WO2007122241A1 - Composés induisant la potentialisation du récepteur ampa et leurs applications en médecine - Google Patents

Composés induisant la potentialisation du récepteur ampa et leurs applications en médecine Download PDF

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WO2007122241A1
WO2007122241A1 PCT/EP2007/054007 EP2007054007W WO2007122241A1 WO 2007122241 A1 WO2007122241 A1 WO 2007122241A1 EP 2007054007 W EP2007054007 W EP 2007054007W WO 2007122241 A1 WO2007122241 A1 WO 2007122241A1
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alkyl
methyl
imino
dihydro
thiazol
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PCT/EP2007/054007
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English (en)
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Daniel Marcus Bradley
Wai Ngor Chan
Stephen Harrison
Owen Hughes
David Drysdale Miller
James Neesom
Kevin Michael Thewlis
Simon Edward Ward
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Glaxo Group Limited
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Priority to EP07728463A priority Critical patent/EP2016061A1/fr
Priority to JP2009507067A priority patent/JP2009534443A/ja
Publication of WO2007122241A1 publication Critical patent/WO2007122241A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds which potentiate the glutamate receptor.
  • the invention also relates to the use of the compounds in treating diseases and conditions mediated by potentiation of the glutamate receptor, compositions containing the derivatives and processes for their preparation.
  • Glutamate receptors which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 1 1 : 25-33).
  • Glutamate receptors can be divided into two distinct families.
  • the G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGlu6, mGlu7, mGlu ⁇ ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237).
  • the "ionotropic" glutamate receptor family which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).
  • NMDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid
  • KA kainic acid
  • AMPA receptors exist as heterotetramers consisting of combinations of four different protein subunits (GluR1-4) (for review see Bettler B and Muller C (1995) 34:
  • Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4.
  • Such editing results in so-called 'flip' and 'flop' receptor isoforms which differ in kinetic and pharmacological properties (Sommer B, Keinanen K, Verdoon TA, Wisden W, Bumashev N, Herb A, Kohler M, Takagi T,
  • GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2.
  • GluR2 is edited in this way.
  • AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198).
  • the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).
  • LTP Long Term Potentiation
  • AMPAR positive allosteric modulators do not activate the receptor directly.
  • AMPAR modulators increase receptor activity.
  • AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.
  • Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559).
  • the invention provides a compound of formula (I), or a salt or solvate thereof for use as a medicament:
  • R 10 is selected from methyl and hydrogen
  • R 1 is selected from H, Ci_ 4 alkyl, C(O)OCi_ 4 alkyl, C(O)Ci_ 4 alkyl, C(O)haloCi_ 4 alkyl, C(O)NR 6 R 7 , cyano, and R 6 and R 7 are each independently selected from H and C 1 . 4 alkyl;
  • R 2 is selected from Ci_ 4 alkyl, C(O)CH 3 , and CN; • R 3 is selected from the group consisting of H, NH 2 , CH 3 , (CH 2 ) n OH and (CH 2 ) n Ci. 4 alkoxy, wherein n is 0 or 1 ; and
  • R 4 is selected from the group consisting of H, halo, d. 4 alkoxy, haloC ⁇ alkoxy, Ci_ 4 alkyl, Ci_ 4 alkylthio, 1IaIoC 1 . 4 alkylthio, haloC 1 . 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;
  • R 4 is selected from H, halo, C 1 ⁇ aIkOXy, haloC 1 . 4 alkoxy, C 1 . 4 alkyl, C ⁇ alkylthio, haloC 1 . 4 alkylthio, haloC 1 . 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;
  • R 4 is selected from the group consisting of H, C 1 ⁇ aIkOXy, chloro, bromo, haloC 1 . 4 alkoxy, Ci_ 4 alkyl, haloC 1 . 4 alkyl, and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and C 1 ⁇ alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;
  • R 4 is selected from C 1 ⁇ aIkOXy and C 1 . 4 alkyl;
  • R 4 is selected from C 1 ⁇ aIkOXy, haloC ⁇ alkoxy, Ci_ 4 alkyl, haloC 1 . 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and C 1 . 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five- or six-membered ring which may optionally contain one or more heteroatoms selected from O, N and S;
  • R 4 is selected from the group consisting of H, halo, C 1 .
  • R 8 and R 9 are independently selected from Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • H refers to hydrogen.
  • CN refers to cyano (C ⁇ N).
  • Ph refers to phenyl.
  • Halo is selected from fluoro, chloro, bromo and iodo.
  • halo is selected from fluoro and chloro, for example fluoro.
  • Ci. 4 alky refers to an alkyl group having from one to four carbon atoms.
  • Ci. 4 alkyl may be a straight chain or branched alkyl group.
  • a Ci. 4 alkyl group may be selected from the group consisting of methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl or t-butyl.
  • Ci_ 4 alkyl is methyl.
  • Me refers to methyl.
  • Et refers to ethyl.
  • Ci- 4 alkoxy refers to a group O-Ci- 4 alkyl where Ci- 4 alkyl is as defined above.
  • Ci. 4 alkylthio refers to a group S-Ci- 4 alkyl where C ⁇ alkyl is as defined above.
  • haloC ⁇ alkyl refers to a Ci- 4 alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • a haloC 1 . 4 alkyl group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloCi_ 4 alkyl group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloC 1 . 4 alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluroethyl and trifluoroethyl.
  • the term "1IaIoC 1 - 4 alkoxy" and "haloC ⁇ alkylthio" refer to C 1 ⁇ aIkOXy and C ⁇ alkylthio groups wherein the C 1 . 4 alkyl groups are substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • Examples of haloC 1 . 4 alkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • Examples of haloC 1 . 4 alkylthio groups include fluoromethylthio, difluoromethylthio and trifluoromethylthio.
  • a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S refers to a five or six membered saturated unsubstituted ring formed by R 8 , R 9 and the nitrogen atom to which they are both attached.
  • Examples include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, iperidyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • R 10 is hydrogen
  • Z is S. In an alternative embodiment Z is O.
