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Definitions

• the present invention relates to novel heterocyclic compounds which contain a heterocylic ring bearing at least one substituent attached by a linker containing an acetylenic group, a vinylic group or an azo group.
• the present invention relates to therapeutic methods of use of heterocyclic compounds for the treatment and prevention of various disease conditions.
• Unsaturated heterocylic compounds find a wide variety of uses.
• compounds of this class find uses as modulators of physiological processes that are mediated by ligand-activated receptors.
• Receptors that are activated by ligands are located throughout the nervous, cardiac, renal, digestive and bronchial systems, among others. Therefore, in the nervous system, for example, heterocyclic compounds are capable of functioning as agonists or antagonists of receptors for neurotransmitters, neurohormones and neuromodulators.
• Ligand-activated receptors have been identified in a wide variety of species, including humans, other mammals and vertebrates as well as in invertebrate species. Therefore, compounds of this class are also able to modulate receptor-mediated processes throughout phylogeny and find uses in a wide variety of applications, e.g., as pharmaceuticals, insecticides and fungicides.
• Receptors activated by excitatory amino acids such as the amino acid L-glutamic acid (glutamate) are a major excitatory neurotransmitter receptor class in the mammalian central nervous system.
• excitatory amino acids such as the amino acid L-glutamic acid (glutamate)
• glutamatergic systems are involved in a broad array of neuronal processes, including fast excitatory synaptic transmission, regulation of neurotransmitter release, long-term potentiation, long-term depression, learning and memory, developmental synaptic plasticity, hypoxic-ischemic damage and neuronal cell death, epileptiform seizures, visual processing, as well as the pathogenesis of several neurodegenerative disorders.
• Glutamate has been observed to mediate its effects through receptors that have been categorized into two main groups: ionotropic and metabotropic.
• Metabotropic glutamate receptors are divided into three groups based on amino acid sequence homology, transduction mechanism and pharmacological properties, namely Group I, Group II and Group III.
• Each Group of receptors contains one or more types of receptors.
• Group I includes metabotropic glutamate receptors 1 and 5 (mGluRl and mGluR5)
• Group II includes metabotropic glutamate receptors 2 and 3 (mGluR2 and mGluR3)
• Group III includes metabotropic glutamate receptors 4, 6, 7 and 8 (mGluR4, mGluR6, mGluR7 and mGluR8).
• mGluRl include metabotropic glutamate receptors 1 and 5 (mGluRl and mGluR5)
• Group II includes metabotropic glutamate receptors 2 and 3 (mGluR2 and mGluR3)
• Group III includes metabo
• mGluRl is expressed in the cerebellum, olfactory bulb, hippocampus, lateral septum, thalamus, globus pallidus, entopeduncular nucleus, ventral pallidum and substantia nigra (Petralia et al, (1997) J. Chem. Neuroanat., 13:77-93; Shigemoto et al, (1992) J. Comp. Neurol, 322:121-135).
• mGluR5 is weakly expressed in the cerebellum, while higher levels of expression are found in the striatum and cortex (Romano et al, (1995) J. Comp. Neurol, 355:455-469). In the hippocampus, mGluR5 appears widely distributed and is diffusely expressed.
• Metabotropic glutamate receptors are typically characterized by seven putative transmembrane domains, preceded by a large putative extracellular amino-terminal domain and followed by a large putative intracelluar carboxy-terminal domain.
• the receptors couple to G-proteins and activate certain second messengers depending on the receptor group.
• Group I mGluRs activate phospholipase C.
• Activation of the receptors results in the hydrolysis of membrane phosphatidylinositol (4,5)-bisphosphate to diacylglycerol, which activates protein kinase C, and inositol trisphosphate, which in turn activates the inositol trisphosphate receptor to promote the release of intracellular calcium.
• Ionotropic glutamate receptors are generally divided into two classes: the N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Both classes of receptors are linked to integral cation channels and share some amino acid sequence homology.
• NMDA N-methyl-D-aspartate
• NMDA N-methyl-D-aspartate
• Both classes of receptors are linked to integral cation channels and share some amino acid sequence homology.
• GluRl-4 are termed AMPA ( ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid) receptors because AMPA preferentially activates receptors composed of these subunits, while GluR5-7 and KAl-2 are termed kainate receptors as these are preferentially sensitive to kainic acid.
• AMPA ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid
• GluR5-7 and KAl-2 are termed kainate receptors as these are prefer
• AMPA receptors include the GluRl-4 family, which form homo-oligomeric and hetero-oligomeric complexes which display different current-voltage relations and calcium permeability. Polypeptides encoded by GluRl-4 nucleic acid sequences can form functional ligand- gated ion channels.
• An AMPA receptor includes a receptor having a GluRl, GluR2, GluR3 and/or GluR4 subunit.
• a NMDA receptor includes a receptor having NMDAR1, NMDAR2a, NMDAR2b, NMDAR2c, NMDAR2d and/or NMDAR3 subunits.
• a novel class of heterocyclic compounds contain a substituted, unsaturated five-, six- or seven- membered heterocyclic ring that includes at least one nitrogen atom and at least one carbon atom.
• the ring additionally includes three, four or five atoms independently selected from carbon, nitrogen, sulfur and oxygen atoms.
• the heterocyclic ring has at least one substituent located at a ring position adjacent to a ring nitrogen atom. This mandatory substituent of the ring includes a moiety (B), linked to the heterocyclic ring via a hydrocarbyl or an azo group.
• the invention also discloses pharmaceutically acceptable salt forms of heterocyclic compounds.
• Invention compounds are useful for a wide variety of applications.
• heterocyclic compounds can act to modulate physiological processes by functioning as agonists and antagonists of receptors in the nervous system.
• Invention compounds may also act as insecticides and as fungicides.
• Pharmaceutical compositions containing invention compounds also have wide utility.
• Diseases contemplated include cerebral ischemia, chronic neurodegeneration, psychiatric disorders, schizophrenia, mood disorders, emotion disorders, disorders of extrapyramidal motor function, obesity, disorders of respiration, motor control and function, attention deficit disorders, concentration disorders, pain disorders, neurodegenerative disorders, epilepsy, convulsive disorders, eating disorders, sleep disorders, sexual disorders, circadian disorders, drug withdrawal, drug addiction, compulsive disorders, anxiety, panic disorders, depressive disorders, skin disorders, retinal ischemia, retinal degeneration, glaucoma, disorders associated with organ transplantation, asthma, ischemia and astrocytomas.
• the invention further discloses methods of preventing disease conditions related to diseases of the pulmonary system, diseases of the nervous system, diseases of the cardiovascular system, diseases of the gastrointestinal system, diseases of the endocrine system, diseases of the exocrine system, diseases of the skin, cancer and diseases of the ophthalmic system.
• DETAILED DESCRTPTION OF THE INVENTION DETAILED DESCRTPTION OF THE INVENTION
• A is a 5-, 6- or 7-membered ring having the structure:
• W, X, Y and Z is (CR)p, wherein p is 0, 1 or 2; the remainder of W, X, Y and Z are each independently O, N or S; and each R is independently halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, heterocycle, mercapto, nitro, carboxyl, carbamate, carboxamide, hydroxy, ester, cyano, amine, amide, amidine, amido, sulfonyl or sulfonamide, wherein q is 0, 1, 2 or 3;
• L is substituted or unsubstituted alkenylene, alkynylene, or azo; and B is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocycle, optionally containing one or more double bonds, or substituted or unsubstituted aryl; provided, that the following compounds are excluded: the compounds wherein A is a 6-membered ring wherein: , X, Y and Z are (CR) P wherein p is 1 ; and R at the W position is hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, amino- lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, unsubstituted or hydroxy- substituted lower alkyleneamino-lower alkyl, lower alkoxy, lower alkanoyloxy, amino-lower alkoxy,
• W, X, Y and Z are (CR) P wherein p is 1; R at the X position is not hydrogen; and R at the W, Y and Z positions are hydrogen;
• L is alkenylene or alkynylene
• B is a substituted or unsubstituted aryl or heterocycle containing two or more double bonds
• A is a 5-membered ring wherein: one of W, X, Y and Z is (CR) P , and p is 0, two of W, X, Y and Z are (CR) P and p is 1, and the remaining variable ring member is O or S; or one of W, X, Y and Z is N, one of W, X, Y and Z is (CR) P and p is 1, one of W, X, Y and Z is (CR) P and p is 0, and the remaining variable ring member is O, S or (CR) P , and p is 1; or two of W, X, Y and Z are N, one of , X, Y and Z is (CR) P, and p is 0, and the remaining variable ring member is , O or S or (CR) P> and p is 1 ; each R is independently hydrogen, nitro, halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl,
• B is substituted or unsubstituted aryl, wherein substituents are independently nitro, cyano, C ⁇ -C 6 -alkyl, C ⁇ -C 4 -haloalkyl, d-C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -alkthio, C C 4 - haloalkylthio, C ⁇ -C 4 -alkoxycarbonyl, C 3 -C 6 -alkenyl, phenyl or phenoxy, wherein phenyl and phenoxy may bear further substituents; and
• W, X, Y and Z are (CR)p, wherein p is 1 and R is hydrogen, L is alkynylene; and B is unsubstituted 1-cyclopenten-l-yl or unsubstituted 1-cyclohexen-l-yl; and
• A is a 5-membered ring wherein: W is (CR)p, and p is 0, Y and Z are (CR)p, and p is 1, X is N or S; and R is phenyl; or
• W is (CR)p, and p is 0, X and Z are (CR)p, and p is 1, Y is O, N or S; and R is phenyl; L is unsubstituted alkenylene and
• B is unsubstituted phenyl
• A is a 5-membered ring containing two double bonds, wherein one of W, X, Y and Z is (CR) P , and p is 0, and the remaining ring members are (CR) P and p is 1;
• A is unsubstituted heterocycle containing two or more double bonds
• L is alkenylene or alkynylene
• B is unsubstituted phenyl
• hydrocarbyl refers to straight or branched chain univalent and bivalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 1 up to 12 carbon atoms.
• exemplary hydrocarbyl moieties include alkyl moieties, alkenyl moieties, dialkenyl moieties, trialkenyl moieties, alkynyl moieties, alkadiynal moieties, alkatriynal moieties, alkenyne moieties, alkadienyne moieties, alkenediyne moieties, and the like.
• substituted hydrocarbyl refers to hydrocarbyl moieties further bearing substituents as set forth below.
• alkyl refers to straight or branched chain alkyl radicals having in the range of about 1 up to 12 carbon atoms; "substituted alkyl” refers to alkyl radicals further bearing one or more substituents such as hydroxy, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amide, amidine, amido, carboxyl, carboxamide, carbamate, ester, sulfonyl, sulfonamide, and the like.
• alkenyl refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently preferred), and “substituted alkenyl” refers to alkenyl radicals further bearing one or more substituents as set forth above.
• alkenylene refers to straight or branched chain divalent alkenyl moieties having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms
• alkynyl refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently being preferred), and "substituted alkynyl” refers to alkynyl radicals further bearing one or more substituents as set forth above.
• alkynylene refers to straight or branched chain divalent alkynyl moieties having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkynyl moieties having two carbon atoms presently being preferred), and "substituted alkynylene” refers to divalent alkynyl radicals further bearing one or more substituents as set forth above.
• cyclohydrocarbyl refers to cyclic (i.e., ring-containing) univalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 3 up to 20 carbon atoms.
• cyclohydrocarbyl moieties include cycloalkyl moieties, cycloalkenyl moieties, cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynyl moieties, spiro hydrocarbon moieties wherein two rings are joined by a single atom which is the only common member of the two rings (e.g., spiro[3.4]octanyl, and the like), bicyclic hydrocarbon moieties wherein two rings are joined and have two atoms in common (e.g., bicyclo [3.2.1]octane, bicyclo [2.2.1]hept-2-ene, norbornene, decalin, and the like), and the like.
