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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
  • C07C323/40—Y being a hydrogen or a carbon atom
  • C07C323/41—Y being a hydrogen or an acyclic carbon atom
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/58—Radicals substituted by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

• the present invention relates to a class of diaryl-enynes, to pharmaceutical compositions containing them and to methods of treating neurological and neuropsychiatric disorders using such compounds.
• Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post-synaptic terminal and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1987:1032).
• Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighbouring synapses, transporters maintain the fidelity of synaptic transmission. Lastly, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization.
• Neurotransmitter transport is dependent upon extracellular sodium and the voltage difference across the membrane; under conditions of intense neuronal firing, as, for example, during a seizure, transporters can function in reverse, releasing neurotransmitter in a calcium-independent non-exocytotic manner (Attwell et al., Neuron, 11, 1993:401-407). Pharmacologic modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.
• the amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter.
• the inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are thus referred to as "strychnine-sensitive".
• Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
• Glycine also functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system (Johnson and Ascher, Nature, 325, 1987:529-531; Fletcher et al, Glycine Transmission, Otterson and Storm- Mathisen, eds., 1990:193-219).
• glycine is an obligatory co-agonist at the class of glutamate receptor termed N-mefhyl-D-aspartate (NMD A) receptor. Activation of NMD A receptors increases sodium and calcium conductance, which depolarizes the neuron, thereby increasing the likelihood that it will fire an action potential.
• NMD A N-mefhyl-D-aspartate
• LTP long-term potentiation
• NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
• Molecular cloning has revealed the existence in mammalian brains two classes of glycine transporters, termed GlyT-1 and GlyT-2.
• GlyT-1 is found throughout the brain and spinal cord, and it has been suggested that its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992:927-935).
• GlyT- la three variants of GlyT- la, GlyT- lb and GlyT-lc.
• GlyT-2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT-1.
• NMDA receptors which receptors are located in the forebrain, among other locations. This concentration increase elevates the activity of NMDA receptors, thereby alleviating schizophrenia and enhancing cognitive function.
• compounds that interact directly with the glycine receptor component of the NMDA receptor can have the same or similar effects as increasing or decreasing the availability of extracellular glycine caused by inhibiting or enhancing GlyT-1 activity, respectively. See, for example, Pitkanen et al., Eur. J. Pharmacol, 253, 125-129 (1994);
• the present invention provides compounds that affect glycine transport.
• the invention also provides compositions useful to treat medical conditions for which a glycine transport modulator, and particularly glycine uptake inhibitors, are indicated.
• Ari and Ar 2 are independently selected aryl groups, optionally substituted with up to five substituents independently selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl, cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl heterocycloalkyl-substituted alkoxy, heterocycloalkyloxy-substitute
• Ri is selected from the group consisting of H and alkyl ;
• R is selected from the group consisting of H, alkyl and benzyl ;
• R 3 is selected from the group consisting of CO 2 R, CONRR', CONH(OH), COSR, SO 2 NRR', PO(OR)(OR') and tetrazolyl, wherein R and R' are independently selected from the group consisting of H and alkyl; and a salt, solvate or hydrate thereof.
• compounds of Formula I inhibit glycine transport (or reuptake) via the GlyT-1 transporter, or are precursors (for example, pro-drugs) of such compounds and, thus, are useful in the treatment of schizophrenia, as well as other CNS-related disorders such as cognitive dysfunction, dementia (including that related to Alzheimer's disease), attention deficit disorder and depression.
• a pharmaceutical composition comprising a compound of Formula I in an amount effective to inhibit glycine transport, and a pharmaceutically acceptable carrier.
• compositions containing the present compounds in amounts for pharmaceutical use to treat medical conditions for which a glycine transport inhibitor is indicated.
• Preferred are those compositions containing compounds useful in the treatment of medical conditions for which GlyT- 1 -mediated inhibition of glycine transport is needed, such as the treatment of schizophrenia or cognitive dysfunction.
• aryl as used herein means a monocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl, and the like, or a benzo-fused aromatic group such as naphthyl, indanyl, quinolinyl, fluorenyl and the like.
• alkyl as used herein means straight- and branched-chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl and the like.
• cycloalkyl as used herein means a carbocyclic ring containing from three to eight carbon atoms and includes cyclopropyl, cyclohexyl and the like.