  • R 1 is selected from Ci_ 4 alkyl, C(O)OC 1 . 4 alkyl, C(O)C 1 . 4 alkyl, C(O)haloC 1 . 4 alkyl, C(O)NR 6 R 7 and cyano, wherein R 6 and R 7 are each independently selected from H and Ci_ 4 alkyl.
  • R 1 is selected from C(O)Me, methyl, cyano, C(O)N(Me) 2 , C(O)NH 2 , C(O)CF 3 , C(O)OEt and C(O)OMe.
  • R 2 is selected from C ⁇ alkyl and C(O)CH 3 . In an embodiment, R 2 is methyl. In one embodiment, R 2 Is C(O)CH 3 .
  • X is
  • R 3 is as defined for formula (I).
  • R 3 is H and R 4 is selected from the group consisting of H, Ci_ 4 alkoxy, chloro, bromo, haloCi- 4 alkoxy, d. 4 alkyl, haloCi_ 4 alkyl, and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and Ci -4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 3 is H and R 4 is selected from the group consisting of H, Ci_ 2 alkoxy, chloro, bromo, haloCi_ 2 alkoxy, Ci_ 2 alkyl, haloCi_ 2 alkyl, and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and Ci_ 2 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
  • R 3 is NH 2 and R 4 is selected from H, halo, Ci_ 4 alkoxy, haloCi_ 4 alkoxy, Ci_ 4 alkyl, Ci_ 4 alkylthio, haloCi_ 4 alkylthio, haloCi_ 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 3 is NH 2 and R 4 is Ci_ 4 alkoxy. In one embodiment, R 3 is NH 2 and R 4 is methoxy or ethoxy.
  • R 3 is CH 3
  • R 4 is selected from the group consisting of H, halo,
  • R 8 and R 9 are independently selected from hydrogen and Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 3 is CH 3
  • R 4 is selected from the group consisting of bromo, C 1- 2 alkoxy, haloC ⁇ alkoxy, d- 4 alkyl, Ci_ 2 alkylthio, halod ⁇ alkylthio, haloCi_ 2 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and C 1 . 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 3 is CH 3
  • R 4 is selected from the group consisting of bromo, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, butyl, methylthio, trifluoromethylthio, trifluoromethyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen, methyl and ethyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
  • R 3 is CH 3
  • R 4 is trifluoromethoxy or ethoxy.
  • R 3 is (CH 2 ) n OH or (CH 2 ) n Ci- 4 alkoxy
  • R 4 is selected from the group consisting of H, halo, C ⁇ alkoxy, haloC 1 . 4 alkoxy, C 1 . 4 alkyl, C 1 . 4 alkylthio, haloC 1 . 4 alkylthio, haloC ⁇ alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 3 is (CH 2 ) n OH or (CH ⁇ n C ⁇ alkoxy
  • R 4 is selected from the group consisting of bromo, C 1 ⁇ aIkOXy, haloC 1 . 2 alkoxy, Ci_ 4 alkyl, C ⁇ alkylthio, haloC 1 . 2 alkylthio, haloC 1 . 2 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 3 is (CH 2 ) n OH or (CH 2 ) n C 1 . 4 alkoxy
  • R 4 is selected from the group consisting of bromo, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, butyl, methylthio, trifluoromethylthio, trifluoromethyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen, methyl and ethyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
  • X is -CH 2 CF 3 and R 4 is selected from C 1 ⁇ aIkOXy and C 1-4 alkyl. In one embodiment, X is -CH 2 CF 3 and R 4 is selected from C ⁇ alkoxy and C 1-2 alkyl. In one embodiment, X is -CH 2 CF 3 and R 4 is ethyl or ethoxy. In one embodiment, X is methyl, and R 4 is selected from Ci- 4 alkoxy, haloCi- 4 alkoxy, Ci_ 4 alkyl, haloC ⁇ alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and Ci. 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five- or six-membered ring which may optionally contain one or more heteroatoms selected from O, N and S.
  • X is methyl
  • R 4 is selected from C 1 ⁇ aIkOXy, haloC ⁇ alkoxy, C 1 . 2 alkyl, haloCi_ 2 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and d ⁇ alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five- or six-membered ring which may optionally contain one or more heteroatoms selected from O, N and S.
  • X is methyl
  • R 4 is selected from methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen, methyl and ethyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
  • X is:
  • R 4 is selected from the group consisting of H, halo, Ci- 4 alkoxy, haloCi- 4 alkoxy, Ci_ 4 alkyl, haloC ⁇ alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from C 1 . 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 4 is haloC 1 . 2 alkyl, C 1 ⁇ aIkOXy or NR 8 R 9 wherein R 8 and R 9 are independently selected from C 1 . 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • R 4 is halomethyl, for example trifluoromethyl, methoxy, ethoxy, or NR 8 R 9 wherein R 8 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
  • the individual isomers (E and Z) and mixtures of these are included within the scope of the present invention.
  • the isomers may be separated one from the other by the usual methods or by methods detailed for the example compounds below. Any given isomer may also be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compounds of formula (I) are E isomers.
  • the compounds of formula (I) are Z isomers.
  • the invention provides a compound of formula (Ia), or a salt, or solvate thereof for use as a medicament:
  • Z is selected from S and O
  • R 1 is selected from H, CM alkyl, C(O)C- M alkyl, C(O)NR 6 R 7 , cyano, and phenyl, the phenyl group optionally being substituted with one or more groups selected from NO 2 , SO or SO 2 R 5 wherein R 5 is CM alkyl and R 6 and R 7 are each independently selected from H and CM alkyl;
  • R 2 is selected from CM alkyl, C(O)CH 3 , and CN
  • R 3 is selected from the group consisting of H, (CH 2 ) n OH and (CH 2 ) n C 1 . 4 alkoxy where n is 0 or 1 ; and • when R 3 is (CH 2 ) n OH or (CH 2 ) n Ci-4 alkoxy, then R 4 is selected from the group consisting of H, halo, C 1 ⁇ aIkOXy, haloC ⁇ alkoxy, Ci_ 4 alkyl, C 1 . 4 alkylthio, 1IaIoC 1 .