• substituted cyclohydrocarbyl refers to cyclohydrocarbyl moieties further bearing one or more substituents as set forth
• cycloalkyl refers to ring-containing alkyl radicals containing in the range of about 3 up to 20 carbon atoms
• substituted cycloalkyl refers to cycloalkyl radicals further bearing one or more substituents as set forth above.
• cycloalkenyl refers to ring-containing alkenyl radicals having at least one carbon-carbon double bond in the ring, and having in the range of about 3 up to 20 carbon atoms
• substituted cycloalkenyl refers to cyclic alkenyl radicals further bearing one or more substituents as set forth above.
• cycloalkynyl refers to ring-containing alkynyl radicals having at least one carbon-carbon triple bond in the ring, and having in the range of about 3 up to 20 carbon atoms
• substituted cycloalkynyl refers to cyclic alkynyl radicals further bearing one or more substituents as set forth above.
• aryl refers to mononuclear and polynuclear aromatic radicals having in the range of 6 up to 14 carbon atoms
• substituted aryl refers to aryl radicals further bearing one or more substituents as set forth above, for example, alkylaryl moieties.
• heterocycle refers to ring-containing radicals having one or more heteroatoms (e.g., N, O, S) as part of the ring structure, and having in the range of 3 up to 20 atoms in the ring. Heterocyclic moieties may be saturated or unsaturated when optionally containing one or more double bonds, and may contain more than one ring.
• Heterocyclic moieties include, for example, monocyclic moieties such as imidazolyl moieties, pyrimidinyl moieties, isothiazolyl moieties, isoxazolyl moieties, moieties, and the like, and bicyclic heterocyclic moieties such as azabicycloalkanyl moieties, oxabicycloalkyl moieties, and the like.
• substituted heterocycle refers to heterocycles further bearing one or more substituents as set forth above.
• halogen refers to fluoride, chloride, bromide or iodide radicals.
• A is a 5-, 6- or 7-membered unsaturated heterocyclic moiety, containing a ring having at least one nitrogen atom located on the ring in a position adjacent to a carbon atom which bears a linking moiety as a substituent.
• the ring further contains 3, 4 or 5 independently variable atoms selected from carbon, nitrogen, sulfur and oxygen.
• A can be pyridinyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazoyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, oxadiazinyl, isothiazolyl, thiazoyl, dioxazolyl, oxathiazolyl, oxathiazinyl, azepinyl, diazepinyl, and the like.
• variable ring atom is carbon, it bears a hydrogen, or is optionally substituted with halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, thiol, nitro, carboxyl, ester, cyano, amine, amide, carboxamide, amidine, amido, sulfonamide, and the like, with presently preferred embodiments having no substituent (i.e., q is 0) or bearing the following substituents: halogen, alkyl, containing one up to four carbon atoms, fluorinated alkyl, containing one up to four carbon atoms, aryl, and amine. Substitution at position Z of the ring is presently preferred.
• A is a 5-, 6- or 7-membered ring containing, as ring members, a nitrogen atom and a sulfur atom.
• Moieties contemplated for use by this embodiment of the invention include those wherein A is isothiazol-3-yl (l,2-thiazol-3-yl), thiazol-4-yl (l,3,-thiazol-4-yl), thiazol-2-yl (l,3-thiazol-2-yl), l,2-thiazin-3-yl, l,3-thiazin-4-yl, l,4-thiazin-3-yl, l,3-thiazin-2-yl, thiazepinyl, and the like.
• moieties include those wherein A is isothiazol-3-yl (l,2-thiazol-3-yl), thiazol-4-yl (l,3-thiazol-4-yl) and thiazol-2-yl (l,3-thiazol-2-yl).
• A is a 5-, 6- or 7-membered ring containing, as ring members, a nitrogen atom and an oxygen atom.
• Moieties contemplated by this embodiment of the invention include those wherein A is l,2-oxazin-3-yl, l,3-oxazin-4-yl, l,4-oxazin-3-yl, l,3-oxazin-2-yl, oxazol-2-yl, isoxazol-3-yl, oxazol-4-yl, oxazepinyl, and the like.
• Presently preferred moieties include those wherein A is oxazol-2-yl, isoxazol-3-yl and oxazol-4-yl.
• A is a 5-, 6- or 7-membered ring containing, as a ring member, a nitrogen atom.
• Moieties contemplated by this embodiment of the invention include those wherein A is 2-pyridinyl and 2-pyrrolyl.
• A is a 5-, 6-, or 7-membered ring containing, as ring members, two nitrogen atoms.
• Moieties contemplated by this embodiment of the invention include those wherein A is 3-pyridazinyl (l,2-diazin-3-yl), pyrimidin-4-yl (l,3-diazin-4-yl), pyrazin-3-yl (l,4-diazin-3-yl), pyrimidin-2-yl (l,3-diazin-2-yl), pyrazol-3-yl (l,2-diazol-3-yl), imidazol-4-yl (l,3-isodiazol-4-yl, imidazol-2-yl (l,3-isodiazol-2-yl), diazepinyl, and the like.
• moieties include those wherein A is 3-pyridazinyl (l,2-diazin-3-yl), pyrimidin-4-yl (l,3-diazin-4-yl), pyrazin-3-yl (l,4-diazin-3-yl), pyrimidin-2-yl (l,3-diazin-2-yl), l,3-isodiazol-4-yl and l,3-isodiazol-2-yl.
• A is a 5-, 6-, or 7-membered ring containing, as ring members, three nitrogen atoms.
• Moieties contemplated by this embodiment of the invention include those wherein A is l,2,3-triazin-4-yl, l,2,4-triazin-6-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,3,5-triazin-2-yl, l,2,3-triazol-4-yl, l,2,4-triazol-3-yl, triazepinyl, and the like.
• moieties include those wherein A is l,2,3-triazin-4-yl, l,2,4-triazin-6-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,3,5-triazin-2-yl, l,2,3-triazol-4-yl, l,2,4-triazol-3-yl.
• A is a 5-, 6-, or 7-membered ring containing, as ring members, four nitrogen atoms.
• Moieties contemplated for use in the practice of the invention include those wherein A is tetrazin-2-yl, tetrazin-3-yl, tetrazin-5-yl, tetrazolyl, tetrazepinyl, and the like.
• Presently preferred moieties include those wherein A is tetrazolyl.
• A is a 5-, 6-, or 7-membered ring containing, as ring members, one sulfur atom and two nitrogen atoms.
• Moieties contemplated by this embodiment of the invention include those wherein A is l,2,6-thiadiazin-3-yl, l,2,5-thiadiazin-3-yl, l,2,4-thiadiazin-3-yl, l,2,5-thiadiazin-4-yl, l,2,3-thiadiazin-4-yl, l,3,4-thiadiazin-5-yl, l,3,4-thiadiazin-2-yl, l,2,4-thiadiazin-5-yl, l,3,5-thiadiazin-4-yl, l,3,5-thiadiazin-2-yl, l,2,4-thiadiazol-3-yl, l,2,3-thiadiazol-4-yl, l,3,4-thiadiazol-2-yl, l,2,5-thiadiazol-3-yl, l,
• A is l,2,4-thiadiazol-3-yl, l,2,3-thiadiazol-4-yl, l,3,4-thiadiazol-2-yl, 1 ,2,5-thiadiazol-3-yl and 1 ,2,4-thiadiazol-5-yl.
• A is a 5-, 6-, or 7-membered ring containing, as ring members, one oxygen atom and two nitrogen atoms.
• Moieties contemplated by this embodiment of the invention include those wherein A is l,2,6-oxadiazin-3-yl, l,2,5-oxadiazin-3-yl, l,2,4-oxadiazin-3-yl, l,2,5-oxadiazin-4-yl, l,2,3-oxadiazin-4-yl, l,3,4-oxadiazin-5-yl, l,3,4-oxadiazin-2-yl, l,2,4-oxadiazin-5-yl, l,3,5-oxadiazin-4-yl, l,3,5-oxadiazin-2-yl, l,2,4-oxadiazol-3-yl, l,2,3-oxadiazol-4-yl, l,3,4-oxadiazol-2-yl, l,2,5-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, oxadiazepinyl, and the
• moieties include those wherein A is l,2,4-oxadiazol-3-yl, l,2,3-oxadiazol-4-yl, l,3,4-oxadiazol-2-yl, l,2,5-oxadiazol-3-yl and 1 ,2,4-oxadiazol-5-yl.
• A is a 5-, 6-, or 7-membered ring containing as ring members, one up to six nitrogen atoms, and/or one up to six carbon atoms, and/or zero up to five sulfur atoms, and/or zero up to five oxygen atoms.
• L is a linking moiety which links moieties A and B.
• L is selected from substituted or unsubstituted alkenylene moieties, alkynylene moieties or azo moieties.
• Presently preferred compounds of the invention are those wherein L is alkenylene or alkynylene moieties containing two carbon atoms, with alkynylene most preferred.
• B is a moiety linked through bridging moiety L to moiety A.
• Radicals contemplated for use in the invention are those wherein B is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocycle, optionally containing one or more double bonds, substituted or unsubstituted aryl, and the like.
• Presently preferred compounds of the invention are those wherein B is a substituted or unsubstituted hydrocarbyl selected from substituted or unsubstituted alkyl moieties, alkenyl moieties, dialkenyl moieties, trialkenyl moieties, alkynyl moieties, alkadiynyl moieties, alkatriynyl moieties, alkenynyl moieties, alkadienynyl moieties, alkenediynyl moieties, and the like.
• B is a substituted or unsubstituted cyclohydrocarbyl selected from substituted or unsubstituted cycloalkyl moieties, cycloalkenyl moieties, cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynyl moieties, bicyclic hydrocarbon moieties wherein two rings have two atoms in common, and the like.
• B is cycloalkyl and cycloalkenyl having in the range of 4 up to about 8 carbon atoms.
• Exemplary compounds include cyclopropanyl, cyclopentenyl and cyclohexenyl. Also especially preferred are bicyclic hydrocarbon moieties wherein two rings have two atoms in common; exemplary compounds include indenyl, dihydroindenyl, naphthalenyl and dihydronaphthalenyl. Still further preferred compounds of the invention are those wherein B is a substituted or unsubstituted heterocycle, optionally containing one or more double bonds.
• Exemplary compounds include pyridyl, thiazolyl, furyl, dihydropyranyl, dihydrothiopyranyl, piperidinyl, isoxazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like.
• B is substituted or unsubstituted aryl.
• substituents are aryl and heterocycle, optionally bearing further substituents as described herein, methyl, trifluoromethyl, cyclopropyl, alkoxy, halogen and cyano.
• B is a bicylic heterocyle moiety wherein two rings have two atoms in common.
• Exemplary compounds include indolyl and isoquinolinyl.
• invention compounds may contain one or more chiral centers, and thus can exist as racemic mixtures.
• Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions.
• invention compounds may exist in polymorphic forms wherein a compound is capable of crystallizing in different forms. Suitable methods for identifying and separating polymorphisms are known in the art.
• esterified carboxy is, for example, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl substituted in the phenyl moiety by one or more substituents selected from lower alkyl, lower alkoxy, halo and halo-lower alkyl.
• Esterified carboxy-lower-alkoxy is, for example, lower alkoxycarbonyl-lower alkoxy.
• Amidated carboxy is, for example, unsubstituted or aliphatically substituted carbamoyl such as carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted N-phenyl- or N-lower-alkyl-N-phenyl-carbamoyl.
• carbamoyl such as carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted N-phenyl- or N-lower-alkyl-N-phenyl-carbamoyl.
• acyl is, for example, lower alkanoyl, lower alkenoyl or unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted benzoyl.
