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  • C07D495/04—Ortho-condensed systems

Definitions

• This invention relates to enzyme inhibitors and methods of treating diseases and conditions, wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective, along with a reduction in undesirable side effects.
• DAAO D-amino acid oxidase
• NMDA N-methyl-D-aspartate
• NMDA receptors are complex ion channels containing multiple protein subunits that act either as binding sites for transmitter amino acids and/or as allosteric regulatory binding sites to regulate ion channel activity.
• D-serine released by glial cells, has a distribution similar to NMDA receptors in the brain and acts as an endogenous ligand of the allosteric "glycine" site of these receptors (Mothet et al., PNAS, 97:4926 (2000)), the occupation of which is required for NMDA receptor operation.
• D-serine is synthesized in brain through serine racemase and degraded by D-amino oxidase (DAAO) after release.
• DAAO D-amino oxidase
• NMDA receptor activity is important in a variety of disease states, such as schizophrenia, psychosis, ataxias, ischemia, several forms of pain including neuropathic pain, and deficits in memory and cognition.
• DAAO inhibitors may also control production of toxic metabolites of D- serine oxidation, such as hydrogen peroxide and ammonia. Thus, these molecules may influence the progression of cell loss in neurodegenerative disorders.
• Neurodegenerative diseases are diseases in which CNS neurons and/or peripheral neurons undergo a progressive loss of function, usually accompanied by (and perhaps caused by) a physical deterioration of the structure of either the neuron itself or its interface with other neurons. Such conditions include Parkinson's disease,
• N-methyl-D- aspartate (NMDA)-glutamate receptors are expressed at excitatory synapses throughout the central nervous system (CNS). These receptors mediate a wide range of brain processes, including synaptic plasticity, that are associated with certain types of memory formation and learning.
• NMDA-glutamate receptors require binding of two agonists to induce neurotransmission. One of these agonists is the excitatory amino acid L-glutamate, while the second agonist, at the so-called “strychnine- insensitive glycine site", is now thought to be D-serine.
• D-serine is synthesized from L-serine by serine racemase and degraded to its corresponding ketoacid by DAAO. Together, serine racemase and DAAO are thought to play a crucial role in modulating NMDA neurotransmission by regulating CNS concentrations of D-serine.
• Known inhibitors of DAAO include benzoic acid, pyrrole-2-carboxylic acids, and indole-2-carboxylic acids, as described by Frisell, et al., J. Biol. Chem., 223:75-83 (1956) and Parikh et al., JACS, 80:953 (1958). Indole derivatives and particularly certain indole-2-carboxylates have been described in the literature for treatment of neurodegenerative disease and neurotoxic injury.
• EP 396124 discloses indole-2-carboxylates and derivatives for treatment or management of neurotoxic injury resulting from a CNS disorder or traumatic event or in treatment or management of a neurodegenerative disease.
• traumatic events that may result in neurotoxic injury are given, including hypoxia, anoxia, and ischemia, associated with perinatal asphyxia, cardiac arrest or stroke.
• Neurodegeneration is associated with CNS disorders such as convulsions and epilepsy.
• U.S. Pat. Nos. 5,373,018; 5,374,649; 5,686,461; 5,962,496 and 6,100,289, to Cugola disclose treatment of neurotoxic injury and neurodegenerative disease using indole derivatives. None of the above references mention improvement or enhancement of learning, memory or cognition.
• DAAO inhibitors including indole-2-carboxylic acids, and methods of enhancing learning, memory and cognition as well as methods for treating neurodegenerative disorders.
• Patent Application No. WO/2005/089753 discloses benzisoxazole analogs and methods of treating mental disorders, such as Schizophrenia.
• a need for additional drug molecules that are effective in treating memory defects, impaired learning, loss of cognition, and other symptoms related to NMDA receptor activity remains. The present invention addresses this and other needs.
• the invention provides novel inhibitors of D-amino acid oxidase that are useful in the prevention and treatment of a variety of diseases and/or conditions including neurological disorders, pain, ataxia, and convulsion.
• the present invention provides a compound having a structure according to Formula (II):
• Q is a member selected from O, S, N and CR 1 .
• X is a member selected from O, S, N, NR 3 and CR 2a and Y is a member selected from O, S, N, NR 3 and CR 2b , wherein R 1 is a member selected from H, F, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, and substituted or unsubstituted C4-C10 heterocycloalkyl.
• R 2a is a member selected from H, F, Cl, Br, CN, substituted or unsubstituted C 3 -C 6 alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C4-C10 cycloalkyl, substituted or unsubstituted C 4 -C 10 heterocycloalkyl and alkenyl.
• R 2b is a member selected from H, F, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, and substituted or unsubstituted C4-C1 0 heterocycloalkyl and alkenyl.
• R 3 is a member selected from H, substituted or unsubstituted Ci-C ⁇ alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C4-C 10 cycloalkyl, and substituted or unsubstituted C4-C 10 heterocycloalkyl.
• R 4 is a member selected from H, F, Cl, Br, CN, unsubstituted Ci-C ⁇ alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C4-C 10 cycloalkyl and alkenyl.
• R 6 is a member selected from O X + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• Q is CF and one member selected from X or Y is S and the other is CH
• R 4 is preferably other than H.
• R 2a and R 4 are other than H.
• Q is CH
• R 2a , R 2b and R 4 is preferably other than H.
• the invention provides a compound having a structure, which is a member selected from Formula (III) and Formula (IV):
• R 1 and R 2 are members independently selected from H, F, substituted or unsubstituted C 3 -C 6 alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, and substituted or unsubstituted C 4 -C 10 heterocycloalkyl and alkenyl.
• R 3 is a member selected from H, substituted or unsubstituted Ci-C ⁇ alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 - C ⁇ o cycloalkyl, and substituted or unsubstituted C 4 -Ci 0 heterocycloalkyl.
• R 4 is a member selected from H, F, Cl, Br, CN, unsubstituted Ci-C 6 alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C4-C10 cycloalkyl and alkenyl.
• R 6 is a member selected from 0 " X + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• X is S
• Y is CH and R 1 is F
• R 4 is preferably other than H.
• the invention provides a a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and a pharmaceutically acceptable carrier:
• Z is a member selected from O and S
• A is a member selected from NR 7 , S and O.
• Q is a member selected from O, S 5 N, NR 3a and CR 1 .
• X and Y are members independently selected from O, S, N, NR 3 and CR 2 , provided that when X and Y are both CR 2 , each R 2 is independently selected.
• R 3 , R 3a and R 7 are members independently selected from H, OR 12 , acyl, SO 2 R 13 , SOR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R 12 and R 13 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 , each R 2 and R 4 are members independently selected from H, F, Cl, Br, CN, CF 3 , acyl, OR 14 , S(O) 2 OR 14 , S(O)pR 14 , NR 14 R 15 , SO 2 NR 14 R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 and R 2 together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• the integer p is selected from 0 to 2.
• R 14 and R 15 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 14 and R 15 together with the nitrogen atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 6 is a member selected from O " X + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 7 is preferably not a member selected from:
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to Formula (VI) or Formula (VII), or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and a pharmaceutically acceptable carrier:
• A is a member selected from NH and S.
• X is a member selected from O, S and NR 3 .
• Y is a member selected from CR 2 and N.
• R 3 and R 7 are members independently selected from H, OR 12 , acyl, SO 2 R 13 , SOR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R 12 and R 13 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 , R 2 and R 4 are members independently selected from H, F, Cl, Br, CN, CF 3 , acyl, OR 14 , S(O) 2 OR 0 , S(O) p R 14 , NR 14 R 15 , SO 2 NR 14 R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; and R 1 and R 2 , together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• the integer p is selected from 0 to 2.
• R 14 and R 15 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 14 and R 15 together with the nitrogen atoms to which they are attached, are optionally joined to form a 5- to 7- membered ring.
• R 6 is a member selected from 0 " X + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• X is S and Y is CH
• R 4 is preferably not C(O)-2-thiophenyl.
• the invention provides a method for treating or preventing a condition which is a member selected from a neurological disorder, pain, ataxia and convulsion, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof:
• Z is a member selected from O and S.
• A is a member selected from NR 7 , S and O.
• Q is a member selected from O, S, N, NR 3a and CR 1 .
• X and Y are members independently selected from O, S, N, NR 3 and CR 2 , provided that when X and Y are both CR 2 , each R 2 is independently selected.
• R 3 , R 3a and R 7 are members independently selected from H, OR 12 , acyl, SO 2 R 13 , SOR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R 12 and R 13 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 , R 2 and R 4 are members independently selected from H, F, Cl, Br, CN, CF 3 , acyl, OR 14 , S(O) 2 OR 14 , S(O)pR 14 , NR 14 R 15 , SO 2 NR 14 R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 and R 2 together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 14 and R 15 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 14 and R 15 together with the nitrogen atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 6 is a member selected from 0 " X + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g., -CH 2 O- is intended to also recite -OCH 2 -.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-Cio means one to ten carbons).
• saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n- heptyl, n-octyl, and the like.
• An unsaturated alkyl group is one having one or more double bonds or triple bonds.
• alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4- pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
• alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl” with the difference that the heteroalkyl group, in order to qualify as an alkyl group, is linked to the remainder of the molecule through a carbon atom.
• Alkyl groups that are limited to hydrocarbon groups are termed "homoalkyl".
• alkenyl by itself or as part of another substituent is used in its conventional sense, and refers to a radical derived from an alkene, as exemplified, but not limited, by substituted or unsubstituted vinyl and substituted or unsubstituted propenyl.
• an alkenyl group will have from 1 to 24 carbon atoms, with those groups having from 1 to 10 carbon atoms being preferred.
• alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by — CH 2 CH 2 CH 2 CH 2 -, and further includes those groups described below as “heteroalkylene.”
• an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
• a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
• alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
• heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si, S, B and P and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
• heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 - CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
• heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -CO 2 R'- represents both -C(O)OR' and -OC(O)R'. [0022]
• the terms "cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl” and “heteroalkyl”, respectively.
• heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
• a "cycloalkyl” or “heterocycloalkyl” substituent may be attached to the remainder of the molecule directly or through a linker, wherein the linker is preferably alkylene.
• linker is preferably alkylene.
• Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
• heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6- tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
• halo or halogen
• haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
• halo(Ci -Chalky 1" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
• aryl means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently.
• heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, S, Si and B, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
• a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
• Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl,
• aryl when used in combination with other terms ⁇ e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
• arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group ⁇ e.g.
• alkyl including those alkyl groups in which a carbon atom ⁇ e.g., a methylene group) has been replaced by, for example, an oxygen atom ⁇ e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
• an oxygen atom ⁇ e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like.
• heteroaryl are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
• R', R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
• each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
• R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, S-, or 7- membered ring.
• -NR'R is meant to include, but not be limited to, 1- pyrrolidinyl and 4-morpholinyl.
• alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , - C(O)CH 2 OCH 3 , and the like).
• haloalkyl e.g., -CF 3 and -CH 2 CF 3
• acyl e.g., -C(O)CH 3 , -C(O)CF 3 , - C(O)CH 2 OCH 3 , and the like.
• Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CRR' ) q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from O to 3.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula — A-(CH 2 )r-B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -
• acyl describes a substituent containing a carbonyl residue, C(O)R.
• R include H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.
• fused ring system means at least two rings, wherein each ring has at least 2 atoms in common with another ring.
• “Fused ring systems may include aromatic as well as non aromatic rings. Examples of “fused ring systems” are naphthalenes, indoles, quinolines, chromenes and the like.
• heteroatom includes oxygen (O), nitrogen (N), sulfur (S), silicon (Si) and boron (B).
