WO2008110566A1 - Compounds which potentiate ampa receptor and uses thereof in medicine - Google Patents

Compounds which potentiate ampa receptor and uses thereof in medicine Download PDF

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Publication number
WO2008110566A1
WO2008110566A1 PCT/EP2008/052906 EP2008052906W WO2008110566A1 WO 2008110566 A1 WO2008110566 A1 WO 2008110566A1 EP 2008052906 W EP2008052906 W EP 2008052906W WO 2008110566 A1 WO2008110566 A1 WO 2008110566A1
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Prior art keywords
tetrahydro
trifluoromethyl
compound
methyl
indazol
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PCT/EP2008/052906
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French (fr)
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Daniel Marcus Bradley
Wai Ngor Chan
Stephen Anthony Harrison
Kevin Michael Thewlis
Simon Edward Ward
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Glaxo Group Limited
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Publication of WO2008110566A1 publication Critical patent/WO2008110566A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D417/10—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 carbon chain containing aromatic rings

Definitions

  • This invention relates to novel compounds which potentiate the AMPA receptor.
  • the invention also relates to the use of the compounds in treating diseases and conditions wherein the potentiation of the AMPA receptor would be beneficial, 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 11 : 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, mGlu ⁇ , 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 (GIuRI -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, Burnashev 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 present invention provides a compound of formula (I) or a salt thereof:
  • A is a group selected from:
  • R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen and Ci -6 alkyl, wherein R 1 , R 2 and R 3 are not all hydrogen;
  • X is selected from the group consisting of CH 2 OH, C(O)R 4 , CH 2 R 4 and CH 2 C(O)R 4 ;
  • R 4 is selected from the group consisting of OR 5 and NR 6 Rz, wherein R 5 is C 1-6 alkyl;
  • R 6 and R 7 are: (i) independently C 1-6 alkyl, wherein one of the alkyl is optionally substituted by hydroxy; or
  • R 6 is hydrogen and R 7 is C 1-6 alkylsulfonyl
  • R 6 and R 7 together with the nitrogen atom to which they are attached, form a 4, 5 or 6-membered heterocyclic ring, which ring is optionally substituted by one or two groups selected from oxo and hydroxy.
  • halo refers to fluoro, chloro, bromo or iodo.
  • C 1-6 alkyl refers to an alkyl group having from one to six carbon atoms; and the term “C 1-4 alkyl” refers to an alkyl group having from one to four carbon atoms. Unless otherwise indicated, C 1-4 alkyl or C 1-6 alkyl may be a straight chain or branched alkyl group. For example, a C 1-4 alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
  • a C 1-6 alkyl group may be selected from the group consisting of a C 1-4 alkyl group, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.
  • C 1-4 alkyl is methyl.
  • haloC 1-6 alkyl refers to a C 1-6 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 1-6 alkyl group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloC 1-6 alkyl group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloC 1-6 alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
  • 4, 5 or 6-membered heterocyclic ring refers to a 4-, 5- or 6-membered non- aromatic ring, which ring may contain one or two further heteroatoms selected from N, O and S. Examples include azetidinyl, pyrrolidinyl imidazolidinyl. pyrazolidinyl, isothiazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl and piperazinyl.
  • 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.
  • independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • A is a group (a) as defined above:
  • R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen and C 1-6 alkyl, wherein R 1 , R 2 and R 3 are not all hydrogen; and X is as defined for formula (I).
  • R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, fluoro and methyl, wherein R 1 , R 2 and R 3 are not all hydrogen.
  • R 1 and R 2 are both fluoro and R 3 is hydrogen.
  • R 1 and R 2 are both hydrogen and R 3 is fluoro.
  • R 1 is fluoro and R 2 and R 3 are both hydrogen.
  • A is a group (b):
  • A is a group (c):
  • A is selected from the group consisting of:
  • X is CH 2 OH.
  • X is selected from the group consisting of C(O)R 4 , CH 2 R 4 and CH 2 C(O)R 4 , wherein R 4 is as defined for formula (I).
  • R 4 is OR 5 , wherein R 5 is C 1-6 alkyl.
  • X is C(O)OR 5 wherein R 5 is Ci -6 alkyl
  • X is selected from the group consisting of C(O)NR 6 R 7 , CH 2 NR 6 R 7 and CH 2 C(O)NR 6 R 7 , wherein R 6 and R 7 are as defined for formula (I).
  • R 6 and R 7 are independently C 1-6 alkyl, wherein the alkyl is optionally substituted by hydroxy.
  • R 6 is methyl and R 7 is ethyl which is optionally substituted by hydroxy.
  • R 6 is hydrogen and R 7 is C 1-6 alkylsulfonyl.
  • R 6 is hydrogen and R 7 is methylsulfonyl.
  • R 6 and R 7 together with the nitrogen atom to which they are attached, form a 4-membered heterocyclic ring, which ring is optionally substituted by one or two groups selected from oxo and hydroxy. In one embodiment, R 6 and R 7 , together with the nitrogen atom to which they are attached, form an azetidinyl ring, optionally substituted by one or two groups selected from oxo and hydroxy.
  • R 6 and R 7 together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring or an isothiazolidinyl ring, which is optionally substituted by one or two groups selected from oxo and hydroxy.
  • R 6 and R 7 together with the nitrogen atom to which they are attached, form a morpholinyl ring, which is optionally substituted by one or two groups selected from oxo and hydroxy.
  • Examples of compounds of formula (I) include: 1-[6-(1-pyrrolidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole
  • the salt of the compound of formula (I) is a pharmaceutically acceptable salt.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt 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.
  • 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 methanesulfonic or ethanesulfonic acid; base addition salts formed with alkali metals and alkaline earth metals; 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.
  • 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 invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. geometric (or "cis-trans") isomers, diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the present invention includes within its scope all such isomers, including mixtures. It will be appreciated, in common with most biologically active molecules that the level of biological activity may vary between the enantiomers of a given molecule.
  • a compound of the invention in chiral form has at least 80% e.e. In another embodiment, a compound of the invention in chiral form has at least 90% e.e., for example at least 95% e.e. In another embodiment the isomers correspond to at least 98% e.e, for example at least 99% e.e.
  • 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.
  • Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the present invention provides a process for the manufacture of a compound of formula (I) or a salt thereof, which process comprises coupling a compound of formula (II):
  • L is a leaving group and A is as defined for formula (I), with 3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole:
  • L is a halogen (for example bromide or iodide).
  • Typical coupling conditions comprise heating a compound of formula (II), 3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole, a base (such as potassium carbonate or cesium carbonate), copper (I) iodide or copper (I) oxide with N,N-dimethylglycine at 180 degC or 190 degC in a microwave reactor or with conventional heating at 130 degC in dimethylsulfoxide.
  • a base such as potassium carbonate or cesium carbonate
  • copper (I) iodide or copper (I) oxide with N,N-dimethylglycine at 180 degC or 190 degC in a microwave reactor or with conventional heating at 130 degC in dimethylsulfoxide.
  • 3-(Trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole is commercially available.
  • a compound of formula (IV) may be prepared by coupling a compound of formula (V) with a secondary amine according to reaction scheme 1.
  • Typical coupling conditions comprise stirring a compound of formula (V) with magnesium chloride and a secondary amine in tetrahydrofuran at room temperature or with heat.
  • Scheme 1 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Scheme 1 is used for compounds of the invention in which R 6 and R 7 are aliphatic and are the same or different, or are linked to form a ring.
  • Compounds of formula (V) can be prepared in a manner similar to that described in Scheme 2.
  • a compound of formula (V) may be prepared by an ester formation reaction from a compound of formula (Vl) according to reaction scheme 2.
  • Typical reaction conditions comprise adding chlorotrimethylsilane to a solution of a compound of formula (Vl) in methanol and stirring at 50 degC for 42 hours.
  • the method of Scheme 2 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (Vl) can be prepared in a manner similar to that described above for compounds of formula (I).
  • n 0 or 1
  • a compound of formula (VII) may be prepared by reduction of a compound of formula (V) according to reaction scheme 3.
  • Typical reaction conditions comprise adding a solution of lithium aluminium hydride in tetrahydrofuran to a solution of a compound of formula (V) in tetrahydrofuran and stirring at ambient temperature for 2 hours.
  • the method of Scheme 3 is used for compounds of the invention in which A is a group (b), (c),
  • a compound of formula (IX) wherein R 6 and R 7 form a ring as defind for formula (1 ) may be prepared by methanesulfonylation of a compound of formula (VII) followed by the alkylation of a compound of formula (VIII) according to reaction scheme 4.
  • Typical reaction conditions comprise the addition of methanesulfonyl chloride to a solution of a compound of formula (VII) and triethylamine in dichloromethane. The product of this reaction is then added to a stirring mix of a compound of formula (VIII) and sodium hydride (available as a 60% suspension in mineral oil) in dimethylformamide.
  • the method of Scheme 4 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (VII) can be prepared in a manner similar to that described in scheme 3.
  • Compounds of formula (VIII) are commercially available.
  • a compound of formula (XV) may be prepared by methanesulfonylation of a compound of formula (XIV) according to reaction scheme 5.
  • Typical reaction conditions comprise the addition of methanesulfonyl chloride to a solution of a compound of formula (XIV) and triethylamine in dichloromethane.
  • the method of Scheme 5 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (XIV) can be prepared in a manner similar to that described in scheme 10.
  • An intermediate compound of formula (Xl) may be prepared by coupling a compound of formula (X) with a secondary amine according to reaction scheme 6.
  • Typical coupling conditions comprise treatment of a compound of formula (X) with either 1 ,1 '- carbonyldiimidazole in dichloromethane followed by addition of the secondary amine after a 15 minute stirring period at ambient temperature or a mixture of HATU and DIPEA with the secondary amine.
  • the method of Scheme 6 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defind above, R 6 and R 7 are aliphatic and may be the same or different, or are linked to form a ring, and M is CH 2 or a bond.
  • L is a halogen such as bromine or iodine.
  • Compounds of formula (X) are commercially available, or can be prepared in a manner similar to that described in scheme 9.