  • R 8 and R 9 are independently selected from C 1-4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;
  • R 4 is selected from the group consisting of H, C 1 ⁇ aIkOXy, chloro, haloC ⁇ alkoxy, C 1 . 4 alkyl, haloC 1 . 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S; and
  • R 4 is selected from the group consisting of H, halo, C 1 . 4 alkoxy, haloC 1 . 4 alkoxy, Ci_ 4 alkyl, haloC 1 . 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from C 1 ⁇ alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • Examples of compounds of formula (I) include: 1 -[2- ⁇ [4-(ethyloxy)phenyl]imino ⁇ -3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone hydrochloride
  • examples of compounds of formula (I) include:
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the salt or solvate of the compound of formula (I) is a pharmaceutically acceptable salt or solvate.
  • the invention provides a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.
  • salt refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation.
  • Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 S)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alg
  • Salts having a non-pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • the salts may have any suitable stoichiometry.
  • a salt may have 1 :1 or 2:1 stoichiometry.
  • Non- integral stoichiometry ratios are also possible.
  • crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
  • Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates as well as compounds containing variable amounts of solvent, where non-stoichiometric solvates may be produced by processes such as lyophilisation.
  • the compounds of the present invention are provided in the form of stoichiometric and non-stoichiometric hydrates.
  • prodrugs for certain compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each optionally provided in substantially pure form, for example at least 60% pure, for example at least 75% pure or at least 85%, or at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • R 1 and R 2 are as defined for formula (I); or (b) reacting a compound of formula (V):
  • typical conditions comprise heating at 90-100degC a mixture of compounds (II) and (III) in a suitable solvent such as toluene and/or ethanol until complete reaction.
  • a suitable solvent such as toluene and/or ethanol
  • R 1 , R 2 , R 4 , R 10 , Z and X are as defined in formula (I), and R 1 is a d- 4 alkoxy group.
  • Compounds of formula (III) are commercially available.
  • Compounds of formula (II) can be prepared as described in scheme 2 below.
  • typical reaction conditions comprise addition of a compound of formula (V) in toluene to the primary amine in solution in toluene and after stirring at ambient temperature for 1-2 hours a compound of formula (III) is added and the whole mixture stirred at 95degC for the required time.
  • R 1 , R 2 , R 4 , R 10 , Z and X are as defined in formula (I), and R 1 is a C 1 ⁇ aIkOXy group.
  • Compounds of formula (III) and formula (V) are commercially available.
  • typical reaction conditions comprise treatment of a mixture of a compound of formula (IX), ammonium chloride and DIPEA (diisopropylamine) in dimethylformamide with HATU (O-( 7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) at room temperature.
  • HATU O-( 7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • a compound of formula (Vl) i.e. a compound of formula (I) where R 10 is hydrogen and R 4 is NR 8 R 9
  • a compound of formula (VII) i.e. a compound of formula (I) where R 10 is hydrogen and R 4 is bromine
  • HNR 8 R 9 a secondary amine
  • Typical reaction conditions comprise refluxing a mixture of a compound of formula (VII) and the secondary amine in the presence of a suitable palladium reagent such as palladium acetate or bis(dibenzylidene)palladium, a suitable ligand such as (R)-(+)-2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP) or 2-biphenylyl[bis(1 ,1- dimethylethyl)]phosphane and a suitable base such as cesium carbonate or sodium tert- butoxide in a suitable solvent such as dioxane or toluene.
  • a suitable palladium reagent such as palladium acetate or bis(dibenzylidene)palladium
  • a suitable ligand such as (R)-(+)-2,2'- bis(diphenylphosphino)-1 ,1 '-binap
  • R 8 and R 9 are independently selected from C 1 . 4 alkyl or together with the nitrogen atom to which they are attached form a 5 or 6-membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.
  • Compounds of formula (VII) can be prepared using processes (a) and (b) above.
  • An intermediate compound of formula (II) may be prepared by the reaction of a compound of formula (V) with a primary amine (X-NH 2 ) according to reaction scheme 2.
  • Typical reaction conditions comprise the addition of a compound of formula (V) in ethyl acetate to a solution of the primary amine (X-NH 2 ) in ethyl acetate, or vice versa, and shaking or stirring at ambient temperature until complete reaction, typically 10 minutes to 2 hours.
  • Compounds of formula (V) are commercially available.
  • An intermediate compound of formula (Xl) may be prepared by a the reaction of a compound of formula (XII), going via the intermediate of formula (XIII) according to reaction scheme 3.
  • Typical reaction conditions comprise the gentle reflux of a compound of formula (XII) in sulfuryl chloride to give the intermediate (XIII) which was added to a sodium hydroxide solution and stirred with cooling.
  • Compounds of formula (XII) are commercially available.
  • An compound of formula (XIV) (i.e. a compound of formula (I) where R 1 is C(O)OMe), can be prepared from a compound of formula (XV) (i.e. a compound of formula (I) where R 1 is C(O)OEt) by transesterification according to reaction scheme 4.
  • Typical reaction conditions comprise treating a compound of formula (XV) with sodium hydroxide and stirring at room temperature in a mixture of water and methanol.
  • Compounds of formula (XV) can be prepared using processes (a) or (b) above.
  • An intermediate compound of formula (IX) (i.e. a compound of formula (I) where R 1 is COOH), can be prepared from a compound of formula (XIV) (i.e. a compound of formula (I) where R 1 is COOMe) by hydrolysis according to reaction scheme 5.
  • Typical reaction conditions comprise heating a mixture of a compound of formula (XIV) and lithium hydroxide monohydrate in a mixture of tetrahydrofuran and water at 70 degC overnight.
  • Compounds of formula (XIV) can be prepared as described in scheme 4.
  • a compound of formula (XVII) may be prepared by the deprotection of an intermediate compound of formula (XVI) according to reaction scheme 6.
  • reaction scheme 6 the R4 group in formula (XVI) is shown with a Boc protecting group.
  • Typical reaction conditions comprise stirring a solution of a compound of formula (XVI) in a mixture of trifluoroacetic acid and dichloromethane at ambient temperature until complete deprotection, typically 1 hour, followed by purification on SCX cartridge.
