulfasalazine
  • pyrazolones azolones
  • sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabalin, tectin, NW-1029, CGX-1002;
  • N-type calcium channel blockers such as Ziconotide, NMED-160, SPI-860; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram;
  • VR1 agonists and antagonists such as NGX-4010, WL-1002, ALGRX-4975, WL-10001, AMG-517;
  • anti-inflammatory and/or immunosuppressive agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus,
  • ADD/ADHD agents e.g., RitalinTM (methylphenidate hydrochloride), StratteraTM (atomoxetine hydrochloride), ConcertaTM (methylphenidate hydrochloride) and AdderallTM (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate);
  • agents to treat alcoholism such as opioid antagonists (e.g., naltrexone (also known under the tradename ReVia M) and nalmefene), disulfiram (also known under the tradename AntabuseTM), and acamprosate (also known under the tradename CampralTM));
  • opioid antagonists e.g., naltrexone (also known under the tradename ReVia M) and nalmefene
  • disulfiram also known under the tradename AntabuseTM
  • acamprosate also known under the tradename CampralTM
  • agents used to treat glaucoma e.g., direct- acting Miotics (cholinergic agonists), indirect acting Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors (e.g., Acetazolamide, Methazolamide, Brinzolamide, Dorzolamide), Selective adrenergic agonists (e.g., Apraclonidine, Brimonidine), Beta-blockers (Timolol, Betaxolol, Carteolol, Levobetaxolol, Levobunolol, Metipranolol), Osmotic diuretics (e.g., Glycerin, Mannitol);
  • anti-emetic agents e.g., 5HT3 antagonists such as ondansetron, granisetron, metoclopramide;
  • antipsychotic medications e.g., ziprasidone (GeodonTM), risperidone
  • PDE4 inhibitors such as theophylline, drotaverine hydrochloride, cilomilast, roflumilast, denbufylline, rolipram, tetomilast, enprofylline, arofylline, cipamfylline, tofimilast, filaminast, piclamilast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2- phenylethyl]pyridine, mesopram, N-(3,5-dichloro-4-pyridinyl)-2-[ l-(4-fluorobenzyl)-5- hydroxy-lH- -indol-3-yl]-2-oxoacetamide, CDC-801 (Celgene), CC-1088 (Celgene), Lirimilast, ONO-6126 (Ono), CC-10004 (Ce
  • corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
  • histamine HI receptor antagonists such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine;
  • histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine;
  • leukotriene antagonists and 5-lipoxygenase inhibitors such as zafirlukast, montelukast, pranlukast and zileuton;
  • P2X3 receptor antagonists such as A-317491 , ISIS- 13920, AZD-9056;
  • NGF agonists and antagonists such as RI-724, RI-1024, AMG-819, AMG- 403, PPH 207;
  • NMDA antagonist such as NER-MD-1 1, CNS-5161, EAA-090, AZ-756, CNP-3381; potassium channel modulators such as CL-888, ICA-69673, retigabine;
  • GABA modulators such as lacosamide and propofol
  • anti-cancer agents such as tyrosine kinase inhibitors imatinib (Gleevec Glivec) and gefitinib (Iressa);
  • anti hyperlipidemia drugs such as statins, ezetimibe, niacin and bile acid sequestrants;
  • appetite suppressing agents e.g., sibutramine, taranabant, rimobamant;
  • anti-diabetic medications such as insulin, tolbutamide (Orinase),
  • GI agents e.g., laxatives (e.g., Lubiprostone (Amitiza), Fybogel®, Regulan®, Normacol® and the like), a gastrointestinal agent used for the treatment of idiopathic chronic constipation and constipation-predominant IBS, GI motility stimulants (e.g., domperidone, metoclopramide, mosapride, itopride), antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine); anti-diarrheal medicines such loperamide (Imodium) and bismuth subsalicylate (as found in Pepto Bismol and Kaopectate), GCC (Guanylate Cyclase C) agonists (e.g., Linaclotide), 5HT4 agonists (e.g., Tegasarod), 5HT3 antagonists (e.g.,
  • the compounds of Formula I may be prepared according to the schemes and examples depicted and described below. Unless otherwise specified, the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds or prepared using well-known synthetic methods.