  • An intermediate compound of formula (XIII), wherein R 6 and R 7 form a ring as defind in formula (I), may be prepared by alkylation of a compound of formula (VIII) with a compound of formula (XII) according to reaction scheme 7.
  • Typical reaction conditions comprise the addition of a compound of formula (XII) to a stirring mix of a compound of formula (VIII) and sodium hydride (available as a 60% suspension in mineral oil) in dimethylformamide.
  • L is a halogen such as bromine or iodine.
  • the method of Scheme 7 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • the compounds of formula (VIII) are commercially available.
  • the compounds of formula (XII) are commercially available or can be prepared as described in schemes 8 and 1 1 , or as described in the literature [Ulrich et. al. Tetrahedron Letters 43, (2002), 1697-1700].
  • An intermediate compound of formula (XII) may be prepared by bromination of a compound of formula (XVI) according to reaction scheme 8.
  • Typical reaction conditions comprise addition of N-bromosuccinimide to a mixture of a compound of formula (XVI) and triphenylphosphine in dichloromethane with cooling, followed with room temperature stirring.
  • L is a halogen such as bromine or iodine.
  • the method of Scheme 8 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (XVI) are commercially available.
  • An intermediate compound of formula (XVII) may be prepared by the hydrolysis of a compound of formula (XVIII) according to reaction scheme 9.
  • Typical reaction conditions comprise the heating of a mixture of a compound of formula (XVIII) with potassium hydroxide in a mixture of ethanol and water at reflux for up to 5 hours.
  • L is a halogen such as bromine or iodine.
  • the method of Scheme 9 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (XVIII) are commercially available.
  • An intermediate compound of formula (XIV) may be prepared by the reduction of a compound of formula (Vl) according to reaction scheme 10.
  • Typical reaction conditions comprise addition of a compound of formula (Vl) to a cooled stirring solution of lithium aluminium hydride in tetrahydrofuran and stirring at ambient temperature.
  • the method of Scheme 10 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (Vl) can be prepared in a manner similar to that described above for compounds of formula (I).
  • An intermediate compound of formula (XII) may be prepared by bromination of a compound of formula (XIX) according to reaction scheme 1 1.
  • Typical reaction conditions comprise heating a mixture of a compound of formula (XIX) with N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride at reflux for approximately 24 hours.
  • L is a halogen such as bromine or iodine.
  • the method of Scheme 11 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (XIX) are commercially available.
  • An intermediate compound of formula (XXI) may be prepared by sulphonylation followed by cyclisation of a compound of formula (XX) according to reaction scheme 12.
  • Typical reaction conditions comprise treatment of a compound of formula (XX) in a dimethylformamide and triethylamine solution with 3-chloropropanesulphonyl chloride, followed by the addition of excess sodium hydride (available as a 60% suspension in mineral oil).
  • L is a halogen such as bromine or iodine.
  • the method of Scheme 12 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above.
  • Compounds of formula (XX) are commercially available.
  • 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 present invention potentiate the AMPA receptor.
  • Compounds which potentiate the AMPA receptor may be useful for treating diseases and conditions which are mediated by or caused by a reduction or imbalance in glutamate receptor function, and which therefore benefit from the potentiation of the AMPA receptor.
  • the present invention provides a compound of formula (I) or a salt thereof for use as a medicament.
  • a compound of the invention in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of the invention for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of the invention; iv) a combination product of a compound of formulathe invention with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient; vi) the use of a combination product as defined in iv) above in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; vii) a combination
  • 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); substance related disorders (including alcohol-related disorders and nicotine-related disorders); 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
  • 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 present invention provides a compound of the invention for use in treating schizophrenia or impairment of cognition.
  • the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.
  • the present invention provides a method of treatment of schizophrenia or impairment of cognition, comprising administering an effective amount of a compound of the invention.
  • treatment includes prophylaxis as well as alleviation of established symptoms.
  • the mammal to be treated is a human.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).
  • antipsychotics such as olanzapine, risperidone, clozapine, ziprazidone, talnetant
  • drugs for extrapyramidal side effects for example anticholinergics
  • the compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of 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; ii) drugs for treating nicotine addition, for example bupropion.
  • nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches
  • drugs for treating nicotine addition for example bupropion.
  • the compounds of the invention may be used in combination with one or more of 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; 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 one or more of 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; 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 one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon
  • barbiturates for
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations, pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, 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; vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil, sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion
  • the compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) 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.
  • 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 to mammals including humans.
  • the compositions may be formulated for administration by any route.
  • the compositions may be formulated for oral, topical, or parenteral administration, and 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 may be included in the composition to facilitate uniform distribution of the compound.
  • 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.
  • 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 5 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).
  • Needle rinse solvent Methanol Methods: There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.
  • the title compound was prepared from 6-iodonicotinic acid and pyrrolidine using a similar procedure to that used for Description 1.
  • the title compound was prepared from 4-bromo-2-fluorobenzoic acid and pyrrolidine using a similar procedure to that used for Description 12.
  • the title compound was prepared from 4-bromo-2-methylbenzoic acid and pyrrolidine using a similar procedure to that used for Description 12.
  • Tetrahydrofuran (10ml) and lithium aluminium hydride in tetrahydrofuran (2M solution, 2.70ml, 5.40mmol) were stirred in an ice bath under argon.
  • a solution of 5-[3- (trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-pyridinecarbonitrile (from Description 4) (0.79Og, 2.70mmol) in tetrahydrofuran (10ml) was added dropwise over 15 minutes and the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 1.5 hours. The reaction mixture was then cooled using the ice bath and quenched with water dropwise. The solvent was removed by rotary evaporation.
  • Residual material was diluted with dichloromethane and water. Insoluble solid was filtered off and the organic layer separated, washed with brine, dried with sodium sulphate and evaporated under reduced pressure. The desired product was isolated by a SCX column eluted initially with dichloromethane, dichloromethane and methanol 1 :1 mixture, methanol and then the desired product eluted with 1 M solution of ammonia in methanol.
  • the title compound was prepared from 2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indazol-1-yl]benzonitrile (0.56Og, 1.81 mmol) and 2M solution of lithium aluminium hydride in tetrahydrofuran (3.62ml, 7.24mmol) using a similar procedure to that used for Description 18 to afford the title compound as an oil (0.316g, 56%).
  • Example 1 1 -[6-(1 -pyrrolidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
  • reaction mix was dried over sodium sulphate and the solvent removed under reduced pressure to give a brown oil which was purified on a 5g isolute pre-packed silica column eluting from 20-100% ethyl acetate in petroleum ether to give the title compound as a yellow oil (221 mg, 32%).
  • reaction mix was then evaporated under reduced pressure and the residue dissolved in dimethylformamide (0.5ml) and added to a mixture of 2-pyrrolidinone (1 1 mg, 0.13mmol) and sodium hydride (60% suspension in mineral oil, 6mg, 0.15mmol) in dimethylformamide (1 ml) which had been prepared 15 minutes earlier.
  • the resulting mix was shaken at room temperature for 18 hours.
  • the reaction mixture was partitioned between dichloromethane (4ml) and water (6ml). The organic layer was removed and added to a 5g isolute pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (8mg, 17%).
  • Example 7 1 -[6-(1 -azetidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
  • Solvent was removed by rotary evaporation and the sample purified on a biotage 12+M silica column using 0-100% ethyl acetate / n-pentane solvent gradient. Relevant fractions were combined and the solvent removed to yield the title compound as a white solid (47mg, 27%).
  • Example 8 ⁇ /-ethyl- ⁇ /-methyl-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]-2-pyridinecarboxamide
  • the title compound was prepared from methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1 H-indazol-1 -yl]-2-pyridinecarboxylate and N-methylethylamine using a similar procedure to that used for Example 7, except the sample required no further purification after the aqueous wash.
  • the title compound was prepared from methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indazol-1-yl]-2-pyridinecarboxylate and 2-(methylamino)ethanol using a similar procedure to that used for Example 7, except the sample required further purification by MDAP.
  • the reaction mixture was treated with fresh copper (I) iodide (10mol%, 0.07mmol, 13mg) and N,N-dimethylglycine (20mol%, 0.14mmol, 14mg) and heating continued for a further 0.5 hours.
  • the reaction mixture was partitioned between dichloromethane (2 x 3ml) and water (5ml). The organic layers were added to a 5g isolute pre-packed silica column and eluted with ethyl acetate. The solvent was removed by rotary evaporation and the residue purified by MDAP to give the title compound as a brown oil (30mg, 1 1%).
  • Example 12 1 -( ⁇ 3-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]phenyl ⁇ methyl)-2-pyrrolidinone
  • reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with sodium sulphate and the solvent was removed by rotary evaporation.
  • desired product was isolated by column chromatography on silica using 5 to 50% ethyl acetate in n-pentane to give the title compound as a white solid (65mg, 15%).
  • Example 14 1 -( ⁇ 2,6-difluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]phenyl ⁇ methyl)-2-pyrrolidinone
  • reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with sodium sulphate and the solvent was removed by rotary evaporation.
  • desired product was isolated by column chromatography on silica using 5 to 50% ethyl acetate in n-pentane which was further purified by MDAP to give the title compound as a colourless gum.(48mg, 10%).
  • Example 16 1-[3-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
  • the title compound was prepared from 1-[(4-bromo-2-chlorophenyl)methyl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 /-/-indazole using a similar procedure to that used for Example 15.
  • Example 18 1 -[3-chloro-4-(1 -pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-
  • Example 19 1 -[3-methyl-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole
  • Example 20 1- ⁇ 4-[(1 J ⁇ ioxido ⁇ -isothiazolidinylJmethyll-S-fluoropheny ⁇ -S- ftrifluoromethylJ ⁇ S. ⁇ .Z-tetrahydro-IH-indazole
  • Example 22 1 -[3-fluoro-4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole
  • the reaction mixture was diluted with ethyl acetate, the mixture was filtered through kieselguhr to remove catalyst and the filtrate was washed with water and brine, the organic layer was dried with sodium sulphate and solvent was removed by rotary evaporation.
  • the desired product was isolated by column chromatography on silica using 10 to 70% ethyl acetate in n-pentane which was further purified by MDAP to give the title compound as a white solid (104mg, 44%).