  • Compounds of formula (XVI) can be prepared as described in schemes (a), (b) and 2.
  • the compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds.
  • Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of the invention.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • compositions may be formulated for administration by any route.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water.
  • a sterile vehicle for example water.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1 % by weight, for example from 10-60% by weight, of the active material, depending on the method of administration.
  • each unit may, for example contain from 0.1 to 20 mg of the active ingredient.
  • such a unit may contain from 1 to 10 mg.
  • the dosage as employed for adult human treatment may, for example, range from 2 to 50 mg per day, for instance 5 to 20 mg per day depending on the route and frequency of administration (though in some instances, a dosage of 50mg to 100mg per day may be appropriate). Based on a 75kg individual, such a dosage corresponds to 0.027 to 0.667 mg/kg per day. Suitably the dosage is from 0.05 to 0.3 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. It is to be understood that "treatment” as used herein includes prophylaxis as well as alleviation of established symptoms. In one embodiment, the mammal to be treated is a human.
  • thiazoline compounds which fall within the scope of formula (I) above are known.
  • 3-ethyl-4-methyl-2-(pheylimino)-4-thiazoline is disclosed as an insecticide.
  • the present invention also provides a compound of formula (A) or a salt or solvate thereof:
  • R 10 is selected from methyl and hydrogen
  • R 1 is selected from H, Ci_ 4 alkyl, C(O)OCi_ 4 alkyl, C(O)Ci_ 4 alkyl, C(O)haloCi_ 4 alkyl, C(O)NR 6 R 7 , cyano, and R 6 and R 7 are each independently selected from H and C 1 . 4 alkyl;
  • R 2 is selected from Ci_ 4 alkyl, C(O)CH 3 , and CN; • R 3 is selected from the group consisting of H, NH 2 , CH 3 , (CH 2 ) n OH and (CH 2 ) ⁇ Ci. 4 alkoxy, wherein n is 0 or 1 ; and
  • R 4 is selected from the group consisting of H, halo, d. 4 alkoxy, haloC ⁇ alkoxy, Ci_ 4 alkyl, Ci_ 4 alkylthio, 1IaIoC 1 . 4 alkylthio, haloC ⁇ alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and C- ⁇ _ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;
  • R 4 is selected from H, halo, C 1 ⁇ aIkOXy, 1IaIoC 1 _ 4 alkoxy, C 1 . 4 alkyl, C ⁇ alkylthio, haloC 1 . 4 alkylthio, haloC 1 .
  • R 8 and R 9 are independently selected from Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S; • when R 3 is H, then R 4 is selected from the group consisting of H, d- 4 alkoxy, chloro, bromo, haloC 1 . 4 alkoxy, C 1 ⁇ aI kyl, haloC 1 . 4 alkyl, and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and C- 1 . 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;
  • R 4 is selected from C 1 ⁇ aIkOXy and C 1 . 4 alkyl;
  • R 4 is selected from Ci. 4 alkoxy, haloCi_ 4 alkoxy, Ci_ 4 alkyl, haloCi_ 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from hydrogen and C- ⁇ _ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five- or six-membered ring which may optionally contain one or more heteroatoms selected from O, N and S;
  • R 4 is selected from the group consisting of H, halo, C 1 . 4 alkoxy, haloCi_ 4 alkoxy, Ci_ 4 alkyl, haloCi_ 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S; with the proviso that the compound is not:
  • the present invention also provides a compound of formula (J) or a salt or solvate thereof:
  • R 1 is selected from H, d_ 4 alkyl, C(O)Cv 4 alkyl, C(O)NR 6 R 7 , cyano, and phenyl, the phenyl group optionally being substituted with one or more groups selected from NO 2 , SO or SO 2 R 5 wherein R 5 is d_ 4 alkyl and R 6 and R 7 are each independently selected from H and Ci_ 4 alkyl; • R 2 is selected from Ci_ 4 alkyl, C(O)CH 3 , and CN
  • R 3 is selected from the group consisting of H, (CH 2 ) n OH and (CH 2 ) n Ci. 4 alkoxy where n is 0 or 1 ;
  • R 4 is selected from the group consisting of H, halo, Ci_ 4 alkoxy, haloCi_ 4 alkoxy, Ci_ 4 alkyl, Ci_ 4 alkylthio, haloCi. 4 alkylthio, haloCi_ 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from Ci -4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;
  • R 4 is selected from the group consisting of H, chloro, Ci- 4 alkoxy, haloCi_ 4 alkoxy, Ci_ 4 alkyl, haloCi_ 4 alkyl and NR 8 R 9 wherein R 8 and R 9 are independently selected from Ci_ 4 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S; and
  • R 4 is selected from the group consisting of H, halo, C 1 .
  • R 8 and R 9 are independently selected from C 1 ⁇ alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S; with the provisos the compound is not:
  • R 4 ethyl, chloro, ethoxy or H
  • R 4 fluoro, isopropyl, ethoxy, difluoromethoxy or difluoromethylthio
  • R 4 chloro
  • a compound of formula (I) or a salt or solvate thereof in the manufacture of a medicament for treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of formula (I) or a salt or solvate thereof for use in treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iii) a pharmaceutical composition comprising a compound of formula (I) or a salt or solvate thereof and at least one pharmaceutically acceptable carrier or diluent; iv) a method of treatment or prevention of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of formula (I) or a salt or solvate thereof.
  • a combination product of a compound of formula (I) with an antipsychotic vi) a pharmaceutical composition comprising such a combination product and at least one pharmaceutically acceptable carrier or diluent; vii) the use of such a combination in the manufacture of a medicament for treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; viii) such a combination product for use in treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; ix) a method of treatment or prevention of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of such a combination product; x) such a combination product for use as a medicament.
  • relevant diseases or conditions are: psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug-induced psychosis, autism, delerium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); cognitive impairment (e.g.