• cycloalkyloxy refers to such a carbocycle that is coupled through an oxygen to another group, and includes cyclohexyloxy and the like.
• heterocycloalkyl as used herein means a three- to eight-membered ring containing up to two heteroatoms selected from the group consisting of N, S and O, and includes piperidinyl, piperazinyl, thiopyranyl and the like.
• Such rings coupled to another group through an oxygen, such as piperidinyloxy and the like, are referred to as heterocycloalkyloxy groups.
• aralkyl, aryloxyalkyl, aralkyloxy and aryloxyalkoxy refer to an alkyl or alkoxy radical substituted with an aryl or aryloxy group and includes benzyl, phenethyl, benzyloxy, 2-phenoxyethyl and the like.
• cycloalkyl- substituted alkyl, cycloalkyl-substituted alkoxy, heterocycloalkyl-substituted alkyl and heterocycloalkyl-substituted alkoxy mean groups such as 2-cyclohexyl-ethyl and the like.
• substituents in which an alkyl or alkoxy group is substituted by another group through a bridging oxygen are groups referred to herein as cycloalkyloxy- substituted alkyl, cycloalkyloxy-substituted alkoxy, heterocycloalkyloxy-substituted alkyl and heterocycloalkyloxy-substituted alkoxy.
• alkylene e.g., -CH2-CH2-
• alkynylene e.g., -CH ⁇ CH-
• alkylene e.g., -CH2-CH2-
• alkynylene e.g., -CH ⁇ CH-
• alkoxy as used herein means straight- and branched-chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy and the like.
• thioalkyl as used herein means straight- and branched-chain alkyl radicals containing from one to six carbon atoms and includes thiomethyl (CH3-S-), thiopropyl and the like.
• thioaryl refers to an aryl group that is bridged to another group through a sulfur.
• a thioarylalkyl group is a thioaryl group bridged to another group through an alkylene group.
• an aralkythio group is an aralkyl group, such as benzyl, which is bridged to another group through a sulfur atom.
• an arylalkylthioalkyl group is an arylalkyl group that is bridged to another group through a thioalkyl group.
• alkanoyl as used herein means straight- and branched-chain radicals containing from one to six carbon atoms and includes acetyl, propionyl and the like.
• halo as used herein means halogen and includes fluoro, chloro, bromo and the like.
• haloalkyl refers to an alkyl group substituted by one or more independently selected halo atoms, such as -CF3.
• haloalkoxy refers to an alkoxy group substituted by one or more independently selected halo atoms, such as -OCF3.
• alkylenedioxy refers to a group of the formula -O-(CH2)n-O-, in which the terminal oxygen typically are fused to atoms on an aryl group to form a bicyclic ring system, and includes methylenedioxy, ethylenedioxy and the like.
• hetero atom as used herein means atoms other carbon and includes N, S and O.
• Compounds of Formula I include those in which Ari and Ar are, independently, optionally-substituted aryl groups.
• Substitution sites on rings Ari and Ar 2 will be limited in practice to the carbon atoms on the ring not bound to the core of the molecule.
• a benzene ring can be substituted with up to 5 substituents;
• pyridine and pyran can accommodate up to 4 substituents
• pyrole furan and thiophene can accommodate up to 3 substituents;
• imidazole 2 substituents and triazole can accommodate only one substituent.
• Ari is an optionally monocyclic aromatic group such as benzene, pyridine, pyran, thiophene, furan, pyrole, imidazole and triazole.
• Ari suitably accomodates 1 , 2 or 3 substituents on the aromatic ring and these can be chosen from such groups as alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl, cycloalkyloxy-substituted alkyl, cycloalkyl- substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alky
• Arj is selected from benzene, pyridine, pyran, thiophene, furan and pyrole, optionally substituted with 1 , 2 or 3 substituents selected from halo, NO2, CF3, CN, OH, alkyl, alkoxy, aryl, aralkyl, and R"(X)n.
• n 0 or 1 ;
• X is CH 2 or a heteroatom; and
• R" is H, alkyl or aryl substituted optionally with up to three substituents selected from alkyl, halo, NO 2 , CF 3 , CN, OH, SO 2 NRR', NRR', and CO R (where R and R' are independently selected from the group consisting of H and alkyl).