  • the ability of the compounds of the invention to potentiate AMPA 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.
  • fluorescent calcium-indicator dyes such as FLUO4
  • glutamate-evoked current recorded from human GluR2 flip unedited HEK293 cells In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).
  • tissue culture medium in the wells were discarded and the wells were 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_
  • the plates were then incubated for 60 minutes in the dark with 2 ⁇ M FLUO4-AM dye (20 ⁇ l_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which was then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well was washed three times with buffer (80 ⁇ l_) (30 ⁇ l_ of buffer remained in each well after washing).
  • DMSO dimethylsulfoxide
  • the cell plate was then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)].
  • a baseline fluorescence reading was 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) was added (to give a final concentration in the range 30 ⁇ M to 3 pM).
  • the fluorescence was read over 5 minute period.
  • 500 ⁇ M glutamate solution (10 ⁇ l_) was added (to give a final concentration of 100 ⁇ M).
  • the fluoresecence was then read over a 4 minute period.
  • the activities of the compounds of the invention and the reference compound were determined by measuring peak fluorescence after the last addition. The activity was 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 5 o 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. For each compound, more than one reading was taken.
  • Example compounds were screened using the assay as described above and the average of the measurable pEC 50 s were taken. All compounds gave an average PEC50 equal to or greater than 4.0 and/or demonstrated an activity of on average 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 may be 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 contained: 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 contained: 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-acetic
  • Electrodes were 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 were back-filled with internal recording solution. Positive pressure was 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 was used to apply extracellular solution to the bath. Rapid solution exchange used a fast step perfusion system (Biologic RSC160).
  • a prospective cell was positioned in the centre of the microscope field of view.
  • Recording electrode was positioned directly above the cell membrane surface.
  • fine manipulator control Liigs and Neumann, SM-6
  • the electrode was lowered, while monitoring the change in electrode resistance during delivery of a 5 mV depolarizing pulse, until a high resistance seal (gigaseal) was achieved.
  • Whole cell configuration was achieved by removing by suction a small fragment of cell membrane immediately beneath the recording electrode tip.
  • the cell membrane potential was held at -70 mV (voltage- clamped) via the electrode (Axopatch 200B Integrating patch clamp amplifier, pClamp software, Axon Instruments). Test solutions were applied using the fast application system using the following protocol and changes in inward current were recorded and stored for off-line analysis.
  • 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 ⁇ M AMPA response in the presence of the compound of the invention and expressing it as % of potentiation of the 30 ⁇ M AMPA alone response (30 ⁇ M AMPA in the absence of the compound of the invention).

Abstract

A compound of formula (I) and salts thereof are provided: wherein A is 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 AMPA receptor. The invention also relates to the use of the compounds in treating diseases and conditions wherein the potentiation of the AMPA receptor would be beneficial, 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 11 : 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, mGluθ, 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 (GIuRI -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, Burnashev 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: 2211-5.) 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 1158-1 1162). 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 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 WO2007/107539. We have discovered novel compounds which potentiate the AMPA receptor.
In the first aspect, the present invention provides a compound of formula (I) or a salt thereof:
Figure imgf000003_0001
wherein A is a group selected from:
Figure imgf000004_0001
(a) (b) (C)
wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen and Ci-6alkyl, wherein R1, R2 and R3 are not all hydrogen; X is selected from the group consisting of CH2OH, C(O)R4, CH2R4 and CH2C(O)R4; R4 is selected from the group consisting of OR5 and NR6Rz, wherein R5 is C1-6alkyl; R6 and R7 are: (i) independently C1-6alkyl, wherein one of the alkyl is optionally substituted by hydroxy; or
(ii) R6 is hydrogen and R7 is C1-6alkylsulfonyl; or
(iii) R6 and R7, together with the nitrogen atom to which they are attached, form a 4, 5 or 6-membered heterocyclic ring, which ring is optionally substituted by one or two groups selected from oxo and hydroxy.
In the definition of A, the "*" indicates that the group is directly attached to the nitrogen atom in the fused pyrazolyl ring in formula (I).
The term "halo" refers to fluoro, chloro, bromo or iodo.
The term "C1-6alkyl" refers to an alkyl group having from one to six carbon atoms; and the term "C1-4alkyl" refers to an alkyl group having from one to four carbon atoms. Unless otherwise indicated, C1-4alkyl or C1-6alkyl may be a straight chain or branched alkyl group. For example, a C1-4alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. A C1-6alkyl group may be selected from the group consisting of a C1-4alkyl group, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl. For example, C1-4alkyl is methyl.
The term "haloC1-6alkyl" refers to a C1-6alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. A haloC1-6alkyl group may, for example contain 1 , 2 or 3 halogen atoms. For example, a haloC1-6alkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloC1-6alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl. The term "4, 5 or 6-membered heterocyclic ring" refers to a 4-, 5- or 6-membered non- aromatic ring, which ring may contain one or two further heteroatoms selected from N, O and S. Examples include azetidinyl, pyrrolidinyl imidazolidinyl. pyrazolidinyl, isothiazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl and piperazinyl.
The term "oxo" refers to the group "=O".
"CO" and "C(=O)" are interchangeable and represent a carbonyl group.
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, A is a group (a) as defined above:
Figure imgf000005_0001
wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen and C1-6alkyl, wherein R1, R2 and R3 are not all hydrogen; and X is as defined for formula (I).
In one embodiment, R1, R2 and R3 are independently selected from the group consisting of hydrogen, fluoro and methyl, wherein R1, R2 and R3 are not all hydrogen.
In one embodiment, R1 and R2 are both fluoro and R3 is hydrogen.
In one embodiment, R1 and R2 are both hydrogen and R3 is fluoro.
In one embodiment, R1 is fluoro and R2 and R3 are both hydrogen.
In one embodiment, A is a group (b):
Figure imgf000005_0002
wherein X is as defined for formula (I).
In one embodiment, A is a group (c):
Figure imgf000006_0001
wherein X is as defined for formula (I).
In one embodiment, A is selected from the group consisting of:
Figure imgf000006_0002
(b) (c) (d) (e) (f) In one embodiment, X is CH2OH.
In one embodiment, X is selected from the group consisting of C(O)R4, CH2R4 and CH2C(O)R4, wherein R4 is as defined for formula (I).
In one embodiment, R4 is OR5, wherein R5 is C1-6alkyl.
In one embodiment, X is C(O)OR5 wherein R5 is Ci-6alkyl,
In one embodiment, X is selected from the group consisting of C(O)NR6R7, CH2NR6R7 and CH2C(O)NR6R7, wherein R6 and R7 are as defined for formula (I).
In one embodiment, R6 and R7 are independently C1-6alkyl, wherein the alkyl is optionally substituted by hydroxy.
In one embodiment, R6 is methyl and R7 is ethyl which is optionally substituted by hydroxy.
In one embodiment, R6 is hydrogen and R7 is C1-6alkylsulfonyl.
In one embodiment, R6 is hydrogen and R7 is methylsulfonyl.
In one embodiment, R6 and R7, together with the nitrogen atom to which they are attached, form a 4-membered heterocyclic ring, which ring is optionally substituted by one or two groups selected from oxo and hydroxy. In one embodiment, R6 and R7, together with the nitrogen atom to which they are attached, form an azetidinyl ring, optionally substituted by one or two groups selected from oxo and hydroxy.
In one embodiment, R6 and R7, together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring or an isothiazolidinyl ring, which is optionally substituted by one or two groups selected from oxo and hydroxy.
In one embodiment, R6 and R7, together with the nitrogen atom to which they are attached, form a morpholinyl ring, which is optionally substituted by one or two groups selected from oxo and hydroxy.
Examples of compounds of formula (I) include: 1-[6-(1-pyrrolidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole
1-[5-(1-pyrrolidinylcarbonyl)-2-pyridinyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole
1-({6-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-3-pyridinyl}methyl)-2- pyrrolidinone methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-pyridinecarboxylate {5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2-pyridinyl}methanol
1-({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-pyridinyl}methyl)-2- pyrrolidinone
1-[6-(1-azetidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole
N-ethyl-N-methyl-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2- pyridinecarboxamide
N-(2-hydroxyethyl)-N-methyl-5-[3-(trifluoromethyl)-4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl]-2- pyridinecarboxamide
1 -({5-[3-(trifluoromethyl)-4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl]-2-pyridinyl}carbonyl)-3- pyrrolidinol 1-[2-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
1 -({3-fluoro-4-[3-(trifluoromethyl)-4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl]phenyl}methyl)-2- pyrrolidinone
1 -({2-fluoro-4-[3-(trifluoromethyl)-4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl]phenyl}methyl)-2- pyrrolidinone
1-({2, 6-difluoro-4-[3-(trifluoromethyl)-4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl]phenyl}methyl)-2- pyrrolidinone
1-{3-fluoro-4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-
1 H-indazole 1-[3-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
1 -({2-chloro-4-[3-(trifluoromethyl)-4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl]phenyl}methyl)-2- pyrrolidinone 1-[3-chloro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
1-[3-methyl-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
1-{4-[(1 ,1-dioxido-2-isothiazolidinyl)methyl]-3-fluorophenyl}-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
N-({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2- pyridinyl}methyl)methanesulfonamide 1-[3-fluoro-4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
N-({2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1- yl]phenyl}methyl)methanesulfonamide and salts thereof.
It will be appreciated that the present invention is intended to include compounds having any combination of the groups listed hereinbefore.
In one embodiment the salt of the compound of formula (I) is a pharmaceutically acceptable salt. In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt 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 methanesulfonic or ethanesulfonic acid; base addition salts formed with alkali metals and alkaline earth metals; 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.
Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) or prodrugs thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".
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.
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances, lsotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. geometric (or "cis-trans") isomers, diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. The present invention includes within its scope all such isomers, including mixtures. It will be appreciated, in common with most biologically active molecules that the level of biological activity may vary between the enantiomers of a given molecule.
In one embodiment a compound of the invention in chiral form has at least 80% e.e. In another embodiment, a compound of the invention in chiral form has at least 90% e.e., for example at least 95% e.e. In another embodiment the isomers correspond to at least 98% e.e, for example at least 99% e.e.