• R is a general abbreviation that represents a substituent group.
• substituent groups include substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl groups.
• terapéuticaally effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing a desired therapeutic effect, at a reasonable benefit/risk ratio applicable to any medical treatment.
• salts includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzene sulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., Journal of Pharmaceutical Science, 66: 1-19
• Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
• the present invention provides compounds, which are in a prodrug form.
• Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
• prodrugs for carboxylic acid analogs of the invention include a variety of esters.
• the pharmaceutical compositions of the invention include a carboxylic acid ester.
• the prodrug is suitable for treatment /prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier.
• the prodrug enters the brain, where it is converted into the active form of the drug molecule.
• prodrug is used to enable an active drug molecule to reach the inside of the eye after topical application of the prodrug to the eye.
• prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms ("polymorphs"). In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the present invention.
• “Compound or a pharmaceutically acceptable salt, hydrate, polymorph or solvate of a compound” intends the inclusive meaning of "or”, in that materials meeting more than one of the stated criteria are included, e.g., a material that is both a salt and a solvate is encompassed.
• Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
• Optically active (R)- and (S)-isomers and d and / isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
• R optical centers
• S optically active
• d and / isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
• the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.
• the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
• compounds that are considered to possess activity as DAAO inhibitors are those displaying 50% inhibition of the enzymatic activity of DAAO (IC 5 0) at a concentration of not higher than about 100 ⁇ M, preferably, not higher than about 10 ⁇ M, more preferably not higher than about 1 ⁇ M, even more preferably not higher than about 100 nM and most preferably not higher than about 25 nM.
• neurodegenerative diseases e.g., Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis
• neuropsychiatric diseases e.g. schizophrenia and anxieties, such as general anxiety disorder
• exemplary neurological disorders include MLS (cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g.
• Neurodegenerative disorder also includes any condition associated with the disorder.
• a method of treating a neurodegenerative disorder includes methods of treating loss of memory and/or loss of cognition associated with a neurodegenerative disorder. Such method would also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.
• Pain is an unpleasant sensory and emotional experience. Pain classifications have been based on duration, etiology or pathophysiology, mechanism, intensity, and symptoms.
• the term "pain” as used herein refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic peripheral neuropathic pain (see, e.g., Harrison's Principles of Internal Medicine,
• Pain is also meant to include mixed etiology pain, dual mechanism pain, allodynia, causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.
• “Somatic” pain refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain (e.g., skin, muscle or joint derived) and visceral pain (e.g., organ derived).
• a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer
• cutaneous pain e.g., skin, muscle or joint derived
• visceral pain e.g., organ derived.
• “Neuropathic pain” is a heterogeneous group of neurological conditions that result from damage to the nervous system.
• “Neuropathic” pain refers to pain resulting from injury to or dysfunctions of peripheral and/or central sensory pathways, and from dysfunctions of the nervous system, where the pain often occurs or persists without an obvious noxious input.
• peripheral neuropathic pain This includes pain related to peripheral neuropathies as well as central neuropathic pain.
• peripheral neuropathic pain include diabetic neuropathy (also called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP), post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN).
• diabetic neuropathy also called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP
• PPN post-herpetic neuralgia
• TGN trigeminal neuralgia
• Central neuropathic pain involving damage to the brain or spinal cord, can occur following stroke, spinal cord injury, and as a result of multiple sclerosis.
• Other types of pain that are meant to be included in the definition of neuropathic pain include pain from neuropathic cancer pain, HIV/ AIDS induced pain, phantom limb pain, and complex regional pain syndrome.
• the compounds of the invention are of use for treating neuropathic pain.
• neuropathic pain Common clinical features of neuropathic pain include sensory loss, allodynia (non-noxious stimuli produce pain), hyperalgesia and hyperpathia (delayed perception, summation, and painful aftersensation). Pain is often a combination of nociceptive and neuropathic types, for example, mechanical spinal pain and radiculopathy or myelopathy.
• Acute pain is the normal, predicted physiological response to a noxious chemical, thermal or mechanical stimulus typically associated with invasive procedures, trauma and disease. It is generally time-limited, and may be viewed as an appropriate response to a stimulus that threatens and/or produces tissue injury. "Acute pain”, as described above, refers to pain which is marked by short duration or sudden onset.
• Chronic pain occurs in a wide range of disorders, for example, trauma, malignancies and chronic inflammatory diseases such as rheumatoid arthritis. Chronic pain usually lasts more than about six months. In addition, the intensity of chronic pain may be disproportionate to the intensity of the noxious stimulus or underlying process. “Chronic pain”, as described above, refers to pain associated with a chronic disorder, or pain that persists beyond resolution of an underlying disorder or healing of an injury, and that is often more intense than the underlying process would predict. It may be subject to frequent recurrence.
• Inflammatory pain is pain in response to tissue injury and the resulting inflammatory process. Inflammatory pain is adaptive in that it elicits physiologic responses that promote healing. However, inflammation may also affect neuronal function. Inflammatory mediators, including PGE 2 induced by the COX2 enzyme, bradykinins, and other substances, bind to receptors on pain-transmitting neurons and alter their function, increasing their excitability and thus increasing pain sensation. Much chronic pain has an inflammatory component. "Inflammatory pain”, as described above, refers to pain which is produced as a symptom or a result of inflammation or an immune system disorder. [0051] "Visceral pain”, as described above, refers to pain which is located in an internal organ.
• Mated etiology pain refers to pain that contains both inflammatory and neuropathic components.
• “Dual mechanism” pain refers to pain that is amplified and maintained by both peripheral and central sensitization.
• Ceralgia refers to a syndrome of sustained burning, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes.
• Central pain refers to pain initiated by a primary lesion or dysfunction in the central nervous system.
• Hydroesthesia refers to increased sensitivity to stimulation, excluding the special senses.
• Hyperpathia refers to a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. It may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia.
• Dysesthesia refers to an unpleasant abnormal sensation, whether spontaneous or evoked. Special cases of dysesthesia include hyperalgesia and allodynia, [0059] “Hyperalgesia”, as described above, refers to an increased response to a stimulus that is normally painful. It reflects increased pain on suprathreshold stimulation.
• Allodynia refers to pain due to a stimulus that does not normally provoke pain.
• pain includes pain resulting from dysfunction of the nervous system: organic pain states that share clinical features of neuropathic pain and possible common pathophysiology mechanisms, but are not initiated by an identifiable lesion in any part of the nervous system.
• DPNP Diabetic Peripheral Neuropathic Pain
• DN diabetic peripheral neuropathy
• DN diabetic peripheral neuropathy
• DPNP diabetic neuropathy
• the classic presentation of DPNP is pain or tingling in the feet that can be described not only as “burning” or “shooting” but also as severe aching pain. Less commonly, patients may describe the pain as itching, tearing, or like a toothache. The pain may be accompanied by allodynia and hyperalgesia and an absence of symptoms, such as numbness.
• VZV varicella zoster virus
• the term "neuropathic cancer pain” refers to peripheral neuropathic pain as a result of cancer, and can be caused directly by infiltration or compression of a nerve by a tumor, or indirectly by cancer treatments such as radiation therapy and chemotherapy (chemotherapy-induced neuropathy).
• HIV/AIDS peripheral neuropathy or "HIV/AIDS related neuropathy” refers to peripheral neuropathy caused by HIV/AIDS, such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy resulting as a side effect of drugs used to treat HIV/AIDS.
• HIV/AIDS peripheral neuropathy or "HIV/AIDS related neuropathy” refers to peripheral neuropathy caused by HIV/AIDS, such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy resulting as a side effect of drugs used to treat HIV/AIDS.
• Phantom Limb Pain refers to pain appearing to come from where an amputated limb used to be. Phantom limb pain can also occur in limbs following paralysis (e.g., following spinal cord injury). "Phantom Limb Pain” is usually chronic in nature.
• TN Trigeminal Neuralgia
• TN Trigeminal Neuralgia
• CRPS Combin Regional Pain Syndrome
• RSD Reflex Sympathetic Dystrophy
• Fibromyalgia refers to a chronic condition characterized by diffuse or specific muscle, joint, or bone pain, along with fatigue and a range of other symptoms. Previously, fibromyalgia was known by other names such as fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and tension myalgias.
• convulsion refers to a CNS disorder and is used interchangeably with “seizure,” although there are many types of seizure, some of which have subtle or mild symptoms instead of convulsions. Seizures of all types may be caused by disorganized and sudden electrical activity in the brain. Convulsions are a rapid and uncontrollable shaking. During convulsions, the muscles contract and relax repeatedly.
• the present invention relates to novel inhibitors of the enzyme D-amino acid oxidase. These compounds are useful for treating or preventing any disease and/or condition, wherein modulation of D-serine levels, and/or its oxidative products, is effective in ameliorating symptoms. Inhibition of the enzyme can lead to increases in D-serine levels and a reduction in the formation of toxic D-serine oxidation products.
• the invention provides methods for the treatment or prevention of neurological disorders.
• the invention provides methods of enhancing learning, memory and/or cognition, for treating or preventing loss of memory and/or cognition associated with neurodegenerative diseases (e.g., Alzheimer's disease) and for preventing loss of neuronal function characteristic of neurodegenerative diseases. Further, methods are provided for the treatment or prevention of pain, ataxia, and convulsion.
• the heterocyclic inhibitors of the invention are characterized by a variety of core-moieties.
• the core-moiety includes a fused heterocyclic ring system of two 5-membered rings.
• Exemplary 5-membered rings include heteroaromatic rings, such as oxazoles, isoxazoles, thiazoles, isothiazoles, imidazoles and pyrazoles and preferably pyrroles, thiophenes and furans.
• the present invention provides compounds having a structure according to Formula (I):
• Q is a member selected from O, S, CR 1 and N, NR 3a .
• X and Y are members independently selected from O, S, NR 3 , CR 2 and N. When both X and Y are CR 2 , then each R 2 is independently selected.
• Z is a member selected from O and S. Z is preferably O.
• A is a member selected from NR 7 , S and O. In a preferred embodiment, A is selected from NH and S.
• R 3a , R 3 and R 7 are members independently selected from H, OR 12 , acyl, SO 2 R 13 , SOR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 12 and R 13 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 , R 2 and R 4 are members independently selected from H, halogen (e.g., F, Cl, Br) 5 CN, CF 3 , acyl, OR 14 , S(O) 2 OR 14 , S(O)pR 14 , NR 14 R 15 , SO 2 NR 14 R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein p is an integer selected from 0 to 2.
• R 1 and R 2 together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 14 and R 15 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 14 and R 15 together with the nitrogen atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 4 in Formula (I) is selected from H, F, Cl, Br and unsubstituted Ci-C ⁇ (preferably unsubstituted C1-C4 alkyl, more preferably unsubstituted C1-C 3 alkyl, and most preferably unsubstituted C1-C 2 alkyl).
• R 6 is a member selected from O-X + , OR 8 , NR 9 R 10 , NR 8 NR 9 R 10 , NR 8 OR 9 , NR 8 SO 2 R 11 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 6 and R 4 together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 6 is selected from O X + , OR 8 .
• R 8 , R 9 and R 10 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 8 is preferably H or C1-C4 unsubstituted alkyl, such as methyl, ethyl, propy).
• R 11 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. At least two of R 8 , R 9 , R 10 and R 11 , together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 1 and R 2 are preferably not both H; (ii) R 1 and R 2 are preferably not both halogen, unless at least one member selected from R 1 and R 2 is fluoro; and (/;;) when one member selected from R 1 and R 2 is halogen other than fluoro, then the other member is preferably not H or unsubstituted C 1 -C 2 alkyl.