• Acylamino is, for example, lower alkanoylamino
• N-acyl-N-lower alkylamino is, for example, N-lower alkanoyl-N-lower-alkylamino or unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted benzoylamino.
• N- lower-alkyl-N-phenylcarbamoyl is, for example, N-C ⁇ -C 4 alkyl-N-phenylcarbamoyl, such as N-methyl, N-ethyl, N-propyl, N-isopropyl or N-butyl-N-phenylcarbamoyl.
• amino-lower alkyl is, for example, amino-C ⁇ -C 4 alkyl, preferably of the formula - (CH 2 ) n ,-NH 2 in which n is 2 or 3, such as aminomethyl, 2-aminoethyl, 3-aminopropyl or 4-aminobutyl.
• Hydroxy-lower alkyl is, for example, hydroxy-C ⁇ -C 4 alkyl, such as hydroxymethyl, 2-hydroxy ethyl, 3- hydroxypropyl, 2-hydroxyisopropyl or 4-hydroxybutyl.
• Halo-lower alkyl is, for example, polyhalo-C r C 4 alkyl, such as trifluoromethyl.
• lower alkoxy is, for example, C ⁇ -C 7 alkoxy, preferably -C alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also represent isobutyloxy, sec.butyloxy, tert.- butyloxy or a C 5 -C 7 alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.
• amino-lower alkoxy is, for example, amino-C 2 -C 4 alkoxy preferably of the formula -0-(CH 2 ) n -NR a R b in which n is 2 or 3, such as 2-aminoethoxy, 3-aminopropyloxy or 4-aminobutyloxy.
• Carboxy-lower-alkoxy is, for example, carboxy-C ⁇ -C 4 alkoxy, such as carboxymethoxy, 2-carboxyethoxy, 3-carboxypropyloxy or 4- carboxybutyloxy.
• Lower alkanoyloxy is, for example, C ⁇ -C 7 alkanoyloxy, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.
• Halo-lower alkoxy is, for example, halo- or polyhalo-C ⁇ -C aIkoxy, preferably halo- or polyhalo-C ⁇ -C 4 alkoxy, such as halo- or polyhaloethoxy, halo- or polyhalopropyloxy or butyl-oxy, wherein "poly” refers, for example, to tri- or pentahalo, and "halo" denotes, for example, fluoro or chloro.
• lower alkylamino-lower alkoxy is, for example, C ⁇ -C alkylamino-C 2 -C alkoxy, preferably of the formula -0-(CH 2 )n-NR a R b in which n is 2 or 3 and R a and R t ,, independently of each other, denote lower alkyl groups as defined hereinbefore, such as methyl, ethyl, propyl or butyl.
• Lower alkylamino-lower alkyl is, for example, C
• Di-lower alkylamino-lower alkyl is, for example, Di-C ⁇ -C alkylamino-C ⁇ -C 4 alkyl, preferably of the formula -(CH 2 ) contend-NR a R b in which n is 2 or 3 and R a and R t ,, independently of each other, denote lower alkyl groups such as methyl, ethyl, propyl or butyl.
• Di-lower alkylamino-lower alkoxy is, for example, Di-C ⁇ -C 4 alkylamino-C 2 -C 4 alkoxy, preferably of the formula -0-(CH 2 ) contend-NR a R b in which n is 2 or 3 and R a and R t ,, independently of each other, denote lower alkyl groups such as methyl, ethyl, propyl or butyl.
• optionally hydroxy-substituted lower alkyleneamino-lower alkyl is, for example, unsubstituted or hydroxy-substituted 5- to 7-membered alkyleneamino-C ⁇ -C alkyl, preferably of the formula -(CH 2 ) n -Rc in which n is 2 or 3 and Re pyrrolidino, hydroxypyrrolidino, piperidino, hydroxypiperidino, homopiperidino or hydroxyhomopiperidino.
• hydroxy- substituted lower alkyleneamino-lower alkoxy is, for example, unsubstituted or hydroxy-substituted 5- to 7-membered alkyleneamino-C ⁇ -C 4 alkoxy, preferably of the formula -0-(CH 2 ) contend-R c in which n is 2 or 3 and R e pyrrolidino, hydroxypyrrolidino, piperidino, hydroxypiperidino, homopiperidino or hydroxyhomopiperidino.
• compositions comprising heterocyclic compounds as described above, in combination with pharmaceutically acceptable carriers.
• invention compounds can be converted into non-toxic acid addition salts, depending on the substituents thereon.
• the above-described compounds (optionally in combination with pharmaceutically acceptable carriers) can be used in the manufacture of medicaments useful for the treatment of a variety of indications.
• Pharmaceutically acceptable carriers contemplated for use in the practice of the present invention include carriers suitable for oral, sublingual intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, epidural, intraoccular, intracranial, inhalation, rectal, vaginal, and the like administration. Administration in the form of creams, lotions, tablets, capsules, pellets, dispersible powders, granules, suppositoiries, syrups, elixirs, lozenges, injectable solutions, sterile aqueous or non- aqueous solutions, suspensions or emulsions, patches, and the like, is contemplated.
• Pharmaceutically acceptable carriers include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, dextrans, and the like.
• Invention compounds can optionally be converted into non-toxic acid addition salts.
• Such salts are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid.
• Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, methanesulfonate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate (tosylate), citrate, malate, maleate, fumarate, succinate, tartrate, napsylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, undecanoate, 2-hydroxyethanesulfonate,ethanesul
• Salts can also be formed with inorganic acids such as sulfate, bisulfate, hemisulfate, hydrochloride, chlorate, perchlorate, hydrobromide, hydroiodide, and the like.
• a base salt include ammonium salts; alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like.
• Such salts can readily be prepared employing methods well known in the art.
• heterocyclic compounds as described above.
• many of the heterocyclic compounds described above can be prepared using synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984) from a precursor of the substituted heterocycle of Formula 1 as outlined in Scheme 1.
• D is a group such as hydrogen, halogen, acyloxy, fluorosulfonate, trifluoromethanesulfonate, alkyl- or arylsulfonate, alkyl- or arylsulfinate, alkyl- or arylsulfide, phosphate, phosphinate, and the like
• E is hydrogen or a metallic or metalloid species such as Li, MgX (X is halogen), SnR 3 , B(OR) 2 , SiR 3 , GeR 3 , and the like.
• the coupling may be promoted by a homogeneous catalyst such as PdCl 2 (PPh 3 ) 2 , or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g., tetrahydrofuran (THF), dimethoxyethane (DME), acetonitrile, dimethylformamide (DMF), etc.).
• a co-catalyst such as copper (I) iodide and a base (e.g., triethylamine, K 2 C0 3 etc.) will also be present in the reaction mixture.
• the coupling reaction typically proceeds by allowing the reaction temperature to warm slowly from about 0° C up to ambient temperature over a period of several hours.
• the reaction mixture is then maintained at ambient temperature, or heated to a temperature anywhere between 30° C and 150° C.
• the reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48 hours, with about 12 hours typically being sufficient.
• the product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like.
• Scheme 2 Another embodiment of the present invention is illustrated in Scheme 2.
• a substituted heterocycle precursor is reacted with an alkene derivative in a mannef similar to the procedure described for Scheme 1.
• Scheme 2
• the alkene derivative product from Scheme 2 may be converted to an alkyne derivative using the approach outlined in Scheme 3.
• the alkene derivative may be contacted with a halogenating agent such as chlorine, bromine, iodine, NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), iodine monochloride, etc. in a suitable solvent (CC1 4 , CHC1 3 , CH 2 CI 2 , acetic acid, and the like).
• a halogenating agent such as chlorine, bromine, iodine, NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), iodine monochloride, etc.
• a suitable solvent CC1 4 , CHC1 3 , CH 2 CI 2 , acetic acid, and the like.
• the reaction is carried out in a suitable solvent such as ethanol, acetonitrile, toluene, etc. at an appropriate temperature, usually between about 0° C and 150° C.
• a substituted heterocyclic derivative is reacted with an aldehyde or ketone to provide a substituted alkene. (See Scheme 4.)
• J is hydrogen, PR 3 , P(0)(OR) 2 , SO 2 R, SiR 3 , and the like
• K is hydrogen, alkyl or aryl (as defined previously)
• R is hydrogen, acetyl, and the like.
• Suitable catalysts for this reaction include bases such as NaH, n-buytllithium, lithium diisopropylamide, lithium hexamethyl disilazide, H 2 NR, HNR 2 , NR 3 etc., or electropositive reagents such as Ac 0, ZnCl 2 , and the like.
• the reaction is carried out in a suitable solvent (THF, acetonitrile, etc.) at an appropriate temperature, usually between about 0° C and 150° C.
• the alkene products from the reactions in Scheme 4 and Scheme 5 may be converted to an alkyne derivative using reagents and conditions as described for Scheme 3.
• Y is O or S and G is halogen or a similar leaving group, and L and B are as defined previously.
• the reagents are contacted in a suitable solvent such as ethanol, DMF, and the like and stirred until the product forms.
• a suitable solvent such as ethanol, DMF, and the like and stirred until the product forms.
• reaction temperatures will be in the range of ambient through to about 150° C, and reaction times will be from about 1 h to about 48 h, with about 70° C and 4 h being presently preferred.
• the heterocycle product can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like. Often, the product will be isolated as the hydrochloride or hydrobromide salt, and this material may be carried onto the next step with or without purification.
• W may be O or S
• G is halogen or a similar leaving group
• L and B are as defined previously.
• the reaction conditions and purification procedures are as described for Scheme 6.
• an alkynyl-substituted heterocycle precursor (prepared using synthetic chemistry techniques well known in the art) is reacted with a species B, bearing a reactive functional group D (See Scheme 8.)
• (R) q , W, X, Y, Z and B are as defined above and D and E are functional groups which are capable of undergoing a transition metal-catalyzed cross-coupling reaction.
• D is a group such as hydrogen, halogen, acyloxy, fluorosulfonate, trifluoromethanesulfonate, alkyl- or arylsulfonate, alkyl- or arylsulfinate, alkyl- or arylsulfide, phosphate, phosphinate, and the like
• E is hydrogen or a metallic or metalloid species such as Li, MgX (X is halogen), SnR 3 , B(OR) 2 , SiR 3 , GeR 3 , and the like.
• the coupling may be promoted by a homogeneous catalyst such as PdCl 2 (PPh 3 ) 2 , or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. tetrahydrofuran (THF), dimethoxyethane (DME), acetonitrile, dimethylformamide (DMF), etc.).
• a suitable solvent e.g. tetrahydrofuran (THF), dimethoxyethane (DME), acetonitrile, dimethylformamide (DMF), etc.
• a co-catalyst such as copper (I) iodide and the like and a base (e.g. triethylamine, K. 2 C0 3 ⁇ etc.) will also be present in the reaction mixture.
• the coupling reaction is typically allowed to proceed by allowing the reaction temperature to warm slowly from about 0° C up to ambient temperature over a period of several hours.
• the reaction mixture is then maintained at ambient temperature, or heated to a temperature anywhere between about 30° C up to about 150° C.
• the reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to about 48 hours, with about 12 hours typically being sufficient.
• the product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like.
• an alkynyl- substituted heterocycle precursor is reacted with a species composed of a carbonyl group bearing substituents R' and CHR"R'".
• R', R" and R"' may be hydrogen or other substituents as described previously, or may optionally combine to form a ring (this portion of the molecule constitutes B in the final compound).
• E is hydrogen or a metallic or metalloid species such as Li, MgX, wherein X is halogen, SnR 3 , B(OR) 2 , SiR 3 , GeR 3 , and the like.
• Suitable catalysts for this reaction include bases such as NaH, n-butyllithium, lithium diisopropylamide, lithium hexamethylsilazide, H 2 NR, HNR , NR 3 , nBu 4 NF, ethylmagnesium halide, etc.