• Ari is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, NO2, CF3, CN, OH, and R"(X) n where n is 0 or 1 ;
• X is CH 2 O, S, or NR; and
• R' ' is H, alkyl or aryl substituted optionally with up to three substituents selected independently from alkyl, halo, NO 2 , CF 3 , CN, OH, SO 2 NRR', NRR', CO 2 R (where R and R' are independently selected from the group consisting of H and alkyl).
• Ari is phenyl optionally substituted with 1 or 2 substituents selected from alkyl, thioalkyl, alkoxy, halo, haloalkyl, haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, and substituted or unsubstituted aralkyl.
• Arj is mono-substituted phenyl where the substituent is located at the 4 position and is selected from methyl, ethyl, rc-propyl, z ' -propyl, «-butyl, 3- furyl, and 3-thienyl.
• Ari is an optionally substituted benzofused aromatic group such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxyphenyl and the like, where the substituents can be selected from halo, NO2, CF3, CN, OH, alkyl, alkoxy, aryl, aralkyl, and R"(X) n.
• n 0 or 1 ;
• X is CH 2 or a heteroatom; and
• R" is H, alkyl or aryl substituted optionally with up to three substituents selected from alkyl, halo, NO 2 , CF 3 , CN, OH, SO 2 NRR', NRR', CO 2 R (where R and R' are independently selected from the group consisting of H and alkyl).
• Ari can be naphthyl, quinolinyl, indanyl, or alkylenedioxyphenyl, optionally substituted with 1 or 2 substituents selected from alkyl, alkoxy, thioalkyl and aryl.
• Ari is selected from unsubstituted naphthalene and methylenedioxyphenyl.
• Ar 2 is an optionally substituted aryl, where aryl, is a monocyclic aromatic group such as benzene, pyridine, pyran, furan, thiophene, pyrrolidine and the like, or is a benzofused aromatic ring system such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxyphenyl and the like. Either 1, 2, or 3 substituents may be present, and these may be independently selected from halo, haloalkyl, alkyl, haloalkoxy, and alkoxy.
• aryl is a monocyclic aromatic group such as benzene, pyridine, pyran, furan, thiophene, pyrrolidine and the like, or is a benzofused aromatic ring system such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxypheny
• A is a monocyclic aromatic ring bearing up to three substituents selected independently from halo, haloalkyl, alkyl, haloalkoxy, and alkoxy.
• A is selected from mono or di-substituted phenyl, where the substituents are selected from halo, haloalkyl, alkyl, haloalkoxy, and alkoxy.
• Ar 2 is a phenyl group that is either unsubstituted or has one substituent selected from halo and alkoxy.
• Ar is selected from unsubstituted or mono substituted phenyl, where the substituent is selected from chloro and flouro.
• R 3 is selected from the group consisting of - CO 2 R, -CONRR', -CONH(OH), -COSR, -SO 2 NRR', -PO(OR)(OR') and tetrazolyl, wherein R and R' are independently selected from the group consisting of H and alkyl.
• R is COOR.
• R 3 is COOH.
• the compounds of Formula I include those in which RI is selected from the group consisting of H and alkyl.
• Ri is H.
• the compounds of Formula I include those in which R? is selected from the group consisting of H, alkyl and benzyl.
• R? is selected from the group consisting of H, alkyl and benzyl.
• compounds of Formula I are those in which R] is H, R 2 is methyl, R 3 is COOH.
• Ari and Ar 2 are desirably substituted or unsubstituted phenyl.
• Ari is either phenyl or 4-(substituted)-phenyl.
• Ari is desirably a 4-(alkyl)-phenyl group, particularly where the alkyl group is a straight-chain alkyl group, including 4-isopropyl-phenyl, 4-ethyl-phenyl, and 4-n- propyl-phenyl.
• Ar 2 is preferably is chloro or fluoro substituted phenyl.
• Rj is H, R 2 is methyl, R 3 is COOH, Ar 2 is unsubstituted phenyl and Ari is 4-alkyl substituted phenyl where alkyl is C straight chain.
• Ri is H, R 2 is methyl, R 3 is COOH, Ar 2 is 2-chloro- phenyl and Ari is 4-alkyl phenyl where the alkyl substituent is selected from ethyl and propyl.
• Rj is H
• R is methyl
• R 3 is COOH
• Ari is naphthyl, especially 2-naphthyl
• Ar 2 is phenyl.
• Rj is H, R is methyl, R 3 is COOH, Ari is 3,4-methylenedioxyphenyl and Ar is 3-fluoro-phenyl.