• Other preferred compounds include those in which Q is C-R 1 , X is S, Y is CH, A is NH, R 1 is H, Z is O and R 4 is not C 1 -C 3 alkyl substituted with halogen; those in which Q is C-R 1 , X is CH, Y is S, A is NH, R 1 is H, Z is O and R 4 is not Ci-C 3 alkyl substituted with halogen; as well as those in which Q is C-R 1 , R 4 is H, Z is O, A is NR 7 and R 7 is not a member selected from: wherein Ar° is substituted or unsubstituted phenyl.
• R 7 is preferably not eye lohexy lmethyl.
• Q is C-R 1
• X is S
• Y is CR 2
• R 4 is H or acyl
• A is NR 7 , in which R 7 is a member selected from H and acyl, and Z is O
• R 1 and R 2 are not both unsubstituted C 1 -C 2 alkyl, and (//) when one member selected from R 1 and R 2 is unsubstituted Cj-C 2 alkyl, another member is not H
• Q is C-R 1
• X is O
• Y is CR 2
• R 4 is H
• A is NH
• Z is O
• R 4 is preferably not C(O)-2-thiophenyl.
• Q is C-R 1 , X is S, Y is CH, Z is O, and R 6 is OR 8 , R 4 is preferably not C(O)-2-thiophenyl.
• Q is C-R 1 , X is O, Y is CH, R 4 is H, A is NH and Z is O, R 1 is preferably not a member selected from Cl, Br, I, CN and unsubstituted C 1 -C 2 alkyl.
• Q is C-R 1 , X is O, Y is CR 2 , R 1 is H, R 4 is H, A is NH, and Z is O, R 2 is preferably not Cl, Br or I.
• A is NR 7 and preferably NH.
• Q is selected from N and C- R 1 , and each of X and Y is a member selected from CR 2 , NR 3 and N. In this example at least one of X and Y is preferably NR 3 .
• Exemplary fused pyrroles have the general structure:
• R 6 is preferably a member selected from O " X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C 1 -C 4 alkyl (e.g., Me, Et, Pr, /so-Pr, n-Bu, iso-Bu).
• Q is C-R 1 and each of X and Y is a member selected from S, CR 2 and N, with the proviso that at least one of X and Y is S.
• exemplary fused pyrroles have the structure:
• R 6 is preferably a member selected from CTX + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C1-C4 alkyl (e.g., Me, Et, Pr, /so-Pr, n-Bu, iso-Bu).
• Q is C-R 1 and each of X and Y is a member selected from O, CR 2 and N, with the proviso that at least one of X and Y is O.
• exemplary fused pyrroles have the general structure:
• R 6 is preferably a member selected from 0 " X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C1-C4 alkyl (e.g., Me, Et, Pr, wo-Pr, n-Bu, iso-Bu).
• Q in Formula (I) is O or S.
• exemplary fused pyrroles have the general structure:
• R 6 is preferably a member selected from O " X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions anfd R 8 is preferably H or C 1 -C 4 alkyl (e.g., Me, Et, Pr, iso-Pr, /j-Bu, iso-Bu).
• X + is a positive ion
• R 8 is preferably H or C 1 -C 4 alkyl (e.g., Me, Et, Pr, iso-Pr, /j-Bu, iso-Bu).
• A is S.
• Q is selected from N and C- R 1 , and each of X and Y is a member selected from CR 2 , NR 3 and N with the proviso that at least one of X and Y is NR 3 .
• Exemplary fused thiophenes have the structure:
• R 6 is preferably a member selected from CTX + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C1-C4 alkyl (e.g., Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).
• Q is C-R 1 and each of X and Y is a member selected from S, CR 2 and N, with the proviso that at least one of X and Y is S.
• exemplary fused thiophenes have the general structure:
• R 6 is preferably a member selected from O " X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C 1 -C4 alkyl (e.g., Me, Et, Pr, iso-Pr, H-Bu, iso-Bu).
• Q is C-R 1 and each of X and Y is a member selected from O, CR 2 and N, with the proviso that at least one of X and Y is O.
• Exemplary fused thiophenes have the general structure:
• R 6 is preferably a member selected from CTX + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C]-C 4 alkyl (e.g., Me, Et, Pr, iso-Pr, M-Bu, iso-B ⁇ ).
• Q in Formula (I) is O or S.
• exemplary fused thiophenes have the general structure:
• each R 2 is independently selected and wherein R 6 is preferably a member selected from O X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C 1 -C 4 alkyl (e.g., Me, Et, Pr, iso-Pr, ⁇ -BU, iso-Bu).
• A is NH and Z is O.
• Q is CR 1 and the compound of the invention has a structure according to Formula (Ha):
• R 1 , X, Y, R 4 and R 6 are defined as above for Formula (I) or Formula (II).
• Q is a member selected from O, S, N and CR 1 .
• X is a member selected from O, S, N, NR 3 and CR 2a and Y is a member selected from O, S, N, NR 3 and CR 2b , wherein R 1 is a member selected from H, F, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C4-C10 cycloalkyl, and substituted or unsubstituted C4-C ⁇ o heterocycloalkyl.
• R 2a is a member selected from H, F, Cl, Br, CN, substituted or unsubstituted C 3 -C 6 alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C4-C1 0 cycloalkyl, substituted or unsubstituted C4-C 1 0 heterocycloalkyl and alkenyl.
• R 2b is a member selected from H, F, substituted or unsubstituted C 3 -C 6 alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 -C10 cycloalkyl, and substituted or unsubstituted C4-C10 heterocycloalkyl and alkenyl.
• R 3 is a member selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, and substituted or unsubstituted C 4 -C 10 heterocycloalkyl.
• R 4 is a member selected from H, F, Cl, Br, CN, unsubstituted Ci-Ce alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl and alkenyl.
• R 4 is a member selected from H, F, Cl, Br, CN and unsubstituted C 1 -C4 alkyl.
• R 6 is a member selected from 0 " X + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 4 is preferably other than H.
• Q is CH
• Y is S, O or CH
• at least one of R 2a and R 4 is other than H.
• R 1 , R 2a , R 2b and R 4 are members independently selected from H and F.
• Q is CR 1 and one member selected from X and Y is S and the other member is CR 2a , CR 2b or N.
• Exemplary compounds have the formula:
• R 4 is preferably a member selected from H, F, Cl, Br, CN and unsubstituted Ci-C 4 alkyl.
• Q is CR 1 and one member selected from X and Y is O and the other member is CR 2a , CR 2b or N.
• Exemplary compounds have the formula:
• R 4 is preferably a member selected from H, F, Cl, Br, CN and unsubstituted Ci-C 4 alkyt.
• the invention provides a compound having a structure, which is a member selected from Formula (III) and Formula (IV):
• X is a member selected from O, S and NR 3 .
• Y is a member selected from CR 2 and N.
• R 3 is a member selected from H, OR 12 , acyl, SO 2 R 13 , SOR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R 12 and R 13 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 , R 2 and R 4 in Formulae (III) and (IV) are members independently selected from H, F, Cl, Br, CN, CF 3 , acyl, OR 14 , S(O) P OR 14 , S(O) 2 R 14 , NR 14 R 15 , S ⁇ 2 NR 14 R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein p is an integer selected from 0 to 2.
• R 1 and R 2 together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 14 and R 15 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 14 and R 15 together with the nitrogen atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 4 in Formula (I) is selected from H, F, Cl, Br and unsubstituted Ci-C ⁇ (preferably unsubstituted Ci -C 4 alkyl, more preferably unsubstituted C1-C 3 alkyl, and most preferably unsubstituted C1-C2 alkyl).
• R 6 is a member selected from O X + , OR 8 , NR 9 R 10 , NR 8 NR 9 R 10 , NR 8 OR 9 , NR 8 SO 2 R 11 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 6 and R 4 together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 8 , R 9 and R 10 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 ' is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. At least two of R 8 , R 9 , R 10 and R 1 ' , together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 8 , R 9 and R 10 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl and R 1 ' is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• X is S
• Y is CR 2
• R 1 and R 2 are preferably not both H
• R 1 and R 2 are preferably not both halogen, unless at least one member selected from R 1 and R 2 is fluoro
• the other member is preferably not H or unsubstituted Ci-C 2 alkyl.
• R 1 is preferably not a member selected from CN and C ⁇ CH.
• R 1 is H and R 6 is OH
• R 4 is preferably not a member selected from H and unsubstituted C 1 -C 2 alkyl.
• Generally preferred compounds include those, in which, in Formula (III), X is S, Y is CH, R 6 is OR 8 , wherein R 8 is unsubstituted Ci-C 6 alkyl, and R 1 is not carboxylic acid ester; and those, in which, in Formula (III), X is S, Y is CR 2 and (i) R 1 and R 2 are not both unsubstituted C1-C2 alkyl, (if) when one member selected from R 1 and R 2 is C 1 -C 2 unsubstituted alkyl, then the other member is not H; and (Uf) when R 1 is unsubstituted Ci-C 2 alkyl, then R 2 is not acyl.
• R 1 and R 2 are preferably not both H, (if) R 1 and R 2 are preferably not both unsubstituted C1-C 2 alkyl, and (Hf) when one member selected from R 1 and R 2 is unsubstituted C1-C 2 alkyl, then the other member is preferably not H.
• X is a member selected from O
• S and NR 3 and Y is a member selected from CR 2 and N.
• R 1 and R 2 are members independently selected from H, F, substituted or unsubstituted C 3 -C 6 alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C4-C1 0 cycloalkyl, and substituted or unsubstituted C 4 -Cioheterocycloalkyl and alkenyl.
• R 3 is a member selected from H, substituted or unsubstituted Ci-C ⁇ alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, and substituted or unsubstituted C 4 -C1 0 heterocycloalkyl.
• R 4 is a member selected from H, F 3 Cl, Br, CN, unsubstituted Ci-C ⁇ alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C 4 - C ⁇ o cycloalkyl and alkenyl.
• R 6 is a member selected from CQC + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• X is S
• Y is CH and R 1 is F
• R 4 is preferably other than H.
• R 1 is H and Y is CH
• R 4 is preferably other than H.
• R 1 is H, at least one of R 2 and R 4 is other than H.
• Exemplary compounds according to Formulae (III) and (IV) include:
• R 6 is preferably a member selected from O ' X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• R 8 is preferably H or C 1 -C 4 alkyl (e.g., Me, Et, Pr, iso-Pr, n-Bu, iso-B ⁇ ).
• Preferred compounds of the invention include those in which, in Formulae (I), (II), (Ha), (III) and (IV), at least one of R 1 , R 2 and R 3 includes an aromatic ring or a fused ring system including an aromatic ring. In one embodiment, at least one of R 1 , R 2 and R 3 has the formula:
• L 1 is a linker moiety, which is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• Particularly preferred compounds are those, in which R ! represents a small group, such as H and F, and a member selected from R 2 and R 3 includes the aromatic moiety.
• Exemplary linker moieties include Ci to Cj substituted or unsubstituted alkyl chains wherein one or more carbon atoms are optionally replaced with a group including one or more heteroatoms, forming e.g., ether, thioether, amines, amides, sulfonamides or sulfones.
• At least one of R 1 , R 2 and R 3 has a formula, which is a member selected from:
• R 16 and R 17 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 16 and R 17 together with the carbon to which they are attached, are optionally joined to form a 3- to 7-membered ring, which is a member selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl, and which is optionally fused to Ar.
• Ar is a phenyl ring and has the formula: wherein m is an integer from (Mo 5.
• Each R 5 can be selected from a variety of substituents.