• R in Scheme 10 may be hydrogen, Ac, and the like.
• the reaction is carried out in a suitable solvent such as diethylether, THF, DME, toluene, and the like, and at an appropriate temperature, usually between -100° C and 25° C.
• the reaction is allowed to proceed for an appropriate length of time, usually from about 15 minutes to about 24 hours.
• the intermediate bearing the -OR group may be isolated and purified as described above, partially purified or carried on to the next step without purification. Elimination of the -OR group to provide the alkene derivative may be accomplished using a variety of methods well known to those skilled in the art.
• the intermediate may be contacted with POCl 3 in a solvent such as pyridine and stirred at a suitable temperature, typically between about 0° C and about 150° C, for an appropriate amount of time, usually between about 1 h and about 48 h.
• a suitable temperature typically between about 0° C and about 150° C, for an appropriate amount of time, usually between about 1 h and about 48 h.
• the product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like.
• methods of modulating the activity of excitatory amino acid receptors comprising contacting said receptors with at least one compound as described above, as well as additional compounds of the same basic structure but having substitution patterns which may have been previously disclosed but never contmplated for use for such purposes.
• compounds contemplated for use in accordance with invention modulations methods include those having the structure A — — B or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, in an amount sufficient to modulate the activity of said excitatory amino acid receptor, wherein:
• A is a 5-, 6- or 7-membered ring having the structure:
• V, W, X, Y and Z is (CR) P , wherein p is 0, 1 or 2; at least one of V, W, X, Y and Z is O, N or S; the remainder of V, W, X, Y and Z are each independently O, N or S; and each R is independently halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, heterocycle, mercapto, nitro, carboxyl, carbamate, carboxamide, hydroxy, ester, cyano, amine, amide, amidine, amido, sulfonyl or sulfonamide, wherein q is 0, 1, 2 or 3;
• L is substituted or unsubstituted alkenylene, alkynylene, or azo; and B is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocycle, optionally containing one or more double bonds, or substituted or unsubstituted aryl;
• A is a 6-membered ring wherein: V, W, X and Y are (CR)p, wherein p is 1, Z is N;
• L is substituted or unsubstituted alkenylene, alkynylene or azo
• B is substituted or unsubstituted aryl or heterocycle having two or more double bonds
• substituents are independently lower alkyl, lower alkenyl, lower alkynyl, phenyl, phenyl-lower alkynyl, hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, phenoxy, phenyl-lower alkoxy, acyl, carboxy, esterified carboxy, amidated carboxy, cyano, nitro, amino, acylamino, N-acyl-N-lower alkylamino, halo and halo-lower alkyl, wherein phenyl, phenyl-lower alkynyl, phenoxy, and phenyl-lower alkoxy may bear further substituents.
• excitatory amino acid receptors refers to a class of cell-surface receptors which are the major class of excitatory neurotransmitter receptors in the central nervous system. In addition, receptors of this class also mediate inhibitory responses.
• Excitatory amino acid receptors are membrane spanning proteins that mediate the stimulatory actions of the amino acid glutamate and possibly other endogenous acidic amino acids. Excitatory amino acids are crucial for fast and slow neurotransmission and they have been implicated in a variety of diseases including Alzheimer's disease, stroke, schizophrenia, head trauma, epilepsy, and the like. In addition, excitatory amino acids are integral to the processes of long-term potentiation and depression which are synaptic mechanisms underlying learning and memory. There are three main subtypes of excitatory amino acid receptors: (1) the metabotropic receptors; (2) the ionotropic NMDA receptors; and (3) the non-NMDA receptors, which include the AMPA receptors and kainate receptors.
• modulating the activity of refers to altered levels of activity so that the activity is different with the use of the invention method when compared to the activity without the use of the invention method.
• Modulating the activity of excitatory amino acid receptors includes the suppression or augmentation of the activity of receptors. Suppression of receptor activity may be accomplished by a variety of means, including blocking of a ligand binding site, biochemical and/or physico-chemical modification of a ligand binding site, binding of agonist recognition domains, preventing ligand-activated conformational changes in the receptor, preventing the activated receptor from stimulating second messengers such as G-proteins, and the like.
• Augmentation of receptor activity may be accomplished by a variety of means including, stabilization of a ligand binding site, biochemical and/or physico-chemical modification of a ligand binding site, binding of agonist recognition domains, promoting ligand-activated conformational changes in the receptor, and the like.
• Excitatory amino acid receptor activity can be involved in numerous disease states.
• modulating the activity of receptors also refers to a variety of therapeutic applications, such as the treatment of cerebral ischemia, chronic neurodegeneration, psychiatric disorders, schizophrenia, mood disorders, emotion disorders, disorders of extrapyramidal motor function, obesity, disorders of respiration, motor control and function, attention deficit disorders, concentration disorders, pain disorders, neurodegenerative disorders, epilepsy, convulsive disorders, eating disorders, sleep disorders, sexual disorders, circadian disorders, drug withdrawal, drug addiction, compulsive disorders, anxiety, panic disorders, depressive disorders, skin disorders, retinal ischemia, retinal degeneration, glaucoma, disorders associated with organ transplantation, asthma, ischemia or astroytomas, and the like.
• therapeutic applications such as the treatment of cerebral ischemia, chronic neurodegeneration, psychiatric disorders, schizophrenia, mood disorders, emotion disorders, disorders of extrapyramidal motor function, obesity, disorders of respiration, motor control and function, attention deficit disorders, concentration disorders, pain disorders, neurodegenerative disorders, epilepsy, convulsive disorders, eating
• the compounds contemplated for use in accordance with of invention modulatory methods are especially useful for the treatment of mood disorders such as anxiety, depression, psychosis, drug withdrawal, tobacco withdrawal, memory loss, cognitive impairment, dementia, Alzheimer's disease, and the like; disorders of extrapyramidal motor function such as Parkinson's disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome, tardive dyskinesia, and the like.
• mood disorders such as anxiety, depression, psychosis, drug withdrawal, tobacco withdrawal, memory loss, cognitive impairment, dementia, Alzheimer's disease, and the like
• disorders of extrapyramidal motor function such as Parkinson's disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome, tardive dyskinesia, and the like.
• Compounds contemplated for use in accordance with invention modulatory methods are also especially useful for the treatment of pain disorders such as neuropathic pain, chronic pain, acute pain, painful diabetic neuropathy, post-herpetic neuralgia, cancer-associated pain, pain associated with chemotherapy, pain associated with spinal cord injury, pain associated with multiple sclerosis, causalgia and reflex sympathetic dystrophy, phantom pain, post-stroke (central) pain, pain associated with HTV or AIDS, trigeminal neuralgia, lower back pain, myofacial disorders, migraine, osteoarthritic pain, postoperative pain, dental pain, post-burn pain, pain associated with systemic lupus, entrapment neuropathies, painful polyneuropathies, ocular pain, pain associated with inflammation, pain due to tissue injury, and the like.
• pain disorders such as neuropathic pain, chronic pain, acute pain, painful diabetic neuropathy, post-herpetic neuralgia, cancer-associated pain, pain associated with chemotherapy, pain associated with spinal cord injury, pain associated with multiple
• Contacting may include contacting in solution or in solid phase.
• “Pharmaceutically acceptable salt” refers to a salt of the compound used for treatment which possesses the desired pharmacological activity and which is physiologically suitable.
• the salt can be formed with organic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tartrate, toluenesulfonate, undecanoate, and the like.
• the salt can also be formed with inorganic acids such as sulfate, bisulfate, chlorate, perchlorate, hemisulfate, hydrochloride, hydrobromide, hydroiodide, and the like.
• the salt can be formed with a base salt, including ammonium salts, alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like.
• Salt forms of compounds herein find several advantages. Certain pharmaceutically acceptable salt forms of heterocyclic compounds described herein, achieve higher solubility as compared with non- salt forms. In addition, certain salt forms are more compatible with pharmaceutical uses.
• the hydrochloric acid salt of 2-(phenylethynl)-l,3-thiazole is an oil while the toluene sulfonic acid salt form of 2-(phenylethynl)-l,3-thiazole is a solid that is soluble in aqueous medium. (See Example 187.) Characteristics of salt forms of compounds depend on the characteristics of the compound so treated, and on the particular salt employed.
• methods of modulating the activity of metabotropic glutamate receptors comprising contacting metabotropic glutamate receptors with a concentration of a heterocylic compound as described above in accordance with invention methods for modulating the acitivity of excitatory amino acid receptors, sufficient to modulate the activity of said metabotropic glutamate receptors.
• metabotropic glutamate receptor refers to a class of cell-surface receptors which participates in the G-protein-coupled response of cells to glutamatergic ligands.
• Three groups of metabotropic glutamate receptors, identified on the basis of amino acid sequence homology, transduction mechanism and binding selectivity are presently known and each group contains one or more types of receptors.
• Group I includes metabotropic glutamate receptors 1 and 5 (mGluRl and mGluR5)
• Group II includes metabotropic glutamate receptors 2 and 3 (mGluR2 and mGluR3)
• Group III includes metabotropic glutamate receptors 4, 6, 7 and 8 (mGluR4, mGluR6, mGluR7 and mGluR8).
• mGluR4 mGluR6, mGluR7 and mGluR8.
• subtypes of each mGluR type may be found; for example, subtypes of mGluRl include mGluRla, mGluRlb and mGlu
• methods of treating a wide variety of disease conditions comprising administering to a patient having a disease condition a therapeutically effective amount of at least one of the heterocyclic compounds described above in accordance with invention methods for modulating the activity of excitatory amino acid receptors.
• treating refers to inhibiting or arresting the development of a disease, disorder or condition and/or causing the reduction, remission, or regression of a disease, disorder or condition.
• Those of skill in the art will understand that various methodologies and assays may be used to assess the development of a disease, disorder or condition, and similarly, various methodologies and assays may be used to assess the reduction, remission or regression of a disease, disorder or condition.
• Disease conditions contemplated for treatment in accordance with the invention include cerebral ischemia, chronic neurodegeneration, psychiatric disorders, schizophrenia, mood disorders, emotion disorders, disorders of extrapyramidal motor function, obesity, disorders of respiration, motor control and function, attention deficit disorders, concentration disorders, pain disorders, neurodegenerative disorders, epilepsy, convulsive disorders, eating disorders, sleep disorders, sexual disorders, circadian disorders, drug withdrawal, drug addiction, compulsive disorders, anxiety, panic disorders, depressive disorders, skin disorders, retinal ischemia, retinal degeneration, glaucoma, disorders associated with organ transplantation, asthma, ischemia, astrocytomas, and the like.
• Disease conditions contemplated for treatment in accordance with the present invention further include diseases of the pulmonary system, diseases of the nervous system, diseases of the cardiovascular system, diseases of the gastrointestinal system, diseases of the endocrine system, diseases of the exocrine system, diseases of the skin, cancer, diseases of the ophthalmic system, and the like.
• the active ingredients may be compounded with non-toxic, pharmaceutically acceptable carriers including, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, dextrans, and the like.
• non-toxic, pharmaceutically acceptable carriers including, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, dextrans, and the like.
• tablets, capsules, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, elixirs and lozenges containing various excipients such as calcium carbonae, lactose, calcium phosphate, sodium phosphate, and the like may be employed along with various granulating and disintegrating agents such as corn starch, potato starch, alginic acid, and the like, together with binding agents such as gum tragacanth, corn starch, gelatin, acacia, and the like.
• Lubricating agents such as magnesium stearate, stearic acid, talc, and the like may also be added.
• Preparations intended for oral use may be prepared according to any methods known to the art for the manufacture of pharmaceutical preparations and such preparations may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, saccharin, and the lake, flavoring agents such as peppermint, oil of wintergreen, and the like, coloring agents and preserving agents in order to provide pharmaceutically palatable preparations.