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. Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the invention. In the following schemes, compounds illustrated are those wherein A is a group (a) as defined for formula (I). However, unless otherwise stated, the schemes are applicable equally to compounds of formula (I) wherein A is a group (b) or (c).
The present invention provides a process for the manufacture of a compound of formula (I) or a salt thereof, which process comprises coupling a compound of formula (II):
(H)
wherein L is a leaving group and A is as defined for formula (I), with 3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole:
Figure imgf000011_0001
and thereafter optionally: - removing any protecting groups; and/or - converting a compound of the present invention into another compound of the present invention.
In one embodiment, L is a halogen (for example bromide or iodide).
Typical coupling conditions comprise heating a compound of formula (II), 3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole, a base (such as potassium carbonate or cesium carbonate), copper (I) iodide or copper (I) oxide with N,N-dimethylglycine at 180 degC or 190 degC in a microwave reactor or with conventional heating at 130 degC in dimethylsulfoxide. 3-(Trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole is commercially available.
A compound of formula (IV) may be prepared by coupling a compound of formula (V) with a secondary amine according to reaction scheme 1. Typical coupling conditions comprise stirring a compound of formula (V) with magnesium chloride and a secondary amine in tetrahydrofuran at room temperature or with heat. In one embodiment, Scheme 1 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. In one embodiment, Scheme 1 is used for compounds of the invention in which R6 and R7 are aliphatic and are the same or different, or are linked to form a ring. Compounds of formula (V) can be prepared in a manner similar to that described in Scheme 2.
Scheme 1
Figure imgf000012_0001
A compound of formula (V) may be prepared by an ester formation reaction from a compound of formula (Vl) according to reaction scheme 2. Typical reaction conditions comprise adding chlorotrimethylsilane to a solution of a compound of formula (Vl) in methanol and stirring at 50 degC for 42 hours. In one embodiment, the method of Scheme 2 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (Vl) can be prepared in a manner similar to that described above for compounds of formula (I).
Scheme 2
Figure imgf000012_0002
n=0 or 1
A compound of formula (VII) may be prepared by reduction of a compound of formula (V) according to reaction scheme 3. Typical reaction conditions comprise adding a solution of lithium aluminium hydride in tetrahydrofuran to a solution of a compound of formula (V) in tetrahydrofuran and stirring at ambient temperature for 2 hours. In one embodiment, the method of Scheme 3 is used for compounds of the invention in which A is a group (b), (c),
(d), (e) or (f) as defined for formula (I). Compounds of formula (V) can be prepared in a manner similar to that described in scheme 2.
Scheme 3
Figure imgf000013_0001
A compound of formula (IX) wherein R6 and R7 form a ring as defind for formula (1 ) may be prepared by methanesulfonylation of a compound of formula (VII) followed by the alkylation of a compound of formula (VIII) according to reaction scheme 4. Typical reaction conditions comprise the addition of methanesulfonyl chloride to a solution of a compound of formula (VII) and triethylamine in dichloromethane. The product of this reaction is then added to a stirring mix of a compound of formula (VIII) and sodium hydride (available as a 60% suspension in mineral oil) in dimethylformamide. In one embodiment, the method of Scheme 4 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (VII) can be prepared in a manner similar to that described in scheme 3. Compounds of formula (VIII) are commercially available.
Scheme 4
Figure imgf000013_0002
A compound of formula (XV) may be prepared by methanesulfonylation of a compound of formula (XIV) according to reaction scheme 5. Typical reaction conditions comprise the addition of methanesulfonyl chloride to a solution of a compound of formula (XIV) and triethylamine in dichloromethane. In one embodiment, the method of Scheme 5 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (XIV) can be prepared in a manner similar to that described in scheme 10.
Scheme 5
Figure imgf000014_0001
An intermediate compound of formula (Xl) may be prepared by coupling a compound of formula (X) with a secondary amine according to reaction scheme 6. Typical coupling conditions comprise treatment of a compound of formula (X) with either 1 ,1 '- carbonyldiimidazole in dichloromethane followed by addition of the secondary amine after a 15 minute stirring period at ambient temperature or a mixture of HATU and DIPEA with the secondary amine. In one embodiment, the method of Scheme 6 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defind above, R6 and R7 are aliphatic and may be the same or different, or are linked to form a ring, and M is CH2 or a bond. In one embodiment, L is a halogen such as bromine or iodine. Compounds of formula (X) are commercially available, or can be prepared in a manner similar to that described in scheme 9.
Scheme 6
Figure imgf000014_0002
An intermediate compound of formula (XIII), wherein R6 and R7 form a ring as defind in formula (I), may be prepared by alkylation of a compound of formula (VIII) with a compound of formula (XII) according to reaction scheme 7. Typical reaction conditions comprise the addition of a compound of formula (XII) to a stirring mix of a compound of formula (VIII) and sodium hydride (available as a 60% suspension in mineral oil) in dimethylformamide. In one embodiment, L is a halogen such as bromine or iodine. In one embodiment, the method of Scheme 7 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. The compounds of formula (VIII) are commercially available. The compounds of formula (XII) are commercially available or can be prepared as described in schemes 8 and 1 1 , or as described in the literature [Ulrich et. al. Tetrahedron Letters 43, (2002), 1697-1700].
Scheme 7
Figure imgf000015_0001
An intermediate compound of formula (XII) may be prepared by bromination of a compound of formula (XVI) according to reaction scheme 8. Typical reaction conditions comprise addition of N-bromosuccinimide to a mixture of a compound of formula (XVI) and triphenylphosphine in dichloromethane with cooling, followed with room temperature stirring. In one embodiment, L is a halogen such as bromine or iodine. In one embodiment, the method of Scheme 8 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (XVI) are commercially available.
Scheme 8
Figure imgf000015_0002
An intermediate compound of formula (XVII) may be prepared by the hydrolysis of a compound of formula (XVIII) according to reaction scheme 9. Typical reaction conditions comprise the heating of a mixture of a compound of formula (XVIII) with potassium hydroxide in a mixture of ethanol and water at reflux for up to 5 hours. In one embodiment, L is a halogen such as bromine or iodine. In one embodiement, the method of Scheme 9 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (XVIII) are commercially available.
Scheme 9
KOH / EtOH / water
Figure imgf000015_0003
Figure imgf000015_0004
n = 0 or 1
An intermediate compound of formula (XIV) may be prepared by the reduction of a compound of formula (Vl) according to reaction scheme 10. Typical reaction conditions comprise addition of a compound of formula (Vl) to a cooled stirring solution of lithium aluminium hydride in tetrahydrofuran and stirring at ambient temperature. In one embodiment, the method of Scheme 10 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (Vl) can be prepared in a manner similar to that described above for compounds of formula (I).
Scheme 10
Figure imgf000016_0001
An intermediate compound of formula (XII) may be prepared by bromination of a compound of formula (XIX) according to reaction scheme 1 1. Typical reaction conditions comprise heating a mixture of a compound of formula (XIX) with N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride at reflux for approximately 24 hours. In one embodiment, L is a halogen such as bromine or iodine. In one embodiement the method of Scheme 11 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (XIX) are commercially available.
Scheme 11
N-bromosuccinimide / benzoyl peroxide / CCI4
Figure imgf000016_0003
Figure imgf000016_0002
An intermediate compound of formula (XXI) may be prepared by sulphonylation followed by cyclisation of a compound of formula (XX) according to reaction scheme 12. Typical reaction conditions comprise treatment of a compound of formula (XX) in a dimethylformamide and triethylamine solution with 3-chloropropanesulphonyl chloride, followed by the addition of excess sodium hydride (available as a 60% suspension in mineral oil). In one embodiment, L is a halogen such as bromine or iodine. In one embodiment, the method of Scheme 12 is used for compounds of the invention in which A is a group (b), (c), (d), (e) or (f) as defined above. Compounds of formula (XX) are commercially available.
Scheme 12
Figure imgf000017_0001
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 present invention potentiate the AMPA receptor. Compounds which potentiate the AMPA receptor may be useful for treating diseases and conditions which are mediated by or caused by a reduction or imbalance in glutamate receptor function, and which therefore benefit from the potentiation of the AMPA receptor.
Thus the present invention provides a compound of formula (I) or a salt thereof for use as a medicament.
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 the invention in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of the invention for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of the invention; iv) a combination product of a compound of formulathe invention with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient; vi) the use of a combination product as defined in iv) above in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; vii) a combination product as defined in iv) above for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; viii) a combination product as defined in iv) above for use as a medicament; ix) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a combination product as defined in iv) above.
In the case of aspects i), ii), iii), vi), vii), viii) and ix), 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); substance related disorders (including alcohol-related disorders and nicotine-related disorders); 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). Treatment of 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-lnduced 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).
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.
In one embodiment, the present invention provides a compound of the invention for use in treating schizophrenia or impairment of cognition.
In one embodiment, the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.
In one embodiment, the present invention provides a method of treatment of schizophrenia or impairment of cognition, comprising administering an effective amount of a compound of the invention.
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.
The compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).
The compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.
The compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.
The compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.
The compounds of the invention may be used in combination with one or more of 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; ii) drugs for treating nicotine addition, for example bupropion.
The compounds of the invention may be used in combination with one or more of 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; iii) Opioid receptor antagonists for example naltrexone.
The compounds of the invention may be used in combination with one or more of 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; iii) vasodilatory antihypertensives for example lofexidine.
The compounds of the invention may be used in combination with one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.
The compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.
The compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.
The compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.
The compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
The compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics.
The compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, 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; vii) 5-HT1A agonists, for example flibanserine.
The compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) 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 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 to mammals including humans. The compositions may be formulated for administration by any route. The compositions may be formulated for oral, topical, or parenteral administration, and 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.
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. A surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
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.
The invention is illustrated by the Examples described below. Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Flash chromatography was carried out using pre-packed 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 5H 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 atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).
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.
Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Unless otherwise stated, all compounds with chiral centre(s) are racemic. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this. All reactions were either carried out under argon or may be carried out under argon, unless otherwise stated.