  • Alzheimer's disease i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment
  • cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, stroke, neurodegeneration, drug-induced states, neurotoxic agents), mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, post- electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or
  • psychotic disorder includes :-
  • Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • Compounds of the invention may also be of use in the treatment of the following disorders:-
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):
  • Substance- related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder,
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23):
  • Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and
  • cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders
  • the compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone and talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • antipsychotics such as olanzapine, risperidone, clozapine, ziprazidone and talnetant
  • drugs for extrapyramidal side effects for example anticholinergics
  • the compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.
  • the compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
  • NMDA receptor antagonists for example acamprosate
  • GABA receptor agonists for example tetrabamate
  • Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.
  • opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine
  • opioid receptor antagonists for example naltrexone
  • vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon
  • barbiturates for example
  • the compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations and pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • alpha adrenoceptor antagonists
  • the compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperi
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, parox
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • NMR spectra were obtained at 298K, at the frequency stated using either a BrukerTM DPX400 or an Oxford InstrumentsTM 250 MHz machine and run as a dilute solution of CDCI 3 unless otherwise stated. All NMR spectra were reference to tetramethylsilane (TMS ⁇ H 0, ⁇ c 0). All coupling constants are reported in hertz (Hz), and multiplicities are labelled s (singlet), bs, (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).
  • the starting material may not necessarily have been prepared from the batch referred to. All quoted retention times are as measured using LC/MS (Liquid Chromatography/Mass Spectrometry). Where appropriate, these retention times were used as a guide for purification using mass-directed auto-preparation (MDAP), which refers to purification by HPLC, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest.
  • MDAP mass-directed auto-preparation
  • UV wavelength range 210-350 nm
  • SCX column chromatography was carried out using a solid supported sulfonic acid column such as a Varian Bond Elut SCX column or 2g Flash SCX-2 cartridges (Isolute®
  • Ion-exchange SPE columns for capture release purification
  • the mixture to be purified is loaded onto the column using a non-basic solvent such as methanol, the column is then flushed with an appropriate volume of this or similar solvent
  • the column is then flushed with a basic solvent system such as methanolic ammonia to release the desired material, and the eluent is collected Removal of the solvent using a rotary evaporator yields the purified product
  • Aqueous solvent Water + 0 1 % Trifluoroacetic Acid
  • Organic solvent Acetonitrile + 0 1 % Trifluoroacetic Acid
  • Method > 4.1 50-100% B (in 14 minutes followed by 5 minutes flush and re-equilibration) Flow rate 20ml/mins.
  • Stationary phase particle size 5um.
  • Methods Five methods used depending on the analytical retention time of the compound of interest. 13.5-minute runtime, comprising
  • Methods Five methods, 15-minute runtime comprising 10-minute gradient followed by a 5-minute column flush and re-equilibration step. The other five have a 25-minute runtime. Methods have the same starting and end points for the organic content of B but the gradients have been extended over a 20-minute period.
  • 5-methylisoxazole (5.Og; 60mmol) was treated with sulfuryl chloride (5.54ml; 69mmol) dropwise through a condenser at such a rate as to maintain a gentle reflux. (The flask was connected to water aspirator to remove HCI and SO 2 ). Upon completion of the addition, refluxing was continued for 1 hour by heating.
  • the crude 4-chloro-5-methylisoxazole was added to a solution of sodium hydroxide (3.6g, 1.5 equiv) in water (30ml) and rinsed in with more water (10ml). This mixture was stirred with intermittent cooling in such a way as to let the reaction proceed without getting hot.
  • Boc-protected-/V-(4-aminophenyl)-/V-methylthiourea (0.67mmol, 188mg) and 3-chloro-2,4- pentanedione (1.01 mmol, 102 ⁇ L) were combined in ethanol (2.5mL) and heated at 100 0 C for 20 minutes by microwaves. Solvents were removed in vacuo to yield the title compound which was used directly without further purification.
  • Boc-protected-/V-(4-aminophenyl)-/V-ethylthiourea (0.67mmol, 198mg) and 3-chloro-2,4- pentanedione (1.01 mmol, 102 ⁇ L) were combined in ethanol (2.5mL) and heated at 100 0 C for 20 minutes by microwaves. Solvents were removed in vacuo to yield the title compound which was used directly without further purification.
  • Example 1 1-[2- ⁇ [4-(ethyloxy)phenyl]imino ⁇ -3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone hydrochloride
  • Residual material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel using 100% diethyl ether to afford the title compound as a yellow solid (92mg, 36%).
  • Residual material was partitioned between dichloromethane and sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel using 20 to 70% ethyl acetate in n-pentane to afford the title compound as a pale yellow solid (167mg, 14%).
  • Residual material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel using 50:50 dichloromethane / n-pentane to 5% methanol in dichloromethane, treated with ethereal hydrochloric acid to afford the title compound as a pale yellow solid (96mg, 35%).
  • Residual material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated in vacuo to afford an oil which was recrystallised from methanol/ethyl acetate to afford the title compound as a pale yellow solid (42mg 16%).
  • Example 13 1- ⁇ 2-[(4-chlorophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1,3-thiazol-5- yljethanone hydrochloride
  • Example 14 1-(3-cyclopropyl-4-methyl-2- ⁇ [4-(trifluoromethyl)phenyl]imino ⁇ -2,3- dihydro-1 ,3-thiazol-5-yl)ethanone hydrochloride
  • the title compound (0.04Og) was prepared from /V-ethyl-/V-[4- (trifluoromethyl)phenyl]thiourea (0.15Og; O. ⁇ Ommol) and 3-chloro-2,4-pentanedione (0.38ml) in toluene (10ml) by the procedure described in Example 10.
  • the title compound was isolated by evaporation of the reaction mixture under reduced pressure, followed by recrystallisation from methanol.
  • Example 16a 1-[3-ethyl-4-methyl-2-( ⁇ 4-[(trifluoromethyl)oxy]phenyl ⁇ imino)-2,3- dihydro-1,3-thiazol-5-yl]ethanone hydrochloride
  • the title compound (0.069g) was prepared from /V-ethyl-/V- ⁇ 4- [(trifluoromethyl)oxy]phenyl ⁇ thiourea (0.30Og; 1.13mmol) and 3-chloro-2,4-pentanedione (0.40ml; 3 equiv) in toluene (10ml) by the procedure described in Example 10.