• Ri is H
• R is methyl
• R 3 is COOH
• Ar 2 is phenyl
• Ari is an optionally substituted aryl substituted phenyl.
• Ri is H
• R 2 is methyl
• R 3 is COOH
• Ar 2 is phenyl
• Ari is phenyl substituted by a 5-membered heteroaryl that is optionally substituted.
• Ri is H
• R 2 is methyl
• R 3 is COOH
• Ar 2 is phenyl
• Ari is 4-(3-furyl)phenyl.
• Compounds of Formula I can be considered to be amino acids or derivatives thereof.
• Compounds which contain, instead of a carboxylate group, a "carboxylate equivalent” group, such as hydroxamic acids, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, amides or tetrazoles, are also considered embodiments of the present invention.
• the compound of Formula I is provided in labeled form, such as radiolabeled form (e.g. labeled by incorporation within its structure 3 H or 14 C or by conjugation to J I).
• labeled form such as radiolabeled form (e.g. labeled by incorporation within its structure 3 H or 14 C or by conjugation to J I).
• such compounds which bind preferentially to GlyT-1, can be used to identify GlyT-1 receptor ligands by techniques common in the art. This can be achieved by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting preparation with an equimolar amount of radiolabeled compound of the invention. GlyT-1 receptor ligands are thus revealed as those that significantly occupy the GlyT-1 site and prevent binding of the radiolabeled compound of the present invention.
• GlyT-1 receptor ligand candidates may be identified by first incubating a radiolabeled form of a compound of the invention then incubating the resulting preparation in the presence of the candidate ligand. A more potent GlyT-1 receptor ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
• Acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.
• Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
• base addition salts such as sodium, potassium and ammonium salts
• Base salts are preferred and sodium and potassium salts are especially preferred.
• the compounds of the present invention can be prepared by processes analogous to those established in the art.
• compounds of Formula I are readily prepared by the method shown in Scheme 1 , below.
• Intermediate C was prepared according to the method of Trost (Trost, B. M.; Sorum, M. T.; Chan, C; Harms, A. E.; Ruther, G. J. Am. Chem. Soc. 1997, 119, 698-708 ; Trost, B. M.; Hachiya, I.; Mclntosh, M. C. Tetrahedron Lett.
• Reagents (i) P (OAc) 2 , phosphine ligand , (n) (a) DIBAL-H (b) NBS , PPh 3 , (in) t-Bu sarcosine , K 2 C0 3 , Kl , (iv) K 2 C0 3 MeOH , (v) Ar,-I , Cul , Pd(PP 3 ), , Et 3 N , (vi) formic acid , 50°C
• such compounds may also be prepared according to the route shown in Scheme 2, below.
• This route complements that shown above, in that it allows the parallel synthesis of a series of related compounds in which group Ari is constant, but group Ar 2 represents a number of different aryl groups.
• common intermediate L can be prepared in bulk, and simply treated with the appropriate arylpropiolic ester O (readily accessible from aryliodide M by treatment with propiolic ester N in the presence of Cul and Pd(PPh 3 ) ), under the conditions outlined above, to yield, after deprotection, products H.
• NMDA receptors which receptors are located in the forebrain, among other locations. This concentration increase elevates the activity of NMDA receptors, thereby alleviating schizophrenia and enhancing cognitive function.
• compounds that interact directly with the glycine receptor component of the NMDA receptor can have the same or similar effects as increasing or decreasing the availability of extracellular glycine caused by inhibiting or enhancing GlyT-1 activity, respectively. See, for example, Pitkanen et al., Eur. J. Pharmacol, 253, 125-129 (1994); Thiels et al., Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16, 1561- 1569 (1996).
• the compounds of the invention are, for instance, administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of a patch or other transdermal delivery device), by pulmonary route by use of an aerosol, or parenterally, including, for example, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intravenously or intrathecally. Administration can be by means of a pump for periodic or continuous delivery.
• the compounds of the invention are administered alone, or are combined with a pharmaceutically-acceptable carrier or excipient according to standard pharmaceutical practice.
• the compounds of the invention are used in the form of tablets, capsules, lozenges, chewing gum, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like.
• carriers that are used include lactose, sodium citrate and salts of phosphoric acid.
• Various disintegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets.