• each R 5 is a member independently selected from H, halogen, CN, halogen substituted alkyl ⁇ e.g., CF3), hydroxy, alkoxy ⁇ e.g., methoxy and ethoxy), acyl ⁇ e.g., acetyl), CO 2 R 18 , OC(O)R 18 , NR 18 R 19 , C(O)NR 18 R 19 , NR 18 C(O)R 20 , NR 18 SO 2 R 20 , S(O) 2 R 20 , S(O)R 20 , substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl and isopropyl), substituted or unsubstituted heteroalkyl, substitute
• R 18 and R 19 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 20 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 18 and a member selected from R 19 and R 20 together with the atoms to which they are attached, are optionally joined to form a 5- to 7- membered ring.
• At least one of R 2 and R 3 has the structure:
• Exemplary structures according to this embodiment include:
• R 2 has the structure:
• Preferred compounds according to this example include:
• R 1 has the structure:
• Certain compounds of the invention include substituents R 1 , R 2 and R 4 that are halogen (e.g., F, Cl, Br), CN, CF 3 or lower alkyl groups, such as substituted or unsubstituted (preferably unsubstituted) C1-C4 alkyl, such as methyl and ethyl.
• Q is a member selected from CR 1 , N and NR 3a .
• One member selected from X and Y is O, S or N and the other member is CR 2 .
• R 1 , R 2 and R 4 are members independently selected from H, F, Cl, Br, CN and CF 3 , provided that at least one member selected from R 1 , R 2 and R 4 is other than H.
• R 6 is a member selected from O " X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions, and wherein R 8 is preferably H or C 1 -C 4 alkyl (e.g., Me, Et, Pr, wo-Pr, H-Bu, wo-Bu).
• the compound is preferably not a member selected from: 2-fiuoro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid; 2-chloro-4H- thieno[3,2-b]pyrrole-5-carboxylic acid; 2-bromo-4H-thieno[3,2-b]pyrrole-5- carboxylic acid; 2-cyano-4H-thieno[3,2-b]pyrrole-5-carboxylic acid; 2,3-dichloro-4H- thieno [3 ,2-b]pyrrole-5 -carboxyl ic acid; 3 -chloro-4H-thieno[3 ,2-b]pyrrole-5 - carboxylic acid; 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid; 3-bromo-4H- fiiro[3,2-b]pyrrole-5-carboxylic acid; 2-chloro-4H-furo[3,2-b]pyrrole-5-
• the compound of Formula (X) has a structure according to Formula (XI):
• R 1 and R 2 are H and R 4 is a member selected from F, Cl, Br, CN, CH 3 and CF 3 .
• Exemplary compounds include:
• R 1 and R 4 are H and X is CR 2 , wherein R 2 is a member selected from F, Cl, Br and CN.
• exemplary compounds include:
• R 2 and R 4 are H and R 1 is CF 3 .
• the invention provides fluoro-substituted analogs.
• the invention provides fluoro-substituted compounds having a structure according to Formula (XII):
• A, Q, X, Y, R 4 and R 6 are defined as in Formula (I), provided that at least one member selected from R 1 , R 2 and R 4 is F.
• R 4 is preferably other than H.
• A is NH
• Q is CF
• X is S and Y is CH
• R 4 is preferably other than H.
• A is NH
• Q is CF
• X is CH
• Y is S
• R 4 is preferably other than H.
• A is S
• Q is CF
• Y is S and X is CH
• R 4 is preferably other than H.
• R 4 is preferably other than H.
• a is S, Q is CF
• X is S and Y is CH
• R 4 is preferably other than H.
• the fluoro-substituted compound of the invention has a structure according to Formula (XIII):
• R 1 , R 2 and R 4 are members independently selected from H and F, provided that at least one member selected from R 1 , R 2 and R 4 is F.
• R 6 is a member selected from O " X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions, and wherein R 8 is preferably H or C 1 -C4 alkyl (e.g., Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).
• R 1 is F
• X is S and Y is CH
• R 4 is preferably other than H.
• R 1 is F Y is S and X is CH
• R 4 is preferably other than H.
• the fluoro-substituted compound of the invention has a structure according to Formula (XIV):
• R 1 , R 2 and R 4 are members independently selected from H and F, provided that at least one member selected from R 1 , R 2 and R 4 is F.
• R 6 is a member selected from 0 ' X + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions, and wherein R 8 is preferably H or C1-C4 alkyl (e.g., Me, Et, Pr, M ⁇ -P ⁇ , n-Bu, wo-Bu).
• R 1 is F
• X is S and R 2 is H
• R 4 is preferably other than H.
• Exemplary compounds according to this embodiment include:
• the compound of the invention has a structure according to Formula (XV):
• R 1 , R 2 and R 4 are members independently selected from H and F, provided that at least one member selected from R 1 , R 2 and R 4 is F.
• R 6 is a member selected from CTX + and OR 8 , wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions, and wherein R 8 is preferably H or C1-C4 alkyl (e.g., Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).
• A is S
• Q is CF
• Y is S and X is CH
• R 4 is other than H.
• Exemplary compounds according to this embodiment include:
• R 1 , R 2 and R 4 are selected from H and F.
• R 1 is F.
• Compounds according to this embodiment include, for example:
• R 2 is F.
• Exemplary compounds according to this embodiment include:
• R 4 is F.
• Exemplary compounds according to this embodiment include:
• R 1 , R 2 and R 4 are F.
• Exemplary compounds according to this embodiment include:
• each of R 1 , R and R 4 is F.
• Exemplary compounds according to this embodiment include:
• F-substituted compounds of the invention are associated with unexpectedly high in vitro and in vivo activities. Some compounds of the invention, are significantly more active than their respective Cl- or Br-substituted counterparts. Compounds of the invention are evaluated in Examples 8 and 9. Supporting data is summarized in Table 9.
• the F-substituted analog has an IC50 (DAAO inhibition) below about 1 ⁇ M, preferably below about 100 nM and more preferably below about 50 nM. In a particularly preferred embodiment, the F-substituted analog has an IC5 0 below about 25 nM. In another example, the F-substituted analog has an IC50 that is at least about one order of magnitude lower than the IC 50 measured for at least one of the respective Br- or Cl-substituted analogs. In one example, the IC 5 0 is measured using an in vitro DAAO enzyme inhibition assay described herein (Example 8).
• the F-substituted compound of the invention increases D-serine levels in the cerebellum of a test animal.
• D-Serine levels may be determined following the experimental procedures described herein (e.g., Example 9).
• the F-substituted analog increases D-serine levels in the cerebellum of mice (measured 2 hours after i.p. dosing) between about 1.5 fold and 2 fold and preferably more than 2 fold when compared to vehicle.
• Several of the analyzed fiuoro-substituted analogs of the invention increased D-serine levels by at least 2 fold, while none of the respective Cl- or Br- substituted analogs that were analyzed had this activity.
• Particularly preferred are those F-substituted compounds of the invention that are capable of maintaining an elevated D-serine level for at least 6 hours.
• those F-substituted compounds that (at 50 mg/kg) increase D-serine levels between about 1.5 fold and 2 fold and preferably more than 2 fold even when measured 6 hours after dosing are generally preferred.
• F-substituted compounds that increase D- serine levels at a lower dose of 10 mg/kg between about 1.5 fold and 2 fold and preferably more than 2 fold when measured 2 hours after dosing.
• the F-substituted analogs when compared to the increases measured for at least one of the respective Br- or Cl- substituted analogs, then those F-substituted analogs are generally preferred.
• the F-substituted analog when under the same test conditions, the F-substituted analog causes an increase in the D-serine level of 2.7 fold, and the respective Cl-substituted analog causes an increase of 1.5 fold, then the F-substituted analog has an activity that is 80% higher than the activity measured for the Cl-substituted analog.
• a pain model such as those described herein (e.g., Chung model)
• a model of cognition such as those described herein (e.g., a contextual fear conditioning model.
• Such experiments are described herein for compounds 1 and 11 (e.g., Examples 10 and 18) but are equally useful for the analysis of other compounds of the invention.
• DAAO D-amino acid oxidase
• the compounds activity is measured using an in vitro DAAO enzyme inhibition assay.
• assays are known in the art.
• An exemplary assay format is described herein (e.g., Example 8).
• the fluoro-substituted compounds of the invention are judged to be sufficiently potent if they have an IC 50 below about 25 nM. This level of activity is particularly important for the treatment of pain, such as neuropathic pain and other types of pain described herein.
• the compounds activity is determined by measuring D- serine levels in vivo. Elevation of the D-serine level in a certain brain area (e.g., the cerebellum) of a test animal (e.g., mouse, rat, pig and the like) is indicative of DAAO inhibition in vivo.
• An exemplary assay format which measures D-serine levels (LC/MS/MS) in the cerebellum of mice two hours and six hours after intraperitoneal (i.p.) dosing, is described herein (e.g., Example 9). Increases in D-serine levels were determined through comparison with vehicle. Useful variations of this assay will be apparent to those of skill in the art.
• Compounds of the invention are judged to be sufficiently active in this assay when at least one, preferably at least two, more preferably at least three and most preferably all four of the following criteria are met:
• test compounds At a dose of 10 mg/kg, compounds must cause an elevation of D-serine level (measured 6 hours after dosing) of greater than about 2 fold when compared to vehicle.
• Activity of the test compounds in this in vivo asay is particularly important for the treatment of pain, such as neuropathic pain and other types of pain described herein.
• fluoro- substituted compounds of the invention which demonstrate sufficient activity against the enzyme DAAO both in vitro (e.g., DAAO enzyme inhibition assay) and in vivo (e.g., elevation of D-serine levels in the cerebellum of mice).
• At least one of R 1 , R 2 and R 4 in any of Formulae (I) to (VII) and (X) to (XV) is deuterium.
• exemplary compounds according to this embodiment include:
• R 6 is a member selected from OH, and OD.
• the compounds can optionally be labeled with another isotope, such as C 13 .
• the carbon atom of the carboxylic acid group is C 13 .
• the compounds of the present invention may be prepared by methods known in the art.
• One of ordinary skill in the art will know how to modify procedures to obtain the analogs of the present invention. Suitable procedures are described e.g., in WO2004/031194 to Murray, P. et al; Yarovenko, V.N., Russian Chemical Bulletin, International Edition (2003), 52(2): 451-456; Krayushkin M.M et al, Organic Letters (2002), 4(22): 3879- 3881; Eras J. et al, Heterocyclic Chem. (1984), 21: 215-217, each of which is incorporated herein by reference in its entirety.
• compounds may be prepared using the methods described below and in Examples 1 through 7 or modified versions thereof.
• the fused pyrrole analogs of the present invention may be prepared according to Scheme 1 or Scheme 2, by condensation of an appropriate five-membered heteroaromatic aldehyde and 2-azidoacetate, followed by cyclization and saponification of the resulting ester to afford the carboxylic acid analog.
• the fused thiophene analogs of the invention can be prepared by condensation of the appropriate aldehyde and rhodanine, followed by hydrolysis of the rhodanine ring and cyclization.
• Substituted aldehydes may be prepared from a halogenated (e.g., Br, I) precursor through Suzuki coupling with an appropriate boronic acid.
• fused pyrrole-pyrazole analogs of the invention are prepared following a procedure outlined in Scheme 4 or Scheme 5 below.
• these compounds can be prepared by condensation of the appropriate pyrazole aldehyde and 2-azidoacetate, followed by cyclization. The resulting ester is then saponified to afford the carboxylic acid analog.
• Fused pyrrole-thiophene analogs of the present invention may be prepared using a procedure such as those outlined in Schemes 6 to 9 below.
• the thiophene derivative carrying a desired R- group, is prepared by Suzuki coupling of a halogenated thiophene aldehyde and the appropriate boronic acid analog. Condensation of the resulting thiophene intermediate and 2-azidoacetate, followed by cyclization and saponification of the ester group affords the final carboxylic acid analog.