LC/MS conditions Column: Waters Atlantis, 4.6mm x 50mm. The stationary phase particle size is 3um. 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 wavelenqth ranqe: 220-330 nm
MDAP conditions
Column: Waters Atlantis, 19mrr
(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: There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 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 5
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
Description 1 : 5-bromo-2-(1-pyrrolidinylcarbonyl)pyridine
Figure imgf000030_0001
A solution of δ-bromopyridine^-carboxylic acid (210mg, 1.04mmol) in dichloromethane (4ml) was treated with 1 ,1 '-carbonyldiimidazole (169mg, 1.04mmol) in one portion at room temperature. This mixture was shaken in a 15ml sarstedt tube for 15 minutes. Pyrrolidine (74mg, 1.04mmol) was then added in one portion and shaking continued for 1 hour. Saturated sodium hydrogen carbonate (3ml) solution was then added and the mixture shaken. The organic layer was removed, dried over sodium sulphate and evaporated under reduced pressure to give the title compound (181 mg, 68%).
LC/MS (ES): Found 255 & 257 (ES+), retention time 2.13mins. Ci0H11BrN2O requires 254 & 256.
Description 2: 2-iodo-5-(1-pyrrolidinylcarbonyl)pyridine
Figure imgf000030_0002
The title compound was prepared from 6-iodonicotinic acid and pyrrolidine using a similar procedure to that used for Description 1.
LC/MS (ES): Found 303 (ES+), retention time 2.05mins. C10H11IN2O requires 302. 1 H-NMR (400MHz, CDCI3): 1.89-2.03 (4H, m), 3.45 (2H, m), 3.65 (2H, m), 7.51 (1 H, dd, J=8Hz & 2Hz), 7.80 (1 H, d, J=8Hz), 8.53 (1 H, d, J=2Hz). Description 3: 1-[(6-bromo-3-pyridinyl)methyl]-2-pyrrolidinone
Figure imgf000031_0001
A solution of 2-pyrrolidinone (170mg, 2mmol) in dimethylformamide (5ml) was cooled in an ice/methanol bath with stirring under argon. Solid sodium hydride (60% suspension in mineral oil, 160mg, 4mmol) was added portionwise over 10 minutes. The reaction was allowed to stir with cooling for 30 minutes. Then 2-bromo-5-(bromomethyl)pyridine [Ulrich et. al. Tetrahedron Letters 43, (2002), 1697-1700] (500mg, 2mmol) was added portionwise over 10 minutes and the whole mix was allowed to warm up slowly to room temperature and stirred under argon for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed and reduced to minimum volume under reduced pressure to give a golden oil which was added to a 5g isolute pre-packed silica column and eluted from ethyl acetate. The solvent was removed under reduced pressure to give the title compound as a yellow oil (108mg, 21%). LC/MS (ES): Found 255 & 257 (ES+), retention time 1.77mins. Ci0H11BrN2O requires 254 & 256.
Description 4: 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2- pyridinecarbonitrile
Figure imgf000031_0002
A mixture of 3-bromo-6-pyridinecarbonitrile (1.83g, lOmmolmmol), 3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole (1.9Og, lOmmol), copper (I) iodide (10mol%, 1 mmol, 191 mg), N,N-dimethylglycine (20mol%, 2mmol, 206mg), and potassium carbonate (21 mmol, 2.9Og) in dimethylsulfoxide (20ml) was stirred at 13O0C in an oil bath under argon for 3h. The reaction mixture was then filtered and the filtrate separated between dichloromethane and brine and the organic layer retained and dried over sodium sulphate. Sample was then purified on a 2Og pre-packed silica column using 20% ethyl acetate/petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a yellow solid (2.56g, 88%).
LC/MS (ES): Found 293 (ES+), retention time 3.37mins. C14H11F3N4 requires 292.
1 H-NMR (400MHz, CDCI3): 1.83-1.92 (4H, m), 2.69 (2H, m), 2.83 (2H, m), 7.83 (1 H, m), 8.10 (1 H, dd, J=8Hz, & 2Hz), 8.97 (1 H, d, J=2Hz). Description 5: 1-[(4-bromo-3-fluorophenyl)carbonyl]pyrrolidine
Figure imgf000032_0001
A suspension of 4-bromo-3-fluorobenzoic acid (1.09g, 5mmol) in dichloromethane (15ml) was treated with 1 ,1 '-carbonyldiimidazole (810mg, 5mmol) in one portion and allowed to stir at room temperature for 15 minutes. Pyrrolidine (355mg, 5mmol) was then added and stirring continued for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and concentrated by rotary evaporation to give the title compound as a yellow oil (1.17g, 86%).
LC/MS (ES): Found 272 & 274 (ES+), retention time 2.55mins. C11H11BrFNO requires 271 & 273.
1 H-NMR (400MHz, CDCI3): 1.87-2.01 (4H, m), 3.42 (2H, m), 3.63 (2H, m), 7.16 (1 H, m), 7.29 (1 H, m), 7.51 (1 H, m).
Description 6: 4-(bromomethyl)-2-fluoro-1-iodobenzene
Figure imgf000032_0002
A mixture of 3-fluoro-4-iodotoluene (2.26g, 9.58mmol), N-bromosuccinimide (2.03g, 11.49mmol) and benzoyl peroxide (5mol%, 116mg, 0.48mmol) in carbon tetrachloride (5ml) was stirred at reflux for 20 hours, cooled, diluted with dichloromethane and filtered. The purple coloured filtrate was washed with saturated sodium thiosulphate solution (aq) (20ml). The organic layer was separated, dried over sodium sulphate and the solvent removed by rotary evaporation to give the title compound as a yellow oil (2.58g, 86%).
1 H-NMR (250MHz, CDCI3): 4.41 (2H, s), 6.94 (1 H, m), 7.11 (1 H, m), 7.72 (1 H, m).
Description 7: 1 -[(3-fluoro-4-iodophenyl)methyl]-2-pyrrolidinone
Figure imgf000032_0003
A solution of 2-pyrrolidinone (765mg, 9mmol) in anhydrous dimethylformamide (25ml) was cooled in an ice/methanol bath with stirring under argon, and then treated with sodium hydride (60% suspension in mineral oil, 360mg, 9mmol) over 10 minutes. The reaction mix was stirred with cooling for 0.5 hours before 4-(bromomethyl)-2-fluoro-1-iodobenzene (2.58g, 8.2mmol) in dimethylformamide (5ml) was added dropwise over 10 minutes. The whole mix was stirred at room temperature for 1 hour. The reaction mix was quenched with water (1 ml), and then partitioned between water (30ml) and dichloromethane (20ml), the aqueous layer was washed again with dichloromethane (10ml). The combined organic fractions were washed twice with water (20ml) and then with brine (10ml), dried over sodium sulphate and the solvent removed via rotary evaporation to give a brown oil (2.45g) which was added to a 2Og isolute pre-packed silica gel column and eluted with 0- 75% ethyl acetate in petroleum ether. The relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a yellow solid (1.27g, 49%).
LC/MS (ES): Found 320 (ES+), retention time 2.66mins. C11H11FINO requires 319. 1 H-NMR (400MHz, CDCI3): 2.05 (2H, m), 2.46 (2H, m), 3.28 (2H, m), 4.41 (2H, s), 6.81 (1 H, m), 6.95 (1 H, m), 7.69 (1 H, m).
Description 8: 1 -[(4-bromo-2-fluorophenyl)methyl]-2-pyrrolidinone
Figure imgf000033_0001
To a solution of 2-pyrrolidinone (0.625g, 7.35mmol) in DMF (20ml) was added sodium hydride (60% suspension in mineral oil, 0.328g, 8.2mmol) portionwise under argon at room temperature and stirred for 15 minutes. Then 2-fluoro-4-bromo-benzyl bromide (2.Og, 7.46mmol) was added. The resulting mixture was allowed to stir at room temperature for 5 hours and allowed to stand at room temperature overnight. The reaction was quenched by the addition of water (2ml) and then evaporated off the dimethylformamide under reduced pressure and partitioned between ethyl acetate and water, dried with sodium sulphate. The solvent was removed by rotary evaporation to give an oil which was purified by column chromatography on silica using 10 to 100% ethyl acetate in n-pentane to give the title compound as a colourless oil (1.7Og, 85%).
LC/MS (ES): Found 272 & 274 (ES+), retention time 2.52mins. C11H11BrFNO requires 271
& 273.
1H-NMR (400MHz, CDCI3): 2.0 (2H, m), 2.43 (2H, m), 3.31 (2H, m), 4.46 (2H, s), 7.13-
7.28 (3H, m).
Description 9: 5-bromo-2-(bromomethyl)-1 ,3-difluorobenzene
Figure imgf000034_0001
A solution of 4-bromo-2,6-difluorobenzylalcohol (2.Og, 8.96mmol) and triphenylphosphine
(2.59g, 9.89mmol) in dichloromethane (40ml) was cooled to O0C and N-bromosuccinimide
(1.74g, 9.78mmol) was added in five portions over 20 minutes. The reaction mixture was warmed to 250C and stirred for 17hours. The reaction was quenched by the addition of dilute aqueous sodium hydrogen carbonate. The resulting mixture was extracted with diethyl ether and the combined organic layers were washed with water and saturated aqueous sodium chloride before being dried with sodium sulphate and concentrated under reduced pressure. The title compound was isolated by column chromatography on silica using 5 to 20% ethyl acetate in n-pentane to give a dark oil (2.08g, 81%).
1H-NMR (400MHz, CDCI3): 4.44 (2H, s), 7.10 (2H, m).
Description 10: 1-[(4-bromo-2,6-difluorophenyl)methyl]-2-pyrrolidinone
Figure imgf000034_0002
The title compound was prepared from 5-bromo-2-(bromomethyl)-1 ,3-difluorobenzene and 2-pyrrolidinone using a similar procedure to that used for Description 8.
LC/MS (ES): Found 290 & 292 (ES+), retention time 2.56mins. C1 1 H10BrF2NO requires 289 & 291.
1H-NMR (400MHz, CDCI3): 1.97 (2H, m), 2.37 (2H, m), 3.27 (2H, m), 4.53 (2H, s), 7.10 (2H, m).
