EP2016061A1 - Compounds which potentiate ampa receptor and uses thereof in medicine - Google Patents

Compounds which potentiate ampa receptor and uses thereof in medicine

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Publication number
EP2016061A1
EP2016061A1 EP07728463A EP07728463A EP2016061A1 EP 2016061 A1 EP2016061 A1 EP 2016061A1 EP 07728463 A EP07728463 A EP 07728463A EP 07728463 A EP07728463 A EP 07728463A EP 2016061 A1 EP2016061 A1 EP 2016061A1
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EP
European Patent Office
Prior art keywords
alkyl
methyl
imino
dihydro
thiazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07728463A
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German (de)
French (fr)
Inventor
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 Ltd
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Glaxo Group Ltd
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Publication of EP2016061A1 publication Critical patent/EP2016061A1/en
Withdrawn legal-status Critical Current

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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%.

Abstract

Compounds of formula (I), and salts and solvates thereof for use as a medicament are provided: (I) wherein R1, R2, R4, R10, X and Z are defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

Description

Compounds which potentiate AMPA receptor and uses thereof in medicine
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, mGluδ) 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), α-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 ).
Native AMPA receptors (AMPAR) exist as heterotetramers consisting of combinations of four different protein subunits (GluR1-4) (for review see Bettler B and Muller C (1995) 34:
123-139.). 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,
Sakmann B, Seeburg PH (1990) Science 249: 1580-1585).
Additionally, post-transcriptional editing of GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2. In normal humans >99% 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). There is a suggestion, however, that 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 ).
AMPAR depolarization removes voltage dependent Mg 2+ block of NMDA receptors which in turn leads to NMDA receptor activation, an integral stage in the induction of Long Term Potentiation ("LTP") (Bliss TVP, Collingridge GL (1993) Nature 361 : 31-9). LTP is a physiological measure of increased synaptic strength following a repetitive stimulus or activity, such as occurs during learning.
It has been reported that direct activation of glutamate receptors by agonists, in conditions where glutamate receptor function is reduced, increases the risk of excitotoxicity and additional neuronal damage. AMPAR positive allosteric modulators do not activate the receptor directly. However, when the ligand (L-glutamate or AMPA) is present AMPAR modulators increase receptor activity. Thus, AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.
Compounds which act as AMPAR positive allosteric modulators have been shown to increase ligand affinity for the receptor (Arai A, Guidotti A, Costa E, Lynch G (1996) Neuroreport. 7: 221 1-5.); reduce receptor desensitization and reduce receptor deactivation (Arai AC, Kessler M, Rogers G, Lynch G (2000) 58: 802-813) and facilitate the induction of LTP both in vitro (Arai A, Guidotti A, Costa E, Lynch G (1996) 7: 221 1-5.) and in vivo (Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91 : 1 1 158-1 1 162). 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 efficacy of various AMPAR positive allosteric modulators in pre-clinical and clinical models of psychiatric disorders, such as schizophrenia, have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579). The ability of AMPAR positive allosteric modulators to improve pre-clinical and clinical cognitive task performance as well as the potential for efficacy in psychiatric disorders, such as schizophrenia, in man have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579).
Compounds which act as AMPAR positive allosteric modulators are known, for example in international patent application WO2006/015828. We have discovered novel compounds which potentiate the AMPA receptor.
According to a first aspect, the invention provides a compound of formula (I), or a salt or solvate thereof for use as a medicament:
wherein:
• R10 is selected from methyl and hydrogen;
• X is selected from:
• Z is selected from S and O;
• R1 is selected from H, Ci_4alkyl, C(O)OCi_4alkyl, C(O)Ci_4alkyl, C(O)haloCi_4alkyl, C(O)NR6R7, cyano, and R6 and R7 are each independently selected from H and C1. 4alkyl;
• R2 is selected from Ci_4alkyl, C(O)CH3, and CN; • R3 is selected from the group consisting of H, NH2, CH3, (CH2)nOH and (CH2)nCi. 4alkoxy, wherein n is 0 or 1 ; and
• when R3 is CH3, (CH2)nOH or then R4 is selected from the group consisting of H, halo, d.4alkoxy, haloC^alkoxy, Ci_4alkyl, Ci_4alkylthio, 1IaIoC1. 4alkylthio, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4alkyl or R8 and R9 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 R3 is NH2, then R4 is selected from H, halo, C1^aIkOXy, haloC1.4alkoxy, C1. 4alkyl, C^alkylthio, haloC1.4alkylthio, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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 R3 is H, then R4 is selected from the group consisting of H, C1^aIkOXy, chloro, bromo, haloC1.4alkoxy, Ci_4alkyl, haloC1.4alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C1^ alkyl or R8 and R9 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 X is -CH2CF3, then R4 is selected from C1^aIkOXy and C1.4alkyl;
• when X is methyl, then R4 is selected from C1^aIkOXy, haloC^alkoxy, Ci_4alkyl, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C1.4alkyl or R8 and R9 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;
• when X is , then R4 is selected from the group consisting of H, halo, C1.
4alkoxy, haloC^alkoxy, Ci_4alkyl, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4alkyl or R8 and R9 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. For example, halo is selected from fluoro and chloro, for example fluoro.
The term "Chalky!" refers to an alkyl group having from one to four carbon atoms. Unless otherwise indicated, Ci.4alkyl may be a straight chain or branched alkyl group. For example, a Ci.4alkyl group may be selected from the group consisting of methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl or t-butyl. For example, Ci_4alkyl is methyl. "Me" refers to methyl. "Et" refers to ethyl.
The term "Ci.4alkoxy" refers to a group O-Ci-4alkyl where Ci-4alkyl is as defined above.
Th term "Ci.4alkylthio" refers to a group S-Ci-4alkyl where C^alkyl is as defined above.
The term "haloC^alkyl" refers to a Ci-4alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. A haloC1.4alkyl group may, for example contain 1 , 2 or 3 halogen atoms. For example, a haloCi_4alkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloC1.4alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluroethyl and trifluoroethyl. Similarly, the term "1IaIoC1- 4alkoxy" and "haloC^alkylthio" refer to C1^aIkOXy and C^alkylthio groups wherein the C1. 4alkyl groups are substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. Examples of haloC1.4alkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy. Examples of haloC1.4alkylthio groups include fluoromethylthio, difluoromethylthio and trifluoromethylthio.
The term "a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S", in the definition of each of R8 and R9 in formula (I) refers to a five or six membered saturated unsubstituted ring formed by R8, R9 and the nitrogen atom to which they are both attached. Examples include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, iperidyl, piperazinyl, morpholinyl and thiomorpholinyl.
"CO" and "C(=O)" are interchangeable and represent a carbonyl group (alternatively called an oxo group).
In one embodiment, R10 is hydrogen.
In an embodiment, Z is S. In an alternative embodiment Z is O. In one embodiment, R1 is selected from Ci_4alkyl, C(O)OC1.4alkyl, C(O)C1.4alkyl, C(O)haloC1.4alkyl, C(O)NR6R7 and cyano, wherein R6 and R7 are each independently selected from H and Ci_4alkyl.
In an embodiment, R1 is selected from C(O)Me, methyl, cyano, C(O)N(Me)2, C(O)NH2, C(O)CF3, C(O)OEt and C(O)OMe.
In one embodiment, R2 is selected from C^alkyl and C(O)CH3. In an embodiment, R2 is methyl. In one embodiment, R2 Is C(O)CH3.
In an embodiment, X is
wherein R3 is as defined for formula (I).
In one embodiment, R3 is H and R4 is selected from the group consisting of H, Ci_4alkoxy, chloro, bromo, haloCi-4alkoxy, d.4alkyl, haloCi_4alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci-4 alkyl or R8 and R9 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.
In one embodiment, R3 is H and R4 is selected from the group consisting of H, Ci_2alkoxy, chloro, bromo, haloCi_2alkoxy, Ci_2alkyl, haloCi_2alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_2alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
In one embodiment, R3 is NH2 and R4 is selected from H, halo, Ci_4alkoxy, haloCi_4alkoxy, Ci_4alkyl, Ci_4alkylthio, haloCi_4alkylthio, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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.
In one embodiment, R3 is NH2 and R4 is Ci_4alkoxy. In one embodiment, R3 is NH2 and R4 is methoxy or ethoxy.
In one embodiment, R3 is CH3, and R4 is selected from the group consisting of H, halo,
Ci_4alkoxy, haloCi_4alkoxy, Ci_4alkyl, Ci_4alkylthio, haloCi_4alkylthio, haloCi_4alkyl and
NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4alkyl or R8 and R9 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.
In one embodiment, R3 is CH3, and R4 is selected from the group consisting of bromo, C1- 2alkoxy, haloC^alkoxy, d-4alkyl, Ci_2alkylthio, halod^alkylthio, haloCi_2alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C1.4alkyl or R8 and R9 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.
In one embodiment, R3 is CH3, and R4 is selected from the group consisting of bromo, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, butyl, methylthio, trifluoromethylthio, trifluoromethyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen, methyl and ethyl, or R8 and R9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
In one embodiment, R3 is CH3, and R4 is trifluoromethoxy or ethoxy.
In one embodiment, R3 is (CH2)nOH or (CH2)nCi-4alkoxy, and R4 is selected from the group consisting of H, halo, C^alkoxy, haloC1.4alkoxy, C1.4alkyl, C1.4alkylthio, haloC1.4alkylthio, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and or R8 and R9 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.
In one embodiment, R3 is (CH2)nOH or (CH^nC^alkoxy, and R4 is selected from the group consisting of bromo, C1^aIkOXy, haloC1.2alkoxy, Ci_4alkyl, C^alkylthio, haloC1.2alkylthio, haloC1.2alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4alkyl or R8 and R9 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.
In one embodiment, R3 is (CH2)nOH or (CH2)nC1.4alkoxy, and R4 is selected from the group consisting of bromo, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, butyl, methylthio, trifluoromethylthio, trifluoromethyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen, methyl and ethyl, or R8 and R9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
In one embodiment, X is -CH2CF3 and R4 is selected from C1^aIkOXy and C1-4alkyl. In one embodiment, X is -CH2CF3 and R4 is selected from C^alkoxy and C1-2alkyl. In one embodiment, X is -CH2CF3 and R4 is ethyl or ethoxy. In one embodiment, X is methyl, and R4 is selected from Ci-4alkoxy, haloCi-4alkoxy, Ci_ 4alkyl, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci.4alkyl or R8 and R9 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.
In one embodiment, X is methyl, and R4 is selected from C1^aIkOXy, haloC^alkoxy, C1. 2alkyl, haloCi_2alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and d^alkyl or R8 and R9 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.
In one embodiment, X is methyl, and R4 is selected from methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen, methyl and ethyl, or R8 and R9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
In one embodiment, X is:
and R4 is selected from the group consisting of H, halo, Ci-4alkoxy, haloCi-4alkoxy, Ci_ 4alkyl, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from C1. 4alkyl or R8 and R9 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.
In a further embodiment when X is cyclopropyl, R4 is haloC1.2alkyl, C1^aIkOXy or NR8R9 wherein R8 and R9 are independently selected from C1.4alkyl or R8 and R9 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.
In a further embodiment when X is cyclopropyl, R4 is halomethyl, for example trifluoromethyl, methoxy, ethoxy, or NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached form a pyrrolidynl, piperidinyl or morpholinyl ring.
The imine bond in formula (I) (between the central nitrogen atom and the carbon atom in the thiazolyl or oxazolyl group) indicates E, Z or a mixture of both E and Z isomers:
In mixtures of E and Z compounds, or compounds in which the E/Z (i.e cis/trans) conformation have not been determined, the imine bond is drawn as a crossed bond as shown in formula (I).
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.
In one embodiment, the compounds of formula (I) are E isomers.
In another embodiment, the compounds of formula (I) are Z isomers.
In one embodiment, the invention provides a compound of formula (Ia), or a salt, or solvate thereof for use as a medicament:
wherein:
• X is selected from:
Z is selected from S and O
R1 is selected from H, CM alkyl, C(O)C-M alkyl, C(O)NR6R7, cyano, and phenyl, the phenyl group optionally being substituted with one or more groups selected from NO2, SO or SO2R5 wherein R5 is CM alkyl and R6 and R7 are each independently selected from H and CM alkyl;
R2 is selected from CM alkyl, C(O)CH3, and CN
R3 is selected from the group consisting of H, (CH2)nOH and (CH2)nC1.4 alkoxy where n is 0 or 1 ; and • when R3 is (CH2)nOH or (CH2)nCi-4 alkoxy, then R4 is selected from the group consisting of H, halo, C1^aIkOXy, haloC^alkoxy, Ci_4alkyl, C1.4alkylthio, 1IaIoC1. 4alkylthio, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from C1-4 alkyl or R8 and R9 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 R3 is H, then R4 is selected from the group consisting of H, C1^aIkOXy, chloro, haloC^alkoxy, C1.4alkyl, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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
when X is , then R4 is selected from the group consisting of H, halo, C1. 4alkoxy, haloC1.4alkoxy, Ci_4alkyl, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from C1^ alkyl or R8 and R9 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.
It will be appreciated that the present invention is intended to include compounds having any combination of the groups listed hereinbefore. It will be understood that, where appropriate, an embodiment described above for one part of the invention may be combined with an embodiment of another part of the invention.
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
1-[2-[(4-ethylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone hydrochloride
1-{2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-[2-(methyloxy)ethyl]-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone
1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-
5-yl)ethanone 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl)ethanone hydrochloride
2-[2-{[4-(ethyloxy)phenyl]imino}-4,5-dimethyl-1 ,3-thiazol-3(2/-/)-yl]ethanol hydrochloride
1-[2-[(4-butylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone hydrochloride 1-[2-{[4-(ethyloxy)phenyl]imino}-3-(3-hydroxypropyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-
5-yl)ethanone
2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazole-5- carbonitrile hydrochloride 3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazole-5-carbonitrile hydrochloride
1-{2-[(4-chlorophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
1-(3-cyclopropyl-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone hydrochloride 1 -(3-ethyl-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone hydrochloride
1-[3-ethyl-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone hydrochloride
1-[2-({4-[(difluoromethyl)oxy]phenyl}imino)-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
[(3-ethyl-4,5-dimethyl-1 ,3-thiazol-2(3/-/)-ylidene][4-(trifluoromethyl)phenyl]amine
1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-oxazol-5-yl)ethanone.
In one embodiment, examples of compounds of formula (I) include:
1. 1 -[2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone
2. 1-[2-[(4-ethylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone
3. 1-{2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-[2-(methyloxy)ethyl]-2,3-dihydro-1 ,3- thiazol-5-yl}ethanone
4. 1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone 5. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone
6. 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl)ethanone
7. 2-[2-{[4-(ethyloxy)phenyl]imino}-4,5-dimethyl-1 ,3-thiazol-3(2/-/)-yl]ethanol
8. 1-[2-[(4-butylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone
9. 1 -[2-{[4-(ethyloxy)phenyl]imino}-3-(3-hydroxypropyl)-4-methyl-2,3-dihydro-1 ,3-thiazol- 5-yl]ethanone
10. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone 1 1. 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazole-5- carbonitrile
12. 3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazole-5-carbonitrile
13. 1-{2-[(4-chlorophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone 14. 1-(3-cyclopropyl-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-
5-yl)ethanone 15. 1 -(3-ethyl-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone 16. 1-[3-ethyl-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-clihyclro-1 ,3-thiazol-5- yl]ethanone 17. 1-[2-({4-[(difluoromethyl)oxy]phenyl}imino)-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-
1 ,3-thiazol-5-yl]ethanone
18. 1 -[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone
19. [(3-ethyl-4,5-dimethyl-1 ,3-thiazol-2(3H)-ylidene][4-(trifluoromethyl)phenyl]amine
20. 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-oxazol-5-yl)ethanone
21. 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
22. 1-(3-ethyl-4-methyl-2-{[4-(1-pyrrolidinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
23. 1-(3-ethyl-4-methyl-2-{[4-(1-piperidinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
24. 3-(2-hydroxyethyl)-N,N,4-trimethyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazole-5-carboxamide 25. 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone
26. 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazole-5- carboxamide
27. 3-(2-hydroxyethyl)-N,N,4-trimethyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3- dihydro-1 ,3-thiazole-5-carboxamide
28. 1-(3-cyclopropyl-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
29. 3-ethyl-N,N,4-trimethyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazole-5- carboxamide 30. 2,2,24rifluoro-1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluorometriyl)oxy]prienyl}irriino)-
2,3-dihydro-1 ,3-thiazol-5-yl]ethanone
31. 3-cyclopropyl-N,N,4-trimethyl-2-{[4-(4-morpriolinyl)prienyl]imino}-2,3-diriydro-1 ,3- thiazole-5-carboxamide
32. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(1-pyrrolidinyl)prienyl]irnino}-2,3-diriydro-1 ,3- thiazol-5-yl)ethanone
33. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(metriyloxy)prienyl]irriino}-2,3-diriydro-1 ,3-triiazol- 5-yl)ethanone
34. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(methyltriio)prienyl]irriino}-2,3-diriydro-1 ,3-triiazol- 5-yl)ethanone 35. 1 -[2-[(3,4-dimethylphenyl)irnino]-3-(2-riydroxyetriyl)-4-metriyl-2,3-diriydro-1 ,3-thiazol-5- yl]ethanone
36. 1 -[3,4-dimethyl-2-({4-[(trifluorometriyl)oxy]prienyl}irnino)-2,3-diriydro-1 ,3-thiazol-5- yl]ethanone 37. i-^-methyl-S-propyl^^l^I^rifluoromethyOoxylphenylJimino^.S-dihydro-I .S-thiazol-S- yl]ethanone
38. 1-[4-methyl-3-[2-(methyloxy)ethyl]-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone 39. 1-(2-{[4-(ethyloxy)phenyl]imino}-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5-yl)ethanone
40. 1-(2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-propyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
41. 1-(3,4-dimethyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone 42. 1 -{2-[(4-ethylphenyl)imino]-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
43. 1-(2-{[4-(dimethylamino)phenyl]imino}-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
44. 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl)ethanone
45. 1 -[2-{[4-(diethylamino)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
46. 1-(2-{[4-(diethylamino)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
47. 1-[2-({4-[(difluoromethyl)oxy]phenyl}imino)-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone 48. 1-(3-ethyl-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
49. 1-(3,4-dimethyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
50. 1-{2-[(4-aminophenyl)imino]-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone 51. 1-{2-[(4-aminophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone 52. 1 -[2-[(4-aminophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone 53. 1 -[2-{[4-(dimethylamino)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone 54. Ethyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazole-5-carboxylate
55. 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-N,N,4-trimethyl-2,3-dihydro-1 ,3- thiazole-5-carboxamide
56. Methyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazole-5-carboxylate
57. 3-(2-hydroxyethyl)-N,N,4-trimethyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazole-5-carboxamide
58. Methyl 3-(2-hydroxyethyl)-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro- 1 ,3-thiazole-5-carboxylate 59. 1-{3-(2-hydroxyethyl)-4-methyl-2-[(4-methylphenyl)imino]-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone
60. 1-{3-ethyl-2-[(4-ethylphenyl)imino]-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
61. 1-[3-ethyl-4-methyl-2-(phenylimino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone 62. 1 -{3-ethyl-4-methyl-2-[(4-methylphenyl)imino]-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
63. 1-(2-{[4-(dimethylamino)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
64. 1-(3-(2-aminoethyl)-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
65. I^S-cyclopropyl^-l^^ethyloxyJphenyφminoH-methyl^.S-dihydro-I .S-thiazol-S- yl)ethanone
66. 1-[2-[(4-ethylphenyl)imino]-4-methyl-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone 67. 1-[2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone and salts and solvates thereof.