• a sweetening agent such as sucrose, lactose, saccharin, and the lake
• flavoring agents such as peppermint, oil of wintergreen, and the like
• coloring agents and preserving agents in order to provide pharmaceutically palatable preparations.
• suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the
• suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
• solutions for the practice of the invention may comprise sterile aqueous saline solutions, or the corresponding water soluble pharmaceutically acceptable metal salts, as previously described.
• solutions of the compounds used in the practice of the invention may also comprise non-aqueous solutions, suspensions, emulsions, and the like.
• non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
• Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
• adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
• They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
• Aqueous solutions may also be suitable for intravenous, intramuscular, intrathecal, subcutaneous, and intraperitoneal injection.
• the sterile aqueous media employed are all readily obtainable by standard techniques well known to those skilled in the art. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, by heating the compositions, and the like. They can also be manufactured in the form of sterile water, or some other sterile medium capable of injection immediately before use.
• compositions contemplated for use in accordance with the present invention may also be administered in the form of suppositories for rectal or vaginal administration.
• suppositories for rectal or vaginal administration.
• These compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, and the like, such materials being solid at ambient temperatures but liquify and/or dissolve in internal cavities to release the drug.
• the preferred therapeutic compositions for inocula and dosage will vary with the clinical indication. Some variation in dosage will necessarily occur depending upon the condition of the patient being treated, and the physician will, in any event, determine the appropriate dose for the individual patient.
• the effective amount of compound per unit dose depends, among other things, on the body weight, physiology, and chosen inoculation regimen.
• a unit dose of compound refers to the weight of compound without the weight of carrier (when carrier is used).
• the route of delivery of compounds and compositions used for the practice of the invention is determined by the disease and the site where treatment is required. Since the pharmacokinetics and pharmacodynamics of compounds and compositions described herein will vary somewhat, the most preferred method for achieving a therapeutic concentration in a tissue is to gradually escalate the dosage and monitor the clinical effects.
• the initial dose, for such an escalating dosage regimen of therapy will depend upon the route of administration.
• a therapeutically effective amount when used in reference to invention methods employing heterocyclic compounds and pharmaceutically acceptable salts thereof, refers to a dose of compound sufficient to provide circulating concentrations high enough to impart a beneficial effect on the recipient thereof.
• the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated, the severity of the disorder, the activity of the specific compound used, the route of administration, the rate of clearance of the specific compound, the duration of treatment, the drugs used in combination or coincident with the specific compound, the age, body weight, sex, diet and general health of the patient, and like factors well known in the medical arts and sciences. Dosage levels typically fall in the range of about 0.001 up to 100 mg/kg/day; with levels in the range of about 0.05 up to 10 mg/kg/day being preferred.
• PI hydrolysis phosphatidylinositol
• Triphenylphosphine (570 mg, 2.0 mmol) was dissolved in tetrahydrofuran (THF) (20 mL), then argon was bubbled through the solution for several minutes to deoxygenate it.
• Palladium(II) acetate 120 mg, 0.54 mmol was added, and the reaction mixture was heated to 60°C for 0.5 h, and then cooled to ambient temperature.
• the resulting dark brownish-red solution was stirred at 0°C for 5 minutes, and then the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring for 16 h at ambient temperature the reaction was quenched by pouring into water and basified by addition of saturated aqueous sodium carbonate. The basic aqueous phase was extracted with CH 2 C1 2 (2 x 50 mL), the combined organics were then dried over Na 2 S0 4 , filtered and concentrated in vacuo. The resulting black viscous oil was filtered through a plug of silica gel and fractions were collected while eluting with 1:1 hexane:ethyl acetate.
• Triphenylphosphine (380 mg, 1.5 mmol) was dissolved in THF (20 mL), then argon was bubbled through the solution for several minutes to deoxygenate it.
• Palladium(II) acetate (82 mg, 0.37 mmol) was added, and the reaction mixture was heated to 60°C for 0.5 h, and then cooled to ambient temperature.
• Cul (210 mg, 1.1 mmol), 2-bromo-l,3-thiazole (1.6 g, 9.8 mmol), potassium carbonate (4.2 g, 31 mmol) and water (0.70 mL, 39 mmol) were dissolved in DME (30 mL) and argon was bubbled through the mixture for several minutes to deoxygenate the mixture.
• 3-Bromopyridine (3.0 mL, 31 mmol), triethylamine (22 mL, 160 mmol), Cul (1.2 g, 6.2 mmol), and PdCl 2 (PPh 3 ) 2 (1.1 g, 1.5 mmol) were combined in DME (92 mL) and cooled to 0°C.
• 2-Methyl-3- butyne-2-ol (9.0 mL, 93 mmol) was then added and the reaction was allowed to slowly warm to ambient temperature. The mixture was then heated to 55-60°C for 16 h. The mixture was filtered through CeliteTM, and the pad was washed thoroughly with ethyl acetate.
• reaction mixture was filtered through a pad of CeliteTM, and the pad was washed thoroughly with ethyl acetate. The filtrate was washed with brine (3 x 20 mL). A partial emulsion was observed. The mixture was concentrated in vacuo and the residue was taken up in CH 2 CI 2 , washed with brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo.
• the crude product was purified by column chromatography on silica gel eluting with 80:20 followed by 30:20 hexane:ethyl acetate to afford 3- (l,3-thiazol-2-ylethynyl)pyridine (160 mg) as a mixture with another product exhibiting a mass of 204 in the GC/MS, assigned as pyridylalkyne dimer.
• a portion of the mixture (100 mg) was further purified by preparative reverse-phase HPLC eluting with a gradient of 80:20 to 0:100 water:acetonitrile over twenty minutes.
• the resulting product was dissolved in pyridine or a mixture of pyridine and methylene chloride (1 :1). POCl 3 (1.2 equiv) was added and the solution refluxed for 4 to 8 hours. The resultant mixture was partitioned between 1M K 2 C0 3 and ethyl acetate. The organic layer was dried over Na 2 SO 4 , and concentrated in vacuo. The resultant product was purified by flash column chromatography on silica gel eluting with 2:1 hexane:ethyl acetate.
• 2-Chloro-5-ethylpyrimidine 500 mg, 3.5 mmol
• PdCl 2 (PPh 3 ) 2 250 mg, 0.35 mmol
• Cul 203 mg, 1.06 mmol
• triethylamine 6.0 mL, 43 mmol
• 7-BU 4 NI 3.85 g, 10.4 mmol
• DMF dimethylformamide
• the mixture was cooled in an ice bath and then phenylacetylene (1.5 mL, 14 mmol) was added.
• the reaction mixture was then heated to 45-50°C and after 1.5 h, additional phenylacetylene (1.5 mL, 14 mmol) was added.
• 5-Ethyl-2-(phenylethynyl)pyrimidine (730 mg, 3.7 mmol) was dissolved in CH 2 C1 2 (3.0 mL) and treated with HC1 in diethyl ether (4.1 mL of a IN solution, 4.1 mmol). Upon addition of the HCI solution a solid precipitated from the solution. The mixture was diluted with diethyl ether (2 mL) and the supernatant decanted. The resultant solid was dried under high vacuum at 50°C to afford 5-ethyl-2- (phenylethynyl)pyrimidine hydrochloride (450 mg, 49 % yield) as an orange solid. M.p. 101-104°C.
• 4,6-Dimethoxy-2-(phenylethynyl)pyrimidine (320 mg, 1.3 mmol) was dissolved in CH 2 CI 2 (1.0 mL), and treated with HC1 in diethyl ether (1.6 mL of a 1.0M solution, 1.6 mmol). A yellow solid precipitated immediately. The mixture was diluted with ethyl acetate and allowed to stand in the freezer for 16 h. The cold supernatant was decanted and the remaining solids were triturated with ethyl acetate (1.5 mL), and then hexane (3 x 2 mL).
• the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 200 mL).
• the combined organic layers were washed with brine (200 mL), dried over MgSU 4 , filtered, and concentrated in vacuo.
• the reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated NaHC0 3 solution (300 mL), water (300 mL), brine (300 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
• the residue was dissolved in ethyl acetate, adsorbed onto silica gel and purified by column chromatography eluting with hexane, 99:1 then 98:2 hexane:ethyl acetate to afford 4-(l-cyclohexen-l-ylethynyl)-2 -methyl- 1,3-thiazole (620 mg, 28% yield) as a yellow powder.
• Cinnamamide (2.0 g, 14 mmol), chloroacetone (0.93 mL, 16 mmol), and K 2 CO 3 (940 mg, 6.8 mmol) were combined under argon and the mixture was heated in a 120° C oil bath. The reaction mixture solidified and stirring stopped upon heating. After 16 h, the cooled reaction mixture was quenched by the addition of water (20 mL) and then diluted with ethyl acetate (100 mL). The organic phase was dried over Na 2 S0 , filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 90:10 hexane:ethyl acetate.
• Ethyl 4-methyl-l,3-thiazole-2-carboxylate (850 mg, 22% yield) was dissolved in ethanol (30 mL) under argon. Chloroacetone (1.8 mL, 22 mmol) was added and the resultant solution was heated at 80° C for 16 h. The reaction mixture was concentrated in vacuo, adsorbed onto silica gel, and purified by column chromatography on silica gel eluting with 97:3, then 95:5 hexane:ethyl acetate to afford ethyl 4-methyl-l,3-thiazole-2-carboxylate (850 mg, 22% yield) as an oil.
• the organic phase was washed with saturated aqueous NaHC0 3 (50 mL), and the basic aqueous solution was then extracted with additionalethyl acetate (2 x 50 mL).
• the combined organic solutions were washed with brine (50 mL), dried over Na 2 S ⁇ 4 , and filtered.
• the filtrate was concentrated in vacuo to afford a yellow waxy solid.
• the crude product was dissolved in a small amount of hot ethyl acetate, diluted with hot hexane, and the resultant solution was allowed to cool to ambient temperature, seeded with a small amount of crude product, and transferred to the freezer.
• Pd(PPh 3 ) 4 (1.23 g, 1.06 mmol) was added to the alkynylzinc solution.
• the resulting yellow solution was treated with chloroacetyl chloride (8.8 mL, 110 mmol) dropwise over 10 minutes.
• the reaction mixture was quenched by the addition of cold aqueous 1M HC1 (50 mL), and diethyl ether (500 mL).
• the acidic aqueous was extracted with diethyl ether (2 x 50 mL) and the combined organic extracts were washed with water (50 mL), saturated NaHC0 3 (50 mL), and brine (50 mL).
• Chloro-4-phenyl-3-butyn-2-one (1.6 g, 9.1 mmol) was dissolved in dry acetonitrile (15 mL), treated with thioacetamide (680 mg, 9.1 mmol), and heated to reflux for 4 h. After cooling, the acetonitrile was removed in vacuo, and the residue was partitioned between water (50 mL) and ethyl acetate (150 mL).
• the hot solution was treated with decolorizing carbon and filtered hot to afford a pale brown solution, which was treated with hexane until cloudy, then heated to afford a clear solution.
• the solution was seeded with authentic product and allowed to crystallize. After cooling to ambient temperature the material was stored in the freezer for 16 h. The supernatant solution was decanted and the crystalline solids were pumped down under high vacuum to afford crystalline 2- methyl-4-(phenylethynyl)- 1,3 -thiazole, p-toluenesulfonic acid salt (260 mg, 52% yield) as brown crystals. M.p. 131-132.5°C.
• N-Bromosuccinimide (30 g, 170 mmol) was suspended in CC1 (150 mL) and 4-methylthiazole (15 g, 150 mmol) was added in one portion. The mixture was heated under reflux for 4 h then allowed to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water, then brine. The organics were dried over Na 2 SC> 4 , filtered and concentrated in vacuo.