Description 11 : (4-bromo-2-fluorophenyl)acetic acid
Figure imgf000034_0003
A solution of (4-bromo-2-fluorophenyl)acetonitrile (2.345g, 10.96mmol) in ethanol (60ml) and water (18ml) was treated with potassium hydroxide (5.2Og, 93mmol, 8.5 equiv) and refluxed for 5 hours. The volatiles were distilled off, the residue was diluted with water and poured into diluted cold hydrochloric acid and the precipitated solid was filtered. The desired product was dried under high vacuum at 370C for 48 hours to afford the title compound (2.283g, 89%). 1H-NMR (400MHz, DMSO-d6): 3.6 (2H, s), 7.30 (1 H, m), 7.39 (1 H, m), 7.53 (1 H, m) 12.57 (1 H, br s).
Description 12: 1-[(4-bromo-2-fluorophenyl)acetyl]pyrrolidine
Figure imgf000035_0001
A mixture of (4-bromo-2-fluorophenyl)acetic acid (1.0g, 4.29mmol), pyrrolidine (305mg, 4.30mmol), DIPEA (1.49ml, 8.58mmol) in dimethylformamide (15ml) was stirred at room temperature under argon. Then HATU (1.794g, 4.72mmol) was added. The reaction mixture was allowed to stir at room temperature for 16 hours. Dimethylformamide was removed by rotary evaporation and the residual material was partitioned between ethyl acetate and water, the organic layer was separated, dried with sodium sulphate and solvent was removed by rotary evaporation. The desired product was isolated by column chromatography on silica using 5 to 100% ethyl acetate in n-pentane to afford a white solid (0.978g, 80%).
LC/MS (ES): Found 286 & 288 (ES+), retention time 2.61 mins. C12H13BrFNO requires 285 & 287.
1H-NMR (400MHz, CDCI3): 1.85 (2H, m), 1.96 (2H, m), 3.46 (4H, m), 3.60 (2H, s), 7.20- 7.28 (3H, m).
Description 13: 1-[(4-bromo-2-fluorophenyl)carbonyl]pyrrolidine
B
Figure imgf000035_0002
The title compound was prepared from 4-bromo-2-fluorobenzoic acid and pyrrolidine using a similar procedure to that used for Description 12.
LC/MS (ES): Found 272 & 274 (ES+), retention time 2.56mins. C11H11BrFNO requires 271 & 273.
1H-NMR (400MHz, CDCI3): 1.83 (4H, m), 2.28 (2H, m), 3.62 (2H, m), 7.27-7.40 (3H, m).
Description 14: 1-[(4-bromo-2-chlorophenyl)methyl]-2-pyrrolidinone
Figure imgf000036_0001
The title compound was prepared from 4-bromo-1-(bromomethyl)-2-chlorobenzene and 2- pyrrolidinone using a similar procedure to that used for Description 8.
LC/MS (ES): Found 288 & 290 (ES+), retention time 2.74mins. CnHnBr35CINO requires 287 & 289.
1H-NMR (400MHz, CDCI3): 2.21 (2H, m), 2.43 (2H, m), 3.33 (2H, m), 4.54 (2H, s), 7.13 (1 H, d, J=8Hz), 7.36 (1 H, m), 7.52 (1 H, s).
Description 15: 1-[(4-bromo-2-chlorophenyl)carbonyl]pyrrolidine
Figure imgf000036_0002
B
The title compound was prepared from 4-bromo-2-chlorobenzoic acid and pyrrolidine using a similar procedure to that described for Description 12.
LC/MS (ES): Found 288 & 290 (ES+), retention time 2.69mins. CnH11Br35CINO requires 287 & 289.
1H-NMR (400MHz, CDCI3): 1.98-2.0 (4H, m), 3.19 (2H, m), 3.66 (2H, m), 7.19 (1 H, d, J=8Hz), 7.44 (1 H, dd, J=6Hz & 2Hz), 7.57 (1 H, d, J=2Hz).
Description 16: 1-[(4-bromo-2-methylphenyl)carbonyl]pyrrolidine
Figure imgf000036_0003
The title compound was prepared from 4-bromo-2-methylbenzoic acid and pyrrolidine using a similar procedure to that used for Description 12.
LC/MS (ES): Found 268 & 270 (ES+), retention time 2.60mins. C12H14BrNO requires 267 & 269.
1H-NMR (400MHz, CDCI3): 1.87 (2H, m), 1.96 (2H, m), 2.30 (3H, s), 3.13 (2H, m), 3.65 (2H, m), 7.08 (1 H, d, J=8Hz), 7.34 (1 H, m), 7.49 (1 H, m). Description 17: 2-[(4-bromo-2-fluorophenyl)methyl]isothiazolidine 1,1 -dioxide
Figure imgf000037_0001
A solution of [(4-bromo-2-fluorophenyl)methyl]amine (2.Og, 9.8mmol) and triethylamine (2.73ml, 19.6mmol) in dimethylformamide (20ml) was treated with 3- chloropropanesulfonyl chloride (1.74g, 9.8mmole) dropwise over 10 minutes with stirring under argon. This mixture was stirred for 30 minutes before being treated with sodium hydride (60% suspension in mineral oil, 1.176g, 29.4mmol) portionwise and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. Sample was then purified by column chromatography on silica using 10 to 90% ethyl acetate in n-pentane to afford the title compound as an oil (1.7g, 55%).
LC/MS (ES): Found 308 & 310 (ES+), retention time 2.73mins. Ci0H11 BrFNO2S requires 307 & 309.
1H-NMR (400MHz, CDCI3): 2.34 (2H, m), 3.19 (4H, m), 4.20 (2H, d, J=I Hz), 7.22-7.35 (3H, m).
Description 18: ({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1 -yl]-2- pyridinyl}methyl)amine
Figure imgf000037_0002
Tetrahydrofuran (10ml) and lithium aluminium hydride in tetrahydrofuran (2M solution, 2.70ml, 5.40mmol) were stirred in an ice bath under argon. A solution of 5-[3- (trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-pyridinecarbonitrile (from Description 4) (0.79Og, 2.70mmol) in tetrahydrofuran (10ml) was added dropwise over 15 minutes and the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 1.5 hours. The reaction mixture was then cooled using the ice bath and quenched with water dropwise. The solvent was removed by rotary evaporation. Residual material was diluted with dichloromethane and water. Insoluble solid was filtered off and the organic layer separated, washed with brine, dried with sodium sulphate and evaporated under reduced pressure. The desired product was isolated by a SCX column eluted initially with dichloromethane, dichloromethane and methanol 1 :1 mixture, methanol and then the desired product eluted with 1 M solution of ammonia in methanol. The relevant ammonia fractions were combined and the solvent was removed by rotary evaporation which was then purified further by column chromatography on silica using dichloromethane - 1% aqueous ammonia 9% methanol in dichloromethane to give the title compound as an oil/gum (75mg, 9%).
LC/MS (ES): Found 297 (ES+), retention time 2.14mins. C14H15F3N4 requires 296.
1H-NMR (400MHz, CDCI3): 1.69 (2H, br s), 1.84 (4H, m), 2.70 (4H, m), 4.06 (2H, s), 7.43 (1 H, d, J=8Hz), 7.84 (1 H, dd, J=6Hz, J=2Hz), 8.70 (1 H, d, J=2Hz).
Description 19: 4-[(2-fluoro-4-iodophenyl)carbonyl]morpholine
Figure imgf000038_0001
The title compound was prepared from 2-fluoro-4-iodobenzoic acid and morpholine using a similar procedure to that used for Description 12.
LC/MS (ES): Found 336 (ES+), retention time 2.40mins. C11H11FINO2 requires 335. 1H-NMR (400MHz, CDCI3): 3.32 (2H, appr s), 3.64 (2H, m), 3.77 (4H, m), 7.13 (1 H, m), 7.49 (1 H, m), 7.58 (1 H, dd, J=7Hz, J=I Hz).
Description 20: 2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yljbenzonitrile
Figure imgf000038_0002
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (2.85g, 15mmol), copper (I) oxide (20mol%, 429mg), cesium carbonate (9.75g, 30mmol), 4-bromo-2-fluorobenzonitrile (3.Og, 15mmol) and N,N-dimethylglycine (1.545g, 15mmol) in dimethylsulfoxide (5ml) was heated at 13O0C for 1 hour. The reaction mixture was diluted with ethyl acetate. The mixture was filtered through kieselguhr to remove catalyst and the filtrate was washed with water, the organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure. Sample was then purified by column chromatography on silica using 30 to 70% dichloromethane in n-pentane and triturated with n-pentane to afford the title compound as a white solid (560mg, 12%).
LC/MS (ES): Found 310 (ES+), retention time 3.51 mins. C15H11F4N3 requires 309. 1H-NMR (400MHz, CDCI3): 1.85 (4H, m), 2.68 (2H, m), 2.81 (2H, m), 7.50 (2H, m), 7.73 (1 H, m).
Description 21 : ({2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1- yl]phenyl}methyl)amine
Figure imgf000039_0001
The title compound was prepared from 2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indazol-1-yl]benzonitrile (0.56Og, 1.81 mmol) and 2M solution of lithium aluminium hydride in tetrahydrofuran (3.62ml, 7.24mmol) using a similar procedure to that used for Description 18 to afford the title compound as an oil (0.316g, 56%).
LC/MS (ES): Found 314 (ES+), retention time 2.24mins. C15H15F4N3 requires 313. 1H-NMR (400MHz, CDCI3): 1.81 (4H, m), 2.70 (4H, m), 3.94 (2H, m), 7.25 (2H, m), 7.45 (1 H, m).
Example 1 : 1 -[6-(1 -pyrrolidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
Figure imgf000039_0002
A mixture of 5-bromo-2-(1-pyrrolidinylcarbonyl)pyridine (179mg, 0.7mmol), 3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole (133mg, 0.7mmol), copper (I) iodide
(10mol%, 0.07mmol, 13mg), N,N-dimethylglycine (20mol%, 0.14mmol, 14mg), and potassium carbonate (1.4mmol, 193mg) in dimethylsulfoxide (3ml) was stirred at 19O0C in a microwave reactor for 0.5h. The reaction mixture was partitioned between dichloromethane and water. The organic layer was added to a 5g isolute pre-packed silica column and eluted from 20-100% ethyl acetate in petroleum ether to give the title compound (38mg, 15%).