For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, 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.
In one embodiment the salt or solvate of the compound of formula (I) is a pharmaceutically acceptable salt or solvate. In one embodiment, the invention provides a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.
As used herein, the term "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, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,5-disulphonic, naphthalene-1 ,3-disulphonic, benzenesulfonic, and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N, N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. 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. For example, a salt may have 1 :1 or 2:1 stoichiometry. Non- integral stoichiometry ratios are also possible.
Furthermore, some of the 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. In one embodiment, the compounds of the present invention are provided in the form of stoichiometric and non-stoichiometric hydrates.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may be administered as prodrugs. Examples of pro-drug forms for certain compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Examples of 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.
Since 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.
Compounds of the invention may be prepared in a variety of ways. These processes form further aspects of the invention. In the following reaction schemes and hereafter, unless otherwise stated, all the groups are as defined in the first aspect. Thus, the present invention provides a process for the manufacture of a compound of formula (I), comprising:
(a) coupling a compound of formula (II):
wherein X, Z, R4 and R10 are as defined for formula (I); with a compound of formula
(ill)
wherein R1 and R2 are as defined for formula (I); or (b) reacting a compound of formula (V):
wherein Z, R4 and R10 are as defined for formula (I); with a primary amine X-NH2, wherein X is as defined for formula (I), followed by coupling with a compound of formula (III) as defined in process (a); or (c) for a compound of formula (I) wherein R1 is CONH2, reacting a compound of formula (IX):
(IX)
wherein Z, X, R2, R4 and R10 are as defined for formula (I), with ammonium chloride and HATU; and thereafter optionally for process (a), (b) or (c):
- removing any protecting groups; and/or
- forming a salt or solvate; and/or - converting a compound of formula (I) or a salt or solvate thereof to another compound of formula (I) or a salt or solvate thereof.
For process (a), 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. In one embodiment, R1 , R2, R4, R10, Z and X are as defined in formula (I), and R1 is a d-4alkoxy group. Compounds of formula (III) are commercially available. Compounds of formula (II) can be prepared as described in scheme 2 below.
For process (b), 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. In one embodiment, R1 , R2, R4, R10, Z and X are as defined in formula (I), and R1 is a C1^aIkOXy group. Compounds of formula (III) and formula (V) are commercially available.
For process (c), 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. Compounds of formula (IX) can be prepared as described in scheme 5 below.
A compound of formula (Vl) (i.e. a compound of formula (I) where R10 is hydrogen and R4 is NR8R9), can be prepared from a compound of formula (VII) (i.e. a compound of formula (I) where R10 is hydrogen and R4 is bromine) by a Buchwald reaction with a secondary amine (HNR8R9) according to reaction scheme 1. 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.
In one embodiment, R8 and R9 are independently selected from C1.4alkyl 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.
Scheme 1
(VII) (Vl)
An intermediate compound of formula (II) may be prepared by the reaction of a compound of formula (V) with a primary amine (X-NH2) 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-NH2) 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.
Scheme 2
X-NH2 / ethyl acetate
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.
Scheme 3
An compound of formula (XIV) (i.e. a compound of formula (I) where R1 is C(O)OMe), can be prepared from a compound of formula (XV) (i.e. a compound of formula (I) where R1 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.
Scheme 4
(XIV)
(XV)
An intermediate compound of formula (IX) (i.e. a compound of formula (I) where R1 is COOH), can be prepared from a compound of formula (XIV) (i.e. a compound of formula (I) where R1 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.
Scheme 5
A compound of formula (XVII) may be prepared by the deprotection of an intermediate compound of formula (XVI) according to reaction scheme 6. In scheme 6 below, 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.
Scheme 6
Further details for the preparation of compounds of formula (I) are found in the Examples section hereinafter.
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. Thus according to a further aspect there is provided 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.
The pharmaceutical 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.
The 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.
The 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. 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.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The 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. Where the compositions comprise dosage units, each unit may, for example contain from 0.1 to 20 mg of the active ingredient. For example, 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.
It will be recognised by one of skill in the art that 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.
Certain thiazoline compounds which fall within the scope of formula (I) above are known. For example, in GB patent no. 1027561 , 3-ethyl-4-methyl-2-(pheylimino)-4-thiazoline is disclosed as an insecticide. Hunter, R F; Parken, E R and Short, Eileen, Journal of the Chemical Society (1959) 184-8; and Hunter, Robert F, Parken, Edwin R, Journal of the Chemical Society (1934) 1 175-7; and Dyson et al, J. Indian Chem. Soc. (1931 ) 8, 147-80 all describe aminothiazole compounds.
The present invention also provides a compound of formula (A) or a salt or solvate thereof:
(A) wherein:
• R10 is selected from methyl and hydrogen;
• X is selected from:
• Z is selected from S and O;
• R1 is selected from H, Ci_4alkyl, C(O)OCi_4alkyl, C(O)Ci_4alkyl, C(O)haloCi_4alkyl, C(O)NR6R7, cyano, and R6 and R7 are each independently selected from H and C1. 4alkyl;
• R2 is selected from Ci_4alkyl, C(O)CH3, and CN; • R3 is selected from the group consisting of H, NH2, CH3, (CH2)nOH and (CH2)πCi. 4alkoxy, wherein n is 0 or 1 ; and
• when R3 is CH3, (CH2)nOH or (CH2)nCi_4alkoxy, then R4 is selected from the group consisting of H, halo, d.4alkoxy, haloC^alkoxy, Ci_4alkyl, Ci_4alkylthio, 1IaIoC1. 4alkylthio, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C-ι_4alkyl or R8 and R9 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 R3 is NH2, then R4 is selected from H, halo, C1^aIkOXy, 1IaIoC1 _4alkoxy, C1. 4alkyl, C^alkylthio, haloC1.4alkylthio, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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 R3 is H, then R4 is selected from the group consisting of H, d-4alkoxy, chloro, bromo, haloC1.4alkoxy, C1^aI kyl, haloC1.4alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C-1.4 alkyl or R8 and R9 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 X is -CH2CF3, then R4 is selected from C1^aIkOXy and C1.4alkyl;
• when X is methyl, then R4 is selected from Ci.4alkoxy, haloCi_4alkoxy, Ci_4alkyl, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C-ι_4alkyl or R8 and R9 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;
when X is , then R4 is selected from the group consisting of H, halo, C1. 4alkoxy, haloCi_4alkoxy, Ci_4alkyl, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4alkyl or R8 and R9 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:
1 ) a compound in which simultaneously R1=CO(CH3), R2=Me, X=CH2CH2R3, R3=OH and R4=ethyl, chloro, ethoxy, methyl or H;
2) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OMe and R4=methoxy, difluoromethylthio, chloro or H;
3) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OEt and R4=difluoromethylthio, ethoxy, fluoro, difluoromethoxy or isopropyl;
4) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OnBu and R4=fluoro, isopropyl, ethoxy, difluoromethoxy or difluoromethylthio;
5) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=0Me and R4= ethoxy, difluoromethoxy, difluoromethylthio or H;
6) a compound in which simultaneously R1=H, R2=Me, X=cyclopropyl and R4=methoxy, isopropyl, ethoxy, hydrogen, chloro, difluoromethoxy or fluoro;
7) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=H and R4= H or chloro;
8) a compound in which simultaneously R1=C(O)CH3, R2=Me, X=CH2CH2R3, R3=CH2OH and R4=H or methyl; 9) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3,
R3=CH2OH, and R4=methyl, chloro, methoxy or H; 10) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=OH and R4=ethoxy, methyl or H;
11 ) a compound in which simultaneously R1=C(O)CH3, R2=Me, X=CH2CH2R3, R3=H and R4=chloro; 12) a compound in which simultaneously R1=H, R2=Me, X=Me and R4=methyl or ethoxy;
13) a compound in which simultaneously R1=H, R2=Et, X=CH2CH2R3, R3=H and R4=chloro or bromo;
14) a compound in which simultaneously R1=Me, R2=Me, X=Me and R4=methyl; and
15) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=Me and R4=isopropyl, fluoro, ethyl, difluoromethoxy or difluoromethylthio.
The present invention also provides a compound of formula (J) or a salt or solvate thereof:
(J) wherein:
• X is selected from:
• Z is selected from S and O
• R1 is selected from H, d_4 alkyl, C(O)Cv4 alkyl, C(O)NR6R7, cyano, and phenyl, the phenyl group optionally being substituted with one or more groups selected from NO2, SO or SO2R5 wherein R5 is d_4 alkyl and R6 and R7 are each independently selected from H and Ci_4 alkyl; • R2 is selected from Ci_4 alkyl, C(O)CH3, and CN
• R3 is selected from the group consisting of H, (CH2)nOH and (CH2)nCi.4 alkoxy where n is 0 or 1 ; and
• when R3 is (CH2)nOH or (CH2)nCi-4 alkoxy, then R4 is selected from the group consisting of H, halo, Ci_4alkoxy, haloCi_4alkoxy, Ci_4alkyl, Ci_4alkylthio, haloCi. 4alkylthio, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci-4 alkyl or R8 and R9 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 R3 is H, then R4 is selected from the group consisting of H, chloro, Ci- 4alkoxy, haloCi_4alkoxy, Ci_4alkyl, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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
• when X is , then R4 is selected from the group consisting of H, halo, C1.
4alkoxy, halod_4alkoxy, Ci_4alkyl, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from C1^ alkyl or R8 and R9 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:
1 ) a compound in which simultaneously R1=CO(CH3), R2=Me, X=CH2CH2R3, R3=OH and
R4=ethyl, chloro, ethoxy or H
2) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OMe and
R4=methoxy, difluoromethylthio, chloro or H 3) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OEt and R4=difluoromethylthio, ethoxy, fluoro, difluoromethoxy or isopropyl
4) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OnBu and
R4=fluoro, isopropyl, ethoxy, difluoromethoxy or difluoromethylthio
5) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=0Me and R4= ethoxy, difluoromethoxy, difluoromethylthio or H
6) a compound in which simultaneously R1=H, R2=Me, X=cyclopropyl and R4=methoxy, isopropyl, ethoxy, hydrogen, chloro, difluoromethoxy or fluoro
7) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=H and
R4=chloro.
It will be appreciated that the invention includes the following further aspects. The embodiments described in respect of the first aspect apply equally to each of these further aspects:
i) the use of 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. v) 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.
The statements above regarding embodiments of compounds of formula (I) apply equally to compounds of formula (A) and (J).
In the case of aspects i), ii), iv), vii), viii), ix) and x), 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. the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including 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 motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias, neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); post-traumatic stress syndrome; attention deficit disorder; attention deficit hyperactivity disorder; drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) disorders; Huntingdon's chorea; tardive dyskinesia; dystonia; myoclonus; spasticity; obesity; stroke; sexual dysfunction; sleep disorders and some forms of epilepsy.
Within the context of the present invention, the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
Within the context of the present invention, the term "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):
Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00):
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, Alcohol- Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant- Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid- Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)- Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic- Induced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide:
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 syndrome:
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 Sexual Disorder Not Otherwise Specified (302.9).
All of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention.
Within the context of the present invention, the term "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 such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
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).
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.
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.
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.
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).
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.
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).
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).
Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
The invention is illustrated by the Examples described below. Starting materials were obtained from commercial suppliers and used without further purification unless otherwise stated. Flash chromatography was carried out using prepacked lsolute Flash™ or Biotage™ silica-gel columns as the stationary phase and analytical grade solvents as the eluent.
NMR spectra were obtained at 298K, at the frequency stated using either a Bruker™ DPX400 or an Oxford Instruments™ 250 MHz machine and run as a dilute solution of CDCI3 unless otherwise stated. All NMR spectra were reference to tetramethylsilane (TMS δH 0, δc 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).
Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and/or atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).
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.
Analytical chromatographic conditions
One of the following methods was used:
Method A
Column: Gemini C18, 50 x 4.6 mm, 5 urn Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CN Gradient: 35% (B) for 0.5 min, 35% (B) ■* 95% (B) in 4.5 min, 95%
(B) for 1.5 min
Flow rate: 2 ml/min
UV wavelength range: 210-350 nm
Ionization: ES+/ES-
Mass range: 100-900 amu
Method B
Column: Waters Atlantis, 4.6mm x 50mm, 3 urn.
Solvents: A : Aqueous solvent = Water + 0.05% Formic Acid;
B : Organic solvent = Acetonitrile + 0.05% Formic Acid Methods: The generic method used has a 5 minute runtime. Time / min %B
0 3
0.1 3
4 97
4.8 97
4.9 3
5.0 3
Flow rate: 3ml/min
Injection volume: 5ul
Column temperature: 30 degC
UV wavelenαth ranαe : 220-330 nm
Method C
Column: 3.3cm x 4.6mm ID, 3um ABZ+PLUS
Flow Rate: 3ml/min
Injection Volume: 5μl
Temp: RT
UV Detectior i Range: 215-330nm
Solvents:
A: 0.1 % Formic Acid + I OmMolar Ammonium
Acetate.
B: 95% Acetonitrile + 0.05% Formic Acid
Time B%
0.00 0
0.70 0
4.20 100
4.60 100
4.80 0
Method D
Column: A Accqquuiitty UPLC BEH C18 1.7μm 2.1 mm x 50mm
Temp: C Coolluurmr n oven set to 40 degrees centigrade
Solvents A A::.. AAcqueous solvent = Water 0.1% Formic Acid + 1OmM
Ammonium Acetate. B:. Organic solvent = MeCN: Water
95:5 +0.05% Formic Acid. Weak wash Solvent = MeOH:
Water 50:50. Strong Wash Solvent = MeOH
Injection volume 0.5μl Injection technique Partial loop overfill
Weak Wash 500μl
Strong Wash 500μl
UV detection 220 - 330 nm
UV sampling rate 40 points per second
MS scan range 100 to 1000 amu
MS scanning rate 0 2 second scan i i/vith a 0 1 second inter scan delay
MS scan function Electrospray with pos neg switching
Cycle time 2 minutes and 30 seconds
Gradient
Time Flow ml/min %A Curve
0 1 97 6
0 1 1 97 6
1 4 1 0 6
1 9 1 0 6
2 1 97 6
SCX column chromatography
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 Typically 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
Mass-directed preparative chromatography conditions
One of the following methods was used
Method A
Column Waters Atlantis, 19mm x 100mm with particle size 5mm
Solvents A Aqueous solvent = Water + 0 1 % Trifluoroacetic Acid B Organic solvent = Acetonitrile + 0 1 % Trifluoroacetic Acid
Make up solvent = Methanol Water 80 20 + 0 1 % Formic Acid Needle rinse solvent = Methanol
Methods Five methods used depending on the analytical retention time of the compound of interest 20 minute runtime, comprising 15 5 minute gradient followed by a 3 5 minute column flush and re-equilibration step Method 1.8-2.1 = 0-30% B
Method 2.1-2.6 = 10-45% B
Method 2.6-3.1 = 15-65% B
Method 3.1-4.1 = 30-75% B
Method > 4.1 = 50-100% B (in 14 minutes followed by 5 minutes flush and re-equilibration) Flow rate 20ml/mins.
Injection volume 50OuI partial loop injection. Column temperature ambient
Method B
Column: Waters Atlantis, 19mm x 100mm (small scale) and 30mm x
100mm (large scale). Stationary phase particle size = 5um.
Solvents: A : Aqueous solvent = Water + 0.1 % Formic Acid;
B : Organic solvent = Acetonitrile + 0.1% Formic Acid.
Make up solvent = Methanol : Water 80:20
Needle rinse solvent = Methanol
Methods: Five methods used depending on the analytical retention time of the compound of interest. 13.5-minute runtime, comprising
10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.