• fused furan pyrrole analogs of the present invention are prepared using a procedure such as those outlined in Schemes 10 and 1 1 below.
• the fused furan pyrrole derivatives of the invention may be prepared by Suzuki coupling of a halogenated furan aldehyde and an appropriate boronic acid. Condensation of the resulting furan intermediate and 2-azidoacetate, followed by cyclization and saponification of the ester group affords the desired carboxylic acid analog.
• fused pyrrole-pyrrole analogs of the current invention are prepared using the synthetic approach outlined in Scheme 12 below.
• fused pyrrole-pyrrole analogs can be prepared by condensation of the appropriate pyrrole aldehyde and 2- azidoacetate, followed by cyclization and saponification of the ester group.
• Substituted pyrrole aldehydes may be prepared by Suzuki coupling of a halogenated pyrrole aldehyde and the appropriate boronic acid analog.
• fused thiazole-pyrrole analogs of the current invention are prepared using the synthetic approach outlined in Scheme 13 below.
• fused thiazole-pyrrole analogs can be prepared by condensation of the appropriate thiazole aldehyde and 2- azidoacetate, followed by cyclization and saponification of the ester group.
• Substituted thiazole aldehydes may be prepared by Suzuki coupling of a halogenated thiazole aldehyde and the appropriate boronic acid analog.
• fused thiophene-thiophene analogs of the invention are synthesized using a procedure such as those outlined in Schemes 14 and
• these compounds can be prepared from commercially available compounds such as A and B.
• formylation of A such as with trimethyl orthoformate and trifluroactetic acid provides aldehyde B.
• Knoevenagel condensation of B provides C, which is protected by standard tosylation conditions to provide compounds such as D.
• Bromination of D such as with N-bromosuccinimide and dibenzoyl peroxide, provides E, which is then reacted with ammonia or with amines such as methyl amine or benzyl amine to form cyclized products such as F.
• Standard deprotection of the N-tosyl group and saponification affords the desired carboxylic acid analog.
• Relevant references, which are incorporated by reference include Sha, Chin-Kang, et al. Heterocycles 1990, 31, 603-609.
• R H, Me, Et.
• these compounds can be prepared from appropriately substituted furans and thiophenes such as A, B, or C, which are easily synthesized using standard literature procedures such as those listed below. Curtius rearrangement of C provides D, which can be allylated and subjected to Heck conditions to afford bicyclic compound E. Standard functional group manipulation, such as acylation, BOC deprotection, and saponification affords the desired carboxylic acid analogs.
• Relevant references, which are incorporated by reference include Yu, Shuyuan et al J. Chem. Soc, Perkin Transactions 1 1991, 10, 2600-2601.
• fluoro-substituted analogs of the invention may be prepared following procedures outlined in Schemes 19 to 24.
• fluoro-substituted analogs of the invention may be prepared following procedures outlined in Schemes 19 to 24.
• fluoro-substituted fused pyrrole analogs of the invention may be prepared following adaptations to procedures outlined in Schemes 1 to 18. Fluorine may be incorporated early, such as in the aldehyde starting materials of Scheme 1 and Scheme 2.
• Fluorinated five membered heteroaromatic aldehydes may be prepared from the corresponding bromo, chloro- or iodo substituted aldehydes, as shown in Schemes 19 and 20, by protecting the aldehyde as an acetal, then subjecting the bromo-, chloro-, or iodo-acetal to transmetalation conditions (such as, for example, with nBuLi or /BuLi) followed by fiuorination (for example, with N- fluorobenzenesulfonimide (NFSI) or Selectfluor®).
• transmetalation conditions such as, for example, with nBuLi or /BuLi
• fiuorination for example, with N- fluorobenzenesulfonimide (NFSI) or Selectfluor®.
• FPSI N- fluorobenzenesulfonimide
• Selectfluor® Selectfluor®
• Fluorinated, five membered heteroaromatic aldehydes may also be prepared from the corresponding bromo- or iodo-substituted protected methyl alcohols following the transmetalation, fluorination protocol used for acetals, as shown in Schemes 21 and 22. Standard deprotection of the alcohol, followed by oxidation (such as, for example, with MnO 2 or pyridinium chlorochromate) provides fluorinated five membered heteroaromatic aldehydes, which may be converted, as shown in Schemes 1 and 2, to the fused pyrrole analogs of the invention.
• fluoro-substituted five membered heteroaromatic aldehydes may be obtained by direct fluorination of a five-membered heteroaromatic aldehyde, protected five-membered heteroaromatic aldehyde, or protected five-membered heteroaromatic methyl alcohol (such as, for example, with wBuLi or /BuLi, or LDA), followed by fluorination conditions (for example, with N-fluorobenzenesulfonimide (NFSI) or Selectfluor®) and optional deprotection to provide fluorinated aldehydes, which may be taken on, as in Scheme 1 and Scheme 2, to the fused pyrrole analogs of the invention.
• fluorination conditions for example, with N-fluorobenzenesulfonimide (NFSI) or Selectfluor®
• fluorinated aldehydes may be obtained by fluorodecarboxylation of a carboxylic acid containing five-membered heteroaromatic precursor.
• Fluoro-substituted five membered heteroaromatic aldehydes may also be obtained by synthesis of the heteroaromatic ring following incorporation of fluorine.
• One example is described, in Example 2, for the synthesis of 4-fluorofuran-2- carbaldehyde starting from (4-bromo-4,4-difluoro-but-2-ynyloxy)-/er/-butyl- dimethyl-silane.
• Fluorine may also be incorporated into the azide intermediates of Schemes 1 and 2, from the corresponding bromo-, chloro-, or iodo-compound, as described above, or from the corresponding carboxylic acid, by fluorodecarboxylation (such as in the synthesis of ethyl 2-azido-3-(5-fluorofuran-2-yl)prop-2-enoate from 5-(2-azido- 3-ethoxy-3-oxoprop-l-enyl)furan-2-carboxylic acid in Example 2.
• fluorine may be incorporated later in the synthesis, into the fused pyrrole esters or acids.
• fused pyrrole esters or acids of Schemes 1 and 2 may be subjected to standard bromination, chlorination or iodination conditions (for example, Br 2 , KOH, I 2 , KOH, NBS, NCS), followed by transmetalation conditions (for example, nBuLi or /BuLi), then fluorination conditions (e.g., N-fluorobenzenesulfonimide (NFSI) or Selectfluor®), to provide fluorinated fused pyrrole esters or acids.
• chlorination or iodination conditions for example, Br 2 , KOH, I 2 , KOH, NBS, NCS
• transmetalation conditions for example, nBuLi or /BuLi
• fluorination conditions e.g., N-fluorobenzenesulfonimide (NFSI) or Selectfluor®
• the fused pyrrole esters or acids of Schemes 1 and 2 may be subjected to direct deprotonation conditions (e.g., AjBuLi or /BuLi, or LDA), then fluorination conditions (e.g., N- fluorobenzenesulfonimide (NFSI) or Selectfluor®), to provide fluorinated fused pyrrole esters or acids.
• direct deprotonation conditions e.g., AjBuLi or /BuLi, or LDA
• fluorination conditions e.g., N- fluorobenzenesulfonimide (NFSI) or Selectfluor®
• R H, methyl, ethyl
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula (I) to Formula (VII) or (X) to (XV) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, together with one or more pharmaceutical carrier and optionally one or more other therapeutic ingredient.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• pharmaceutically acceptable carrier includes vehicles and diluents.
• the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration, as well as those for administration by inhalation.
• the most suitable route may depend upon the condition and disorder of the recipient.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
• Oral formulations are well known to those skilled in the art, and general methods for preparing them are found in any standard pharmacy school textbook, for example, Remington: The Science and Practice of Pharmacy., A.R. Gennaro, ed. (1995), the entire disclosure of which is incorporated herein by reference.
• compositions containing compounds of Formula (I) to Formula (VII) and (X) to (XV) may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
• Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof.
• the magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.
• the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 7000 mg per day, preferably about 1 mg per day to about 100 mg per day, and more preferably, from about 10 mg per day to about 100 mg per day, and even more preferably from about 20 mg to about 100 mg, to about 80 mg or to about 60 mg.
• the total daily dose may range from about 50 mg to about 500 mg per day, and preferably, about 100 mg to about 500 mg per day. It is further recommended that children, patients over 65 years old, and those with impaired renal or hepatic function, initially receive low doses and that the dosage be titrated based on individual responses and/or blood levels.
• the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or molding, optionally using one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
• Oral and parenteral sustained release drug delivery systems are well known to those skilled in the art, and general methods of achieving sustained release of orally or parenterally administered drugs are found, for example, in Remington: The Science and Practice of Pharmacy, pages 1660-1675 (1995).
• Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
• Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate- buffered saline (PBS) or the like, immediately prior to use.
• a sterile liquid carrier for example saline, phosphate- buffered saline (PBS) or the like, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
• Formulations for topical administration in the mouth, for example, buccally or sublingually include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
• the pharmaceutically acceptable carrier may take a wide variety of forms, depending on the route desired for administration, for example, oral or parenteral (including intravenous).
• any of the usual pharmaceutical media may be employed, such as, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents in the case of oral liquid preparation, including suspension, elixirs and solutions.
• Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents may be used in the case of oral solid preparations such as powders, capsules and caplets, with the solid oral preparation being preferred over the liquid preparations.
• Preferred solid oral preparations are tablets or capsules, because of their ease of administration. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Oral and parenteral sustained release dosage forms may also be used.
• the invention provides a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound having the formula:
• R 1 is a member selected from the group consisting of H, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl.
• R 2 is a member selected from the group consisting of H, substituted or unsubstituted alkenyl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl.
• R 3 is a member selected from the group consisting of H, C ⁇ -C$ substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl.
• R 4 is a member selected from OH and CTX + wherein X + is a positive ion which is a member selected from organic positive ions and inorganic positive ions, wherein substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl have the formula:
• the invention provides a method for treating or preventing a disease or condition which is a member selected from a neurological disorder, pain, ataxia and convulsion.
• the method includes administering to a subject in need thereof a therapeutically effective amount of a compound of the invention (e.g., those of Formula (I) to (VIII) or Formula (X) to (XV)) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
• the method of the invention includes administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:
• Z is a member selected from O and S.
• A is a member selected from NR 7 , S and O.
• Q is a member selected from O, S, N, NR 3a and CR 1 .
• X and Y are members independently selected from O, S, N, NR 3 and CR 2 ; with the proviso that - when X and Y are both CR 2 , each R 2 is independently selected.
• R 3 , R 3a and R 7 are members independently selected from H, OR 12 , acyl, SO 2 R 13 , SOR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R 12 and R 13 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 1 , R 2 and R 4 are members independently selected from H, F, Cl, Br, CN, CF 3 , acyl, OR 14 , S(O) 2 OR 14 , S(O)pR 14 , NR 14 R 15 , SO 2 NR 14 R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R 1 and R 2 , together with the atoms to which they are attached, are optionally joined to form a 5- to 7- membered ring, wherein p is an integer selected from 0 to 2.
• R 1 , R 2 and R 4 are members independently selected from H, F, Cl, Br and unubstituted C 1 -C 4 alkyl.
• R 14 and R 15 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 14 and R 15 together with the nitrogen atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.
• R 6 is a member selected from 0 " X + and OH, wherein X + is a positive ion, which is a member selected from inorganic positive ions and organic positive ions.