• the filter pad was washed thoroughly with ethyl acetate and the combined filtrates were washed with water (20 mL), brine (20 mL), dried over Na 2 S0 4 , and filtered.
• the filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 95:5 hexane:ethyl acetate to afford 5-[(2-fluorophenyl)ethynyl]-4-methyl- 1,3- thiazole (690 mg, 56% yield) as a red oil.
• Example 51 2-fPhenylethynvD-1.3-thiazole, p-toluenesulfonic acid salt 2-Bromo- 1,3-thiazole (2.0 g, 12 mmol) and Cul (460 mg, 2.4 mmol) were combined in DME
• Example 52 4-Bromo-2-(phenylethynyl)-1.3-thiazole 2,4-Dibromo- 1,3-thiazole (2.0 g, 8.2 mmol) and Cul (312 mg, 1.64 mmol) were combined in
• N-[(Dimethylamino)methylene] -cinnamamide (1.0 g, 5.0 mmol) was added to a solution of hydroxylamine hydrochloride (415 mg, 6.0 mmol) in acetic acid (5 mL of 70% aqueous) and aqueous ⁇ aOH (1.2 mL, 5 M, 6.0 mmol). After stirring for 1.5 h water (5 mL) was added , and the reaction mixture was cooled to 5° C in an ice bath.
• the cooled solution was made basic (pH 8) with K 2 C0 3 , and partitioned between ethyl acetate and water. The organics were dried over Na 2 S0 , and concentrated in vacuo. The resultant solids were triturated with hot ethyl acetate, and the soluble portion was purified by flash column chromatography on silica eluting with 2:1 hexane:ethyl acetate to afford 5-[(E)-2-phenylethenyl]- 1,2,4- oxadiazole (60 mg, 8% yield) as a white powder. M.p. 53-55°C.
• N-[(Dimethylamino)methylene] -cinnamamide (2.0 g, 10 mmol) was added to a mixture of acetic acid (20 mL) and methylhydrazine (0.6 mL, 11 mmol). The mixture was heated to 90° C for 2 h. The cooled mixture was concentrated in vacuo, and made basic (pH 9) with solid K 2 C0 3 . The aqueous residue was partitioned between ethyl acetate and water, the organics were dried over ⁇ a 2 S0 , and concentrated in vacuo. The resultant powder was recrystallized from a minimum of boiling Ethyl acetate.
• Cinnamamide (1.9 g, 13 mmol) was mixed with chlorocarbonylsulphenylchloride (1.0 mL, 13 mmol) in chloroform and heated to reflux for 18 h.
• the reaction mixture was concentrated in vacuo and the resultant material was taken up in boiling hexane (100 mL). The solvent was decanted from the remaining solid, the volume of this solution was reduced by half, and the solution was allowed to cool.
• Phenylethenyl]-l,3,4-oxathiazol-2-one (1.4 g, 7.0 mmol) was mixed with ethyl cyanoformate (2.4 g, 25 mmol) in xylenes, and heated to reflux for 3 h. The reaction mixture was concentrated in vacuo, and the resulting material was recrystallized from ethyl acetate-ethanol (1:1) to give ethyl 3-[(E)-2- phenylethenyl]-l,2,4-thiadiazole-5-carboxylate (1.2 g, 66% yield) as a light yellow solid. M.p. 79- 80°C.
• 2-Indanone (l.Og, 7.6 mmol) was dissolved in THF (60 mL) and cooled to -78°C in an argon blanketed flask. Potassium hexamethyl disilazide (9.1 mmol, 18.2 mL of a 0.5M solution in toluene) was added dropwise to this stirred solution. After 30 min, N-phenyl trifluoromethanesulfonimide (4.05 g, 11.4 mmol) was added as a solution in THF (15 mL).
• reaction was stirred for 15 min at -78°C, then brought to ambient temperature and stirred for an additional 1 h, after which time it was quenched with H 2 0 (15 mL) and diluted with ethyl acetate (500 mL). The ethyl acetate solution was washed with H 2 0 (3 x 100 mL) and brine (100 mL), then dried (MgS0 ), filtered, and concentrated in vacuo.
• the enol triflate (500 mg, 1.89 mmol) and 2-ethynyl pyridine (579 mg, 5.62 mmol) were dissolved in DME (10 mL) and deoxygenated via argon bubbling for 20 min and then added via syringe to a deoxygenated DME (25 mL) solution of triphenylphosphine (100 mg, 0.38 mmol), t ⁇ -triphenylphosphine palladium dichloride (133 mg, 0.19 mmol), Cul (72 mg, 0.38 mmol), and triethylamine (954 mg, 1.32 mL, 9.45 mmol).
• the reaction was capped with a reflux condenser and stirred at 80°C for 1.5 h, after which time it was cooled to ambient temperature and poured in to a separatory funnel containing ethyl acetate (300 mL), where it was washed with ⁇ 2 0 (2 x 100 mL) and brine (100 mL). The ethyl acetate layer was dried (MgS0 4 ), filtered, and concentrated in vacuo.
• 2,6-Lutidine (547 mg, 594 ⁇ L, 5.1 mmol) was added neat, via syringe to a stirred, argon blanketed solution of ⁇ -tetralone (500 mg, 3.4 mmol) in methylene chloride (30 mL) at ambient temperature. After 5 min, trifluoromethanesulfonic anhydride (1.439 g, 858 ⁇ L, 5.1 mmol) was added slowly via syringe. After 1.5 h, the reaction was quenched with saturated aqueous NaHC ⁇ 3 (5 mL) and partitioned between ethyl acetate (200 mL) and H 2 0 (50 mL).
• the reaction was then warmed to ambient temperature, stirred for 1 h, and quenched with 5 mL H 2 0.
• the reaction was then diluted with ethyl acetate (250 mL) and extracted with H 2 0 (3 x 75 mL). The combined aqueous portions were back-extracted with ethyl acetate (100 mL). The ethyl acetate layers were combined, dried over MgS0 , filtered, and concentrated in vacuo.
• Example 70 Synthesis of 2-[(7grt-butoxycarbonvDaminolbenzoic acid Anthranilic acid (1.37 g, 10.0 mmol) and di-tert-butyl dicarbonate (3.12 g, 14.3 mmol) were added to a stirred mixture of 0.5M NaOH (20.0 mL), dioxane (10.0 mL), and CH 3 CN (2.0 mL) at 0°C. The cold bath was removed, and the reaction mixture was stirred at ambient temperature for 16 h before quenching with 10% aqueous citric acid (30 mL). The mixture was diluted with H 0 (100 mL) in a separatory funnel and extracted with methylene chloride (3 x 100 mL).
• the tert-butyl 2-formylphenylcarbamate from Example 73 (250 mg, 0.77 mmol) was deprotected without incident by dissolving the compound in dioxane (10 mL), treating it with 4M HCl in dioxane (30 mL, 120 mmol HCl), and stirring for 2.5 h, resulting in precipitation from solution of the l-(2-aminophenyl)-3-(2-pyridinyl)-2-propyn-l-ol as the hydrochloride salt.
• the dioxane solvent was decanted, the precipitate was triturated with diethyl ether (3 x 20 mL) and dried in vacuo to obtain the crude deprotected material as a pale pink solid.
• the deprotection was assumed to be quantitative, and the crude material was therefore carried on to the next step, dissolving it in a solution of diisopropylethylamine (500 mg, 674 ⁇ L, 3.87 mmol) in methylene chloride (20 mL).
• the reaction flask was cooled to 0°C, and phosgene (1.935 mmol, 1.02 mL of a 1.89M solution in toluene) was added dropwise to the stirred solution.
• N-Carbethoxy-4-tropinone 500 mg, 2.54 mmol was dissolved in THF (25 mL) and cooled to -
• the toluenesulfonate salt was then prepared by adding solid toluenesulfonic acid to a solution of ethyl 3-(2- pyridinylethynyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (200 mg, 0.69 mmol) in ethanol (10 mL). The mixture was stirred for 5 min until all solids were dissolved, after which time the solution was concentrated in vacuo. The resulting red oil was triturated with ether (3 x 10 mL) and placed under high vacuum, where it foamed to a dark red semi-solid.
• reaction mixture was warmed to 60°C, and tetrabutylammonium fluoride (1.33 mmol, 1.33 mL of a 1.0 M solution in THF) was added slowly over 1.5 h.
• the reaction was then cooled to ambient temperature and poured into a separatory funnel containing 1: 1 hexanes:ethyl acetate (200 mL) where it was washed with 50% dilute brine (3 x 75 mL), dried (MgS0 4 ), filtered, and concentrated in vacuo.
• Example 79 4-bromoisoquinoline (691 mg, 3.32 mmol) and 4-[(trimethylsilyl)ethynyl]-l,3-thiazol-2-amine from Example 78 (500 mg, 2.55 mmol) were cross-coupled to obtain 4-(4-isoquinolinylethynyl)-l,3-thiazol-2-amine (262 mg, 41% yield) as a tannish-orange solid after eluting with 2:1 hexanes:ethyl acetate from a silica gel column. This material was then solubilized in ether (15 mL) and precipitated as the yellow hydrochloride salt (M.p.
• PdCl 2 (166 mg, 0.93 mmol), Cul (481 mg, 2.52 mmol), and triethylamine (18 mL, 129 mmol) were combined in DME (50 mL) under argon. Argon gas was bubbled through the resulting dark suspension while it was warmed to 70°C in an oil bath. Triphenylphosphine (978 mg, 3.73 mmol) was added and the argon flow was continued for 10 min.
• reaction was warmed to 50°C, and tetrabutylammonium fluoride (2.10 mmol, 2.10 mL of a 1.0M solution in THF) was added slowly over 1.5 h.
• tetrabutylammonium fluoride (2.10 mmol, 2.10 mL of a 1.0M solution in THF) was added slowly over 1.5 h.
• the reaction was then cooled to ambient temperature and poured in to a separatory funnel containing 1 :1 hexanes:ethyl acetate (200 mL) where it was washed with 50%) dilute brine (3 x 75 mL), dried (MgS0 ), filtered, and concentrated in vacuo.
• reaction was warmed to 50°C, and tetrabutylammonium fluoride (14.0 mmol, 14.0 mL of a 1.0M solution in THF) was added via syringe pump over 1.5 h.
• the reaction was then cooled to ambient temperature and poured into a separatory funnel containing 1:1 hexanes: ethyl acetate (400 mL) where it was washed with 50% dilute brine (3 x 100 mL). The aqueous portion was back-extracted with 1:1 hexanes:ethyl acetate (100 mL).
• Example 79 Following the procedure and mole equivalents indicated above for Example 79 the 3-iodo-l-(methylsulfonyl)-lH- indole (350 mg, 1.09 mmol) and 2-methyl-4-[(trimethylsilyl)ethynyl]-l,3-thiazole from Example 77 (150 mg, 0.77 mmol) were cross-coupled to obtain l-(methylsulfonyl)-3-[(2-methyl-l,3-thiazol-4- yl)ethynyl]-lH-indole (55 mg, 23% yield) as a tan solid after eluting with 4:1 hexanes:ethyl acetate from a silica gel column.
• reaction was warmed to 50°C, and tetrabutylammonium fluoride (13.8 mmol, 13.8 mL of a 1.0M solution in THF) was added via syringe pump over 1.5 h. The reaction was then cooled to ambient temperature and poured into a separatory funnel containing 1 :1 hexanes:ethyl acetate (200 mL) where it was washed with 50%) dilute brine (3 x 75 mL), dried (MgS0 4 ), filtered, and concentrated in vacuo.