Large/Small Scale 1.0-1.5 = 5-30% B
Large/Small Scale 1.5-2.2 = 15-55% B
Large/Small Scale 2.2-2.9 = 30-85% B
Large/Small Scale 2.9-3.6 = 50-99% B
Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by
7.5 minutes flush and re-equilibration)
Flow rate: 20mls/min (Small Scale) or 40mls/min (Large Scale).
Method C
Columns: Small Scale Prep Column: Supelcosil ABZ+Plus column 21.2mm x 100mm. Stationary phase particle size is 5μm. Large scale Prep Column: Supelcosil ABZ+Plus column 30.0mm x 150mm. Stationary phase particle size is 12μm.
Solvents: A: Aqueous solvent = Water + 0.1 % Formic Acid; B: Organic solvent = MeCN: Water 95:5 +0.05% Formic Acid. Make up solvent to ZQ = MeOH: Water 80:20 +5OmMoI Ammonium Acetate. 2767 Needle rinse solvent = MeOH: Water: DMSO 80:10:10
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.
Small Scale Large Scale
MDP 1.5-2.2 = 00-30% B MDP 1.5-2.2 = 00-30% B MDP 2.0-2.8 = 10-40% B MDP 2.0-2.8 = 10-40% B MDP 2.5-3.0 = 15-55% B MDP 2.5-3.0 = 25-55% B MDP 2.8-4.0 = 30-80% B MDP 2.8-4.0 = 40-75% B MDP 3.8-5.5 = 60-90% B MDP 3.8-5.5 = 60-90% B
Flow rates: 20 ml/min (small scale) or 40 ml/min (large scale).
Preparatory and analytical conditions for Example 31 were the same as the conditions given above, except that:
For preparatory conditions:
Column Waters X-bridge 30mm x 100mm; stationary phase particle size is 5um. Solvent: A : Aqueous solvent = 1 OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution. B : Organic solvent = Acetonitrile. Make up solvent = Methanol : Water 80:20. Needle rinse solvent = Methanol
For analytical conditions:
Column Waters X-Bridge 4.6mm x 50mm; stationary phase particle size is 3.5m.
Solvent: A : Aqueous solvent = 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution. B : Organic solvent =
Acetonitrile.
Abbreviations
TEA Triethylamine
TMS-CI Trimethylsilyl chloride DME Dimethyl ether ss saturated solution
TFA Trifluoroacetic acid
DAD Diode Array Detector
CD Circular dichroism a/a% percentage by area unde the curve
LC/MS Liquid Chromatography / Mass Spectrometry
NMR Nuclear Magnetic Resonance
SCX Chromatography column supplied by Varian™ THF Tetrahydrofuran
DMSO Dimethylsulfoxide
DMF Dimethylformamide
DCM / MDC Dichloromethane / Methylene dichloride
CDI 1 ,1'-Carbonyldiimidazole
LDA Lithium diisopropylamide
EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimide
MsCI Methanesulfonyl chloride
AcOH Acetic acid
HOAt 1 -hydroxy-7-azabenzotriazole
HOBt 1 -hydroxybenzotriazole
Pd on C Palladium on Charcoal
MeCN Acetonitrile
MDAP Mass-directed auto-preparation
LCMS Rt LC/MS Retention time
Intermediates
Description 1 : Λf-(4-ethylphenyl)-Λf'-(2-hydroxyethyl)thiourea
A solution of 4-ethylphenyl isothiocyanate (2.Og; 12.3mmol) in ethyl acetate (10ml) was added dropwise to a stirring solution of 2-aminoethanol (0.74ml; 12.3mmol) in ethyl acetate (10ml) over 10 minutes at 250C. Then the reaction mixture was allowed to stir at 250C overnight. Filtered off solid, washed with ethyl acetate and dried under reduced pressure to afford the title compound as a white solid (1.449g, 52%). 1H NMR (400MHz, DMSO D6) δ: 9.51 (1 H, br s), 7.58 (1 H, br s), 7.28 (2H, m), 7.14 (2H, m), 4.79 (1 H, br s), 3.52 (4H, app s), 2.58 (2H, m), 1.17 (3H, t, J=7Hz); LC/MS retention time 2.17/(ES+) 225 (M+H, CnH17N2OS requires 225).
Description 2: /V-[4-(ethyloxy)phenyl]-W-(2-hydroxyethyl)thiourea
The title compound (1.25g) was prepared from 1-(ethyloxy)-4-isothiocyanatobenzene (1.Og; 5.5mmol) and 2-aminoethanol (0.335g; 5.5mmol) in ethyl acetate (10ml) by the procedure described in Description 1. 1H NMR (400MHz, DMSO D6) δ: 9.39 (1 H, br s), 7.43 (1 H, br s), 7.22 (2H, m), 6.86 (2H, m), 4.78 (1 H, br s), 4.00 (2H, m), 3.52 (4H, app s), 1.03 (3H, t, J=7Hz); LC/MS retention time 1.89/(ES+) 241 (M+H, C11H17N2O2S requires 241 ).
Description 3: Λ/-[4-(ethyloxy)phenyl]-Λ/1-[2-(methyloxy)ethyl]thiourea
A solution of 1-(ethyloxy)-4-isothiocyanatobenzene (1.Og; 5.57mmol) in ethyl acetate (5ml) was added dropwise to a stirring solution of 2-methoxyethylamine (0.419g; 5.57mmol) in ethyl acetate (5ml) over 10 minutes at 250C. Then the reaction mixture was allowed to stir at 250C overnight. Filtered off solid, washed with ethyl acetate and dried under reduced pressure to afford the title compound as a white solid (1.288g, 91 %). 1H NMR (400MHz, DMSO D6) δ: 9.37 (1 H, br s), 7.50 (1 H, br s), 7.21 (2H, m), 6.87 (2H, m), 4.00 (2H, m), 3.61 (2H, m), 3.45 (2H, m), 3.26 (3H, s), 1.30 (3H, t, J=7Hz); LC/MS retention time 2.40/(ES+) 255 (M+H, C12H19N2O2S requires 255).
Description 4: Λ/-(2-hydroxyethyl)-Λ/'-{4-[(trifluoromethyl)oxy]ρhenyl}thiourea
A solution of 1-isothiocyanato-4-[(trifluoromethyl)oxy]benzene (1.Og; 4.56mmol) in ethyl acetate (5ml) was added dropwise to a stirring solution of 2-aminoethanol (0.274ml; 4.56mmol) in ethyl acetate (5ml) over 10 minutes at 250C. Then the reaction mixture was allowed to stir at 250C overnight. Then the solvent was removed in vacuo to give the title compound as an off-white solid (1.085g, 85%). 1H NMR (400MHz, DMSO D6) δ: 9.72 (1 H, br s), 7.88 (1 H, br s), 7.58 (2H, m), 7.29 (2H, m), 4.82 (1 H, br s), 3.55 (4H, app s); LC/MS retention time 2.43/(ES+) 281 (M+H, C10H12N2F3O2S requires 281 ).
Description 5: Λf-(2-hydroxyethyl)-Λf'-[4-(trifluoromethyl)phenyl]thiourea
A solution of 1-isothiocyanato-4-(trifluoromethyl)benzene (2.Og; 9.84mmol) in ethyl acetate (10ml) was added dropwise to a stirring solution of 2-aminoethanol (0.60ml; 9.84mmol) in ethyl acetate (10ml) over 10 minutes at 250C. Then the reaction mixture was allowed to stir at 250C overnight. Then the solvent was removed in vacuo to give the title compound as an off-white solid (2.55g, 98%). 1H NMR (400MHz, DMSO D6) δ: 9.94 (1 H, br s), 8.02 (1 H, br s), 7.75 (2H, m), 7.12 (2H, m), 4.84 (1 H, br s), 3.54 (4H, app s); LC/MS retention time 2.36/(ES+) 265 (M+H, Ci0H12N2F3OS requires 265).
Description 6: N-ethyl-W-[4-(ethyloxy)phenyl]thiourea
The title compound (1.147g) was prepared from 1-(ethyloxy)-4-isothiocyanatobenzene (1.Og; 5.5mmol) and ethylamine (2.79ml of 2M solution in THF; 5.5mmol) in ethyl acetate
(10ml) by the procedure described in Description 1.
1H NMR (400MHz, DMSO D6) δ: 9.20 (1 H, br s), 7.47 (1 H, br s), 7.18 (2H, m), 6.86 (2H, m), 4.0 (2H, m), 3.42 (2H, m), 1.30 (3H, t, J=7Hz), 1.10 (3H, t, J=7Hz); LC/MS retention time 2.40/(ES+) 225 (M+H, CnH17N2OS requires 225).
Description 7: /V-(4-butylphenyl)-W-(2-hydroxyethyl)thiourea
The title compound (0.51 1g) was prepared from 1-butyl-4-isothiocyanatobenzene (0.40Og;
2.1 mmol) and 2-aminoethanol (0.13ml; 2.1 mmol) in ethyl acetate (10ml) by the procedure described in Description 1.
1H NMR (400MHz, DMSO D6) δ: 9.50 (1 H, br s), 7.58 (1 H, br s), 7.28 (2H, m), 7.12 (2H, m), 4.79 (1 H, br s), 3.52 (4H, app s), 2.52 (2H, m), 1.52 (2H, m), 1.30 (2H, m), 0.90 (3H, t, J=7Hz); LC/MS retention time 2.61/(ES+) 253 (M+H, C13H21N2OS requires 253).
Description 8: W-[4-(ethyloxy)phenyl]-W-(3-hydroxypropyl)thiourea
The title compound (0.729g) was prepared from 1-(ethyloxy)-4-isothiocyanatobenzene
(0.5g; 2.79mmol) and 3-amino-1-propanol (0.209g; 2.79mmol) in ethyl acetate (10ml) by the procedure described in Description 1.
1H NMR (400MHz, DMSO D6) δ: 9.28 (1 H, br s), 7.50 (1 H, br s), 7.20 (2H, m), 6.86 (2H, m), 4.50 (1 H, br s), 4.20 (2H, m), 3.46 (4H, m), 1.63 (2H, m), 1.30 (3H, t, J=7Hz); LC/MS retention time 1.93/(ES+) 255 (M+H, C12H19N2O2S requires 255). Description 9: Λ/-(2-hydroxyethyl)-Λ/'-[4-(4-morpholinyl)phenyl]thiourea
A solution of 4-(4-isothiocyanatophenyl)morpholine (0.25Og; 1.14mmol) in ethyl acetate (5ml) was added dropwise to a stirring solution of 2-aminoethanol (0.07ml; 1.14mmol) in ethyl acetate (5ml) over 10 minutes at 250C. Then the reaction mixture was allowed to stir at 250C overnight. Then the solvent was removed in vacuo to give the title compound as a white solid (0.237g, 74%). 1H NMR (400MHz, DMSO D6) δ: 9.35 (1 H, br s), 7.38 (1 H, br s), 7.18 (2H, m), 6.90 (2H, m), 4.75 (1 H, br s), 3.72 (4H, m), 3.51 (4H, app s), 3.07(4H, m); LC/MS retention time 1.45/(ES+) 282 (M+H, Ci3H20N3O2S requires 282).
Description 10: /V-(4-chlorophenyl)-W-ethylthiourea
The title compound (0.313g) was prepared from 1 (0.5g; 2.94mmol) and ethylamine (1.47ml of 2M solution in THF; 2.94mmol) in ethyl acetate (10ml) by the procedure described in Description 1. 1H NMR (400MHz, DMSO D6) δ: 9.50 (1 H, br s), 7.82 (1 H, br s), 7.43 (2H, m), 7.34 (2H, m), 3.46 (2H, m), 1.1 1 (3H, t, J=7Hz); LC/MS retention time 2.52/(ES+) 215 (M+H, C9Hi2N2SCI requires 215).
Description 11 : tø-cyclopropyl-Λf-[4-(trifluoromethyl)phenyl]thioιιrea
The title compound (0.318g) was prepared from 1-isothiocyanato-4- (trifluoromethyl)benzene (0.30Og; 1.48mmol) and cyclopropylamine (0.084g; 1.48mmol) in ethyl acetate (5ml) by the procedure described in Description 1.
1H NMR (400MHz, DMSO D6) δ: 9.62 (1 H, br s), 8.23 (1 H, br s), 7.72 (2H, m), 7.62 (2H, m), 2.92 (1 H, br s), 0.78 (2H, m), 0.60 (2H, app s); LC/MS retention time 2.77/(ES+) 261 (M+H, CnHi2N2F3S requires 261 ).
Description 12: Λ/-ethyl-Λ/'-[4-(trifluoromethyl)phenyl]thiourea
A solution of 4-(trifluoromethyl)phenylisothiocyanate (2.15g) in ethyl acetate (14ml) was added to a stirring solution of ethylamine (2M solution in THF; 10ml) in ethyl acetate (37ml). After standing for six days, the solvent was removed in vacuo, giving the title molecule as an off-white solid (2.57g).
1H NMR (400 MHz; CDCI3) δ: 7.76 (1 H, br s), 7.69 (2H, d, J=8Hz), 7.34 (2H, d, J=8Hz), 6.07 (1 H, br s), 3.70 (2H, m), 1.24 (3H, t, J=7Hz); LC/MS retention time 2.75/(ES+) 249 (M+H, Ci0H12F3N2S requires 249).
Description 13: Λ/-ethyl-Λ/'-{4-[(trifluoromethyl)oxy]phenyl}thiourea
The title compound (1 -2Og) was prepared from 1-isothiocyanato-4- [(trifluoromethyl)oxy]benzene (1.0g; 4.56mmol) and ethylamine (2.73ml of 2M solution in THF; 4.56mmol) in ethyl acetate (20ml) by the procedure described in Description 1. 1H NMR (400MHz, DMSO D6) δ: 9.58 (1 H, br s), 7.89 (1 H, br s), 7.52 (2H, m), 7.30 (2H, m), 3.48 (2H, br m), 1.13 (3H, t, J=7Hz); LC/MS retention time 2.76/(ES+) 265 (M+H, Ci0H12N2F3SO requires 265).
Description 14: W-{4-[(difluoromethyl)oxy]phenyl}-W-(2-hydroxyethyl)thiourea
The title compound (0.64g) was prepared from 1-[(difluoromethyl)oxy]-4- isothiocyanatobenzene (0.5g; 2.48mmol) and 2-aminoethanol (0.15ml ; 2.48mmol) in ethyl acetate (10ml) by the procedure described in Description 1.
LC/MS retention time 2.03/(ES+) 263 (M+H, Ci0Hi3N2F2SO2 requires 263).
Description 15: Λ/-(2-hydroxyethyl)-Λ/'-{4-[(trifluoromethyl)thio]phenyl}thiourea
A solution of 1-isothiocyanato-4-[(trifluoromethyl)thio]benzene (0.50Og; 2.13mmol) in ethyl acetate (5ml) was added dropwise to a stirring solution of 2-aminoethanol (0.128ml; 2.13mmol) in ethyl acetate (5ml) over 10 minutes at 250C. Then the reaction mixture was allowed to stir at 250C overnight. Then the solvent was removed in vacuo to give the title compound as a white solid (0.73Og, 91%).
1H NMR (400MHz, DMSO D6) δ: 9.93 (1 H, br s), 8.03 (1 H, br s), 7.72 (2H, m), 7.62 (2H, m), 4.86 (1 H, br s), 3.56 (4H, app s); LC/MS retention time 2.61/(ES+) 297 (M+H, Ci0H12N2F3OS2 requires 297).
Description 16: 2-chloro-3-oxobutanenitrile
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 SO2). 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. When a clear solution had formed, it was chilled in ice and treated with 12ml of concentrated HCI acid (ca 2 equiv), The resulting yellow solution was saturated with sodium chloride and extracted with ether (x3). The combined extracts were dried over Na2Sθ4 and the ether was removed under reduced pressure. A pale yellow liquid was obtained (5.17g, 58%). The desired product was used without further purification >80% pure. 4-chloro-5-methylisoxazole
1NMR (400MHz, CDCI3) δ: 8.18 (1 H, s), 2.43 (3H, s); LC/MS retention time 2.03 2-chloro-3-oxobutanenitrile LC/MS retention time 1.70/(ES") 1 16, 1 18 (M-H, C4H4 35CINO requires 1 17).
Description 17: /V-(4-bromophenyl)-W-(2-hydroxyethyl)thiourea
The title compound (6.32g; 100%) was prepared from 1-bromo-4-isothiocyanatobenzene (5.Og; 23mmol) and 3-aminoethanol (2.1 1 ml; 34.5mmol) in ethyl acetate (50ml) by the procedure described in Description 1. LC/MS retention time 2.14/(ES+) 275 & 277 (M+H, C9H12BrN2OS requires 275 & 277). Description 18: Ethyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazole-5-carboxylate hydrochloride
A mixture of /V-[4-(ethyloxy)phenyl]-/V-(2-hydroxyethyl)thiourea (1.5Og; 6.25mmol) and ethyl 2-chloro-3-oxobutanoate (2.057g; 12.5mmol) in toluene (40ml) was heated with stirring at 9O0C for 1 hour. The mixture was left to cool down overnight and the solvent was removed by rotary evaporation to afford the title compound (1.68g; 70%). LC/MS retention time 2.58/(ES+) 351 (M+H, C17H23N2O4S requires 351 ).
Description 19: Methyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl- 2,3-dihydro-1,3-thiazole-5-carboxylate
A mixture of ethyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-
1 ,3-thiazole-5-carboxylate hydrochloride (1.37g; 3.93mmol), sodium hydroxide (0.63g;
15.7mmol) in methanol (20ml) and water (5ml) was stirred at room temperature overnight.