• useful diluents are lactose and high molecular weight polyethylene glycols. If desired, certain sweetening and/or flavoring agents are added.
• sterile solutions of the compounds of the invention are usually prepared, and the pHs of the solutions are suitably adjusted and buffered.
• the total concentration of solutes should be controlled to render the preparation isotonic.
• ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers.
• Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzylchromium chloride, and the usual quantities of diluents and/or carriers.
• diluents and/or carriers will be selected to be appropriate to allow the formation of an aerosol.
• Suppository forms of the compounds of the invention are useful for vaginal, urethral and rectal administrations.
• Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature.
• the substances commonly used to create such vehicles include theobroma oil, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weight and fatty acid esters of polyethylene glycol. See, Remington's
• Analogous gels or creams can be used for vaginal, urethral and rectal administrations.
• Numerous administration vehicles will be apparent to those of ordinary skill in the art, including without limitation slow release formulations, liposomal formulations and polymeric matrices.
• Examples of pharmaceutically acceptable acid addition salts for use in the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p- toluenesulphonic and arylsulphonic acids, for example.
• Examples of pharmaceutically acceptable base addition salts for use in the present invention include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organoamino salts such as triethylamine salts. Numerous appropriate such salts will be known to those of ordinary skill.
• the physician or other health care professional can select the appropriate dose and treatment regimen based on the subject's weight, age, and physical condition. Dosages will generally be selected to maintain a serum level of compounds of the invention between about 0.01 ⁇ g/cc and about 1000 ⁇ g/cc, preferably between about 0.1 ⁇ g/cc and about 100 ⁇ g/cc.
• an alternative measure of preferred amount is from about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be administered.
• an alternative measure of preferred administration amount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg).
• an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg.
• eukaryokic cells For use in assaying for activity in inhibiting glycine transport, eukaryokic cells, preferably QT-6 cells derived from quail fibroblasts, have been transfected to express one of the three known variants of human GlyT-1, namely GlyT- la, GlyT- lb or GlyT- lc, or human GlyT-2.
• the sequences of these GlyT-1 transporters are described in Kim et al., Molec. Pharm. 45: 608-617, 1994, excepting that the sequence encoding the extreme N-terminal of GlyT- la was merely inferred from the corresponding rat-derived sequence.
• Suitable expression vectors include pRc/CMV (Invitrogen), Zap Express Vector (Stratagene Cloning Systems, LaJolla, CA; hereinafter "Stratagene"), pBk/CMV or pBk-RSV vectors (Stratagene), Bluescript II SK +/- Phagemid Vectors (Stratagene), LacSwitch (Stratagene), pMAM and pMAM neo (Clontech), among others.
• a suitable expression vector is capable of fostering expression of the included GlyT DNA in a suitable host cell, preferably a non- mammalian host cell, which can be eukaryotic, fungal, or prokaryotic.
• Such preferred host cells include amphibian, avian, fungal, insect, and reptilian cells.
• Example 1 l-Methoxycarbonyl-2-phenyl-4-trimethylsilyl-l-buten-4-yne (C).
• Example 6-1 N-(5-(4-Fluorophenyl)-3-phenyl-2-penten-4-yn-l-yl)-sarcosine, 'butyl ester, (G).
• 6-32 N-(5-(4-pyrrolylphenyl)-3-phenyl-2-penten-4-yn-l-yl)-sarcosine, 'butyl ester,
• 6-36 N-(5-(indanyl)-3-phenyl-2-penten-4-yn-l-yl)-sarcosine, 'butyl ester, (G).
• Example 7-1 N-(5-(4-Fluorophenyl)-3-phenyl-2-penten-4-yn-l-yl)-sarcosine, (H).
• Example 8-1 N-(3-Phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-l -yl)-sarcosine,
• Example 10-1 N-(5-(4-(3furyl)phenyl)-3-phenyl-2-penten-4-yn-l-yl)-sarcosine 'Butyl ester, (G').
• Example 11-1 N-(5-(4-(3furyI)phenyl)-3-phenyl-2-penten-4yn-l-yl)-sarcosine, (H').
• Example 12-1 Ethyl 4-(trifluoromethyl)phenylpropiolate (A).
• Example 13-1 l-Ethoxycarbonyl-2-(4-(trifluoromethyl)phenyI)-4-trimethylsilyI-l- buten-4-yne (C).