  • the title compound was isolated by evaporation of the reaction mixture under reduced pressure, followed by recrystallisation from methanol.
  • Example 16b 1-[3-ethyl-4-methyl-2-( ⁇ 4-[(trifluoromethyl)oxy]phenyl ⁇ imino)-2,3- dihydro-1,3-thiazol-5- l ethanone
  • Example 17 1-[2-( ⁇ 4-[(difluoromethyl)oxy]phenyl ⁇ imino)-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1,3-thiazol-5-yl]ethanone
  • the title compound (0.076g) was prepared from /V- ⁇ 4-[(difluoromethyl)oxy]phenyl ⁇ -/V-(2- hydroxyethyl)thiourea (0.20Og; 0.76mmol) and 3-chloro-2,4-pentanedione (0.40ml; 3 equiv) in toluene (10ml) by the procedure described in Example 6, but without treatment with ethereal hydrochloric acid.
  • the title compound (0.093g) was prepared from A/-(2-hydroxyethyl)-/V- ⁇ 4- [(trifluoromethyl)thio]phenyl ⁇ thiourea (0.25Og; 0.84mmol) and 3-chloro-2,4-pentanedione (0.30ml; 3 equiv) in toluene (10ml) by the procedure described in Example 6, but without treatment with ethereal hydrochloric acid.
  • 3-Chloro-2-butanone (9OuI) was added in one portion to a stirring solution of /V-ethyl-/V-[4- (trifluoromethyl)phenyl]thiourea (102mg) in toluene (2ml). The mixture was heated to 95 0 C for 20 minutes, and more 3-chloro-2-butanone (6OuI) was added in one portion. The reaction was stirrer at this temperature for 27 hours, cooled to room temperature, and purified by SCX column chromatography, giving the target molecule as a yellow oil (67mg).
  • Example 21 1- ⁇ 2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1,3-thiazol-5- yljethanone
  • reaction mixture was allowed to cool and most of the toluene was removed by rotary evaporation and the residue was partitioned between ethyl acetate (100ml) and saturated aqueous sodium bicarbonate solution (100ml).
  • the organic layer was separated and dried over sodium sulphate and the solvent removed by rotary evaporation to give a golden coloured oil which was purified by column chromatography using a 5Og isolute silica column, eluting from 0-50% ethyl acetate in petroleum ether.
  • Example 22 1-(3-ethyl-4-methyl-2- ⁇ [4-(1-pyrrolidinyl)phenyl]imino ⁇ -2,3-dihydro-1,3- thiazol-5-yl)ethanone hydrochloride
  • Reaction mix was filtered through a bed of kieselguhr, and the filtrate evaporated to residue by rotary evaporation to give a dark oil (730mg) which was added to a 5g pre-packed isolute silica gel column and eluted from 20-100% ethyl acetate in petroleum ether, then 5% ammonia (2M in methanol) in ethyl acetate. Relevant fractions were combined and the solvent removed by rotary evaporation to give a brown oil (205mg), which was further purified by mass directed auto-preparation (MDAP) to give an orange solid (69mg).
  • MDAP mass directed auto-preparation
  • A/-(4-bromophenyl)-/V-(2-hydroxyethyl)thiourea (6.32g; 23mmol) was dissolved in ethanol (20ml) and toluene (100ml). Then 3-chloro-2,4-pentanedione (5.45ml; 46mmol) was added. The resulting mixture was heated at 9O 0 C under argon for 30 minutes. The desired product was isolated by evaporating off the solvent under reduced pressure.
  • Residual material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated under vacuum, the recovered material was then recrystallised from ethyl acetate/n-pentane to afford the title compound as a yellow solid (5.59g; 68%).
  • HATU O-( 7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HATU O-( 7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Dimethylformamide was removed under rotary evaporation and the residual material was partitioned between ethyl acetate and water.
  • the aqueous phase was extracted with ethyl acetate (4 x 10ml), the combined organic layers were washed with brine (100ml) and dried with sodium sulphate, filtered and evaporated.
  • the title compound (193mg; 83%) was prepared from /V-ethyl-/V-[4-(4- morpholinyl)phenyl]thiourea (150mg; 0.57mmol) and 2-chloro- ⁇ /, ⁇ /-dimethyl-3- oxobutanamide (0.23ml; 1.7mmol) in ethanol (10ml) by the procedure described in Example 28.
  • reaction mixture was cooled to room temperature and diluted with diethyl ether.
  • the mixture was filtered through a pad of kieselguhr to remove the catalyst and the filtrate concentrated under vacuum to give a yellow oil.
  • the desired product was isolated by MDAP (mass directed auto prep) to afford the title compound as a yellow solid (33mg; 17%).
  • Example 36 1-[3,4-dimethyl-2-( ⁇ 4-[(trifluoromethyl)oxy]phenyl ⁇ imino)-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone
  • Example 40 1-(2- ⁇ [4-(ethyloxy)phenyl]imino ⁇ -4-methyl-3-propyl-2,3-dihydro-1,3- thiazol-5-yl)ethanone
  • Example 41 1 -(3,4-dimethyl-2- ⁇ [4-(trifluoromethyl)phenyl]imino ⁇ -2,3-dihydro-1 ,3- thiazol-5-yl)ethanone
  • i-ethyl-4-isothiocyanatobenzene (0.25mmol, 40.75mg) was combined in ethyl acetate (2ml) with 33 wt% methylamine in ethanol solution (0.25mmol, 7.77mg methylamine ⁇ 23.3mg of solution). This reaction was stirred for 10 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (2ml_). A 31.3 ⁇ l_ (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 100 0 C for 20 minutes by microwaves.