• Phenylboronic acid (569 mg, 4.26 mmol) and 2-chloro-5-[(2-methyl-l,3-thiazol-4- yl)ethynyl]pyridine from Example 88 (1.00 g, 4.26 mmol) were dissolved in DME (10 mL) and deoxygenated via argon bubbling for 20 min.
• Example 89 Following the procedure and mole equivalents indicated above for Example 89, 4-chloro phenylboronic acid (74 mg, 0.47 mmol) and 2-chloro-5-[(2-methyl-l,3-thiazol-4-yl)ethynyl]pyridine from Example 88 (100 mg, 0.43 mmol) were cross-coupled to obtain 2-(4-chlorophenyl)-5-[(2-methyl- l,3-thiazol-4-yl)ethynyl]pyridine (105 mg, 79% yield) as a white solid after eluting with 3:1 hexanes:ethyl acetate from a silica gel column.
• Example 89 4-methoxy phenylboronic acid (106 mg, 0.70 mmol) and 2-chloro-5-[(2-methyl-l,3-thiazol-4-yl)ethynyl]pyridine from Example 88 (150 mg, 0.64 mmol) were cross-coupled to obtain 2-(4-methoxyphenyl)-5-[(2- methyl-l,3-thiazol-4-yl)ethynyl]pyridine (156 mg, 80% yield) as a white solid, M.p. 125-126°C, after eluting with 2:1 hexanes:ethyl acetate from a silica gel column.
• Example 89 Following the procedure and mole equivalents indicated above for Example 89, pyridine-3- boronic acid (86 mg, 0.70 mmol) and 2-chloro-5-[(2-methyl-l,3-thiazol-4-yl)ethynyl]pyridine from Example 88 (150 mg, 0.64 mmol) were cross-coupled to obtain 2-(3-pyridyl)-5-[(2-methyl-l,3-thiazol- 4-yl)ethynyl]pyridine (80 mg, 45% yield) as a pale yellow solid after eluting with 1:1 hexanes:ethyl acetate from a silica gel column.
• Example 89 Following the procedure and mole equivalents indicated above for Example 89, pyridine-4- boronic acid (86 mg, 0.70 mmol) and 2-chloro-5-[(2-methyl-l,3-thiazol-4-yl)ethynyl]pyridine from Example 88 (150 mg, 0.64 mmol) were cross-coupled to obtain 2-(4-pyridyl)-5-[(2-methyl-l,3-thiazol- 4-yl)ethynyl]pyridine (30 mg, 17% yield) as an off-white solid after eluting with 2: 1 ethyl acetate :hexanes from a silica gel column.
• Phenylboronic acid (566 mg, 4.4.64 mmol) and 2,5-dibromopyridine (1.00 g, 4.22 mmol) were dissolved in DME (10 mL) and deoxygenated via argon bubbling for 20 min. This solution was then added via syringe to a deoxygenated solution of triphenylphosphine (111 mg, 0.42 mmol), bis- triphenylphosphine palladium dichloride (148 mg, 0.21 mmol), and potassium carbonate (1.17 g, 8.44 mmol) in DME (15 mL) and H 2 0 (25 mL) at 40°C.
• triphenylphosphine 111 mg, 0.42 mmol
• bis- triphenylphosphine palladium dichloride 148 mg, 0.21 mmol
• potassium carbonate (1.17 g, 8.44 mmol
• reaction 16 h, the reaction was cooled to ambient temperature and chloroformate polystyrene (95 mg of 1.0 mmol/g beads, 0.10 mmol) was added. The reaction was allowed to shake at 40°C for 1 hour, cooled to ambient temperature, and treated with tris (2-aminoethyl)amine polystyrene (22 mg of 4.5 mmol/g beads, 0.10 mmol). The reaction was then allowed to shake at 40°C for 1 hour, then cooled, and diethyl ether (0.6 ml) was added. The reaction was vortexed and filtered using a fritted syringe attached to a vacuum block.
• Trimethylphosphonoacetate (462 mg, 2.5 mmol) was dissolved in THF (20 mL) and the solution was cooled to 0° C at which time LiHDMS (2.6 mL, 1.0 M in THF) was added slowly. After 30 min 3-(2-pyridinylethynyl)-2-cyclohexen-l-one from Example 104 (0.5 g, 2.5 mmol) was added and the solution was allowed to warm to ambient temperature.
• Example 110 The procedure was carried out as for Example 110 using 3-trifluoromethylcyclohexanone (960 mg, 6.0 mmol), to yield a 3:1 mixture of 2- ⁇ [5-(trifluoromethyl)-l-cyclohexen-l-yl]ethynyl ⁇ pyridine and 2- ⁇ [3 -(trifluoromethyl)- l-cyclohexen-l-yl]ethynyl ⁇ pyridine (0.51 g, 43% ) as a brown oil.
• 3-trifluoromethylcyclohexanone 960 mg, 6.0 mmol
• Example 110 The procedure was carried out as for Example 110 using cis/trans 2-decalone (1.83 g, 12 mmol) to yield a mixture of four stereoisomers each of 2-(l,4,4a,5,6,7,8,8a-octahydro-2- naphthalenylethynyl)pyridine & 2-(3,4,4a,5,6,7,8,8a-octahydro-2-naphthalenylethynyl)pyridine (0.50 g, 9%) as a brown oil.
• reaction mixture was then cooled to 22°C and filtered through a pad of CeliteTM.
• the filtrate was concentrated under reduced pressure to give, after purification by flash chromatography on silica gel eluting with 3:1 hexane:ethyl acetate, the desired compound as a brown crystal which was subsequently treated with a solution of IM HCl in diethyl ether (20 mL) to yield 4,6-dimethyl-2- (phenylethynyl)pyrimidine hydrochloride as a yellow solid (3.0 g, 55%).
• reaction mixture was allowed to cool to 22°C and filtered through a pad of CeliteTM.
• the filtrate was concentrated under reduced pressure to give, after purification by flash chromatography on silica gel eluting with 4:1 hexane:ethyl acetate, methyl 2-(2- pyridinylethynyl)-l-cyclopentene-l -carboxylate as a brown solid (1.2 g, 72 %).
• Example 127 (100 mg, 0.47 mmol) in CH 2 C1 2 (2 mL) was added HOBT (95 mg, 0.70 mmol), EDCI (135 mg, 0.70 mmol), triethylamine (0.2 mL, 1.4 mmol) and 1-methylpiperazine (123 mg, 0.70 mmol) at 22°C.
• the reaction mixture was stirred for 18 h and then diluted with an additional amount of CH 2 CI 2 (50 mL).
• the organic phase was washed with sat. NaHC0 3 (2 x 25 mL) and sat. NaCl (2 x 25), dried (MgS ⁇ 4 ), filtered and concentrated in vacuo to give a yellow oil.
• Example 135 Synthesis of 5- ⁇ 5-[(2-methyl-1 -thiazol-4-v0ethvnyll-3-pyridinyUpyrimidine hydrochloride A solution of 3-bromo-5-[(2-methyl-l,3-thiazol-4-yl)ethynyl]pyridine from Example 132 (100 mg, 0.36 mmol) in 2: 1 DMF:H 2 0 (5 mL) was degassed with argon for 10 min.
• reaction mixture was heated at 90°C under argon overnight, allowed to cool to 22°C and filtered through a pad of CeliteTM.
• the filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel eluting with 2:1 hexane:ethyl acetate to give 3-(3,5-dimethyl-4-isoxazolyl)-5-[(2-methyl-l,3-thiazo-4- yl)ethynyl]pyridine as a yellow solid.
• reaction mixture was heated at 90°C under argon for 1 h, then allowed to cool to 22°C and filtered through a pad of CeliteTM.
• the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 1: 1 hexane:ethyl acetate to give 3-(4-methoxyphenyl)-5-[(2-methyl-l,3-thiazol-4- yl)ethynyl]pyridine as a yellow solid.
• PdCl 2 (45 mg, 0.25 mmol) was suspended in DME (20 mL), then argon was bubbled through the solution for several min to deoxygenate it.
• H 2 0 (6.6 mL)
• K 2 C0 3 (4.5 g, 32 mmol)
• CH 3 OH (20 mL)
• 2-bromo- 1,3 -thiazole (2.63 g, 16.1 mmol)
• PPh 3 280 mg, 1.07 mmol
• Cul 204 mg, 1.07mmol
• the orange- brown solution was concentrated in vacuo, diluted with ethyl acetate (300 mL), washed with saturated aqueous NaHCC> 3 (2 x 75 mL), brine (150 mL), dried over Na 2 S0 4 , filtered and concentrated in vacuo to afford an orange semi-solid.
• the crude product was purified by column chromatography on silica gel eluting with hexane, then 3:1 hexane:ethyl acetate to afford 3-ethoxy-5,5-dimethyl-2-cyclohexen-l-one (13.5 g, 44%) as an orange oil that slowly solidified.
• PdCl 2 (27 mg, 0.15mmol) was suspended in DME (20 mL), then argon was bubbled through the solution for several min to deoxygenate it.
• K 2 C0 3 (2.5 g, 18 mmol)
• CH 3 OH (20 mL)
• 2- bromo-l,3-thiazole (1.0 g, 6.1 mmol)
• PPh 3 160 mg, 0.61 mmol
• Cul 118 mg, 0.61 mmol
• Example 156 Synthesis of l-[(6-methyl-2-pyridinyl)ethvnyllcvclopentanol PdCl 2 (PPh 3 ) 2 (320 mg, 0.45 mmol) was suspended in DME (20 mL) then argon was bubbled through the solution for several min to deoxygenate it. 2-Bromo-6-methylpyridine (1.9 g, 11 mmol), triethylamine (6.3 mL, 45 mmol) and Cul (170 mg, 0.91 mmol) were added and the reaction was heated to 50°C. After a few min 1-ethynyl cyclopentanol (1.0 g, 9.1 mmol) was added to the dark brown suspension.
• the reaction was heated to 60°C, and after 16 h at 60°C GC/MS and TLC analysis showed the reaction to be complete.
• the mixture was diluted with ethyl acetate (200 mL), and filtered through CeliteTM. The filter pad was then thoroughly washed with ethyl acetate and the combined filtrates were washed with H 2 O (200 mL), brine (200 mL), dried over Na 2 S0 4 , and filtered.
• Example 158 Synthesis of Racemic 2-([( " cis)-3,4-dimethyl-l-cyclopenten-l-yllethvnyl)pyridine
• n-BuLi 16.8 mL of a 2.5M solution in hexanes, 42.0 mmol
• diisopropylamine 5.9 mL, 42 mmol
• dry THF 40 mL
• the reaction was allowed to warm gradually to ambient temperature, and after stirring for 16 h at ambient temperature GC/MS showed no remaining cis-3,4-dimethylcyclopentanone.
• the reaction was quenched with NaHC ⁇ 3 (2mL), DME (30 mL) was added, and argon was bubbled through the solution for several min to deoxygenate it.
• a cis-trans mixture of 2-[(3,4-dimethyl-l-cyclopenten-l-yl)ethynyl]pyridine was separated by preparative reverse phase HPLC (Zorbax SB-C18 15cm x 21 mm x 5 ⁇ m dp; Mobile phase A: 100:0.1 H 2 0:TFA, Mobile phase B: 100:0.1 acetonitrile:TFA; 30% B at 20 mL/min.)
• the resulting trifluoroacetic acid salt of the trans isomer was suspended in aqueous K CO 3 and the resulting aqueous suspension was extracted with ethyl acetate.
• Triethylamine (0.8 mL, 5 mmol), was added, and the reaction mixture was warmed to 40°C, then a solution of 2-bromo- 1,3-thiazole (218 mg, 1.32 mmol) and 2-methyl-4-[(trimethylsilyl)ethynyl]-l,3-thiazole from Example 77 (200 mg, 1.02 mmol) in DMF (10 mL) added.