Methanol was removed under reduced pressure and 5N HCI was added until pH=7. The title compound was collected by filtration and dried (0.751 g, 59%).
LC/MS retention time 2.41/(ES+) 337 (M+H, C16H21N2O4S requires 337).
Description 20: 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazole-5-carboxylic acid
A mixture of methyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro- 1 ,3-thiazole-5-carboxylate (0.69g; 2.05mmol) and lithium hydroxide monohydrate (0.177g; 4.1 mmol) in tetrahydrofuran (10ml) and water (10ml) was heated at 7O0C overnight. Solvent was removed under reduced pressure and the solution was acidified with 5N HCI solution until pH 5-6 and water was removed under reduced pressure and dried under vacuum to give the title compound as a crude product mixed with lithium chloride (1.08g). LC/MS retention time 1.72/(ES+) 323 (M+H, Ci5H19N2O4S requires 323).
Description 21 : Λf-cyclopropyl-ΛT-[4-(4-morpholinyl)phenyl]thiourea
Cyclopropylamine (0.4ml; 5.5mmol) was dissolved in ethyl acetate (10ml) and 4-(4- isothiocyanatophenyl)morpholine (600mg; 2.72mmol) was added portionwise with stirring over 10 minutes at room temperature. The reaction mixture was allowed to stir at room temperature for 5 hours. Then solvent was removed by rotary evaporation to afford the title compound as a yellow solid (0.76Og; 100%).
LC/MS retention time 1.89/(ES+) 278 (M+H, Ci4H20N3OS requires 278).
Description 22: W-ethyl-W-[4-(4-morpholinyl)phenyl]thiourea
A mixture of ethylamine in tetrahydrofuran (2M solution, 3.78ml; 7.57mmol) and ethyl acetate (10ml) was cooled in an ice bath under argon. Then 4-(4- isothiocyanatophenyl)morpholine (417mg; 1.89mmol) was added portionwise with stirring over 10 minutes. The reaction mixture was allowed to stir in an ice bath for 1 hour. Then solvent was removed by rotary evaporation to afford the title compound as a yellow solid (0.498g; 99%). LC/MS retention time 1.94/(ES+) 266 (M+H, Ci3H20N3OS requires 266).
Description 23: W-[4-(diethylamino)phenyl]-W-(2-hydroxyethyl)thiourea
Λ/,Λ/-diethyl-4-isothiocyanatoaniline (0.37mmol, 83mg) and 2-aminoethanol (0.37mmol, 23μL) were dissolved in ethyl acetate and stirred at room temperature for 1 hour. Solvents were removed in vacuo to yield the title compound which was used directly without further purification.
LCMS Rt 1.50 min, m/z (ES+) 268 (M+H, C13H2iN3OS + H requires 268).
Description 24: W-[4-(diethylamino)phenyl]-W-ethylthiourea
Λ/,Λ/-diethyl-4-isothiocyanatoaniline (0.37mmol, 83mg) and ethylamine (2M solution in THF, I .OOmmol, 500μL) were dissolved in ethyl acetate and stirred at room temperature for 1 hour. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 1.73 min, m/z (ES+) 252 (M+H, C13H21N3S + H requires 252).
Description 25: Λ/-{4-[(difluoromethyl)oxy]phenyl}-Λf-ethylthiourea
1-[(difluoromethyl)oxy]-4-isothiocyanatobenzene (0.37mmol. 75mg) and ethylamine (2M solution in THF, I .OOmmol, 500μL) were dissolved in ethyl acetate and stirred at room temperature for 1 hour. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.76 min, m/z (ES+) 247 (M+H, C10H12F2N2OS + H requires 247).
Description 26: Λf-ethyl-Λf'-[4-(4-morpholinyl)phenyl]thiourea
A solution of ethylamine (2M solution in THF, 2.00mmol, 1 mL) in ethyl acetate (3mL) was added to 4-(4-isothiocyanatophenyl)morpholine. The solution was stirred for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.29 min, m/z (ES+) 266 (M+H, C13H19N3OS + H requires 266). Description 27: Λ/-methyl-Λf-[4-(4-morpholinyl)phenyl]thioιιrea
A solution of methylamine (33% solution in ethanol, 1 mL) in ethyl acetate (3ml_) was added to 4-(4-isothiocyanatophenyl)morpholine. The solution was stirred for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.07 min, m/z (ES+) 252 (M+H, Ci2H17N3OS + H requires 252).
Description 28: Boc-protected 1-{2-[(4-aminophenyl)imino]-3,4-dimethyl-2,3- dihydro-1,3-thiazol-5-yl}ethanone
Boc-protected-/V-(4-aminophenyl)-/V-methylthiourea (0.67mmol, 188mg) and 3-chloro-2,4- pentanedione (1.01 mmol, 102μL) were combined in ethanol (2.5mL) and heated at 1000C for 20 minutes by microwaves. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 3.08 min, m/z (ES+) 362 (M+H, Ci8H23N3O3S + H requires 362).
Description 29: Boc-protected-1-{2-[(4-aminophenyl)imino]-3-ethyl-4-methyl-2,3- dihydro-1,3-thiazol-5-yl}ethanone
Boc-protected-/V-(4-aminophenyl)-/V-ethylthiourea (0.67mmol, 198mg) and 3-chloro-2,4- pentanedione (1.01 mmol, 102μL) were combined in ethanol (2.5mL) and heated at 1000C for 20 minutes by microwaves. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 3.27 min, m/z (ES+) 376 (M+H, Ci9H25N3O3S + H requires 376). Description 30: Boc-protected-1-[2-[(4-aminophenyl)imino]-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1,3-thiazol-5-yl]ethanone
Boc-protected-/V-(4-aminophenyl)-/V-(2-hydroxyethyl)thiourea (0.67mmol, 208mg) and 3-chloro-2,4-pentanedione (1.01 mmol, 102μl_) were combined in ethanol (2.5ml_) and heated at 1000C for 20 minutes by microwaves. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.95 min, m/z (ES+) 392 (M+H, C19H25N3O4S + H requires 392).
Description 31 : Boc-protected-Λ/-(4-aminophenyl)-ΛT-methylthiourea
Methylamine (33% in ethanol, 3ml_) was added to Boc-protected-4-isothiocyanatoaniline (0.67mmol, 167mg) and the solution was stirred for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.73 min, m/z (ES+) 282 (M+H, C13H19N3O2S + H requires 282).
Description 32: Boc-protected-Λ/-(4-aminophenyl)-ΛT-ethylthiourea
Ethylamine (2M in THF, 3mL) was added to Boc-protected^-isothiocyanatoaniline (0.67mmol, 167mg) and the solution was stirred for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.91 min, m/z (ES+) 296 (M+H, C14H21N3O2S + H requires 296).
Description 33: Boc-protected-Λ/-(4-aminophenyl)-ΛT-(2-hydroxyethyl)thiourea
A solution of 2-aminoethanol (0.67mmol, 40μL) in ethyl acetate (3ml_) was added to Boc- protected-4-isothiocyanatoaniline (0.67mmol, 167mg) and the solution was stirred for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.56 min, m/z (ES+) 312 (M+H, C14H2IN3O3S + H requires 312).
Description 34: W-[4-(dimethylamino)phenyl]-W-(2-hydroxyethyl)thiourea
2-Aminoethanol was dissolved in ethyl acetate (3ml_). 4-isothiocyanato-Λ/,Λ/- dimethylaniline was dissolved in ethyl acetate (1 mL) and added dropwise to the 2- aminoethanol solution. The resultant solution was stirred for 4 hours at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 1.54 min, m/z (ES+) 240 (M+H, CH HI7N3OS + H requires 240).
Description 35: Λf-(2-hydroxyethyl)-Λf'-(4-methylphenyl)thiourea
1-isothiocyanato-4-methylbenzene (0.37mmol, 56mg) and 2-aminoethanol (0.37mmol, 23μL) were dissolved in ethyl acetate (3mL) and shaken for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.18 min, m/z (ES+) 21 1 (M+H, C10H14N2OS + H requires 21 1 ).
Description 36: W-ethyl-W-(4-ethylphenyl)thiourea
i-ethyl-4-isothiocyanatobenzene (0.37mmol, 61 mg) and ethylamine (2M in THF, 100μL) were dissolved in ethyl acetate (3ml_) and shaken for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.85 min, m/z (ES+) 209 (M+H, CnH16N2S + H requires 209).
Description 37: /V-ethyl-W-phenylthiourea
Isothiocyanatobenzene (0.37mmol, 50mg) and ethylamine (2M in THF, 100μl_) were dissolved in ethyl acetate (3ml_) and shaken for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.25 min, m/z (ES+) 181 (M+H, C9H12N2S + H requires 181 ).
Description 38: Λf-ethyl-Λf'-(4-methylphenyl)thiourea
1-isothiocyanato-4-methylbenzene (0.37mmol, 56mg) and ethylamine (2M in THF, 100μL) were dissolved in ethyl acetate (3mL) and shaken for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 2.59 min, m/z (ES+) 195 (M+H, C10H14N2S + H requires 195).
Description 39: Λ/-[4-(dimethylamino)phenyl]-Λ/1-ethylthioιιrea
4-isothiocyanato-Λ/,Λ/-dimethylaniline (0.37mmol, 66mg) and ethylamine (2M in THF, 100μl_) were dissolved in ethyl acetate (3ml_) and shaken for 1 hour at room temperature. Solvents were removed in vacuo to yield the title compound which was used directly without further purification. LCMS Rt 1.90 min, m/z (ES+) 224 (M+H, C11H17N3S + H requires 224).
Description 40: /V-(2-aminoethyl)-W-[4-(ethyloxy)phenyl]thiourea
To a solution of ethylenediamine (22μl_, 0.33mmol) in ethyl acetate (2ml_) was added 4- ethoxyphenylisothiocyanate (0.059g, 0.33mmol) dropwise, with stirring. The reaction was stirred at room temperature overnight. Solvents were then removed under a stream of nitrogen to yield the crude title compound as a white solid, (75% by LCMS), which was used directly in the next step without further purification. LCMS Rt 1.73 min, m/z (ES+) 240 (M+H, CnH17N3OS + H requires 240)
Description 41 : /V-cyclopropyl-W-[4-(ethyloxy)phenyl]thiourea
To a solution of cyclopropylamine (23μL, 0.33mmol) in ethyl acetate (2mL) was added 4- ethoxyphenylisothiocyanate (0.059g, 0.33mmol) dropwise, with stirring. The reaction was stirred at room temperature overnight. After this time a further portion of cyclopropylamine (0.16mmol) in ethyl acetate (0.5mL) was added and the reaction continued stirring for 3 hours. Solvents were then removed under a stream of nitrogen to yield the crude title compound as a white solid, (complete conversion by LCMS), which was used directly in the next step without further purification. LCMS Rt 2.60 min, m/z (ES+) 237 (M+H, C12H16N2OS + H requires 237)
Description 42: /V-(4-ethylphenyl)-W-(2,2,2-trifluoroethyl)thiourea
Following the procedure described in Description 40, the crude title compound (81 % by LCMS) was prepared from 2,2,2-trifluoromethylethylamine (0.03mL, 0.33mmol) and 4- ethylphenylisothiocyanate (0.054g, 0.33mmol) in ethyl acetate (3mL), for use directly in the next step without further purification.
LCMS Rt 3.16 min, m/z (ES+) 263 (M+H, CnH13F3N2S + H requires 263)
Description 43: W-^ethyloxyJphenylJ-W^^^-trifluoroethylJthiourea
Following the procedure described in Description 40, the crude title compound (73% by LCMS) was prepared from 2,2,2-trifluoromethylethylamine (0.03mL, 0.33mmol) and 4- (ethyloxy)phenylisothiocyanate (0.059g, 0.33mmol) in ethyl acetate (3mL), for use directly in the next step without further purification. LCMS Rt 2.96 min, m/z (ES+) 279 (M+H, CnH13F3N2OS + H requires 279)
Example 1 : 1-[2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone hydrochloride
A mixture of Λ/-[4-(ethyloxy)phenyl]-Λ/-(2-hydroxyethyl)thiourea (0.30Og, 1.25mmol) and 3- chloro-2,4-pentanedione ( 0.176g; 1.31 mmol) in toluene (5ml) was heated at 9O0C for 15 minutes. Evaporated off solvent under reduced pressure. The residual material was recrystallised from methanol/ethyl acetate to afford the title compound as a white solid
(0.296g).
1H NMR (400MHz, DMSO D6) δ: 7.17-7.08 (2H, m), 7.02-6.96 (2H, m), 4.21 (2H, m), 4.03 (2H, m), 3.77 (2H, m), 2.66 (3H, s), 2.40 (3H, s), 1.33 (3H, t, J=7Hz); LC/MS retention time
2.21/(ES+) 321 (M+H, C16H21N2O3S requires 321 ).
Example 2: 1-[2-[(4-ethylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1,3- thiazol-5-yl]ethanone hydrochloride
The title compound (0.198g) was prepared from /V-(4-ethylphenyl)-/V-(2- hydroxyethyl)thiourea [European patent EP0021806] (0.20Og; 0.89mmol), and 3-chloro- 2,4-pentanedione (1.05 mol) in toluene (4ml) by the procedure described in Example 1. 1H NMR (400MHz, DMSO D6) δ: 7.25 (2H, m), 7.03 (2H, m), 4.12 (2H, m), 3.73 (2H, m), 2.66 (3H, s), 2.63-2.57 (2H, m), 2.38 (3H, s), 1.17 (3H, t, J=7Hz); LC/MS retention time 2.57/(ES+) 305 (M+H, C16H2IN2O2S requires 305).
Example 3: 1-{2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-[2-(methyloxy)ethyl]-2,3- dihydro-1,3-thiazol-5-yl}ethanone
A mixture of Λ/-[4-(ethyloxy)phenyl]-Λ/'-[2-(methyloxy)ethyl]thiourea (0.20Og; 0.78mmol), and 3-chloro-2,4-pentanedione (1.05 mmol) in ethanol (5ml) was heated at 9O0C for 15 minutes. The desired product was isolated by evaporating off ethanol in vacuo. Residual material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated in vacuo. Recryatallised from ethyl acetate/n-pentane to afford the title compound (123mg) as a yellow solid. 1H NMR (400MHz, CDCI3) δ: 6.97 (2H, m), 6.90 (2H, m), 4.12 (2H, m), 4.04 (2H, m), 3.70 (2H, m), 3.36 (3H, s), 2.66 (3H, s), 2.27 (3H, s), 1.41 (3H, t, J=7Hz); LC/MS retention time 2.87/(ES+) 335 (M+H, C17H23N2O3S requires 335).
Example 4: 1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)- 2,3-dihydro-1,3-thiazol-5-yl]ethanone
A mixture of /V-(2-hydroxyethyl)-/V-{4-[(trifluoromethyl)oxy]phenyl}thiourea (0.20Og; 0.71 mmol), and 3-chloro-2,4-pentanedione (0.1 ml; 0.75mmol) in toluene (10ml) was heated at 950C for 1 hour. The desired product was isolated by evaporating off toluene in vacuo. 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%). 1H NMR (400MHz, CDCI3) δ: 7.20 (2H, d, J=9Hz), 7.05 (2H, d, J=8Hz), 4.17 (2H, m), 3.98 (2H, m), 3.35 (1 H, br s), 2.62 (3H, s), 2.30 (3H, s); LC/MS retention time 2.94/(ES+) 361 (M+H, Ci5H16F3N2O3S requires 361 ).
Example 5: 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3- dihydro-1,3-thiazol-5-yl)ethanone
A mixture of /V-(2-hydroxyethyl)-/V-[4-(trifluorometriyl)phenyl]thiourea (0.90Og; 3.40mmol), and 3-chloro-2,4-pentanedione (0.01 mol) in toluene (30ml) was heated at 950C for 30 minutes. The desired product was isolated by evaporating off toluene in vacuo. 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%).
1H NMR (400MHz, CDCI3) δ: 7.61 (2H, d, J=8Hz), 7.14 (2H, d, J=8Hz), 4.18 (2H, m), 4.01 (2H, m), 3.13 (1 H, m), 2.66 (3H, s), 2.28 (3H, s); LC/MS retention time 2.87/(ES+) 345 (M+H, C15H16F3N2O2S requires 345).
Example 6: 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1,3-thiazol- 5-yl)ethanone hydrochloride
A mixture of /V-ethyl-/V-[4-(ethyloxy)phenyl]thiourea (0.20Og; 0.89mmol), and 3-chloro-2,4- pentanedione (2.68mmol) in toluene (5ml) was heated at 950C for 2 hours. The desired product was isolated by evaporating off toluene in vacuo. 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%).
1H NMR (400MHz, DMSO D6) δ: 7.10 (2H, d, J=9Hz), 6.97 (2H, d, J=9Hz), 4.13 (2H, m), 4.03 (2H, m), 2.63 (3H, s), 2.40 (3H, s), 1.30 (6H, m); LC/MS retention time 2.56/(ES+) 305 (M+H, C16H21N2O2S requires 305). Example 7: 2-[2-{[4-(ethyloxy)phenyl]imino}-4,5-dimethyl-1,3-thiazol-3(2H)-yl]ethanol hydrochloride
A mixture of N-[4-(ethyloxy)phenyl]-/V-(2-hydroxyethyl)thiourea (0.20Og; 0.83mmol) and 3- chloro-2-butanone (0.55ml; 5.42mmol) in toluene (5ml) was heated at 9O0C for 16 hours. Evaporated off solvent under reduced pressure. The residual material was recrystallised from methanol/ethyl acetate to afford the title compound as a white solid (90mg, 37%). 1H NMR (400MHz, DMSO D6) δ: 1 1.40 (1 H br s), 7.35 (2H, d, J=9Hz), 7.06 (2H, m), 4.30 (2H, m), 4.07 (2H, m), 3.78 (2H, m), 3.40 (1 H br s), 2.25 (3H, s), 2.17 (3H, s), 1.32 (3H, t, J=7Hz); LC/MS retention time 1.67/(ES+) 293 (M+H, C15H2IN2O2S requires 293).