  • Example 45 1 -[2- ⁇ [4-(diethylamino)phenyl]imino ⁇ -3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone
  • Example 48 1-(3-ethyl-4-methyl-2- ⁇ [4-(4-morpholinyl)phenyl]imino ⁇ -2,3-dihydro-1,3- thiazol-5-yl)ethanone
  • Example 50 1 - ⁇ 2-[(4-aminophenyl)imino]-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5- yljethanone
  • Boc-protected-1- ⁇ 2-[(4-aminophenyl)imino]-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5- yl ⁇ ethanone (0.67mmol, 242mg) was dissolved in trifluoroacetic acid (2mL) and DCM (2mL) and the mixture stirred at room temperature for 1 hour. Purified by 2g SCX cartridges, 0.0646g of the title compound was isolated.
  • Boc-protected-1- ⁇ 2-[(4-aminophenyl)imino]-3-ethyl-4-methyl-2,3-dihyclro-1 ,3-thiazol-5- yl ⁇ ethanone (0.67mmol, 251 mg) was dissolved in trifluoroacetic acid (2ml_) and DCM (2ml_) and the mixture stirred at room temperature for 1 hour. Purified by 2g SCX cartridges, 0.0705g of the title compound was isolated.
  • Boc-protected-1-[2-[(4-aminophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone (0.67mmol, 262mg) was dissolved in trifluoroacetic acid (2ml_) and DCM (2ml_) and the mixture stirred at room temperature for 1 hour. Purified by 2g SCX cartridges, 0.0824g of the title compound was isolated.
  • N-[4-(dimethylamino)phenyl]-/V-(2-hydroxyethyl)thiourea (0.17mmol, 41 mg) was dissolved in ethanol (2ml_) and 3-chloro-2,4-pentanedione (0.51 mmol, 61 ⁇ l_) added. The vial was heated at 100 0 C for 10 minutes by microwaves. Purified by MDAP, 0.0066g of the title compound was isolated.
  • N-[4-(ethyloxy)phenyl]-/V-(2-hydroxyethyl)thiourea (0.45mmol, 107mg) was dissolved in ethanol (2ml_).
  • 2-Chloro- ⁇ /, ⁇ /-dimethyl-3-oxobutanamide (0.45mmol, 73mg) was added, and the reaction heated at 100 0 C for 10 minutes by microwaves.
  • a further 0.5 equivalents of 2-chloro- ⁇ /, ⁇ /-dimethyl-3-oxobutanamide was added and the mixture heated for 5 minutes. Purified by MDAP, 0.0072g of the title compound was isolated.
  • Example 59 1- ⁇ 3-(2-hydroxyethyl)-4-methyl-2-[(4-methylphenyl)imino]-2,3-dihydro- 1 ,3-thiazol-5-yl ⁇ ethanone
  • Example 60 1- ⁇ 3-ethyl-2-[(4-ethylphenyl)imino]-4-methyl-2,3-dihydro-1,3-thiazol-5- yljethanone
  • Example 65 i- ⁇ -cyclopropyl- ⁇ -ft ⁇ ethyloxyJphenylliminoM-methyl- ⁇ jS-dihydro- 1 ,3-thiazol-5-yl)ethanone
  • the title compound (0.02g) was prepared from /V-cyclopropyl-/V-[4- (ethyloxy)phenyl]thiourea (0.078g, 0.33mmol) and 3-chloro-2,4-pentanedione (39.3 ⁇ L, 0.33mmol) in ethanol (5.OmL), following the procedure described in Example 64.
  • Example 66 1-[2-[(4-ethylphenyl)imino]-4-methyl-3-(2,2,2-trifluoroethyl)-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone
  • the title compound (0.015g) was prepared from /V-(4-ethylphenyl)-/V-(2,2,2- trifluoroethyl)thiourea (0.33mmol) and 3-chloro-2,4-pentanedione (39.3 ⁇ L, 0.33mmol) in ethanol (5.OmL), following the procedure described in Example 64, with heating increased to 20 minutes.
  • the title compound (0.009g) was prepared from /V-[4-(ethyloxy)phenyl]-/V-(2,2,2- trifluoroethyl)thiourea (0.33mmol) and 3-chloro-2,4-pentanedione (39.3 ⁇ L, 0.33mmol) in ethanol (5.OmL), following the procedure described in Example 64, with heating increased to 20 minutes.
  • the ability of the compounds of the invention to potentiate glutamate receptor-mediated response may be determined a) by using fluorescent calcium-indicator dyes such as
  • FLUO4 and additionally b) by measuring glutamate-evoked current recorded from human GluR2 flip unedited HEK293 cells.
  • 384 well plates are prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells form functional homotetrameric AMPA receptors.
  • tissue culture medium in the wells are discarded and the wells are each washed three times with standard buffer (80 ⁇ L) for the stable cell line (145 mM NaCI, 5 mM KCI, 1 mM MgCI 2 , 2 mM CaCI 2 , 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI).
  • standard buffer 80 ⁇ L
  • Each dilution (1 ⁇ l_) is transferred to another compound plate and buffer (50 ⁇ l_) is added.
  • An agonist stimulus (glutamate) plate is prepared by dissolving sodium glutamate in water to give a concentration of 100 mM. This solution is diluted with buffer to give a final concentration of 500 ⁇ M and dispensed into another 384-well plate (50 ⁇ l_/well) using a Multidrop (Thermolabsystems).
  • the cell plate is then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)].
  • a baseline fluorescence reading is taken over a 10 to 240 second period, and then 10 ⁇ l_ from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 ⁇ M to 10 pM) is added (to give a final concentration in the range 30 ⁇ M to 3 pM).
  • the fluorescence is read over 5 minute period.
  • 500 ⁇ M glutamate solution (10 ⁇ l_) is added (to give a final concentration of 100 ⁇ M).
  • the fluoresecence is then read over a 4 minute period.
  • the activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by cyclothiazide at their maximum response (i.e. greater than 30 ⁇ M).
  • the assay described above is believed to have an effective limit of detection of a pEC 5Q in the region of 3.5-4.0 due to the limitations of compound solubility.
  • the pEC 50 result is generally considered to be accurate +/- 0.3. Accordingly, a compound exhibiting a pEC 50 value within this range from such an assay may indeed have a reasonable affinity for the receptor, but equally it may also have a lower affinity, including a considerably lower affinity.