  • a compound of Formula 3 can be synthesized by the alkylation of a compound of Formula 2a by reaction with the appropriate protected (trapped) enolate compound of Formula 2b, wherein X is a leaving group and PG is an oxygen protecting group (Scheme la). Deprotection of the alcohol functionality (e.g., under acidic conditions), then releases the enolate, which tautomerizes in situ to the carbonyl compound of Formula 3.
  • a compound of Formula 5 can be prepared from a compound of Formula 4 via the magnesium-mediated radical reduction of the ⁇ , ⁇ -unsaturation in the presence of trimethylsilyl chloride, followed by nucleophilic attack of the resulting ⁇ -carbanion onto an electrophile such as an acid chloride or anhydride. (Scheme lb).
  • a compound of Formula 7 can be synthesized by the condensation reaction of a primary amine of general formula R 6 NH 2 , and a 1 ,4-dicarbonyl moiety of Formula 3 (Scheme 2).
  • a compound of Formula 8 can then be obtained from the intermediate of Formula 7 by electrophilic aromatic substitution at position three of the pyrrole ring using oxalyl chloride. This creates an intermediate a-keto acid chloride, which is subsequently aminated by a primary amine of general formula R 6 NH 2 to produce a pyrrole of Formula 8.
  • a compound of Formula 10 can be synthesized by the condensation of a
  • the pyrrole nitrogen of a compound of Formula 12 can be alkylated to form the corresponding compound of Formula 13 using an appropriate alkylating agent. As in
  • LC/MS was run on a Waters Acquity system using a Polar CI 8 column, and 5 to 60% acetonitrile/water over 5 min.
  • the ionization method for the MS was electrospray.
  • Microwave reactions were run on a Personal Chemistry Optimizer, at 0-240 °C, a power of 0-300 W and a pressure of 0-21 bar.
  • Solvent A 0.1% Trifluoroacetic acid in water
  • Solvent B 0.1% Trifluoroacetic acid in acetonitrile
  • I- 10 was prepared according to Schemes la and 2. ⁇ NMR (CDCl 3 /400 MHz) ⁇ 8.81 (s, IH), 7.82 (d, IH), 7.50 (d, IH), 7.30 (d, 2H), 7.14 (d, IH), 6.88 (d, 2H), 5.01 (s, 2H), 2.78 (t, 2H), 2.57-2.54 (m, 2H), 2.36 (s, 3H), 1.68-1.60 (m, 2H), 1.42-1.34 (m, 6H); MS m/z: 468 (M + 1).
  • resuspension buffer 50 mM Tris-HCl buffer, pH 7.4, containing 1 mM EDTA and 3 mM MgCl 2 .
  • a Bradford Protein assay was performed to determine protein
  • the protein was aliquotted into screw cap Cryo tubes each containing ⁇ 400iL, flash frozen in liquid nitrogen and stored at -80 °C until used for the assay. A similar protocol was used to obtain brain membrane homogenates from mice.
  • mice housed at the animal care facility of Ironwood Pharmaceuticals were anesthetized by isoflurane anesthesia and rapidly decapitated using a small decapitator (Harvard Apparatus part # PY8 SS-0012, Holliston, Massachusetts).
  • Whole brain tissue from these mice was collected (approximately 9.4 g total) and placed on aluminum foil sitting on dry ice to flash freeze the tissue. Tissue was thawed and used to prepare microsomes as described above for rat brain homogenates.
  • RBM rat brain membrane
  • Assay of FAAH activity in rat brain membrane (RBM) homogenates RBM homogenates (7 ⁇ g protein in 20 pL final volume of 10 mM Tris pH 6.5) were mixed with 180 ⁇ _, of a mixture of the following: 2.0 ⁇ unlabelled anandamide, 0.03 ⁇ ' radio labeled anandamide [ethanolamine 1- H] (40-60 Cis/mmol, product number ART- 626, American Radiolabeled Chemicals, St.
  • Bovine Serum Albumin fatty acid-free BSA, electrophoresis grade, Sigma, St. Louis, MO
  • 10 mM Tris-HCl pH 6.5
  • 1 mM EDTA in the presence and absence of test compounds (vehicle was DMSO at a final concentration of 1%) and incubated for 10 minutes at 37 °C. Samples were placed on ice to terminate the reactions.