Example 8: 1-[2-[(4-butylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1,3- thiazol-5-yl]ethanone hydrochloride
The title compound (0.146g) was prepared from /V-(4-butylphenyl)-/V-(2- hydroxyethyl)thiourea (0.20Og; O.δOmmol), and 3-chloro-2,4-pentanedione (1.2mmol) in toluene (5ml) by the procedure described in Example 6.
1H NMR (400MHz, DMSO D6) δ: 7.22 (2H, d, J=8Hz), 7.03 (2H, m), 4.14 (2H, m), 3.71 (2H, m), 2.65 (3H, s), 2.57 (2H, t, J=7Hz), 2.35 (3H, s), 1.56 (2H, m), 1.30 (2H, m), 0.90 (3H, t, J=7Hz); LC/MS retention time 3.07/(ES+) 333 (M+H, C18H25N2O2S requires 333).
Example 9: 1-[2-{[4-(ethyloxy)phenyl]imino}-3-(3-hydroxypropyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone hydrochloride
The title compound (0.105g) was prepared from /V-[4-(ethyloxy)phenyl]-/V-(3- hydroxypropyl)thiourea (0.20Og; 0.86mmol), and 3-chloro-2,4-pentanedione (1.29mmol) in toluene (5ml) by the procedure described in Example 6. 1H NMR (400MHz, DMSO D6) δ: 7.13 (2H, d, J=9Hz), 6.97 (2H, d, J=9Hz), 6.84-5.68 (2H, br s), 4.18 (2H, m), 4.03 (2H, m), 3.52 (2H, m), 2.63 (3H, s), 2.39 (3H, s), 1.90 (2H, m), 1.32 (3H, t, J=7Hz); LC/MS retention time 2.31/(ES+) 335 (M+H, C17H23N2O3S requires 335).
Example 10: 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3- dihydro-1,3-thiazol-5-yl)ethanone
A mixture of /V-(2-hydroxyethyl)-/V-[4-(4-morpholinyl)phenyl]thiourea (0.20Og; 0.71 mmol), and 3-chloro-2,4-pentanedione (0.13ml; 1.07mmol) in toluene (10ml) was heated at 950C for 2 hours, and excess of 3-chloro-2,4-pentanedione (0.26ml; 2.14mmol) was added in one portion. The resulting mixture was heated at 950C for a further 10 hours. The desired product was isolated by evaporating off toluene in vacuo. 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%). 1H NMR (400MHz, CDCI3) δ: 7.01 (2H, m), 6.91 (2H, m), 4.18 (2H, m), 3.95 (2H, m), 3.84 (4H, m), 3.12 (4H, m), 2.60 (3H, s), 2.27 (3H, s); LC/MS retention time 1.74/(ES+) 362 (M+H, Ci8H24N3O3S requires 362).
Example 11 : 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro- 1,3-thiazole-5-carbonitrile hydrochloride
A mixture of /V-[4-(ethyloxy)phenyl]-/V-(2-hydroxyethyl)thiourea (0.30Og; 1.24mmol) and 2- chloro-3-oxobutanenitrile ( 0.294g; 2.48mmol) in toluene (10ml) was heated at 9O0C for 15 minutes. Evaporated off solvent under reduced pressure. The residual material was recrystallised from ethyl acetate to afford the title compound as a white solid (0.326g,
77%).
1H NMR (400MHz, DMSO D6) δ: 6.93 (4H, s), 6.57 (1 H, br s), 4.00 (4H, m), 3.72 (2H, m),
2.41 (3H, s), 1.30 (3H, t, J=7Hz); LC/MS retention time 2.75/(ES+) 304 (M+H,
C15H18N3O2S requires 304).
Example 12: 3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1,3-thiazole- 5-carbonitrile hydrochloride
A mixture of Λ/-ethyl-/V-[4-(ethyloxy)phenyl]thiourea (0.20Og; 0.89mmol) and 2-chloro-3- oxobutanenitrile ( 0.21 Og; 1.78mmol) in toluene (10ml) was heated at 9O0C for 15 minutes. Evaporated off solvent under reduced pressure. The residual material was recrystallised from ethyl acetate to afford the title compound as a white solid (0.185g; 64%). 1H NMR (400MHz, DMSO D6) δ: 6.92 (4H, s), 6.71 (1 H, br s), 3.98 (4H, m), 2.39 (3H, s), 1.33 (3H, t, J=7Hz), 1.27 (3H, t, J=7Hz); LC/MS retention time 3.28/(ES+) 288 (M+H, C15H18N3OS requires 288).
Example 13: 1-{2-[(4-chlorophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1,3-thiazol-5- yljethanone hydrochloride
The title compound (0.083g) was prepared from Λ/-(4-chlorophenyl)-Λ/'-ethylthiourea (0.15Og; 0.70mmol) and 3-chloro-2,4-pentanedione (0.39ml; 3.14mmol) in toluene (10ml) by the procedure described in Example 1.
1H NMR (400MHz, DMSO D6) δ: 7.17 (2H, m), 6.98 (2H, m), 4.04 (2H, m), 2.58 (3H, s), 2.32 (3H, s), 1.26 (3H, t, J=7Hz); LC/MS retention time 2.87/(ES+) 295 (M+H, C14H16 35CIN2OS requires 295).
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 (0.102g) was prepared from /V-cyclopropyl-/V-[4- (trifluoromethyl)phenyl]thiourea (0.15Og; 0.57mmol) and 3-chloro-2,4-pentanedione (0.85mmol) in toluene (10ml) by the procedure described in Example 1.
1H NMR (400MHz, DMSO D6) δ: 7.79 (2H, m), 7.19 (2H, m), 6.68 (1 H, br s), 3.03 (1 H, m), 2.64 (3H, s), 2.33 (3H, s), 1.17 (2H, m), 1.03 (2H, m); LC/MS retention time 3.23/(ES+) 341 (M+H, Ci6H16F3N2OS requires 341 ).
Example 15: 1-(3-ethyl-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.δOmmol) 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. 1H NMR (400MHz, DMSO D6) δ: 7.70 (2H, d, J=8Hz), 7.18 (2H, d, J=8Hz), 4.06 (2H, m), 2.61 (3H, s), 2.33 (3H, s), 1.29 (3H, t, J=7Hz); LC/MS retention time 3.41/(ES+) 329 (M+H, C15H16F3N2OS requires 329).
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. 1H NMR (400MHz, DMSO D6) δ: 7.50 (2H, m), 7.25 (2H, m), 4.18 (2H, m), 2.56 (3H, s), 2.50 (3H, s), 1.40 (3H, t, J=7Hz); LC/MS retention time 3.45/(ES+) 345 (M+H, Ci5H16F3N2O2S requires 345).
Example 16b: 1-[3-ethyl-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3- dihydro-1,3-thiazol-5- l ethanone
1-isothiocyanato-4-[(trifluoromethyl)oxy]benzene (0.25mmol, 40.59mg) was combined with 2M ethylamine in tetrahydrofuran (0.25 mmol, 0.125ml) in ethyl acetate (2ml_). This reaction was stirred for 20 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (2ml_). A 31.3μl_ (0.263 mmol) portion of 3-chloro-2,4- pentanedione was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 10.5mg of the title compound. 1H NMR (400MHz, MeOD): δ 7.22-7.27 (2H, m, ArH), 7.06-7.1 1 (2H, m, ArH), 4.05-4.12 (2H, m), 2.61 (3H, s), 2.32 (3H, s), 1.34 (3H, t) LCMS Rt 3.52 min, m/z (ES+) 345 (M+H, C15H15F3N2O2S + H requires 345).
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.
1H NMR (400MHz, DMSO D6) δ: 7.16 (2H, m), 7.01 (2H, m), 5.04 (1 H, m), 4.03 (2H, m),
3.71 (2H, m), 2.61 (3H, s), 2.32 (3H, s); LC/MS retention time 2.57/(ES+) 343 (M+H,
C15H17F2N2O3S requires 343).
Example 18: 1-[3-(2-hydroxyethyl)-4-methyl-2-({4-
[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1,3-thiazol-5-yl]ethanone
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.
1H NMR (400MHz, DMSO D6) δ: 7.61 (2H, m), 7.09 (2H, m), 4.18 (2H, m), 4.01 (2H, m), 3.15 (1 H, br s), 2.67 (3H, s), 2.32 (3H, s); LC/MS retention time 3.13/(ES+) 377 (M+H Ci5H16F3N2O2S2 , requires 377).
Example 19: Λ/-[3-ethyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4- (trifluoromethyl)aniline
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 950C 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).
1H NMR (400 MHz; CDCI3) δ: 7.53 (2H, d, J=8Hz), 7.13 (2H, d, J=8Hz), 3.92 (2H, q, J=7Hz), 2.07 (3H, s), 2.04 (3H, s), 1.30 (3H, t, J=7Hz); LC/MS Retention time 2.37/ (ES+) 301 (M+H, Ci4H16F3N2S requires 301 ).
Example 20: 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1,3- oxazol-5-yl)ethanone
Ethylamine (2M solution in THF; 94OuI) was added dropwise over ten seconds to a stirring solution of 4-ethoxyphenylisocyanate (27OuI) in toluene (9ml). After stirring at room temperature for two hours, the reaction was heated in an oil bath at 950C, and 3-chloro- 2,4-pentandione (1 ml) was added by syringe pump dropwise over approximately five hours. After stirring at this temperature for 17 hours, the reaction was heated to reflux, and more 3-chloro-2,4-pentandione (50OuI) was added dropwise over ten hours. After refluxing for a total of three days, the desired product was isolated using SCX column chromatography. The resulting brown oil (57mg) was further purified by mass directed auto prep, giving the title compound as a brown oily solid (7.51 mg). 1H NMR (400 MHz, CDCI3) δ: 7.24-7.17 (2H, m), 6.79 (2H, m), 4.03 (2H, q, J=7Hz), 3.79 (2H, q, J=7Hz), 2.45 (3H, s), 2.32 (3H, s), 1.37 (3H, t, J=7Hz), 1.33 (3H, t, J=7Hz); LC/MS Retention time 2.06/ (ES+) 289 (M+H, Ci6H2IN2O3 requires 289).
Example 21 : 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1,3-thiazol-5- yljethanone
A solution of 4-bromophenyl isothiocyanate (6.42g; 30mmol) in toluene (25ml) was added to a stirring solution of ethylamine (available as a 2M solution in tetrahydrofuran; 15ml; 30mmol) in toluene (25ml) over 15 minutes at room temperature. The reaction mixture was allowed to stir at room temperature for 1.5 hours. The reaction mixture was diluted with further toluene (40ml), and 3-chloro-2,4-pentanedione (4.24g; 31.5mmol; 3.8ml) was added in one portion and the resulting mix stirred at 9O0C (oilbath temperature) for 2 hours. The 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. The relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil (8.1g) which was then passed through 2 x 10g SCX columns in ethyl acetate and the solvent removed under reduced pressure to give the title compound as a yellow solid (3.4Og, 34%). 1H NMR (400MHz, CDCI3) δ: 7.45 (2H, m), 6.94 (2H, m), 4.03 (2H, quartet, J=7Hz), 2.62 (3H, s), 2.26 (3H, s), 1.35 (3H, t, J=7Hz); LC/MS retention time 3.34/(ES+) 339 & 341 (M+H, C14H16BrN2OS requires 339 & 341 ).
Example 22: 1-(3-ethyl-4-methyl-2-{[4-(1-pyrrolidinyl)phenyl]imino}-2,3-dihydro-1,3- thiazol-5-yl)ethanone hydrochloride
A mixture of palladium acetate (10mol%, 22.5mmol; O.i mmol), (R)-(+)-2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl (15mol%, 93mg; 0.15mmol) and cesium carbonate (489mg; 1.5mmol) in anhydrous dioxin (25ml) were sonicated for 0.5 hours under a blanket of argon. The 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl}ethanone (338mg; 1 mmol) and pyrrolidine (71 mg; 1 mmol; 0.08ml) were then added and the whole mix stirred at reflux for 22 hours. More palladium acetate (10mol%, 22.5mmol; O.i mmol) and (R)-(+)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (15mol%, 93mg; 0.15mmol) was sonicated in anhydrous dioxin (10ml) for 20 minutes and this mix then added to the refluxing reaction mix and reflux continued for a further 24 hours, and the reaction allowed to cool to room temperature. 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). The free base was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml), and the solvent removed with air drying. The product was triturated in ether and vacuum oven dried to give the title compound as a yellow solid (63mg; 17%).
1H NMR (400 MHz, MeOD-d4) δ: 7.49 (2H, d, J=9Hz), 7.22 (2H, d, J=8Hz), 4.30 (2H, quart. J=7Hz), 3.56 (4H, m), 2.75 (3H, s), 2.51 (3H, s), 2.18 (4H, m), 1.48 (3H, t, J=7Hz); LC/MS Retention time 2.44/ (ES+) 330 (M+H, C18H24N3OS requires 330).
Example 23: 1-(3-ethyl-4-methyl-2-{[4-(1-piperidinyl)phenyl]imino}-2,3-dihydro-1,3- thiazol-5-yl)ethanone hydrochloride
A mixture of 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone (338mg; 1 mmol), piperidine (85mg; 1 mmol), sodium tert-butoxide (134mg; 1.4mmol), bis(dibenzylideneacetone)palladium (3mol%, 0.03mmol; 17.3mg) and 2-(di-t- butylphosphino)biphenyl (10mol%, O.i mmol; 30mg) in toluene (10ml) was stirred at 1 1O0C (oilbath temperature) for 5 hours. Fresh piperidine (85mg; 1 mmol), bis(dibenzylideneacetone)palladium (3mol%, 0.03mmol; 17.3mg) and 2-(di-t- butylphosphino)biphenyl (10mol%, O.i mmol; 30mg) was added and stirring continued for a further 2 hours. The reaction mix was allowed to cool to room temperature, diluted with diethyl ether (20ml) and filtered through a pad of kieselguhr. The filtrate was concentrated by rotary evaporation and the residue chromatographed on a 1 Og silica pre-packed isolute column eluting from 0-100% ethyl acetate in petroleum ether. Relevant fractions were combined and evaporated under reduced pressure to give an orange solid (194mg) which was further purified by mass directed auto-preparation (MDAP). Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow solid (91 mg). The free base was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml), and the solvent removed with air drying. The product was triturated in ether and vacuum oven dried to give the title compound as a pale yellow solid (102mg; 27%).
1H NMR (400 MHz, MeOD-d4) δ: 7.95 (2H, d, J=9Hz), 7.75 (2H, d, J=9Hz), 4.33 (2H, quart, J=7Hz), 3.71 (4H, t, J=6Hz), 2.76 (3H, s), 2.52 (3H, s), 2.10 (4H, m), 1.84 (2H, m), 1.49 (3H, t, J=7Hz); LC/MS Retention time 1.98/ (ES+) 344 (M+H, C19H26N3OS requires 344).
Example 24: 3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2-{[4-(trifluoromethyl)phenyl]imino}- 2,3-dihydro-1,3-thiazole-5-carboxamide hydrochloride
A mixture of /V-(2-hydroxyethyl)-/V-[4-(trifluoromethyl)phenyl]thiourea (500mg; 1.89mmol) and 2-chloro-Λ/,Λ/-dimethyl-3-oxobutanamide (680mg; 4.16mmol) in toluene (15ml) was heated at 9O0C for 2 hours. The solvent was evaporated off under reduced pressure. The residual material was recrystallised from methanol/ethyl acetate to afford the title compound as a solid (460mg; 65%).
1H NMR (400MHz, DMSO D6) δ: 7.87 (1 H, br, s), 7.69 (2H, d, J=8Hz), 7.26 (2H, d, J=8Hz), 4.02 (2H, m), 3.73 (2H, m), 2.94 (6H, s), 2.26 (3H, s); LC/MS retention time 2.53/(ES+) 374 (M+H, C16H19F3N3O2S requires 374).
Example 25: 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro- 1,3-thiazol-5-yl]ethanone
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 9O0C 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%). 1H NMR (400MHz, CDCI3) δ: 7.45 (2H, m), 6.94 (2H, m), 4.17 (2H, m), 3.99 (2H, appr s), 3.35 (1H, s), 2.63 (3H, s), 2.29 (3H, s); LC/MS retention time 2.79/(ES+) 355 & 357 (M+H, Ci4H16BrN2O2S requires 355 & 357).
Example 26: 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro- 1,3-thiazole-5-carboxamide
A mixture of 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazole-5-carboxylic acid (264mg; 0.82mmol), DIPEA (diisopropylethylamine) (1.38ml; 9mmol) and ammonium chloride (0.44g; 8.2mmol) in dimethylformamide (20ml) was stirred in a stoppered flask at room temperature. HATU (O-( 7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate) (0.312g; 0.82mmol) was added to the stirring solution. The mixture was allowed to stir for 4 hours at room temperature. 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 desired product was isolated by column chromatography on silica using 0 to10% methanol in ethyl acetate to afford the title compound (68mg; 26%). 1H NMR (400MHz, DMSO D6) δ: 7.05 (2H, s), 6.89 (4H, appr s), 5.00 (1 H br s) 3.97 (2H, m), 3.92 (2H, m), 3.68 (2H, m), 2.51 (3H, s), 1.29 (3H, m); LC/MS retention time 1.67/(ES+) 322 (M+H, C15H20N3O3S requires 322).