• Example 14-1 l-Hydroxy-3-(4-(trifluoromethyl)phenyl)-5-trimethylsilyl-2- penten-4-yne.
• Example 15-1 N-(3-(4-(Trifluoromethyl)phenyl)-5-(trimethylsilyI)-2-penten-4-yn-l- yl)-sarcosine, 'butyl ester (E).
• 15-2 N-(3-(4-fluorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-l-yl)-sarcosine, 'butyl ester (E).
• Intermediate 14-2 N-(3-(4-fluorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-l-yl)-sarcosine, 'butyl ester (E).
• Example 16-1 N-(3-(4-(Trifluoromethyl)phenyl)-2-penten-4-yn-l-yl)sarcosine, 'butyl ester (F).
• Example 17-1 N-(5-(4-IsopropylphenyI)-3-(4-(trifluoromethyl)phenyl)-2-penten-4- yn-l-yl)-sarcosine, 'butyl ester (G).
• Example 18-1 N-(5-(4-Isopropylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-penten-4- yn-l-yl)-sarcosine (H).
• This example illustrates a method for the measurement of glycine uptake by transfected cultured cells.
• HBS HEPES buffered saline
• a range of concentrations of the candidate drug was used to generate data for calculating the concentration resulting in 50% of the effect (e.g., the IC 0 s, which are the concentrations of drug inhibiting glycine uptake by 50%>).
• the cells were then incubated another 10 minutes at 37°C, after which the cells were aspirated and washed three times with ice- cold HBS.
• the cells were harvested, scintillant was added to the cells, the cells were shaken for 30 minutes, and the radioactivity in the cells was counted using a scintillation counter. Data were compared between the same cells contacted or not contacted by a candidate agent, depending on the assay being conducted.
• the compounds of the present invention were active as GlyT-1 inhibitors.
• This example illustrates binding assays to measure interaction of compounds with the glycine site on the NMDA receptor.
• the binding test was performed in eppendorf tubes containing 150 ⁇ g of membrane protein and 50 nM [ Hjglycine in a volume of 0.5 ml. Non-specific binding was determined with 1 mM glycine. Drugs were dissolved in assay buffer (50 mM Tris- acetate, pH 7.4) or DMSO (final concentration of 0.1%>). Membranes were incubated on ice for 30 minutes and bound radioligand was separated from free radioligand by filtration on Whatman GF/B glass fiber filters or by centrifugation (18,000 x g, 20 min). Filters or pellet was washed three times quickly with ice-cold 5 mM Tris-acetate buffer. Filters were dried and placed in scintillation tubes and counted. Pellets were dissolved in deoxycholate/NaOH (0.1 N) solution overnight, neutralized and radioactivity was determined by scintillation counting.
• a second binding test for the NMDA-glycine site used [3H]dichlorokynurenic acid (DCKA) and membranes prepared as above. See, Yoneda et al., J. Neurochem., 60,634- 645 (1993). The binding assay was performed as described for [ 3 H]glycine above except that [ 3 H]DCKA was used to label the glycine site. The final concentration of [ 3 H]DCKA was 10 nM, and the assay was performed for 10 minutes on ice.
• a third binding test used for the NMDA-glycine site used indirect assessment of affinity of ligands for the site by measuring the binding of [3HJMK-801 (dizocilpine). See, Palmer and Burns, J. Neurochem., 62, 187-196 (1994). Preparation of membranes for the test was the same as above. The binding assay allowed separate detection of antagonists and agonists.
• the third binding test was operated to identify antagonists as follows: 100 ⁇ g of membranes were added to wells of a 96-well plate, along with glutamate (10 ⁇ M) and glycine (200 nM) and various concentrations of the ligand to be tested.
• the assay was started by the addition of 5 nM [ 3 H]MK-801 (23.9 Ci/mmol), which binds to the ion channel associated with NMDA receptors.
• the final volume of the assay was 200 ⁇ l.
• the assay was performed for 1 hour at room temperature. Bound radioactivity was separated from free by filtration, using a TOMTEC harvester. Antagonist activity was indicated by decreasing radioactivity associated with the NMDA receptor with increasing concentration of the tested ligand.
• the third binding test was operated to identify agonists by performing the test as above, except that the concentration of glycine was 200 nM. Agonist activity was indicated by increasing radioactivity associated with the NMDA receptor with increasing concentration of the tested ligand.

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