• the subject is preferably not in need of treatment for a condition, which is a member selected from a KU-receptor mediated disease, a monocyte chemoattractant protein-1 (MCP-I) receptor mediated disease, type-2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischemia, obesity, artherosclerosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hyperglycemia, hypertension, tissue ischemia and myocardial ischemia.
• a condition which is a member selected from a KU-receptor mediated disease, a monocyte chemoattractant protein-1 (MCP-I) receptor mediated disease, type-2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischemia, obesity, artherosclerosis, diabetic neuropathy, diabetic nephropathy, diabetic
• the subject is preferably not in need of inhibiting glycogen phosphorylase.
• AU compounds exemplified herein are useful in the methods of the inventions.
• Preferred compounds of Formula (I) include those in which Z is O and R 6 is a member selected from 0 " X + and OR 8 , wherein R 8 is preferably H or C 1 -C4 unsubstituted alkyl.
• the compound of Formula (I) has the formula:
• A is a member selected from NH
• X is a member selected from O
• Y is a member selected from CR 2 and N.
• R 6 is preferably a member selected from 0 " X + and OR 8 , wherein R 8 is preferably H or C 1 -C 4 unsubstituted alkyl.
• the compound of Formula (I) has the formula:
• A is a member selected from NH and S.
• Y is a member selected from O, S and NR 3 and X is a member selected from CR 2 and N.
• R 6 is preferably a member selected from O ' X + and OR 8 , wherein R 8 is preferably H or C]-C 4 unsubstituted alkyl.
• R 6 is a member selected from O ' and OH
• A is a member selected from S and NH
• R 1 is a member selected from H, CN and halogen (e.g., F, Cl or Br).
• Preferred compounds of the invention include those in which the substituents R 1 , R 2 and R 4 are each independently selected from H and F.
• Particularly preferred compounds include those in which, in Formula (I), R 6 is a member selected from O " X + and OH, A is NH, and wherein one or more of the following selections are made: a) Q is C-R 1 , wherein R 1 is a member selected from H and F. b) Y is C-R 2 , wherein R 2 is a member selected from H and F. c) R 4 is a member selected from H and F.
• Other preferred compounds of Formula (I) include those, in which X is a member selected from S and O and Y is selected from N and CR 2 . In one exemplary embodiment, R 2 is a member selected from H and methyl.
• preferred compounds of Formual (I) include those, in which Y is a member selected from S and O and X is CR 2 . In one exemplary embodiment, R 2 is a member selected from H and methyl. [0209] Accordingly, preferred compounds useful in the methods of the invention include:
• R 1 , R 2 and R 3 include an aromatic ring or a fused ring system with at least one aromatic ring.
• at least one of R 1 , R 2 and R 3 has the formula:
• L 1 is a linker moiety, which is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• Particularly preferred compounds are those, in which R 1 represents a small group, such as H and F, and a member selected from R 2 and R 3 includes the aromatic moiety.
• Exemplary linker moieties include Ci to Cs substituted or unsubstituted alkyl chains wherein one or more carbon atoms are optionally replaced with a moiety including one or more heteroatoms, forming e.g., ether, thioether, amines, amides, sulfonamides or sulfones.
• R 1 , R 2 and R 3 has a formula, which is a member selected from: I" (CR 16 R 17 J n -Ar . ⁇
• R 16 and R 17 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 16 and R 17 together with the carbon to which they are attached, are optionally joined to form a 3- to 7-membered ring, which is a member selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl, and which is optionally fused to Ar.
• Ar is a phenyl ring and has the formula: wherein m is an integer from 0 to 5.
• Each R 5 can be selected from a variety of substituents.
• each R 5 is a member independently selected from H, halogen, CN, halogen substituted alkyl (e.g., CF 3 ), hydroxy, alkoxy (e.g., methoxy and ethoxy), acyl (e.g., acetyl), carbamate, sulfonamide, urea, CO 2 R' 8 , OC(O)R 18 , NR 18 R 19 , C(O)NR 18 R 19 , NR 18 C(O)R 20 , NR 18 SO 2 R 20 , S(O) 2 R 20 , S(O)R 20 , substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl and isopropyl), substituted or unsubstituted alkyl
• R 18 and R 19 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 20 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
• R 18 and a member selected from R 19 and R 20 together with the atoms to which they are attached, are optionally joined to form a 5- to 7- membered ring.
• Subjects for treatment according to the present invention include humans (patients) and other mammals in need of therapy for the stated condition.
• Compounds of the invention possess unique pharmacological characteristics with respect to inhibition of DAAO and influence the activity of the NMDA receptor in the brain, particularly by controlling the levels of D-serine. Therefore, these compounds are effective in treating conditions and disorders (especially CNS-related disorders), which are modulated by DAAO, D-serine and/or NMDA receptor activity. In one embodiment, compounds of the invention are associated with diminished side effects compared to administration of the current standards of treatment.
• the present invention relates to methods for increasing the concentration of D-serine and/or decreasing the concentration of toxic products of D- serine oxidation by DAAO in a mammal.
• Each of the methods comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, for example those of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt or solvate thereof.
• Compounds of the invention are typically more selective than known DAAO inhibitors, including indole-2-carboxylates, and demonstrate higher selectivity for DAAO inhibition relative to binding at the NMDA receptor's D-serine binding site.
• the compounds also exhibit an advantageous profile of activity including good bioavailability. Accordingly, they offer advantages over many art-known methods for treating disorders modulated by DAAO, D-serine or NMDA receptor activity.
• DAAO inhibitors can produce a desirable reduction in the cognitive symptoms of schizophrenia.
• Conventional antipsychotics often produce undesirable side effects, including tardive dyskinesia (irreversible involuntary movement disorder), extra pyramidal symptoms, and akathesia, and these may be reduced or eliminated by administering compounds of the invention.
• Compounds of the present invention may also be used in conjunction with therapy involving administration of D-serine or an analog thereof, such as a salt of D- serine, an ester of D-serine, alkylated D-serine, D-cycloserine or a precursor of D- serine, or can be used in conjunction with therapy involving administration of antipsychotics, antidepressants, psychostimulants, and/or Alzheimer's disease therapeutics.
• the compounds of the invention may also be used in conjunction with therapy involving administration of antipsychotics (for treating schizophrenia and other psychotic conditions), psychostimulants (for treating attention deficit disorder, depression, or learning disorders), antidepressants, nootropics (for example, piracetam, oxiracetam or aniracetam), acetylcholinesterase inhibitors (for example, the physostigmine related compounds, tacrine or donepezil), GABA analogs (e.g., gabapentin) or GABA receptor modulators, Alzheimer's disease therapeutics (e.g., nemantine hydrochloride) and/or analgesics (for treating of persistant or chronic pain, e.g. neuropathic pain).
• antipsychotics for treating schizophrenia and other psychotic conditions
• psychostimulants for treating attention deficit disorder, depression, or learning disorders
• antidepressants for treating attention deficit disorder, depression, or learning disorders
• nootropics for example, piracetam, oxiracetam or anirace
• the compounds of the present invention are useful for the treatment of neurological disorders, pain (e.g., neuropathic pain), ataxia and convulsion.
• Neurological disorders include neurodegenerative diseases (e.g., Alzheimers disease) and neuropsychiatric disorders (e.g., schizophrenia).
• Neuropsychiatric disorders include schizophrenia, autism, and attention deficit disorder. Clinicians recognize a distinction among such disorders, and there are many schemes for categorizing them.
• DSM-IV The Diagnostic and Statistical Manual of Mental Disorders, Revised, Fourth Ed., (DSM-IV-R), published by the American Psychiatric Association, provides a standard diagnostic system upon which persons of skill rely, and is incorporated herein by reference.
• the mental disorders of Axis I include: disorders diagnosed in childhood (such as Attention Deficit Disorder (ADD) and Attention Deficit-Hyperactivity
• ADHD Alzheimer's disease
• disorders diagnosed in adulthood include (1) schizophrenia and psychotic disorders; (2) cognitive disorders; (3) mood disorders; (4) anxiety related disorders; (5) eating disorders; (6) substance related disorders; (7) personality disorders; and (8) "disorders not yet included" in the scheme.
• ADD and ADHD are disorders that are most prevalent in children and are associated with increased motor activity and a decreased attention span. These disorders are commonly treated by administration of psychostimulants such as methylphenidate and dextroamphetamine sulfate.
• the compounds (and their mixtures) of the present invention are also effective for treating disruptive behavior disorders, such as attention deficit disorder (ADD) and attention deficit disorder/hyperactivity (ADHD), which is in accordance with its accepted meaning in the art, as provided in the DSM-IV-TRTM.
• disruptive behavior disorders such as attention deficit disorder (ADD) and ADHD deficit disorder/hyperactivity (ADHD), which is in accordance with its accepted meaning in the art, as provided in the DSM-IV-TRTM.
• Schizophrenia represents a group of neuropsychiatric disorders characterized by dysfunctions of the thinking process, such as delusions, hallucinations, and extensive withdrawal of the patient's interests from other people. Approximately one percent of the worldwide population is afflicted with schizophrenia, and this disorder is accompanied by high morbidity and mortality rates. So-called negative symptoms of schizophrenia include affect blunting, anergia, alogia and social withdrawal, which can be measured using SANS (Andreasen, 1983, Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa).
• Positive symptoms of schizophrenia include delusion and hallucination, which can be measured using PANSS (Positive and Negative Syndrome Scale) (Kay et al, 1987, Schizophrenia Bulletin 13:261-276).
• Cognitive symptoms of schizophrenia include impairment in obtaining, organizing, and using intellectual knowledge which can be measured by the Positive and Negative Syndrome Scale-cognitive subscale (PANSS-cognitive subscale) (Lindenmayer et al, 1994, J. Nerv. Merit. Dis. 182:631-638) or with cognitive tasks such as the Wisconsin Card Sorting Test.
• Conventional antipsychotic drugs which act on the dopamine D2 receptor, can be used to treat the positive symptoms of schizophrenia, such as delusion and hallucination.
• disorders treatable with the compounds of the present invention include, but are not limited to, depression, bipolar disorder, chronic fatigue disorder, seasonal affective disorder, agoraphobia, generalized anxiety disorder, phobic anxiety, obsessive compulsive disorder (OCD), panic disorder, acute stress disorder, social phobia, posttraumatic stress disorder, premenstrual syndrome, menopause, perimenopause and male menopause.
• Eating disorders are defined as a disorder of one's appetite or eating habits or of inappropriate somatotype visualization. Eating disorders include, but are not limited to, anorexia nervosa; bulimia nervosa, obesity and cachexia.
• compounds of the present invention provide the additional benefit of avoiding one or more of the adverse effects associated with conventional mood disorder treatments.
• side effects include, for example, insomnia, breast pain, weight gain, extrapyramidal symptoms, elevated serum prolactin levels and sexual dysfunction (including decreased libido, ejaculatory dysfunction and anorgasmia).
• compounds of the invention can be used for improving or enhancing learning and memory in subjects without cognitive deficits or patients suffering from cognitive deficits.
• Patients, who may benefit from such treatment include those exhibiting symptoms of dementia or learning and memory loss.
• Individuals with an amnesic disorder are impaired in their ability to learn new information or are unable to recall previously learned information or past events.
• the memory deficit is most apparent on tasks to require spontaneous recall and may also be evident when the examiner provides stimuli for the person to recall at a later time.
• the memory disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning and must represent a significant decline from a previous level of functioning.
• the memory deficit may be age-related or the result of disease or other cause.