Example 27: 3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2-({4- [(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1,3-thiazole-5-carboxamide hydrochloride
Λ/-(2-hydroxyethyl)-Λ/'-{4-[(trifluoromethyl)oxy]phenyl}thiourea (0.5g; 1.78mmol) was dissolved in ethanol (30ml). Then 2-chloro-Λ/,Λ/-dimethyl-3-oxobutanamide (0.5ml; 3.56mmol) was added. The reaction mixture was heated at 950C for 2 hours. The ethanol was removed by rotary evaporation and the residual material was recrystallised from ethyl acetate to give a white solid which was further purified by MDAP (mass directed auto- prep) and treated with ethereal hydrochloride, triturated with diethyl ether to afford the title compound as a white solid (251 mg; 33%). 1H NMR (400MHz, DMSO D6) δ: 7.39 (2H, m), 7.25 (2H, m), 4.70 (1 H br s), 4.06 (2H, appr s), 3.74 (2H, m), 2.94 (6H, s), 2.26 (3H, s); LC/MS retention time 2.38/(ES+) 390 (M+H, Ci6H19F3N3O3S requires 390).
Example 28: 1-(3-cyclopropyl-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3- dihydro-1,3-thiazol-5-yl)ethanone hydrochloride
A mixture of /V-cyclopropyl-/V-[4-(4-morpholinyl)phenyl]thiourea (200mg; 0.72mmol), 3- chloro-2,4-pentanedione (0.3ml; 2.2mmol) in ethanol (20ml) was heated at 9O0C for 20 minutes. The solvent was removed by rotary evaporation and the sample purified by
MDAP (mass directed auto-prep). The solvent was removed by rotary evaporation to give the desired product which was treated with ethereal hydrochloride to afford the title compound as a yellow solid (108mg; 38%). 1H NMR (500MHz, DMSO D6) δ: 7.30 (2H, m), 7.20 (2H, m), 5.21 (1 H br s), 3.80 (4H, appr s), 3.30-3.19 (5H, m), 2.72 (3H, s), 2.47 (3H, s), 1.34 (2H, m), 1.20 ( 2H, m); LC/MS retention time 1.72/(ES+) 358 (M+H, Ci9H24N3O2S requires 358).
Example 29: 3-ethyl-Λ/,Λ/,4-trimethyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro- 1 ,3-thiazole-5-carboxamide hydrochloride
The title compound (193mg; 83%) was prepared from /V-ethyl-/V-[4-(4- morpholinyl)phenyl]thiourea (150mg; 0.57mmol) and 2-chloro-Λ/,Λ/-dimethyl-3- oxobutanamide (0.23ml; 1.7mmol) in ethanol (10ml) by the procedure described in Example 28.
1H NMR (400MHz, DMSO D6) δ: 7.46 (2H, m), 7.14 (2H, m), 5.21 (1 H, br s), 4.26 (2H, m), 3.77 (4H, m), 3.72 (4H, m), 2.94 (6H, s), 2.31 (3H, s), 1.35 (3H, m); LC/MS retention time 1.53/(ES+) 375 (M+H, C19H27N4O2S requires 375).
Example 30: 2,2,2-trifluoro-1-[3-(2-hydroxyethyl)-4-methyl-2-({4-
[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone hydrochloride
The title compound (49mg; 15%) was prepared from /V-(2-hydroxyethyl)-/V-{4-
[(trifluoromethyl)oxy]phenyl}thiourea (200mg; 0.71 mmol) and 3-chloro-1 ,1 ,1-trifluoro-2,4- pentanedione (540mg; 2.86mmol) in ethanol (10ml) by the procedure described in
Example 28.
1H NMR (400MHz, MeOD) δ: 7.61 (2H, m), 7.50 (2H, m), 4.38 (2H, m), 3.97 (2H, m), 3.38
(1 H, s), 2.50 (3H, s); LC/MS retention time 3.45/(ES+) 415 (M+H, C15H13F6N2O3S requires
415).
Example 31 : 3-cyclopropyl-Λ/,Λ/,4-trimethyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3- dihydro-1,3-thiazole-5-carboxamide hydrochloride
A mixture of /V-cyclopropyl-/V-[4-(4-morpholinyl)phenyl]thiourea (200mg; 0.72mmol), 2- chloro-Λ/,Λ/-dimethyl-3-oxobutanamide (0.3ml; 2.2mmol) in ethanol (20ml) was heated at 900C for 1 hour. The solvent was removed by rotary evaporation and the sample purified by high pH MDAP. The solvent was removed by rotary evaporation to give the desired product, treated with ethereal hydrochloride to afford the title compound as a yellow solid (52mg; 17%).
1H NMR (500MHz, DMSO D6) δ: 1 1.40 (1 H, br s), 7.35 (2H, m), 7.1 1 (2H, m), 4.78 (1 H, br s), 3.75 (4H, m), 3.25-3.13 (4H, m), 2.95 (6H, s), 2.33 (3H, s) 1.32 (2H, m), 1.22 (2H, m); LC/MS High pH retention time 2.14/(ES+) 387 (M+H, C20H27N4O2S requires 387).
Example 32: 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(1-pyrrolidinyl)phenyl]imino}-2,3- dihydro-1,3-thiazol-5-yl)ethanone
A mixture of 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone (200mg; 0.56mmol), pyrrolidine (294mg in total; 4.1 mmol), bis(dibenzylideneacetone)palladium (10mg; 3mol%), 2-biphenylyl[bis(1 ,1- dimethylethyl)]phosphane (17mg; 10mol%) and sodium tert-butoxide (75mg; 0.78mmol) in toluene (5ml) was heated at 1 1 O0C for 8 hours. The 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%).
1H NMR (400MHz, DMSO D6) δ: 6.84 (2H, m), 6.54 (2H, m), 5.02 (1 H, br s), 4.00 (2H, m), 3.70 (2H, m), 3.20 (4H, m), 2.60 (3H, s) 2.29 (3H, s), 1.94 (4H, m); LC/MS retention time 2.00/(ES+) 346 (M+H, C18H24N3O2S requires 346).
Example 33: 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(methyloxy)phenyl]imino}-2,3- dihydro-1 ,3-thiazol-5-yl)ethanone
1-isothiocyanato-4-(methyloxy)benzene (0.25mmol, 41.3mg) was dissolved in ethyl acetate (1 mL). To this solution was added a 1 mL solution of ethyl acetate containing ethanolamine (15.1 μL, 0.25mmol). This reaction was shaken for 20-30 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (1 mL). A 31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione in ethanol (1 mL) was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 1 1.1 mg of the title compound.
1H NMR (400MHz, MeOD): δ 7.9 (4H, s, ArH), 5.01 (1 H, m, OH), 4.01 (2H, m), 3.68-3.75 (5H, m), 2.60 (3H, s), 2.40 (3H, s) LCMS Rt 2.57 min, m/z (ES+) 307 (M+H, C15H18N2O3S + H requires 307).
Example 34: 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(methylthio)phenyl]imino}-2,3- dihydro-1,3-thiazol-5-yl)ethanone
1-isothiocyanato-4-(methylthio)benzene (0.25mmol, 45.3mg) was dissolved in ethyl acetate (1 mL). To this solution was added a 1 mL solution of ethyl acetate containing ethanolamine (15.1 μL, 0.25mmol). This reaction was shaken for 20-30 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (1 mL). A
31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione in ethanol (1 mL) was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 40.5mg of the title compound.
1H NMR (400MHz, MeOD): δ 7.25-7.29 (2H, m, ArH), 6.95-6.99 (2H, m, ArH), 4.12 (2H, m), 3.88 (2H, m), 2.66 (3H, s), 2.46 (3H, s), 2.32 (3H, t)
LCMS Rt 2.96 min, m/z (ES+) 323 (M+H, C15H18N2O2S2 + H requires 323).
Example 35: 1-[2-[(3,4-dimethylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone
4-isothiocyanato-1 ,2-dimethylbenzene (0.25mmol, 40.8mg) was dissolved in ethyl acetate (1 mL). To this solution was added a 1 mL solution of ethyl acetate containing ethanolamine (15.1 μL, 0.25mmol). This reaction was shaken for 20-30 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (1 mL). A 31.3μL (0.263mmol) portion of 3-chloro-2,4-pentanedione in ethanol (1 mL) was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 8.1 mg of the title compound.
1H NMR (400MHz, MeOD): δ 7.06-7.1 (1 H, m, ArH), 6.77-6.80 (1 H, m, ArH), 6.70-6.75 (1 H, m, ArH), 4.1 1 (2H, m), 3.88 (2H, m), 2.66 (3H, s), 2.30 (3H, s), 2.22-2.26 (6H, m) LCMS Rt 2.93 min, m/z (ES+) 305 (M+H, C16H20N2O2S + H requires 305).
Example 36: 1-[3,4-dimethyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone
1-isothiocyanato-4-[(trifluoromethyl)oxy]benzene (0.25mmol, 40.59mg) was combined with 33 wt% methylamine in ethanol solution (0.25mmol, 7.77mg methylamine ≡ 23.3mg of solution) in ethyl acetate (2ml_). This reaction was stirred for 20 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (2ml_). A 31.3μl_ (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 8.2mg of the title compound. 1H NMR (400MHz, MeOD): δ 7.21-7.27 (2H, m, ArH), 7.06-7.1 1 (2H, m, ArH), 3.50 (3H, s), 2.61 (3H, s), 2.32 (3H, s)
LCMS Rt 3.35 min, m/z (ES+) 331 (M+H, C14H13F3N2O2S + H requires 331 ).
Example 37: 1-[4-methyl-3-propyl-2-({4-[(trifluoromethyl)oxy]ρhenyl}imino)-2,3- dihydro-1,3-thiazol-5-yl]ethanone
1-isothiocyanato-4-[(trifluoromethyl)oxy]benzene (0.25mmol, 40.59mg) was combined with n-propylamine (0.25mmol, 14.8 mg) in ethyl acetate (2mL). This reaction was stirred for 20 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (2mL). A 31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 3.1 mg of the title compound.
1H NMR (400MHz, MeOD): δ 7.26-7.30 (2H, m, ArH), 7.1 1-7.17 (2H, m, ArH), 4.00 (2H, m), 2.63 (3H, s), 2.33 (3H, s), 1.81 (2H, m), 1.32 (3H, t)
LCMS Rt 3.67 min, m/z (ES+) 359 (M+H, C16H17F3N2O2S + H requires 359).
Example 38: 1-[4-methyl-3-[2-(methyloxy)ethyl]-2-({4-
[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1,3-thiazol-5-yl]ethanone
1-isothiocyanato-4-[(trifluoromethyl)oxy]benzene (0.25mmol, 40.59mg) was combined with [2-(methyloxy)ethyl]amine (0.25mmol, 18.8 mg) in ethyl acetate (2ml_). This reaction was stirred for 20 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (2ml_). A 31.3μl_ (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 2.1 mg of the title compound. 1H NMR (400MHz, MeOD): δ 7.22-7.27 (2H, m, ArH), 7.06-7.1 1 (2H, m, ArH), 4.20 (2H, m), 3.72 (2H, m), 3.35 (3H, s), 2.64 (3H, s), 2.32 (3H, s) LCMS Rt 3.47 min, m/z (ES+) 375 (M+H, C16H17F3N2O3S + H requires 375).
Example 39: 1-(2-{[4-(ethyloxy)phenyl]imino}-3,4-dimethyl-2,3-dihydro-1,3-thiazol-5- yl)ethanone
1-(ethyloxy)-4-isothiocyanatobenzene (0.25mmol, 44.8 mg) was combined with 33 wt% methylamine in ethanol solution (0.25mmol, 7.77mg methylamine ≡ 23.3mg of solution) in ethyl acetate (2mL). This reaction was stirred for 20 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (2mL). A 31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 3.0 mg of the title compound. 1H NMR (400MHz, MeOD): δ 6.87-6.95 (4H, m, ArH), 4.01 (2H, m,), 3.47 (3H, s), 2.60 (3H, s), 2.30 (3H, s), 1.37 (3H, t) LCMS Rt 3.84 min, m/z (ES+) 291 (M+H, C15H18N2O2S + H requires 291 ).
Example 40: 1-(2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-propyl-2,3-dihydro-1,3- thiazol-5-yl)ethanone
1-(ethyloxy)-4-isothiocyanatobenzene (0.25mmol, 44.8 mg) was combined with propylamine (0.25mmol, 14.8 mg) in ethyl acetate (2ml_). This reaction was stirred for 20 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (2ml_). A 31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 15 minutes by microwaves. The solvent was then removed in vacuo and the residues from this reaction purified by mass directed autoprep to yield 1.9mg of the title compound.
1H NMR (400MHz, MeOD): δ 6.87-6.94 (4H, m, ArH), 3.92-4.04 (4H, m), 2.61 (3H, s), 2.29
(3H, s), 1.78 (2H, m), 1.37 (3H, t), 1.01 (3H, t)
LCMS Rt 3.35 min, m/z (ES+) 319 (M+H, C17H22N2O2S + H requires 319).
Example 41 : 1 -(3,4-dimethyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone
1-isothiocyanato-4-(trifluoromethyl)benzene (0.25mmol, 50.75 mg) 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 31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 20 minutes by microwaves. The solvent was then removed in vacuo and the residue from this reaction purified by mass directed autoprep to yield 14.8mg of the title compound.
1H NMR (400MHz, DMSO D6 ): δ 7.72-7.67 (2H, m, ArH), 7.17-7.21 (2H, m, ArH), 3.48 (3H, s), 2.58 (3H, s), 2.34 (3H, s) LCMS Rt 3.37 min, m/z (ES+) 315 (M+H, C14H13F3N2OS + H requires 315).
Example 42: 1-{2-[(4-ethylphenyl)imino]-3,4-dimethyl-2,3-dihydro-1,3-thiazol-5- yljethanone
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 31.3μl_ (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 20 minutes by microwaves. The solvent was then removed in vacuo and the residue from this reaction purified by mass directed autoprep to yield 3.3mg of the title compound. 1H NMR (400MHz, MeOD): δ 7.15-7.20 (2H, m, ArH), 6.89-6.94 (2H, m, ArH), 3.48 (3H, s), 2.59 (5H, s), 2.29 (3H, s), 1.22 (3H, t)
LCMS Rt 3.42 min, m/z (ES+) 275 (M+H, C15H18N2OS + H requires 275).
Example 43: 1-(2-{[4-(dimethylamino)phenyl]imino}-3,4-dimethyl-2,3-dihydro-1,3- thiazol-5-yl)ethanone
4-(isothiocyanatophenyl)dimethylamine (0.25mmol, 44.5mg) 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 31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione was added to this and the mixture heated at 1000C for 20 minutes by microwaves. The solvent was then removed in vacuo and the residue from this reaction purified by mass directed autoprep to yield 21.2mg of the title compound.
1H NMR (400MHz, MeOD): δ 6.98-7.06 (4H, m, ArH), 3.48 (3H, s), 2.98 (6H, t) 2.57 (3H, s), 2.34 (3H, s) LCMS Rt 2.15 min, m/z (ES+) 290 (M+H, C15H19N3OS + H requires 290).
Example 44: 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1,3- thiazol-5-yl)ethanone
1-(ethyloxy)-4-isothiocyanatobenzene (1.5 mmol, 304.8mg) was dissolved in 5 ml of ethyl acetate. 2M ethylamine in tetrahydrofuran (1.5mmol, 0.75ml) was added to this solution. This reaction was stirred for 20 minutes before the solvent was removed in vacuo. The residue was then dissolved in 5ml of ethanol. A 268μl_ (2.25 mmol) portion of 3-chloro- 2,4-pentanedione was added to this and the mixture heated at 1000C for 20 minutes by microwaves. The solvent was then removed in vacuo and -20% of the residues from this reaction purified by mass directed autoprep to yield 10.2mg of the title compound. 1H NMR (400MHz, MeOD): δ 6.90 (4H, s, ArH), 4.00 (4H, m), 2.58 (3H, s), 2.30 (3H, s), 1.31 (3H, t) 1.24 (3H, t) LCMS Rt 3.10 min, m/z (ES+) 305 (M+H, C16H20N2O2S + H requires 305).
Example 45: 1 -[2-{[4-(diethylamino)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone
/V-[4-(diethylamino)phenyl]-/V-(2-hydroxyethyl)thiourea (0.37mmol, 99mg) and 3-chloro- 2,4-pentanedione (0.56mmol, 67μL) were combined in ethanol (2.5mL) and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.079g of the title compound was isolated.
1H NMR (400MHz, CDCI3): δ 6.97-7.01 (2H, m, ArH), 6.68-6.74 (2H, m, ArH), 4.18 (2H, m), 3.98 (2H, m), 3.35 (2x2H, q), 2.61 (3H, s), 2.29 (3H, s), 1 .16 (2x3H, t) LCMS Rt 1.96 min, m/z (ES+) 348 (M+H, C18H25N3O2S + H requires 348). Example 46: 1-(2-{[4-(diethylamino)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1,3- thiazol-5-yl)ethanone
/V-[4-(diethylamino)phenyl]-Λ/'-ethylthiourea (0.37mmol, 93mg) and 3-chloro-2,4- pentanedione (0.56mmol, 67μL) were combined in ethanol (2.5ml_) and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.005g of the title compound was isolated.
1H NMR (400MHz, CDCI3): δ 6.95-7.00 (2H, m, ArH), 6.70-6.73 (2H, m, ArH), 4.04 (2H, q), 3.35 (2x2H, q), 2.61 (3H, s), 2.26 (3H, s), 1.35 (3H, t), 1.17 (2x3H, t) LCMS Rt 2.19 min, m/z (ES+) 332 (M+H, C18H25N3OS + H requires 332).