• the reaction was warmed to 70°C and tetrabutylammonium fluoride (1.3 L of a l.OM solution in THF, 1.3 mmol) was added by syringe pump over 1 h. After stirring for an additional 2 h, GC/MS analysis showed the reaction to be complete.
• Triethylamine (0.8 mL, 5 mmol), was added, the reaction mixture was warmed to 40°C, then a solution of 3-bromopyridine (210 mg, 1.32 mmol) and 4-[(trimethylsilyl)ethynyl]-l,3-thiazol-2-ylamine from Example 78 (200 mg, 1.02 mmol) in DMF (10 mL) added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (1.3 mL of a l .OM solution in THF, 1.3 mmol) was added by syringe pump over 1 h. After stirring for an additional 2 h, GC/MS analysis showed the reaction to be complete.
• Example 163 Synthesis of 4-[(2-methyl-1 -thiazol-4-yl)ethvnyllisothiazole Cul (60.0 mg, 0.31 mmol), PdCl 2 (PPh 3 ) 2 (109 mg, 0.15 mmol), PPh 3 (82 mg, 0.31 mmol), and tetrabutylammonium iodide (440 mg, 1.2 mmol) were combined in dry DMF (20 mL) and argon gas was bubbled through the mixture for several min to deoxygenate it.
• Triethylamine (0.8 mL, 5 mmol), was added, and the reaction mixture was warmed to 40°C, then a solution of 4-bromoisothiazole (200 mg, 1.2 mmol) and 2-methyl-4-[(trimethylsilyl)ethynyl]-l,3-thiazole from Example 77 (360 mg, 1.8 mmol) in DMF (10 mL) was added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (1.6 mL of a l.OM solution in THF, 1.6 mmol) was added by syringe pump over 1 h. After stirring for an additional 2 h, GC/MS analysis showed the reaction to be complete.
• Triethylamine (0.8 mL, 5 mmol), was added, the reaction mixture was warmed to 40°C, then a solution of 4-bromo-l,3-thiazole (200 mg, 1.2 mmol) and 2-methyl-4-[(trimethylsilyl)ethynyl]-l,3-thiazole from Example 77 (360 mg, 1.8 mmol) in DMF (10 mL) was added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (1.6 mL of a l.OM solution in THF, 1.6 mmol) was added via syringe pump over 1 h. After stirring for an additional 2 h, GC/MS analysis showed the reaction to be complete.
• Example 165 Synthesis of 5-[(2-methyl-l ,3-thiazol-4-vDethvnyl1isothiazole Cul (60 mg, 0.31 mmol), PdCl 2 (PPh 3 ) 2 (110 mg, 0.15 mmol), PPh 3 (82 mg, 0.31 mmol), and tetrabutylammonium iodide (440 mg, 1.2 mmol) were combined in dry DMF (20 mL) and argon gas was bubbled through the mixture for several min to deoxygenate it.
• PdCl 2 (PPh 3 ) 2 110 mg, 0.15 mmol
• PPh 3 82 mg, 0.31 mmol
• tetrabutylammonium iodide 440 mg, 1.2 mmol
• Triethylamine (0.8 mL, 5 mmol), was added, and the reaction mixture was warmed to 40°C, then a solution of 5-bromoisothiazole (200 mg, 1.2 mmol) and 2-methyl-4-[(trimethylsilyl)ethynyl]-l,3-thiazole from Example 77 (360 mg, 1.8 mmol) in DMF (10 mL) was added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (1.6 mL of a l.OM solution in THF, 1.6 mmol) was added by syringe pump over 1 h. After stirring for an additional 2 h, GC MS analysis showed the reaction to be complete.
• Triethylamine (1 mL, 8 mmol), was added, and the reaction mixture was warmed to 40°C, then a solution of 4-bromobiphenyl (515 mg, 2.2 mmol) and 2-[(trimethylsilyl)ethynyl]pyrimidine from Example 81 (300 mg, 1.7 mmol) in DMF (10 mL) was added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (2.2 mL of a l.OM solution in THF, 2.2 mmol) was added by syringe pump over 2 h. After stirring for an additional 2 h, GC/MS analysis showed the reaction to be complete.
• the mixture was diluted with ethyl acetate (50 mL) and filtered through CeliteTM.
• the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were washed with H 2 0 (2 x 200 mL), brine (200 mL), dried over Na 2 S ⁇ 4 _ filtered, and concentrated in vacuo.
• the residue was purified by column chromatography on silica gel eluting with hexane, 9: 1, then 8.5:1.5 hexane:ethyl acetate to afford 2-([l,P-biphenyl]-4-ylethyny ⁇ )pyrimidine (200 mg, 46%) as a yellow solid.
• PdCl 2 (15 mg, 85 ⁇ mol), and Cul (23 mg, 120 ⁇ mol) were combined in DME (3 mL) under argon. H 2 0 (1 mL) was added and argon was bubbled through the resulting dark suspension while it was warmed to 40°C in an oil bath. Triphenylphosphine (84 mg, 320 ⁇ mol) was added and the argon flow was continued for 10 min.
• Triethylamine (1.0 mL, 7.4 mmol), was added, the reaction mixture was warmed to 40°C, and a solution of 4-bromo-l,l'- biphenyl (446 mg, 1.9 mmol) and 2,4-dimethyl-6-[(trimethylsilyl)ethynyl]pyrimidine from Example 170 (300 mg, 1.47 mmol) in DMF (10 mL) was added. The reaction mixture was warmed to 70°C and tetrabutylammonium fluoride (1.9 mL of a 1.0 M solution in THF, 1.3 mmol) was added by syringe pump over 2 h.
• Triethylamine (0.8 mL, 8 mmol), was added, the reaction mixture was warmed to 40°C, and a solution of 4-bromo- l,l'-biphenyl (515 mg, 2.2 mmol) and 2-[(trimethylsilyl)ethynyl]pyrazine from Example 172 (300 mg, 1.7 mmol) in DMF (10 mL) was added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (2.2 mL of a 1.0 M solution in THF, 2.2 mmol) was added by syringe pump over 2 h. After stirring for an additional 2 h, TLC and GC/MS analysis showed the reaction to be complete.
• the mixture was diluted with ethyl acetate (50 mL) and filtered through CeliteTM.
• the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were washed with H 2 0 (2 x 200 mL), brine (200 mL), dried over Na 2 S0 , filtered, and concentrated in vacuo.
• the residue was purified by column chromatography on silica gel eluting with hexane, 18:1, 9:1, then 8.5: 1.5 hexane:ethyl acetate to afford 2-([l,l'-biphenyl]-4-ylethynyl)pyrazine (100 mg, 23%) as a yellow solid.
• PdCl 2 (234 mg, 1.32 mmol), Cul (737 mg, 3.87 mmol), and triethylamine (23 mL, 165 mmol) were combined in DME (50 mL) under argon. Argon was bubbled through the suspension, and after 10 min triphenylphosphine (1.37 g, 5.22 mmol) was added and the reaction flask was immersed in a 50°C oil bath.
• Triethylamine (0.8 mL, 8 mmol), was added, the reaction mixture was warmed to 40°C, and a solution of 4-bromo-l,l'- biphenyl (515 mg, 2.2 mmol) and 4,6-dimethyl-2-[(trimethylsilyl)ethynyl]pyrimidine from Example 174 (340 mg, 1.7 mmol) in DMF (10 mL) was added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (2.2 mL of a 1.0 M solution in THF, 2.2 mmol) was added by syringe pump over 2 h.
• Triethylamine (0.20 mL in 20 mL dry diethylether, 1.5 mmol) was added by addition funnel during 2 h. After stirring for an additional 2 h, TLC and GC/MS analysis showed the reaction was not complete, another 1.5 mmol of N-hydroxybenzenecarboximidoyl chloride and triethylamine was added as described above. After stirring for an additional 2h, the mixture was diluted with diethylether (50 mL) and washed with H 2 0 (100 mL), brine (100 mL), dried over Na 2 S0 4 , filtered, and concentrated in vacuo.
• Triethylamine (0.71 mL, 5.1 mmol) was added, the reaction mixture was warmed to 40°C, and a solution of 5-bromo-2- methoxypyridine (231 mg, 1.23 mmol) and 2-methyl-4-[(trimethylsilyl)ethynyl]-l,3-thiazole from Example 77 (200 mg, 1.0 mmol) in DMF (10 mL) was added. The reaction was warmed to 70°C and tetrabutylammonium fluoride (1.3 mL of a 1.0 M solution in THF, 1.3 mmol) was added by syringe pump over 2 h.
• the activity of compounds was examined against the hmGluR5a receptor stably expressed in mouse fibroblast Ltk " cells (the hmGluR5a/L38-20 cell line). See generally Daggett et al, Neuropharmacology 34:871-886 (1995). Receptor activity was detected by changes in intracellular calcium ([Ca ⁇ ],) measured using the fluorescent calcium-sensitive dye, fura-2. hmGluR5a/L38-20 cells were plated onto 96-well plates, and loaded with 3 ⁇ M fura-2 for 1 h.
• Mouse fibroblast Ltk cells expressing hmGluR5 (hmGluR5/L38-20 cells) were seeded in 24-well plates at a density of 8xl0 5 cells/well.
• HBS Hepes buffered saline buffer
• the cells were washed with HBS containing 10 mM LiCl, and 400 ⁇ l buffer added to each well. Cells were incubated at 37°C for 20 min. For testing, 50 ⁇ l of 10X compounds used in the practice of the invention (made in HBS/LiCl (100 mM)) was added and incubated for 10 minutes. Cells were activated by the addition of 10 ⁇ M glutamate, and the plates left for 1 hour at 37°C.
• HBS Hepes buffered saline buffer
• IPs inositol phosphates
• Example 186 Analgesic Animal Model (CFA Model) Compounds that modulate receptor-mediated analgesic responses were tested in an animal model. Robust inflammation was induced by the injection of complete Freund's adjuvant (CFA, 10 mg/ml) subcutaneously into the hind paw of male Sprague-Dawley rats (150-175 g). The inflammatory response to CFA began approximately 12-hrs post-CFA injection and persisted for several days following inoculation. The inflamed hind paw became sensitive to noxious (paw pinch, plantar test) or innocuous (cold plate, Von Frey filaments) stimuli compared to the contralateral hind paw. Test compounds (240 ⁇ mol/kg) were administered via intraperitoneal injection.
• CFA complete Freund's adjuvant
• the analgesic activity of compounds was evaluated one to 24-hours post administration by assessing (1) the duration of analgesic effect; (2) threshold to elicit response; and (3) time from painful stimulus to response.
• a general increase in duration of analgesic effect, threshold to painful stimuli or time to respond following compound administration suggested analgesic efficacy.
• responses following administration of certain exemplary compounds were compared to responses prior to compound administration. Results are presented in Table 1.
• 2-(phenylethynyl)- 1,3 -thiazole Various salt forms of 2-(phenylethynyl)- 1,3 -thiazole were prepared, and their solubility, hygroscopicity, and physical state were assessed.
• the compound 2-phenylethynl- 1,3 -thiazole was prepared (see Example 8) as well as hydrochloric acid, fumaric acid, methylsulfonic acid and toluene sulfonic acid salt forms of the compound.
• the hydrochloric acid salt form of 2-(phenylethynyl)- 1,3- thiazole is an oil.
• a fumaric acid salt form was not obtained by preparative steps including trituration with diethylether.
• the methylsulfonate form results in a semi solid, hygroscopic material.
• These salt forms are typically unsuitable for certain pharmaceutical formulations, such as for tablets, capsules, and the like.
• the tosylate salt form i.e., the toluene sulfonic acid salt
• the tosylate salt form is a solid having a melting point of about 129 up to 131°C and is non-hygroscopic. Therefore, this form is presently preferred for pharmaceutical formulations of tablets, capsules, and the like.

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