• Dementia is characterized by multiple clinically significant deficits in cognition that represent a significant change from a previous level of functioning, including memory impairment involving inability to learn new material or forgetting of previously learned material. Memory can be formally tested by measuring the ability to register, retain, recall and recognize information. A diagnosis of dementia also requires at least one of the following cognitive disturbances: aphasia, apraxia, agnosia or a disturbance in executive functioning. These deficits in language, motor performance, object recognition and abstract thinking, respectively, must be sufficiently severe in conjunction with the memory deficit to cause impairment in occupational or social functioning and must represent a decline from a previously higher level of functioning.
• Compounds of the invention are useful for preventing loss of neuronal function, which is characteristic of neurodegenerative diseases.
• Therapeutic treatment with a compound of the invention improves and/or enhances memory, learning and cognition.
• the compounds of the invention can be used to treat a neurodegenerative disease such as Alzheimer's, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as MLS (cerebellar ataxia), Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g. AIDS, encephalopathies), epilepsy, benign forgetfulness, and closed head injury.
• a neurodegenerative disease such as Alzheimer's, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as MLS (cerebellar ataxia), Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.
• Compounds of the invention are useful for treating or preventing loss of memory and/or cognition associated with a neurodegenerative disease.
• the compounds also ameliorate cognitive dysfunctions associated with aging and improve catatonic schizophrenia
• Alzheimer's disease is manifested as a form of dementia that typically involves mental deterioration, reflected in memory loss, confusion, and disorientation.
• dementia is defined as a syndrome of progressive decline in multiple domains of cognitive function, eventually leading to an inability to maintain normal social and/or occupational performance.
• Early symptoms include memory lapses and mild but progressive deterioration of specific cognitive functions, such as language (aphasia), motor skills (apraxia) and perception (agnosia).
• Alzheimer's disease The earliest manifestation of Alzheimer's disease is often memory impairment, which is required for a diagnosis of dementia in both the National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease-and the Alzheimer's Disease and Related Disorders Association (NINCDS- ADRDA) criteria (McKhann et al., 1984, Neurology 34:939-944), which are specific for Alzheimer's disease, and the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, which are applicable for all forms of dementia.
• the cognitive function of a patient may also be assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS- cog; Rosen et al., 1984, Am. J.
• Alzheimer's disease is typically treated by acetylcholine esterase inhibitors such as tacrine hydrochloride or donepezil.
• acetylcholine esterase inhibitors such as tacrine hydrochloride or donepezil.
• tacrine hydrochloride or donepezil.
• the few forms of treatment for memory loss and impaired learning available at present are not considered effective enough to make any significant difference to a patient, and there is currently a lack of a standard nootropic drug for use in such treatment.
• Benign forgetfulness refers to a mild tendency to be unable to retrieve or recall information that was once registered, learned, and stored in memory ⁇ e.g., an inability to remember where one placed one's keys or parked one's car). Benign forgetfulness typically affects individuals after 40 years of age and can be recognized by standard assessment instruments such as the Wechsler Memory Scale. Closed head injury refers to a clinical condition after head injury or trauma. Such a condition, which is characterized by cognitive and memory impairment, can be diagnosed as "amnestic disorder due to a general medical condition" according to DSM-IV.
• cerebral function disorder includes cerebral function disorders involving intellectual deficits, and may be exemplified by senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, Parkinson's disease and autism.
• the compounds of the invention are useful to treat any kind of acute or chronic pain.
• the compounds of the invention are useful to treat chronic pain.
• the compounds of the invention are useful to treat neuropathic pain.
• the term "pain” includes central neuropathic pain, involving damage to the brain or spinal cord, such as may occur following stroke, spinal cord injury, and as a result of multiple sclerosis. It also includes peripheral neuropathic pain, which includes diabetic neuropathy (DN or DPN), post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN).
• DN or DPN diabetic neuropathy
• PPN post-herpetic neuralgia
• TGN trigeminal neuralgia
• CRPS Complex Regional Pain Syndrome
• RSD Reflex Sympathetic Dystrophy
• causalgia neuropathic pain symptoms
• neuropathic pain symptoms such as sensory loss, allodynia, hyperalgesia and hyperpathia.
• mixed nociceptive and neuropathic pain types for example, mechanical spinal pain and radiculopathy or myelopathy, and the treatment of chronic pain conditions such as fibromyalgia, low back pain and neck pain due to spinal nerve root compression, and reflex sympathetic dystrophy.
• Other conditions and disorders include, but are not limited to, autism, childhood learning disorders, depressions, anxieties and sleep disorders.
• Compounds of the invention may also be useful for the treatment of neurotoxic injury that follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest.
• treating when used in connection with the foregoing disorders means amelioration, prevention or relief from the symptoms and/or effects associated with these disorders and includes the prophylactic administration of a compound of the invention, a mixture thereof, a solvate (e.g., hydrate), prodrug (e.g., ethyl or methyl esters of the current carboxylic acid inhibitors) or a pharmaceutically acceptable salt of either, to substantially diminish the likelihood or seriousness of the condition.
• a solvate e.g., hydrate
• prodrug e.g., ethyl or methyl esters of the current carboxylic acid inhibitors
• the Morris water maze is one of the best-validated models of learning and memory, and it is sensitive to the cognitive enhancing effects of a variety of pharmacological agents.
• the task performed in the maze is particularly sensitive to manipulations of the hippocampus in the brain, an area of the brain important for spatial learning in animals and memory consolidation in humans.
• improvement in Morris water maze performance is predictive of clinical efficacy of a compound as a cognitive enhancer. For example, treatment with cholinesterase inhibitors or selective muscarinic cholinergic agonists reverse learning deficits in the Morris maze animal model of learning and memory, as well as in clinical populations with dementia.
• this animal paradigm accurately models the increasing degree of impairment with advancing age and the increased vulnerability of the memory trace to pre-test delay or interference which is characteristic of amnesiac patients.
• Contextual fear conditioning is a form of associative learning in which animals learn to fear a new environment (or an emotionally neutral conditioned stimulus) because of its temporal association with an aversive unconditioned stimulus (US), such as a foot shock. When exposed to the same context or conditioned stimulus at a later time, conditioned animals show a variety of conditioned fear responses, including freezing behavior. Because robust learning can be triggered with a single training trial, contextual fear conditioning has been used to study temporally distinct processes of short-term and long-term memory. Contextual fear conditioning is believed to be dependent on both the hippocampus and amygdale function.
• Extinction of fear refers to the reduction in the measured level of fear to a cue previously paired with an aversive event when that cue is presented repeatedly in the absence of the aversive event. Extinction of fear is not the erasure of the original fear memory, but instead results from a new form of learning that acts to inhibit or suppress the original fear memory (Bouton, M.D.; Bolles, R.C. J. Exp. Psychol. Anim. Behav. Process. 1979, 5, 368-378; Konorski, J.
• NMDA antagonists such as 2-amino-5-phosphopentanoic acid (APV) are known to block fear extinction (Davis, M.; Ressler, K.; Rothbaum, B.O.; Richardson, R. Biol. Psychiatry, 2006, 60, 369-375; Kehoe, EJ.; Macrae, M.; Hutchinson, CL. Psychobiol. 1996, 24, 127-135; Lee, H.; Kim, J.J. J. Neurosci.
• AAV 2-amino-5-phosphopentanoic acid
• Psychiatry 2006, 60, 369-375; Ressler, K.J.; Rothbaum, B.O.; Tannenbaum, L.; Anderson, P.; Graap, K.; Zimand, E.; Hodges, L.; Davis, M. Archives Gen. Psychiatry 2004, 61, 1136-1144.), exposure to phobic situations as therapy for panic disorders (For social anxiety disorder, see Hoffmann, S.G.; Meuret, A.E.; Smits, J.A.; Simon, N.M.; Pollack, M.H.; Eisenmenger, K.; Shiekh, M.; Otto, M.W. Arch. Gen.
• compounds of the invention are useful as an adjunct with psychotherapy for the treatment of these conditions.
• compounds of the invention are useful as an adjunct to shorten the number of therapy sessions required or improve the therapeutic outcome of therapy.
• Methods for improving learning and memory may be measured by such tests as the Wechsler Memory Scale and the Minimental test.
• a standard clinical test for determining if a patient has impaired learning and memory is the Minimental Test for Learning and Memory (Folstein et al., J. Psychiatric Res. 12:185, 1975), especially for those suffering from head trauma, Korsakoff s disease or stroke.
• the test result serves as an index of short-term, working memory of the kind that deteriorates rapidly in the early stages of dementing or amnesiac disorders.
• Ten pairs of unrelated words e.g., army-table
• Subjects are then asked to recall the second word when given the first word of each pair.
• the measure of memory impairment is a reduced number of paired-associate words recalled relative to a matched control group.
• Improvement in learning and memory constitutes either (a) a statistically significant difference between the performance of treated patients as compared to members of a placebo group; or (b) a statistically significant change in performance in the direction of normality on measures pertinent to the disease model. Animal models or clinical instances of disease exhibit symptoms which are by definition distinguishable from normal controls. Thus, the measure of effective pharmacotherapy will be a significant, but not necessarily complete, reversal of symptoms. Improvement can be facilitated in both animal and human models of memory pathology by clinically effective "cognitive enhancing" drugs which serve to improve performance of a memory task.
• cognitive enhancers which function as cholinomimetic replacement therapies in patients suffering from dementia and memory loss of the Alzheimer's type significantly improve short-term working memory in such paradigms as the paired-associate task.
• Another potential application for therapeutic interventions against memory impairment is suggested by age-related deficits in performance which are effectively modeled by the longitudinal study of recent memory in aging mice.
• the Wechsler Memory Scale is a widely used pencil-and-paper test of cognitive function and memory capacity. In the normal population, the standardized test yields a mean of 100 and a standard deviation of 15, so that a mild amnesia can be detected with a 10-15 point reduction in the score, a more severe amnesia with a 20- 30 point reduction, and so forth.
• a battery of tests including, but not limited to, the Minimental test, the Wechsler memory scale, or paired-associate learning are applied to diagnose symptomatic memory loss. These tests provide general sensitivity to both general cognitive impairment and specific loss of learning/memory capacity (Squire, 1987).
• age-related cognitive decline which reflects an objective diminution in mental function consequent to the aging process that is within normal limits given the person's age (DSM IV, 1994).
• "improvement" in learning and memory within the context of the present invention occurs when there is a statistically significant difference in the direction of normality in the paired-associate test, for example, between the performance of therapeutic agent treated patients as compared to members of the placebo group or between subsequent tests given to the same patient.
• PCP stereotypy test Meltzer et al (In “PCP (Phencyclidine): Historical and Current Perspectives", ed. E.F. Domino, NPP Books, Ann Arbor, 1981, 207-242)
• Amphetamine stereotypy test Simon and Chermat, J. Pharmacol. (Paris), 1972, 3, 235-238
• PCP hyperactivity Gleason, S.D.; Shannon, H.E. Psychopharmacology (Berl).
• the prepulse inhibition test may be used to identify compounds that are effective in treating schizophrenia. The test is based upon the observations that animals or humans that are exposed to a loud sound will display a startle reflex and that animals or humans exposed to a series of lower intensity sounds prior to the higher intensity test sound will no longer display as intense of a startle reflex. This is termed prepulse inhibition.
• Tests of acute pain include the tail flick (d'Amour and Smith, J. Pharmacol. Exp. Ther. 1941, 72, 14-19), hot plate (Eddy, N.B.; Leimbach, D. J Pharmacol Exp Ther. 1953, 707(3):385-93), and paw withdrawal tests.
• the phenylbenzoquinone writhing assay is a measure of peritoneovisceral or visceral pain.
• Persistent pain tests which use an irritant or foreign chemical agent as the nociceptive stimulus, include the formalin test (Wheeler-Aceto, H; Cowan, A Psychopharmacology (Berl).