Example 47: 1-[2-({4-[(difluoromethyl)oxy]phenyl}imino)-3-ethyl-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone
Λ/-{4-[(difluoromethyl)oxy]phenyl}-Λ/'-ethylthiourea (0.37mmol, 91 mg) and 3-chloro-2,4- pentanedione (0.56mmol, 67μl_) were combined in ethanol (2.5ml_) and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.0605g of the title compound was isolated. 1H NMR (400MHz, CDCI3): δ 7.10-7.15 (2H, m, ArH), 7.01-7.07 (2H, m, ArH), 6.50 (1 H, t, CHF2), 4.05 (2H, q), 2.63 (3H, s), 2.27 (3H, s), 1.36 (3H, t)
LCMS Rt 3.22 min, m/z (ES+) 327 (M+H, C15H16F2N2O2S + H requires 327).
Example 48: 1-(3-ethyl-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1,3- thiazol-5-yl)ethanone
A/-ethyl-/V-[4-(4-morpholinyl)phenyl]thiourea (0.23mmol, 61 mg) and 3-chloro-2,4- pentanedione (0.35mmol, 35μl_) were combined in ethanol (2.5ml_) and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.016g of the title compound was isolated.
1H NMR (400MHz, DMSO D6): δ 6.87-6.97 (4H, m, ArH), 4.01 (2H, q), 3.73 (2x2H, m),
3.06 (2x2H, m), 2.58 (3H, s), 2.30 (3H, s), 1.24 (3H, t)
LCMS Rt 2.64 min, m/z (ES+) 346 (M+H, C18H23N3O2S + H requires 346).
Example 49: 1-(3,4-dimethyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone
A/-methyl-/V-[4-(4-morpholinyl)phenyl]thiourea (0.23mmol, 58mg) and 3-chloro-2,4- pentanedione (0.35mmol, 35μl_) were combined in ethanol (2.5ml_) and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.0067g of the title compound was isolated. 1H NMR (400MHz, DMSO D6): δ 6.87-6.97 (4H, m, ArH), 3.73 (2x2H, m), 3.43 (3H, s), 3.06 (2x2H, m), 2.56 (3H, s), 2.30 (3H, s)
LCMS Rt 2.42 min, m/z (ES+) 332 (M+H, C17H21N3O2S + H requires 332).
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.
1H NMR (400MHz, CDCI3): δ 6.85-6.90 (2H, m, ArH), 6.67-6.72 (2H, m, ArH), 3.46 (3H, s), 2.59 (3H, s), 2.25 (3H, s) LCMS Rt 1.95 min, m/z (ES+) 262 (M+H, C13H15N3OS + H requires 262). Example 51 : 1-{2-[(4-aminophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yljethanone
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.
1H NMR (400MHz, CDCI3): δ 6.85-6.90 (2H, m, ArH), 6.67-6.72 (2H, m, ArH), 4.00 (2H, q),
2.59 (3H, s), 2.23 (3H, s), 1.32 (3H, s)
LCMS Rt 2.13 min, m/z (ES+) 276 (M+H, Ci4H17N3OS + H requires 276).
Example 52: 1-[2-[(4-aminophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro- 1,3-thiazol-5-yl]ethanone
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. 1H NMR (400MHz, CDCI3): δ 6.86-6.91 (2H, m, ArH), 6.67-6.72 (2H, m, ArH), 4.14 (2H, m), 3.96 (2H, m), 2.60 (3H, s), 2.27 (3H, s)
LCMS Rt 1.90 min, m/z (ES+) 292 (M+H, C14H17N3O2S + H requires 292).
Example 53: 1-[2-{[4-(dimethylamino)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone
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 μl_) added. The vial was heated at 1000C for 10 minutes by microwaves. Purified by MDAP, 0.0066g of the title compound was isolated.
1H NMR (400MHz, DMSO D6): δ 6.84-6.89 (2H, m, ArH), 6.71-6.76 (2H, m, ArH), 5.01 (1 H, t, OH), 4.00 (2H, t), 3.70 (2H, q), 2.86 (2x3H, s), 2.60 (3H,s), 2.29 (3H, s) LCMS Rt 2.03 min, m/z (ES+) 320 (M+H, C16H2IN3O2S + H requires 320).
Example 54: Ethyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazole-5-carboxylate
/V-[4-(ethyloxy)phenyl]-/V-(2-hydroxyethyl)thiourea (0.45mmol, 107mg) was dissolved in ethanol (2ml_). Ethyl 2-chloro-3-oxobutanoate (0.45mmol, 74mg) was added, and the reaction heated at 1000C for 10 minutes by microwaves. A further 0.5 equivalents of ethyl 2-chloro-3-oxobutanoate was added and the mixture heated for 5 minutes. Purified by MDAP, 0.0373g of the title compound was isolated.
1H NMR (400MHz, DMSO D6): δ 6.86-6.92 (4H, m, ArH), 5.01 (1 H, m, OH), 4.13 (2H, q), 3.94-4-02 (2x2H, m), 3.70 (2H, m), 2.60 (3H, s), 1 .31 (3H, t), 1.19 (3H, t) LCMS Rt 3.11 min, m/z (ES+) 351 (M+H, C17H22N2O4S + H requires 351 ).
Example 55: 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2,3- dihydro-1,3-thiazole-5-carboxamide
N-[4-(ethyloxy)phenyl]-/V-(2-hydroxyethyl)thiourea (0.45mmol, 107mg) was dissolved in ethanol (2ml_). 2-Chloro-Λ/,Λ/-dimethyl-3-oxobutanamide (0.45mmol, 73mg) was added, and the reaction heated at 1000C for 10 minutes by microwaves. A further 0.5 equivalents of 2-chloro-Λ/,Λ/-dimethyl-3-oxobutanamide was added and the mixture heated for 5 minutes. Purified by MDAP, 0.0072g of the title compound was isolated. 1H NMR (400MHz, DMSO D6): δ 6.85-6.90 (4H, m, ArH), 4.99 (1 H, m, OH), 3.97 (2H, q), 3.89 (2H, m), 3.69 (2H, m), 2.92 (2x3H, s), 2.21 (3H, s), 1.30 (3H, t) LCMS Rt 2.16 min, m/z (ES+) 350 (M+H, C17H23N3O3S + H requires 350).
Example 56: Methyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazole-5-carboxylate
/V-[4-(ethyloxy)phenyl]-/V-(2-hydroxyethyl)thiourea (0.45mmol, 107mg) was dissolved in ethanol (2ml_). Methyl 2-chloro-3-oxobutanoate (0.45mmol, 68mg) was added, and the reaction heated at 1000C for 10 minutes by microwaves. Purified by MDAP, 0.0266g of the title compound was isolated.
1H NMR (400MHz, DMSO D6): δ 6.89-6.91 (4H, m, ArH), 5.02 (1 H, t, OH), 3.95-4.02
(2x2H, m), 3.70 (2H, m), 3.67 (3H, s), 2.62 (3H, s), 1.31 (3H, t)
LCMS Rt 2.96 min, m/z (ES+) 337 (M+H, C16H20N2O4S + H requires 337).
Example 57: 3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2-{[4-(trifluoromethyl)phenyl]imino}- 2,3-dihydro-1,3-thiazole-5-carboxamide
A/-(2-hydroxyethyl)-/V-[4-(trifluoromethyl)phenyl]thiourea (0.39mmol, 104mg) was dissolved in ethanol (2ml_). 2-Chloro-Λ/,Λ/-dimethyl-3-oxobutanamide (0.59mmol, 98mg) was added, and the reaction heated at 1000C for 20 minutes by microwaves. Purified by
MDAP, 0.0296g of the title compound was isolated.
1H NMR (400MHz, DMSO D6): δ 7.63-7.68 (2H, m, ArH), 7.14-7.19 (2H, m, ArH), 5.02
(1 H, t, OH), 3.95 (2H, t), 3.72 (2H, m), 2.93 (2x3H, s), 2.24 (3H, s)
LCMS Rt 2.90 min, m/z (ES+) 374 (M+H, C16H18F3N3O2S + H requires 374).
Example 58: Methyl 3-(2-hydroxyethyl)-4-methyl-2-{[4-
(trifluoromethyl)phenyl]imino}-2,3-dihydro-1,3-thiazole-5-carboxylate
Λ/-(2-hydroxyethyl)-Λ/'-[4-(trifluoromethyl)phenyl]thiourea (0.39mmol, 104mg) was dissolved in ethanol (2ml_). Methyl 2-chloro-3-oxobutanoate (0.59mmol, 90mg) was added, and the reaction heated at 1000C for 20 minutes by microwaves. Purified by
MDAP, 0.0261g of the title compound was isolated.
1H NMR (400MHz, DMSO D6): δ 7.67-7.72 (2H, m, ArH), 7.17-7.21 (2H, m, ArH), 5.05
(1 H, t, OH), 4.02 (2H, t), 3.73 (2H, m), 3.69 (3H, s), 2.64 (3H, s)
LCMS Rt 3.38 min, m/z (ES+) 361 (M+H, C15H15F3N2O3S + H requires 361 ).
Example 59: 1-{3-(2-hydroxyethyl)-4-methyl-2-[(4-methylphenyl)imino]-2,3-dihydro- 1 ,3-thiazol-5-yl}ethanone
Λ/-(2-hydroxyethyl)-Λ/'-(4-methylphenyl)thiourea (0.37mmol, 78mg), 3-chloro-2,4- pentanedione (0.41 mmol, 49μL) and ethanol (2ml_) were combined and heated at 1000C for 10 minutes by microwaves. A further 0.5 equivalents of 3-chloro-2,4-pentanedione was added and the reaction heated for a further 10 minutes at 1000C by microwaves. Purified by MDAP, 0.0184g of the title compound was isolated.
1H NMR (400MHz, CDCI3): δ 7.18-7.25 (2H, m, ArH), 7.00-7.05 (2H, m, ArH), 4.25 (2H, m), 4.02 (2H, m), 2.67 (3H, s), 2.36 (3H, s), 2.29 (3H, s)
LCMS Rt 2.82 min, m/z (ES+) 291 (M+H, C15H18N2O2S + H requires 291 ).
Example 60: 1-{3-ethyl-2-[(4-ethylphenyl)imino]-4-methyl-2,3-dihydro-1,3-thiazol-5- yljethanone
A/-ethyl-/V-(4-ethylphenyl)thiourea (0.37mmol, 77mg), 3-chloro-2,4-pentanedione (0.56mmol, 67μl_) and ethanol (2.5ml_), were combined and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.006g of the title compound was isolated. 1H NMR (400MHz, CDCI3): δ 7.17-7.21 (2H, m, ArH), 6.96-7.00 (2H, m, ArH), 4.05 (2H, q), 2.65 (2H, q), 2.63 (3H, s), 2.25 (3H, s), 1.36 (3H, t), 1.25 (3H, t) LCMS Rt 3.36 min, m/z (ES+) 289 (M+H, C16H20N2OS + H requires 289).
Example 61 : 1-[3-ethyl-4-methyl-2-(phenylimino)-2,3-dihydro-1,3-thiazol-5- yl]ethanone
/V-ethyl-/V-phenylthiourea (0.37mmol, 67mg), 3-chloro-2,4-pentanedione (0.56mmol, 67μL) and ethanol (2.5mL), were combined and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.0071 g of the title compound was isolated. 1H NMR (400MHz, CDCI3): δ 7.34-7.40 (2H, m, ArH), 7.05-7.13 (3H, m, ArH), 4.08 (2H, q), 2.63 (3H, s), 2.26 (3H, s), 1.37 (3H, t) LCMS Rt 3.05 min, m/z (ES+) 261 (M+H, C14H16N2OS + H requires 261 ). Example 62: 1-{3-ethyl-4-methyl-2-[(4-methylphenyl)imino]-2,3-dihydro-1,3-thiazol-5- yljethanone
Λ/-ethyl-/V-(4-methylphenyl)thiourea (0.37mmol, 72mg), 3-chloro-2,4-pentanedione (0.56mmol, 67μL) and ethanol (2.5ml_), were combined and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.0133g of the title compound was isolated. 1H NMR (400MHz, CDCI3): δ 7.16-7.20 (2H, m, ArH), 6.96-7.01 (2H, m, ArH), 4.08 (2H, q), 2.63 (3H, s), 2.35 (3H, s), 2.26 (3H, s), 1.37 (3H, t)
LCMS Rt 3.16 min, m/z (ES+) 275 (M+H, Ci5H18N2OS + H requires 275).
Exmaple 63: 1-(2-{[4-(dimethylamino)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro- 1,3-thiazol-5-yl)ethanone
/V-[4-(dimethylamino)phenyl]-/V-ethylthiourea (0.37mmol, 83mg), 3-chloro-2,4- pentanedione (0.56mmol, 67μL) and ethanol (2.5mL), were combined and heated at 1000C for 20 minutes by microwaves. Purified by MDAP, 0.0057g of the title compound was isolated.
1H NMR (400MHz, CDCI3): δ 6.96-7.01 (2H, m, ArH), 6.75-6.80 (2H, m, ArH),
4.05 (2H, q), 2.94 (2x3H, s), 2.63 (3H, s), 2.26 (3H, s), 1.35 (3H, t)
LCMS Rt 2.31 min, m/z (ES+) 304 (M+H, Ci6H2iN3OS + H requires 304).
Example 64: 1-(3-(2-aminoethyl)-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-
1,3-thiazol-5-yl)ethanone
To a suspension of N-(2-aminoethyl)-W-[4-(ethyloxy)phenyl]thiourea (0.079g, 0.33mmol) in ethanol (2.5ml_) was added a solution of 3-chloro-2,4-pentanedione (39.3μL, 0.33mmol) in ethanol (2.5mL). The mixture was then heated at 1000C, by microwaves, for 10 minutes. The resulting solution was concentrated in vacuo and purified by MDAP, to provide the title compound (0.022g).
1H NMR (400MHz, DMSO D6): δ 6.89-6.96 (4H, m, ArH), 4.15 (2H, t), 3.99 (2H, q), 3.12 (2H, t), 2.59 (3H, s), 2.32 (3H, s), 1.32 (3H, t)
LCMS Rt 2.27 min, m/z (ES+) 320 (M+H, C16H2IN3O2S + H requires 320)
Example 65: i-β-cyclopropyl-Σ-ft^ethyloxyJphenylliminoM-methyl-ΣjS-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 (39.3μL, 0.33mmol) in ethanol (5.OmL), following the procedure described in Example 64. 1H NMR (400MHz, DMSO D6): δ 7.19 (2H, d, ArH), 7.01 (2H, d, ArH), 4.06 (2H, q), 2.38 (3H, s), 2.32 (1 H, quintet), 2.15 (3H, s), 1.34 (3H, t), 0.67 (2H, dt), 0.30 (2H, dt) LCMS Rt 2.09 min, m/z (ES+) 317 (M+H, C17H20N2O2S + H requires 317)
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 (39.3μL, 0.33mmol) in ethanol (5.OmL), following the procedure described in Example 64, with heating increased to 20 minutes.
1H NMR (400MHz, DMSO D6): δ 7.18 (2H, d, ArH), 6.90 (2H, d, ArH), 4.87 (2H, q), 2.62 (2H, q), 2.61 (3H, s), 2.33 (3H, s), 1.22 (3H, t) LCMS Rt 3.54 min, m/z (ES+) 343 (M+H, Ci6H17F3N2OS + H requires 343)
Example 67: 1-[2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-(2,2,2-trifluoroethyl)-2,3- dihydro-1,3-thiazol-5-yl]ethanone
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 (39.3μL, 0.33mmol) in ethanol (5.OmL), following the procedure described in Example 64, with heating increased to 20 minutes.
1H NMR (400MHz, DMSO D6): δ 6.88-6.97 (4H, m, ArH), 4.89 (2H, q), 4.02 (2H, q), 2.62
(3H, s), 2.34 (3H, s), 1.38 (3H, t)
LCMS Rt 3.38 min, m/z (ES+) 359 (M+H, C16H17F3N2O2S + H requires 359)
Biological Assays
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.
a) Calcium Influx Fluorescence Assay
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. The tissue culture medium in the wells are discarded and the wells are each washed three times with standard buffer (80 μL) for the stable cell line (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 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). The plates are then incubated for 60 minutes in the dark with 2 μM FLUO4-AM dye (20 μL) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well is washed three times with buffer (80 μL) (30 μL of buffer remained in each well after washing). Compounds of the invention (or reference compounds such as cyclothiazide) are dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 μl_) is transferred to another compound plate and buffer (50 μl_) 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 μM and dispensed into another 384-well plate (50μl_/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 μl_ from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 μM to 10 pM) is added (to give a final concentration in the range 30 μM to 3 pM). The fluorescence is read over 5 minute period. 500 μM glutamate solution (10μl_) is added (to give a final concentration of 100 μM). 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 μM).
The assay described above is believed to have an effective limit of detection of a pEC5Q in the region of 3.5-4.0 due to the limitations of compound solubility. The pEC50 result is generally considered to be accurate +/- 0.3. Accordingly, a compound exhibiting a pEC50 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.
The Example compounds were screened using the assay as described above. All the Examples gave an average pEC50 equal to or greater than 3.7 and demonstrated an activity at least 20% that of cyclothiazide (at its maximal response).
b) Whole cell voltage-clamp electrophvsioloqy Assay
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 MgCI2, 1.5 mM CaCI2, 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. Recording electrodes are prepared from glass capillary tubes (Clark Electromedical GC120-F10) pulled into two equal lengths using a Zeitz Instruments DMZ Universal Puller, program 09, resulting in electrodes with a resistance of approximately 3-6 MOhms when measured in extracellular solution. 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. Using fine manipulator control (Luigs 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 μM AMPA (2 s application time, 30 s interval between applications) repeated until measurements are stable.