  • Example compounds were screened using the assay as described above. All the Examples gave an average pEC 50 equal to or greater than 3.7 and demonstrated an activity at least 20% that of cyclothiazide (at its maximal response).
  • the ability of the compounds of the invention to potentiate AMPA-subtype glutamate receptor-mediated response are determined by measuring AMPA-evoked current recorded from rat cultured hippocampal neurons.
  • This assay involves the electrophysiological characterisation of AMPA receptor positive modulators using rat cultured hippocampal neurons.
  • the extracellular recording solution contains: 145 mM NaCI, 2.5 mM KCI, 1.2 mM MgCI 2 , 1.5 mM CaCI 2 , 10 mM N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM D-glucose, pH 7.3 with NaOH.
  • the intracellular solution contains : 80 mM CsCI, 80 mM CsF, 10 mM N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM ethylene glycol-bis(g- aminoethylether)-N,N,N',N,-tetra-acetic acid (EGTA), 14 mM MgATP, 14 mM DiTris Creatine Phosphate, 50 U/ml Creatine Phosphokinase pH 7.3 with CsOH.
  • HEPES hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid
  • EGTA ethylene glycol-bis(g- aminoethylether)-N,N,N',N,-tetra-acetic acid
  • EGTA ethylene glycol-bis(g- aminoethylether)-N,N,N',N,-tetra-ace
  • Electrodes are back filled with internal recording solution. Positive pressure is applied to the electrode to prevent mixture of internal and external solutions and assist in formation of high resistance seal when the electrode makes contact with the cell membrane. Glass coverslip fragment, bearing rat cultured hippocampal neurons, is placed in the recording chamber positioned on the stage of an inverted microscope. A tube at the edge of the chamber is used to apply extracellular solution to the bath. Rapid solution exchange uses a fast step perfusion system (Biologic RSC160).
  • Two outlet tubes attached together along their length are positioned close to a chosen cell so that the outflow from only one tube can pass directly over the cell surface.
  • a motorized stepper could re-position the tubes such that the outflow from the second outlet tube flows over the cell allowing solution exchange at the cell membrane surface to occur within 10-20 ms. Excess bath solution is removed via a tube positioned at the edge of the chamber connected to a vacuum line.
  • a prospective cell is positioned in the centre of the microscope field of view.
  • Recording electrode is positioned directly above the cell membrane surface.
  • fine manipulator control Liigs and Neumann, SM-6
  • the electrode is lowered, while monitoring the change in electrode resistance during delivery of a 5 mV depolarizing pulse, until a high resistance seal (gigaseal) is achieved.
  • Whole cell configuration is achieved by removing by suction a small fragment of cell membrane immediately beneath the recording electrode tip.
  • the cell membrane potential is held at -70 mV (voltage-clamped) via the electrode (Axopatch 200B Integrating patch clamp amplifier, pClamp software, Axon Instruments).
  • Test solutions are applied using the fast application system using the following protocol and changes in inward current are recorded and stored for off-line analysis. 1 ) Control current - exchange from extracellular solution to extracellular solution + 30 ⁇ M AMPA (2 s application time, 30 s interval between applications) repeated until measurements are stable.
  • the concentration of compound of invention is increased to 100 nM in both solutions and step 2 is repeated. Subsequent 10 fold increases in concentration are tested to a maximum of 100 uM.
  • Examples 4, 5 and 24 above were investigated using this assay. When applied at 10 nM, they increased 30 ⁇ M AMPA-mediated currents by between 15 and 42%.

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Abstract

La présente invention concerne des composés de formule (I), ainsi que des sels et des solvates desdits composés, pour une utilisation en tant que médicament : (I) où R1, R2, R4, R10, X et Z sont tels que définis dans la description de l'invention. La présente invention a également pour objet des procédés de synthèse, des compositions pharmaceutiques et leurs applications en tant que médicament, par exemple dans le traitement d'une maladie ou d'un état pathologique faisant intervenir une réduction ou un déséquilibre du fonctionnement du récepteur de glutamate, tel que la schizophrénie ou les déficits cognitifs.
PCT/EP2007/054007 2006-04-26 2007-04-24 Composés induisant la potentialisation du récepteur ampa et leurs applications en médecine WO2007122241A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053449A1 (fr) * 2007-10-26 2009-04-30 Glaxo Group Limited Thiazoles qui potentialisent le récepteur ampa et utilisations médicinales de ceux-ci
WO2009053448A1 (fr) * 2007-10-26 2009-04-30 Glaxo Group Limited Composés qui potentialisent le récepteur ampa et leurs utilisations en médecine
CN102127032A (zh) * 2011-01-20 2011-07-20 北京大学 一种多取代5-酰基-2-亚胺噻唑啉的合成方法
WO2014078611A1 (fr) 2012-11-16 2014-05-22 Bristol-Myers Squibb Company Modulateurs dihydropyrazoles de gpr40
CN105130923A (zh) * 2015-10-13 2015-12-09 浙江工业大学 一种多取代2-亚氨基噻唑类化合物的制备方法
WO2021083182A1 (fr) * 2019-10-28 2021-05-06 南京明德新药研发有限公司 Agent uricosurique, son procédé de synthèse et son application pharmaceutique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1027561A (en) * 1962-01-19 1966-04-27 Ciba Ltd Thiazoline compounds, and pest-controlling agents containing them
JPS57197218A (en) * 1981-05-29 1982-12-03 Nippon Soda Co Ltd Central nervous system depressant containing thiazoline- 5-carboxylic acid derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1027561A (en) * 1962-01-19 1966-04-27 Ciba Ltd Thiazoline compounds, and pest-controlling agents containing them
JPS57197218A (en) * 1981-05-29 1982-12-03 Nippon Soda Co Ltd Central nervous system depressant containing thiazoline- 5-carboxylic acid derivative

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002442481 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002442482 *
DYSON ET AL., J. INDIAN CHEM. SOC., vol. 8, 1931, pages 147 - 163 *
HUNTER ET AL., J. CHEM. SOC., 1934, pages 1175 *
HUNTER ET AL., J. CHEM. SOC., 1959, pages 784 - 787 *

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