• Neuropathic pain models are reviewed in Wang and Wang, Advanced Drug Delivery Reviews 2003, and include the Spinal Nerve Ligation (SNL) model (also called the Chung Model; Kim, S.H.; Chung, J.M.
• SNL Spinal Nerve Ligation
• Hypersensitivity (PTH) model (Decosterd, I. Pain, 2002, 100(1), 155-162; Anesth. Analg. 2004, 99, 457-463), Spared Nerve Injury (SNI) model (Decosterd, I. Pain, 2002, 700(1), 155-162; Anesth. Analg. 2004, 99, 457-463), the lumbar nerve ligation model (Ringkamp, M; Eschenfelder, S; Grethel, E.J.; Habler, H.J., Meyer, R.A., Janig, W., Raja, S.N.
• Opioids such as morphine, display robust efficacy in models of acute pain, such as the tail flick and hot plate tests, as well as in both the initial, acute phase and the second, inflammatory phase of persistent pain tests, such as the formalin test. Opioids also display efficacy in neuropathic pain models, such as the Spinal Nerve Ligation (SNL) model.
• SNL Spinal Nerve Ligation
• neuropathic pain a compound that is useful specifically for the treatment of persistent or chronic pain states (e.g., neuropathic pain), such as gabapentin, tend to display efficacy in models of persistent inflammatory and neuropathic pain, such as the formalin (second phase) and SNL models.
• PWT paw withdrawal threshold
• these compounds fail to display efficacy in acute tests such as the tail flick test and the hot plate test, and also fail to display efficacy in the initial, acute phase of the formalin test.
• the lack of effect of compounds in the acute pain tests supports the notion that the antinociceptive action of these compounds is related to specific mechanisms associated with a central sensitized state following injury.
• compounds that are efficacious in neuropathic pain model(s), such as the SNL (Chung) model, and the second phase of the formalin test but are not efficacious in acute pain models, such as hot plate and tail flick, or in the first phase of the formalin test suggest that these compounds are more likely to be effective in persistent and chronic, rather than acute, pain states (see Table 1).
• the compounds of the invention are useful for the treatment of persistent or chronic pain states (e.g., neuropathic pain).
• neuropathic pain e.g., chronic pain states
• such compounds may be profiled in vivo by evaluating their efficacy in models of both acute and neuropathic pain.
• Preferred compounds demonstrate efficacy in neuropathic pain models, but not in acute pain models.
• Table 1 Profile of morphine and gabapentin in a variety of animal models
• seizures in these models can be used for testing of antiepileptic drug effects.
• a comparison of the pharmacology of chronic models with models of acute (reactive or provoked) seizures in previously healthy (non-epileptic) animals, such as the maximal electroshock seizure test, demonstrates that drug testing in chronic models of epilepsy yields data which are more predictive of clinical efficacy and adverse effects.
• anhydrous EtOH e.g., 10.5 mL
• sodium e.g., 0.8 g
• anhydrous EtOH e.g., 50.0 mL
• the reaction mixture was stirred for about 1 hour (h) while the temperature was maintained below 0 0 C and was then allowed to warm to ambient temperature (also called room temperature, rt) (e.g., overnight).
• the mixture was quenched with a cold solution of saturated aqueous NH4CI or was diluted with water (e.g., 0.5 L).
• the product was extracted with diethyl ether or ethyl acetate (EtOAc) (e.g., 3 x 0.2 L) and the combined organic phases were washed with saturated aqueous NaCl solution (2 x 0.1 L), dried (e.g., over Na 2 SO_j) and filtered.
• the solvent was removed in vacuo to give the ethyl azidoacrylate.
• the solvent was reduced in vacuo (e.g., to about 50 mL) and the resulting solution was used in the next reaction step.
• a solution of the above ethyl azidoacrylate in o- or m-xylene e.g., 150 mL was heated to reflux for a time period between about 15 minutes (min) and 14 h (typically about 1 h). The reaction mixture was then allowed to cool to ambient temperature. The solution was concentrated in vacuo and the crude product was purified (e.g., silica gel column chromatography) to give the fused pyrrole ethyl ester.
• the mixture was poured into water (e.g., 200 mL) and the pH of the resulting mixture was adjusted to about pH 1-2 with HCl.
• excess solvent was removed in vacuo and the residue was dissolved in 5% citric acid (e.g., 15 mL).
• the solvent was removed in vacuo and the residue was dissolved in a saturated solution OfNH 4 Cl (e.g., 15 mL).
• the acidified solution was then extracted (e.g., 3 x 100 mL EtOAc) and the combined organic layers were washed (e.g., with brine), dried (e.g., over Na 2 SO 4 ), filtered and concentrated in vacuo to give the carboxylic acid.
• a solution mixture OfPd(OAc) 2 (144 mg, 0.64 mmol) and triphenylphosphine (TPP) (136 mg, 0.52 mmol) were weighed into a vial, dissolved in acetonitrile and transferred into a 40 mL Wheaton vial containing diethyl 4- chlorobenzyl phosphate (Org. Lett. 2005, 7, 4875-4878; 3.08 g, 11.6 mmol), 5- formylthiophen-3-ylboronic acid (2.0 g, 12.8 mmol), K 3 PO 4 (2.72 g, 12.8 mmol) and a stir-bar. Nitrogen gas was bubbled through the mixture.
• 4-(4-Chlorophenethyl)thiophene-3-carbaldehyde was synthesized from 4- [2-(4-chlorophenyl)-vinyl]-thiophene-3-carbaldehyde (260 mg, 1.04 mmol) following the conditions used to hydrogenate 4-(phenylethynyl)thiophene-2-carbaldehyde to 4- phenethylthiophene-2-carbaldehyde (Example 1.1. b). Purification by flash chromatography (0-10% EtO Ac/heptane) yielded 4-(4-chlorophenethyl)thiophene-3- carbaldehyde (188 mg, 72%).
• S-Phenethylthiophene- ⁇ -carbaldehyde was synthesized from 5- (phenylethynyl)thiophene-2-carbaldehyde (4.0 g, 18.8 mmol) following the conditions used to hydrogenate 4-(phenylethynyl)thiophene-2-carbaldehyde to 4- phenethylthiophene-2-carbaldehyde (Example 1.1. b).
• reaction mixture was subsequently taken up in 75 mL DCM and washed with water. The organic layer was then dried (Na 2 SO.)), filtered, and evaporated in vacuo. The resulting residue was chromatographed over silica gel (0 — 10% EtOAc in heptane over 18 min. — retention time (tiO of product: 4 - 12 min) to give the desired ((4-bromothiophen-2- yl)methoxy)-/er/-butyl diphenyl silane (4.3929 g, 98%).
• N-fluorobenzenesulfonimide (2.54 g, 8 mmol, 1.2 equiv) was dissolved in 7 mL of anhydrous THF (0.9 mL/mmol reagent) in a separate vessel under inert atmosphere, and was then added dropwise over 10 to 15 min to the reaction vial.
• the reaction temperature was maintained at -78 0 C for 4 h, and was subsequently allowed to equilibrate to rt overnight.
• the reaction was quenched by the addition of approx. 30 mL of saturated aqueous ammonium chloride solution.
• the resulting aqueous mixture was extracted with ether (4 x 20 mL).
• TBAF tetra M-butyl ammonium fluoride
• (E)-5-styrylthiophene-3-carbaldehyde was synthesized from 5-iodo-3- thiophene carboxaldehyde and (E)-styrylboronic acid using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde.
• the crude product was chromatographed over silica gel (0 to 25% EtOAc in heptane over 30 min) to give (E)-5-styrylthiophene-3-carbaldehyde (0.115 g, 20% yield).
• Ethyl 2-azido-3-(5-phenethylthiophen-2-yl)acrylate was synthesized from 5-phenethylthiophene-2-carbaldehyde (1.5 g, 6.9 mmol) and was isolated as an orange oil (832 mg, 37%) after purification by flash column chromatography (100 % heptane).
• Ethyl 2-azido-3-(4-phenylthiophen-3-yl)acrylate was synthesized from 4- formylthiophen-3-ylboronic acid (300 mg, 1.59 mmol) and was isolated after purification by flash chromatography (Isco CombiFlash, 0-5% EtOAc/heptane) (270 mg, 60%).
• Ethyl-2-azido-3-(4-(4-chlorobenzyl)thiophene-3-yl)acrylate 230 mg, 60% was prepared from 4-(4-chlorobenzyl)-thiophene-3-carbaldehyde (260 mg, 1.1 mmol) and was isolated after purification by flash chromatography (Isco CombiFlash, 0-5% EtOAc/heptane).
• Ethyl 2-azido-3-(thiophen-3-yl)acrylate was synthesized from thiophene- 3-carboxaldehyde (4.50 g, 40.0mmol) and isolated after purification by silica gel column chromatography (0 to 25% EtOAc in heptane over 30 min.). 2.8 g of the purified intermediate were used in the next step.
• Ethyl 2-azido-3-(5-phenethylthiophen-3-yl)acrylate was prepared from 5- phenethylthiophene-3-carboxaldehyde (0.106 g, 0.49 mmol) in EtOH (2.0 mL) and chromatographed over silica gel (0 to 10% EtOAc in heptane over 20 min).
• Ethyl 2-azido-3-(5-fluorothiophen-3-yl)acrylate was prepared from 5- fluorothiophene-3-carbaldehyde (as a mixture with 3-thiophenecarboxaldehyde, 0.29 g, ⁇ 2.2 mmol) in EtOH (8.5 mL) and used without purification in the next reaction step.
• Methyl 2-azido-3-(4-fluorothiophen-3-yl)acrylate was prepared from 4- fluorothiophene-3-carbaldehyde (Ozaki et al US 6,995,144 B2 (2006); 6.0 mmol in 10 mL of DCM) and purified by chromatography (0.53g, 37%).
• B) The title compound was synthesized from methyl 2-azido-3-(4- fluorothiophen-3-yl)acrylate and purified by preparative RP-HPLC. The acetonitrile was removed under vacuum and the aqueous layer was extracted with methyl tert- butyl ether (MTBE).
• MTBE methyl tert- butyl ether
• the title compound was synthesized from ethyl 6//-thieno[2,3-6]pyrrole-5- carboxylate (0.20 g, 1.02 mmol) and NCS (0.17 g, 1.2 mmol) using the halogenation conditions to synthesize ethyl 4-bromo-6H-thieno[2,3-6]pyrrole-5-carboxylate. Separation of the desired product by RP-HPLC (10-100% gradient 0.1% formic acid in H 2 O to CH 3 CN over 10 min) afforded ethyl 4-chloro-6H-thieno[2,3- ⁇ ]pyrrole-5- carboxylate (0.044 g, 19% yield).
• the title compound was synthesized from 4-bromo-furan-2-carbaldehyde (300 mg, 1.71 mmol) and cyclopropylboronic acid (171 mg, 1.99 mmol), using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in toluene (7.5 mL) and water (0.5 mL), and triphenylphosphine was replaced with tricyclohexylphosphine (48 mg, 0.17 mmol).
• Ethyl 2-azido-3-(4-vinylfuran-2-yl)acrylate (398 mg, 52%) was synthesized from 4-vinylfi ⁇ ran-2-carbaldehyde (0.4 g, 3.28 mmol) and was purified by flash chromatography (Isco CombiFlash, 0-5% EtO Ac/heptane).
• Ethyl 2-azido-3-(5-(trifluoromethyl)furan-2-yl)acrylate was synthesized from 5-(trifluoromethyl)fiiran-2-carbaldehyde (1.00 g, 6.09 mmol) and was purified by silica gel column chromatography (0 to 25% EtOAc in heptane over 20 min) to give a yellow oil (0.512 g, 30%).

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