2) Test current - exchange from extracellular solution + 10 nM of compound of invention to extracellular solution + 10 nM of compound of invention + 30 μM 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.
All experiments are performed at ambient temperature (20 to 22 0C). The activity of a compound of the invention is determined by measuring the area under the curve (during 2 s period of application) for the 30 μM AMPA response in the presence of the compound of the invention and expressing it as % of potentiation of the 30 μM AMPA alone response (30 μM AMPA in the absence of the compound of the invention).
Examples 4, 5 and 24 above were investigated using this assay. When applied at 10 nM, they increased 30 μM AMPA-mediated currents by between 15 and 42%.

Claims

Claims
1. A compound of formula (I), or a salt, or solvate thereof for use as a medicament:
(I) wherein:
• R10 is selected from methyl and hydrogen;
• X is selected from:
• Z is selected from S and O;
• R1 is selected from H, Ci_4alkyl, C(O)OCi_4alkyl, C(O)Ci_4alkyl, C(O)haloCi_4alkyl, C(O)NR6R7, cyano, and R6 and R7 are each independently selected from H and Ci_ 4alkyl;
• R2 is selected from Ci_4alkyl, C(O)CH3, and CN; • R3 is selected from the group consisting of H, NH2, CH3, (CH2)nOH and (CH2)nCi. 4alkoxy, wherein n is 0 or 1 ; and
• when R3 is CH3, (CH2)nOH or (CH^nC^alkoxy, then R4 is selected from the group consisting of H, halo, d.4alkoxy, haloC^alkoxy, Ci_4alkyl, Ci_4alkylthio, 1IaIoC1. 4alkylthio, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4alkyl or R8 and R9 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 R3 is NH2, then R4 is selected from H, halo, d.4alkoxy, haloC^alkoxy, C1. 4alkyl, C^alkylthio, haloC1.4alkylthio, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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 R3 is H, then R4 is selected from the group consisting of H, C1^aIkOXy, chloro, bromo, haloC1.4alkoxy, Ci_4alkyl, haloC1.4alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4 alkyl or R8 and R9 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 X is -CH2CF3, then R4 is selected from C1^aIkOXy and C1.4alkyl; when X is methyl, then R4 is selected from Ci-4alkoxy, haloCi-4alkoxy, Ci-4alkyl, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C1.4alkyl or R8 and R9 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;
• when X is , then R4 is selected from the group consisting of H, halo, C1.
4alkoxy, haloC^alkoxy, Ci_4alkyl, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4alkyl or R8 and R9 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.
2. A compound as claimed in claim 1 , wherein R1 is selected from C1.4alkyl, C(O)OC1. 4alkyl, C(O)C1.4alkyl, C(O)haloC1.4alkyl, C(O)NR6R7 and cyano, wherein R6 and R7 are each independently selected from H and Ci.4alkyl.
3. A compound as claimed in claim 1 or claim 2, wherein R2 is selected from C1.4alkyl and C(O)CH3.
4. A compound as claimed in claim 1 , 2 or 3, wherein X is
wherein R3 is H and R4 is selected from the group consisting of H, C1^aIkOXy, chloro, bromo, haloC1.4alkoxy, C1.4alkyl, haloC^alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4 alkyl or R8 and R9 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.
5. A compound as claimed in claim 1 , 2 or 3, wherein X is
wherein R3 is NH2 and R4 is selected from H, halo, C1^aIkOXy, haloC1.4alkoxy, C1.4alkyl, C1.4alkylthio, haloC1.4alkylthio, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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.
5. A compound as claimed in claim 1 , 2 or 3, wherein X is
wherein R3 is CH3, (CH2)nOH or (CH2)nCi-4alkoxy, and R4 is selected from the group consisting of H, halo, C1^aIkOXy, haloC^alkoxy, Ci_4alkyl, Ci_4alkylthio, haloC^alkylthio, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4alkyl or R8 and R9 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.
6. A compound as claimed in claim 1 , 2 or 3, wherein X is -CH2CF3 and R4 is selected from C^alkoxy and Ci_4alkyl.
7. A compound as claimed in claim 1 , 2 or 3, wherein X is methyl, and R4 is selected from Ci.4alkoxy, haloCi_4alkoxy, Ci_4alkyl, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4alkyl or R8 and R9 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.
8. A compound as claimed in claim 1 , 2 or 3, wherein X is
and R4 is selected from the group consisting of H, halo, d.4alkoxy, haloC^alkoxy, C1. 4alkyl, haloCi_4alkyl and NR8R9 wherein R8 and R9 are independently selected from C1. 4alkyl or R8 and R9 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.
9. A compound as claimed in claim 1 , which is:
1. 1 -[2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
2. 1 -[2-[(4-ethylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone
3. 1-{2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-[2-(methyloxy)ethyl]-2,3-dihydro-1 ,3- thiazol-5-yl}ethanone
4. 1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone 5. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone
6. 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
7. 2-[2-{[4-(ethyloxy)phenyl]imino}-4,5-dimethyl-1 ,3-thiazol-3(2/-/)-yl]ethanol 8. 1-[2-[(4-butylphenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone 9. 1-[2-{[4-(ethyloxy)phenyl]imino}-3-(3-hydroxypropyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
10. 1 -(3-(2-hydroxyethyl)-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone
1 1. 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazole- 5-carbonitrile
12. 3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazole-5- carbonitrile
13. 1 -{2-[(4-chlorophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
14. ^(S-cyclopropyl^-methyl^-l^-^rifluoromethyOphenyφmino^.S-dihydro-I .S- thiazol-5-yl)ethanone
15. 1 -(3-ethyl-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
16. 1 -[3-ethyl-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
17. 1 -[2-({4-[(dif luoromethyl)oxy]phenyl}imino)-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone
18. 1 -[3-(2-hydroxyethyl)-4-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone
19. [(3-ethyl-4,5-dimethyl-1 ,3-thiazol-2(3/-/)-ylidene][4-(trifluoromethyl)phenyl]amine
20. 1 -(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-oxazol-5- yl)ethanone
21. 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
22. 1-(3-ethyl-4-methyl-2-{[4-(1-pyrrolidinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
23. 1-(3-ethyl-4-methyl-2-{[4-(1-piperidinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
24. 3-(2-hydroxyethyl)-N,N,4-trimethyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro- 1 ,3-thiazole-5-carboxamide
25. 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone
26. 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazole- 5-carboxamide
27. 3-(2-hydroxyethyl)-N,N,4-trimethyl-2-({4-[(trifluoromethyl)oxy]phenyl}imino)-2,3- dihydro-1 ,3-thiazole-5-carboxamide
28. 1-(3-cyclopropyl-4-methyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone
29. 3-ethyl-N,N,4-trimethyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazole- 5-carboxamide
30. 2,2,2-trifluoro-1 -[3-(2-hydroxyethyl)-4-metriyl-2-({4- [(trifluoromethyl)oxy]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone
31. 3-cyclopropyl-N,N,4-trimetriyl-2-{[4-(4-morpriolinyl)prienyl]imino}-2,3-dihydro-1 ,3- thiazole-5-carboxamide
32. 1-(3-(2-hydroxyethyl)-4-metriyl-2-{[4-(1-pyrrolidinyl)prienyl]imino}-2,3-diriydro-1 ,3- thiazol-5-yl)ethanone
33. 1 -(3-(2-hydroxyethyl)-4-metriyl-2-{[4-(metriyloxy)prienyl]irnino}-2,3-diriydro-1 ,3- thiazol-5-yl)ethanone
34. 1-(3-(2-hydroxyethyl)-4-metriyl-2-{[4-(metriyltriio)prienyl]imino}-2,3-diriydro-1 ,3- thiazol-5-yl)ethanone
35. 1 -[2-[(3,4-dimethylphenyl)irnino]-3-(2-riydroxyetriyl)-4-metriyl-2,3-diriydro-1 ,3- thiazol-5-yl]ethanone
36. 1 -[3,4-dimethyl-2-({4-[(trifluorometriyl)oxy]prienyl}irnino)-2,3-diriydro-1 ,3-thiazol-5- yl]ethanone
37. 1 -[4-methyl-3-propyl-2-({4-[(trifluorometriyl)oxy]prienyl}irnino)-2,3-diriydro-1 ,3- thiazol-5-yl]ethanone
38. 1-[4-methyl-3-[2-(methyloxy)etriyl]-2-({4-[(trifluorometriyl)oxy]prienyl}irriino)-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone
39. 1 -(2-{[4-(ethyloxy)phenyl]imino}-3,4-dimetriyl-2,3-diriydro-1 ,3-thiazol-5-yl)ethanone
40. 1 -(2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-propyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
41. 1-(3,4-dimethyl-2-{[4-(trifluorometriyl)prienyl]irnino}-2,3-diriydro-1 ,3-thiazol-5- yl)ethanone
42. 1-{2-[(4-ethylphenyl)imino]-3,4-dimetriyl-2,3-diriydro-1 ,3-triiazol-5-yl}etrianone
43. 1-(2-{[4-(dimethylamino)prienyl]irriino}-3,4-dimetriyl-2,3-diriydro-1 ,3-triiazol-5- yl)ethanone
44. 1-(3-ethyl-2-{[4-(ethyloxy)phenyl]imino}-4-metriyl-2,3-diriydro-1 ,3-thiazol-5- yl)ethanone
45. 1-[2-{[4-(diethylamino)phenyl]imino}-3-(2-riydroxyetriyl)-4-ιτietriyl-2,3-diriydro-1 ,3- thiazol-5-yl]ethanone
46. 1-(24[4-(diethylamino)prienyl]imino}-3-etriyl-4-metriyl-2,3-diriydro-1 ,3-triiazol-5- yl)ethanone
47. 1 -[2-({4-[(difluoromethyl)oxy]prienyl}imino)-3-etriyl-4-metriyl-2,3-diriydro-1 ,3- thiazol-5-yl]ethanone
48. I^S-ethyW-methyl^-l^^^morpholinyOphenyllimino^.S-dihydro-I .S-thiazol-S- yl)ethanone
49. 1-(3,4-dimethyl-2-{[4-(4-morpholinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
50. 1-{2-[(4-aminophenyl)imino]-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
51. 1-{2-[(4-aminophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
52. 1 -[2-[(4-aminophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl]ethanone
53. 1-[2-{[4-(dimethylamino)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone
54. Ethyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazole-5-carboxylate
55. 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-N,N,4-trimethyl-2,3-dihydro-1 ,3- thiazole-5-carboxamide
56. Methyl 2-{[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazole-5-carboxylate
57. 3-(2-hydroxyethyl)-N,N,4-trimethyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3-dihydro- 1 ,3-thiazole-5-carboxamide
58. Methyl 3-(2-hydroxyethyl)-4-methyl-2-{[4-(trifluoromethyl)phenyl]imino}-2,3- dihydro-1 ,3-thiazole-5-carboxylate
59. 1 -{3-(2-hydroxyethyl)-4-methyl-2-[(4-methylphenyl)imino]-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone
60. 1-{3-ethyl-2-[(4-ethylphenyl)imino]-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone
61. 1-[3-ethyl-4-methyl-2-(phenylimino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone
62. 1-{3-ethyl-4-methyl-2-[(4-methylphenyl)imino]-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone
63. 1-(2-{[4-(dimethylamino)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone
64. 1-(3-(2-aminoethyl)-2-{[4-(ethyloxy)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol- 5-yl)ethanone
65. I^S-cyclopropyl^-l^^ethyloxyJphenyφminoH-methyl^.S-dihydro-I .S-thiazol-S- yl)ethanone
66. 1-[2-[(4-ethylphenyl)imino]-4-methyl-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1 ,3-thiazol- 5-yl]ethanone 67. 1-[2-{[4-(ethyloxy)phenyl]imino}-4-methyl-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone or a salt or solvate thereof.
10. A pharmaceutical composition comprising a compound as claimed in any of claims 1-9 and at least one pharmaceutically acceptable carrier or diluent.
1 1. A compound as claimed in any of claims 1-9 for use in treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal.
12. A compound as claimed in claim 1 1 wherein the disease is schizophrenia.
13. A compound as claimed in claim 11 wherein the disease is impairment of cognition.
14. A use of a compound of as claimed in any of claims 1-9 in the manufacture of a medicament for treating or preventing a disease or a condition caused by a reduction or imbalance in glutamate receptor function.
15. The use as claimed in claim 14 wherein the disease is schizophrenia.
16. The use as claimed in claim 14 wherein the disease is impairment of cognition.
17. 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 the compound as claimed in any of claims 1-9.
18. A method as claimed in claim 17 wherein the disease is schizophrenia.
19. A method as claimed in claim 18 wherein the disease is impairment of cognition.
20. A combination product comprising a compound as claimed in any of claims 1-9 with an antipsychotic.
21. A compound of formula (A) or a salt or solvate thereof:
(A) wherein:
• R10 is selected from methyl and hydrogen;
• X is selected from:
• Z is selected from S and O; • R1 is selected from H, Ci_4alkyl, C(O)OCi-4alkyl, C(O)Ci-4alkyl, C(O)haloCi-4alkyl, C(O)NR6R7, cyano, and R6 and R7 are each independently selected from H and C1. 4alkyl;
• R2 is selected from C1-4alkyl, C(O)CH3, and CN; • R3 is selected from the group consisting of H, NH2, CH3, (CH2)nOH and (CH2)nCi. 4alkoxy, wherein n is 0 or 1 ; and
• when R3 is CH3, (CH2)nOH or (CH2)nC1.4alkoxy, then R4 is selected from the group consisting of H, halo, d.4alkoxy, haloC^alkoxy, Ci_4alkyl, Ci.4alkylthio, 1IaIoC1. 4alkylthio, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C1.4alkyl or R8 and R9 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 R3 is NH2, then R4 is selected from H, halo, C1^aIkOXy, haloC1.4alkoxy, C1. 4alkyl, C^alkylthio, haloC1.4alkylthio, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from Ci_4 alkyl or R8 and R9 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 R3 is H, then R4 is selected from the group consisting of H, C1^aIkOXy, chloro, bromo, haloC1.4alkoxy, Ci_4alkyl, haloC1.4alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Ci_4 alkyl or R8 and R9 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 X is -CH2CF3, then R4 is selected from C1^aIkOXy and C1.4alkyl;
• when X is methyl, then R4 is selected from C1^aIkOXy, haloC^alkoxy, C1.4alkyl, haloC1.4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and C1.4alkyl or R8 and R9 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;
when X is , then R4 is selected from the group consisting of H, halo, C1. 4alkoxy, haloC^alkoxy, Ci_4alkyl, haloC^alkyl and NR8R9 wherein R8 and R9 are independently selected from C1.4alkyl or R8 and R9 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:
1) a compound in which simultaneously R1=C0(CH3), R2=Me, X=CH2CH2R3, R3=OH and R4=ethyl, chloro, ethoxy, methyl or H;
2) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OMe and R4=methoxy, difluoromethylthio, chloro or H; 3) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OEt and R4=difluoromethylthio, ethoxy, fluoro, difluoromethoxy or isopropyl;
4) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=(CH2)OnBu and R4=fluoro, isopropyl, ethoxy, difluoromethoxy or difluoromethylthio;
5) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=OMe and R4= ethoxy, difluoromethoxy, difluoromethylthio or H;
6) a compound in which simultaneously R1=H, R2=Me, X=cyclopropyl and R4=methoxy, isopropyl, ethoxy, hydrogen, chloro, difluoromethoxy or fluoro;
7) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=H and R4=H or chloro;
8) a compound in which simultaneously R1=C(O)CH3, R2=Me, X=CH2CH2R3, R3=CH2OH and R4=H or methyl; 9) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3,
R3=CH2OH, and R4=methyl, chloro, methoxy or H;
10) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=OH and R4=ethoxy, methyl or H;
11 ) a compound in which simultaneously R1=C(O)CH3, R2=Me, X=CH2CH2R3, R3=H and R4=chloro;
12) a compound in which simultaneously R1=H, R2=Me, X=Me and R4=methyl or ethoxy;
13) a compound in which simultaneously R1=H, R2=Et, X=CH2CH2R3, R3=H and R4=chloro or bromo; 14) a compound in which simultaneously R1=Me, R2=Me, X=Me and
R4=methyl; and
15) a compound in which simultaneously R1=H, R2=Me, X=CH2CH2R3, R3=Me and R4=isopropyl, fluoro, ethyl, difluoromethoxy or difluoromethylthio.
22. A process for the manufacture of a compound as defined in claim 1 , the process comprising:
(a) coupling a compound of formula (II):
wherein X, Z, R and R are as defined in claim 1 ; with a compound of formula (III)
wherein R1 and R2 are as defined in claim 1 ; or (b) reacting a compound of formula (V):
wherein Z, R4 and R10 are as defined in claim 1 ; with a primary amine X-NH2, wherein X is as defined in claim 1 , followed by coupling with a compound of formula (III) as defined in process (a); or
(c) for a compound of formula (I) in claim 1 wherein R1 is CONH2, reacting a compound of formula (IX):
(IX) wherein Z, X, R2, R4 and R10 are as defined in claim 1 , with ammonium chloride and
HATU; and thereafter optionally for process (a), (b) or (c):
- removing any protecting groups; and/or - forming a salt or solvate; and/or
- converting a compound of formula (I) as defined in claim 1 or a salt or solvate thereof to another compound of formula (I) as defined in claim 1 or a salt or solvate thereof.
EP07728463A 2006-04-26 2007-04-24 Compounds which potentiate ampa receptor and uses thereof in medicine Withdrawn EP2016061A1 (en)

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