LC/MS (ES): Found 365 (ES+), retention time 3.15mins. C18H19F3N4O requires 364. 1 H-NMR (400MHz, CDCI3): 1.87 (4H, m), 1.95 (4H, m), 2.70 (2H, m), 2.76 (2H, m), 3.71 (2H, m), 3.79 (2H, m), 7.94-8.02 (2H, m), 8.80 (1 H, bs). Example 2: 1 -[5-(1 -pyrrolidinylcarbonyl)-2-pyridinyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
Figure imgf000040_0001
The title compound was prepared from 2-iodo-5-(1-pyrrolidinylcarbonyl)pyridine and 3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole using a similar procedure to that used for Example 1.
LC/MS (ES): Found 365 (ES+), retention time 3.44mins. C18H19F3N4O requires 364. 1 H-NMR (400MHz, CDCI3): 1.83 (4H, m), 1.91-2.02 (4H, m), 2.66 (2H, m), 3.19 (2H, m), 3.49 (2H, t, J=6Hz), 3.68 (2H, t, J=7Hz), 7.99 (2H, m), 8.61 (1 H, m).
Example 3: 1 -({6-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-3- pyridinyl}methyl)-2-pyrrolidinone
Figure imgf000040_0002
A mixture of 1-[(6-bromo-3-pyridinyl)methyl]-2-pyrrolidinone (102mg, 0.4mmol), 3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole (76mg, 0.4mmol), copper (I) iodide (10mol%, 0.04mmol, 8mg), N,N-dimethylglycine (20mol%, O.Oδmmol, 8mg), and potassium carbonate (O.δmmol, 110mg) in dimethylsulfoxide (3ml) was stirred at 19O0C in a microwave reactor for 0.5h. The reaction mixture was partitioned between dichloromethane and water. The organic layer was added to a 5g isolute pre-packed silica column and eluted from ethyl acetate, the solvent was removed under reduced pressure and the residue further purified by MDAP to give the title compound as a brown oil (17mg, 12%).
LC/MS (ES): Found 365 (ES+), retention time 3.24mins. C18H19F3N4O requires 364. 1 H-NMR (400MHz, CDCI3): 1.77-1.87 (4H, m), 2.04 (2H, m), 2.46 (2H, m), 2.65 (2H, m), 3.15 (2H, m), 3.30 (2H, m), 4.49 (2H, s), 7.72 (1 H, dd, J=8Hz & 2Hz), 7.90 (1 H, d, J=8Hz), 8.32 (1 H, d, J=2Hz). Example 4: methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2- pyri d i necarboxy I ate
Figure imgf000041_0001
A solution of 5-[3-(trifluoromethyl)-4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl]-2- pyridinecarbonitrile (2.56g, 8.8mmol) in dry methanol (10ml) was added to an oven dried round bottomed flask. Trimethylchlorosilane (2.23ml, 17.6mmol) was added dropwise with stirring under argon and the reaction mixture heated at 5O0C for 42 hours. The reaction mixture was cooled to room temperature and neutralised with saturated sodium hydrogen carbonate solution, dried over sodium sulphate and the methanol removed by rotary evaporation. Sample was then partitioned between dichloromethane and saturated sodium hydrogen carbonate solution, the organic layer was retained and dried over sodium sulphate. The solvent was removed by rotary evaporation to give the title compound as a pale brown solid (2.19g, 77%).
LC/MS (ES): Found 326 (ES+), retention time 3.19mins. C15H14F3N3O2 requires 325. 1 H-NMR (400MHz, CDCI3): 1.86 (4H, m), 2.69 (2H, m), 2.80 (2H, m), 4.05 (3H, s), 8.10 (1 H, dd, J=8Hz & 2Hz), 8.28 (1 H, m), 8.93 (1 H, m).
Example 5: {5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2- pyridinyl}methanol
Figure imgf000041_0002
A solution of methyl 5-[3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2- pyridinecarboxylate (761 mg, 2.3mmol) in dry tetrahydrofuran (20ml) was cooled to O0C in an ice/methanol bath. A 1.0M solution of lithium aluminium hydride in tetrahydrofuran (4.6ml) was added dropwise with stirring under argon and the whole mix stirred at room temperature for 2 hours. The reaction mix was quenched with water (0.5ml), 2M sodium hydroxide solution (0.8ml) and water again (0.5ml) with ice/methanol cooling. The reaction mix was dried over sodium sulphate and the solvent removed under reduced pressure to give a brown oil which was purified on a 5g isolute pre-packed silica column eluting from 20-100% ethyl acetate in petroleum ether to give the title compound as a yellow oil (221 mg, 32%).
LC/MS (ES): Found 298 (ES+), retention time 2.65mins. Ci4H14F3N3O requires 297. 1 H-NMR (250MHz, CDCI3): 1.76-1.89 (4H, m), 2.70 (4H, m), 4.84 (2H, s), 7.44 (1 H, m), 7.89 (1 H, dd, J=8Hz, 2Hz), 8.72 (1 H, d, J=2Hz).
Example 6: 1 -({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2- pyridinyl}methyl)-2-pyrrolidinone
Figure imgf000042_0001
To a solution of {5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2- pyridinyl}methanol (40mg, 0.13mmol) in dichloromethane (1 ml) was added triethylamine (26mg, 0.26mmol) followed by methanesulfonyl chloride (15mg, 0.13mmol). The mixture was stirred at 2O0C for 2 hours. The reaction mix was then evaporated under reduced pressure and the residue dissolved in dimethylformamide (0.5ml) and added to a mixture of 2-pyrrolidinone (1 1 mg, 0.13mmol) and sodium hydride (60% suspension in mineral oil, 6mg, 0.15mmol) in dimethylformamide (1 ml) which had been prepared 15 minutes earlier. The resulting mix was shaken at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane (4ml) and water (6ml). The organic layer was removed and added to a 5g isolute pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (8mg, 17%).
LC/MS (ES): Found 365 (ES+), retention time 2.78mins. C18H19F3N4O requires 364. 1 H-NMR (400MHz, CDCI3): 1.84 (4H, m), 2.06 (2H, m), 2.46 (2H, m), 2.71 (4H, m), 3.43 (2H, m), 4.65 (2H, s), 7.40 (1 H, d, J=8Hz), 7.84 (1 H, dd, J=8Hz & 2Hz), 8.70 (1 H, d, J=2Hz).
Example 7: 1 -[6-(1 -azetidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
Figure imgf000042_0002
Methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2-pyridinecarboxylate (164mg, 0.5mmol) and anhydrous magnesium chloride (24mg, 0.25mmol) was placed in an oven dried microwave vial. Anhydrous tetrahydrofuran was added (4ml) and the reaction stirred at room temperature for 5 minutes, then azetidine (42mg, 0.74mmol) was added in one portion and the reaction stirred for a further 2 hours. The reaction mixture was then dried to residue by rotary evaporation and partitioned between dichloromethane and water. The organic layer was retained and dried with sodium sulphate. Solvent was removed by rotary evaporation and the sample purified on a biotage 12+M silica column using 0-100% ethyl acetate / n-pentane solvent gradient. Relevant fractions were combined and the solvent removed to yield the title compound as a white solid (47mg, 27%).
LC/MS (ES): Found 351 (ES+), retention time 3.25mins. Ci7H17F3N4O requires 350. 1 H-NMR (400MHz, CDCI3): 1.85 (4H, m), 2.38 (2H, m), 2.69 (2H, m), 2.78 (2H, m), 4.27 (2H, m), 4.73 (2H, t, J=8Hz), 7.96 (1 H, dd, J=9Hz & 3Hz), 8.23 (1 H, m), 8.80 (1 H, m).
Example 8: Λ/-ethyl-Λ/-methyl-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]-2-pyridinecarboxamide
Figure imgf000043_0001
The title compound was prepared from methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1 H-indazol-1 -yl]-2-pyridinecarboxylate and N-methylethylamine using a similar procedure to that used for Example 7, except the sample required no further purification after the aqueous wash.
LC/MS (ES): Found 353 (ES+), retention time 3.03mins. Ci7H19F3N4O requires 352. 1 H-NMR (250MHz, CDCI3): 1.18-1.31 (3H, m), 1.85 (4H, m), 2.73 (4H, m), 3.08 & 3.12 (3H, s, rotomers), 3.44 & 3.63 (2H, m, rotomers), 7.77 (1 H, m), 7.96 (1 H, m), 8.78 (1 H, m).
Example 9: Λ/-(2-hydroxyethyl)-Λ/-methyl-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1 -yl]-2-pyridinecarboxamide
Figure imgf000044_0001
The title compound was prepared from methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indazol-1-yl]-2-pyridinecarboxylate and 2-(methylamino)ethanol using a similar procedure to that used for Example 7, except the sample required further purification by MDAP.
LC/MS (ES): Found 369 (ES+), retention time 2.64mins. Ci7H19F3N4O2 requires 368. 1 H-NMR (400MHz, CDCI3): 1.86 (4H, m), 2.69 (2H, m), 2.78 (2H, m), 3.19 (3H, s), 3.61 (2H, m), 3.89 (2H, m), 7.99 (1 H, m), 8.07 (1 H, dd, J=8Hz & 2Hz), 8.77 (1 H, m).
Example 10: (+/-) 1-({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2- pyridinyl}carbonyl)-3-pyrrolidinol
Figure imgf000044_0002
Methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2-pyridinecarboxylate (40mg, 0.12mmol) and anhydrous magnesium chloride (6mg, 0.06mmol) was placed in an oven dried microwave vial. Anhydrous tetrahydrofuran was added (1 ml) and the reaction stirred at room temperature for 5 minutes, then 3-pyrrolidinol was added (0.05ml) in one portion and the reaction stirred for a further 20 hours. Reaction mixture was then heated at 1000C for 35 minutes in a microwave reactor. A further portion of magnesium chloride (6mg, 0.06mmol) and 3-pyrrolidinol (0.05ml) was added and microwave heating continued for 1 hour. The reaction mixture was then dried to residue by rotary evaporation and partitioned between dichloromethane and water. The organic layer was retained and dried with sodium sulphate. Solvent was removed by rotary evaporation and the sample purified on a biotage 12+M silica column using 0-100% ethyl acetate / n-pentane solvent gradient. Relevant fractions were combined and the solvent removed to yield the title compound as a white solid (7mg, 15%).