  • Radioactivity (corresponding to FAAH-catalyzed breakdown of 3 H-anandamide) found in aliquots (0.2 mL) of the aqueous phase was determined by liquid scintillation counting with quench correction. IC50 values were determined as described by Jonsson et al. (2001 Br. J Pharmacol. 133: 1263). Alternatively, reactions were purified using a modification of the solid-phase extraction method described by Wilson et al (2003 Anal. Biochem. 318 : 270). This method was modified as follows: after reactions were incubated at 37 °C for 10 minutes and chilled on ice, the reaction mixtures were acidified by adding 10 ⁇ . of sodium phosphate solution [0.5M (pH 2.0)].
  • the known FAAH inhibitors 3'-(aminocarbonyl)biphenyl-3-yl cyclohexylcarbamate (URB597), [ l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]acetic acid (indomethacin) and 5- benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (Ketorolac) were used as controls in these assays.
  • Example 6 Whole cell anandamide hydrolysis assay:
  • cDNA expression clone for human FAAH-1 (in pcDNA3 vector) (Genbank Accession U82535; obtained from Benjamin Cravatt, Scripps Research Institute, La Jolla, California) was linearized by digestion with BglH (New England Biolabs) and transfected by calcium phosphate into human HeLa cells (ATCC catalog #CCL-2).
  • the HeLa cell line was selected as a host because it does not express FAAH or exhibit FAAH activity such that all subsequent activity can be attributed to the transfected gene.
  • Clone 5c5 (50,000 cells in 150 ⁇ ) was seeded into 96- well plates and incubated overnight (5% C0 2 , 37 °C). Media was carefully replaced with 180
  • the charcoal glass fiber filter plates were pre-washed with methanol by centrifugation 650 x g for 10 min). Next, 80 ⁇ . of water was added to the wells of the pre-washed 96-well charcoal filter plate. Then, 90 ⁇ , of the acidified reaction mixture was added to the water in the wells of the charcoal plate. The samples were centrifuged as above. The substrate remained bound to the charcoal, whereas the [ H]-ethanolamine product formed flowed through and was transferred to the microplates containing scintillation cocktail and quantified in a micro-plate scintillation counter (Perkin-Elmer Microbeta).
  • the LC/MS MS method used a Waters 2777 sample manager, 1525 binary pump, and Quattro micro mass spectrometer. The separation was performed on a Waters Xterra MS C8, 5 ⁇ ⁇ ⁇ , 2.1 x 20 mm analytical LC column with a Thermo Electron Javelin Basic 8, 2 x 10 mm guard column at a flow rate of 0.30 mL/min and a 25 ⁇ _ injection volume. A binary linear gradient of mobile phase A (10 mM ammonium acetate in water (pH 9.5)) and mobile phase B (80:20 acetonitrile:methanol) was used from 2.0 to 2.2 minutes from 25% to 90% B, with a total run time of 6.0 minutes per sample injection.
  • mobile phase A (10 mM ammonium acetate in water (pH 9.5)
  • mobile phase B 80:20 acetonitrile:methanol

Abstract

La présente invention concerne des composés de N-benzylpyrrole de formule (I) utiles en tant qu'inhibiteurs de l'enzyme amide d'acide gras hydrolase (FAAH). La présente invention concerne en outre des compositions pharmaceutiquement acceptables comprenant les composés de l'invention et des procédés d'utilisation des compositions dans le traitement ou la prévention de différents troubles.
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US8637577B2 (en) 2009-01-22 2014-01-28 Absorption Pharmaceuticals, LLC Desensitizing drug product
WO2011123719A3 (fr) * 2010-03-31 2011-12-15 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes
WO2012088431A1 (fr) * 2010-12-23 2012-06-28 Ironwood Pharmaceuticals, Inc. Inhibiteurs de faah
WO2013079223A1 (fr) * 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolocarboxamides en tant que modulateurs de l'activité d'un récepteur orphelin gamma (rorϒ, nr1f3) apparenté au récepteur nucléaire orphelin rar et destinés au traitement de maladies inflammatoires chroniques et auto-immunes
US9815851B2 (en) 2011-12-02 2017-11-14 Phenex Pharmaceuticals Ag Pyrrolo carboxamides as modulators of orphan nuclear receptor RAR-related orphan receptor-gamma (RORγ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases
WO2013180698A1 (fr) * 2012-05-30 2013-12-05 Alcon Research, Ltd. Utilisation d'antagonistes de la faah pour le traitement de la kératoconjonctivite sèche et de la douleur oculaire
US8865723B2 (en) 2012-10-25 2014-10-21 Tetra Discovery Partners Llc Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury

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