LC/MS (ES): Found 381 (ES+), retention time 2.69mins. Ci8H19F3N4O2 requires 380. 1 H-NMR (400MHz, CDCI3): 1.86 (4H, m), 2.08 (2H, m), 2.69 (2H, m), 2.76 (2H, m), 3.80- 4.15 (4H, m), 4.57 (1 H, m), 7.97 (1 H, m), 8.05 (1 H, m), 8.81 (1 H, m). Example 11 : 1-[2-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
Figure imgf000045_0001
A mixture of 1-[(4-bromo-3-fluorophenyl)carbonyl]pyrrolidine (190mg, 0.7mmol), 3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole (133mg, 0.7mmol), copper (I) iodide (10mol%, 0.07mmol, 13mg), N,N-dimethylglycine (20mol%, 0.14mmol, 14mg), and potassium carbonate (1.4mmol, 193mg) in dimethylsulfoxide (3ml) was stirred at 19O0C in a microwave reactor for 0.5 hours. The reaction mixture was treated with fresh copper (I) iodide (10mol%, 0.07mmol, 13mg) and N,N-dimethylglycine (20mol%, 0.14mmol, 14mg) and heating continued for a further 0.5 hours. The reaction mixture was partitioned between dichloromethane (2 x 3ml) and water (5ml). The organic layers were added to a 5g isolute pre-packed silica column and eluted with ethyl acetate. The solvent was removed by rotary evaporation and the residue purified by MDAP to give the title compound as a brown oil (30mg, 1 1%).
LC/MS (ES): Found 382 (ES+), retention time 3.27mins. Ci9H19F4N3O requires 381. 1 H-NMR (400MHz, CDCI3): 1.82 (4H, m), 1.87-2.04 (4H, m), 2.48-2.76 (4H, m), 3.44 (2H, m), 3.64 (2H, m), 7.41 (1 H, m), 7.48-7.60 (2H, m).
Example 12: 1 -({3-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]phenyl}methyl)-2-pyrrolidinone
Figure imgf000045_0002
The title compound was prepared from 1-[(3-fluoro-4-iodophenyl)methyl]-2-pyrrolidinone and 3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole using a similar procedure to that used for Example 3.
LC/MS (ES): Found 382 (ES+), retention time 3.19mins. C19H19F4N3O requires 381. 1 H-NMR (400MHz, CDCI3): 1.82 (4H, m), 2.05 (2H, m), 2.48 (4H, m), 2.66 (2H, m), 3.31 (2H, m), 4.50 (2H, s), 7.14 (2H, m), 7.44 (1 H, m). Example 13: 1 -({2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]phenyl}methyl)-2-pyrrolidinone
Figure imgf000046_0001
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole (210mg, 1.1 mmol), copper (I) iodide (21 mg, 10mol%), potassium carbonate (305mg, 2.2mmol) and dimethylsulfoxide (3ml) was stirred for 1 minute, then 1-[(4-bromo-2-fluorophenyl)methyl]-2-pyrrolidinone (300mg, 1.1 mmol) and N,N-dimethylglycine (20mol%, 23mg) were successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 18O0C for 40 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with sodium sulphate and the solvent was removed by rotary evaporation. The desired product was isolated by column chromatography on silica using 5 to 50% ethyl acetate in n-pentane to give the title compound as a white solid (65mg, 15%).
LC/MS (ES): Found 382 (ES+), retention time 3.28mins. C19H19F4N3O requires 381. 1H-NMR (400MHz, CDCI3): 1.82 (4H, m), 2.20 (2H, m), 2.43 (2H, m), 2.66 (2H, m), 2.72 (2H, m), 3.32 (2H, m), 4.54 (2H, s), 7.22-7.30 (2H, m), 7.50 (1 H, t, J=8Hz).
Example 14: 1 -({2,6-difluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]phenyl}methyl)-2-pyrrolidinone
Figure imgf000046_0002
The title compound was prepared from 1-[(4-bromo-2,6-difluorophenyl)methyl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 13.
LC/MS (ES): Found 400 (ES+), retention time 3.34mins. C19H18F5N3O requires 399. 1H-NMR (400MHz, CDCI3): 1.85 (4H, m), 2.0 (2H, m), 2.40 (2H, m), 2.65 (2H, m), 2.79 (2H, m), 3.30 (2H, m), 4.60 (2H, s), 7.14 (2H, m). Example 15: 1 -{3-fluoro-4-[2-oxo-2-(1 -pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole
Figure imgf000047_0001
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole (232mg, 1.22mmol), copper (I) iodide (23mg, 10mol%), potassium carbonate (337mg, 2.44mmol) and dimethylsulfoxide (3ml) was stirred for 1 minute, then 1-[(4-bromo-2- fluorophenyl)acetyl]pyrrolidine (0.35Og, 1.22mmol) and N,N-dimethylglycine (20mol%, 25mg) were successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 18O0C for 40 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with sodium sulphate and the solvent was removed by rotary evaporation. The desired product was isolated by column chromatography on silica using 5 to 50% ethyl acetate in n-pentane which was further purified by MDAP to give the title compound as a colourless gum.(48mg, 10%).
LC/MS (ES): Found 396 (ES+), retention time 3.31 mins. C20H2IF4N3O requires 395. 1H-NMR (400MHz, CDCI3): 1.80 (4H, m), 1.88 (2H, m), 1.98 (2H, m), 2.65 (2H, appr br s), 2.72 (2H appr br s), 3.50 (4H, m), 3.69 (2H, s), 7.24 (2H, m), 7.42 (1 H, m).
Example 16: 1-[3-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole
The title compound was prepared from 1-[(4-bromo-2- fluorophenyl)carbonyl] pyrrolidine and 3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole using a similar procedure to that used for Example 15.
LC/MS (ES): Found 382 (ES+), retention time 3.29mins. Ci9H19F4N3O requires 381. 1H-NMR (400MHz, CDCI3): 1.80 (4H, m), 1.90 (2H, m), 1.98 (2H, m), 2.65 (2H, m), 2.75 (2H, m), 3.32 (2H, m), 3.67 (2H, m), 7.35 (2H, m), 7.53 (1 H, m). Example 17: 1 -({2-chloro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]phenyl}methyl)-2-pyrrolidinone
Figure imgf000048_0001
The title compound was prepared from 1-[(4-bromo-2-chlorophenyl)methyl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 /-/-indazole using a similar procedure to that used for Example 15.
LC/MS (ES): Found 398 (ES+), retention time 3.42mins. C19H19F3CIN3O requires 397. 1H-NMR (400MHz, CDCI3): 1.83 (4H, m), 2.07 (2H, m), 2.46 (2H, m), 2.65 (2H, m), 2.71 (2H, m), 3.33 (2H, m), 4.63 (2H, s), 7.37 (2H, d, J=I Hz), 7.58 (1 H, m).
Example 18: 1 -[3-chloro-4-(1 -pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-
4,5,6,7-tetrahydro-1 H-indazole
Figure imgf000048_0002
The title compound was prepared from 1-[(4-bromo-2-chlorophenyl)carbonyl] pyrrolidine and 3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole using a similar procedure to that used for Example 15.
LC/MS (ES): Found 398 (ES+), retention time 3.42mins. C19H19F3CIN3O requires 397. 1H-NMR (400MHz, CDCI3): 1.82 (4H, m), 1.88-2.20 (4H, m), 2.67 (2H, m), 2.72 (2H, m), 3.20 (2H, m), 3.66 (2H, m), 7.38-7.48 (2H, m), 7.60 (1 H, d, J=2Hz).
Example 19: 1 -[3-methyl-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole
Figure imgf000048_0003
The title compound was prepared from 1-[(4-bromo-2-methylphenyl)carbonyl] pyrrolidine and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole using a similar procedure to that used for Example 15.
LC/MS (ES): Found 378 (ES+), retention time 3.34mins. C20H22F3N3O requires 377. 1H-NMR (400MHz, CDCI3): 1.80 (4H, m), 1.88 (2H, m), 1.97 (2H, m), 2.37 (3H, s), 2.67 (4H, m), 3.1 1 (2H, m), 3.66 (2H, m), 7.29 (2H, m), 7.38 (1 H, s).
Example 20: 1-{4-[(1 J ^ioxido^-isothiazolidinylJmethyll-S-fluoropheny^-S- ftrifluoromethylJ^S.Θ.Z-tetrahydro-IH-indazole
Figure imgf000049_0001
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (200mg, 1.05mmol), copper (I) oxide (20mol%, 30mg), cesium carbonate (685mg, 2.10mmol), 2-[(4-bromo-2- fluorophenyl)methyl]isothiazolidine 1 ,1-dioxide (324mg, 1.05mmol) and N, N,- dimethylglycine (108mg, 1.05mmol) in dimethylsulfoxide (2ml) was heated at 13O0C for 3 hours. The reaction mixture was diluted with ethyl acetate. The mixture was filtered through kieselguhr to remove catalyst and the filtrate was washed with water, the organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure. Sample was then purified by column chromatography on silica using 10 to 50% ethyl acetate in n-pentane and followed by MDAP to afford the title compound as a colourless gum (55mg, 13%).
LC/MS (ES): Found 418 (ES+), retention time 3.38mins. C18H19F4N3O2S requires 417. 1H-NMR (400MHz, CDCI3): 1.84 (4H, m), 2.35 (2H, m), 2.67 (2H, m), 2.72 (2H, m), 3.21 (4H, m), 4.29 (2H, s), 7.31 (2H, m), 7.55 (1 H, m).
Example 21 : Λ/-({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2- pyridinyl}methyl)methanesulfonamide
Figure imgf000049_0002
A solution of ({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2- pyridinyl}methyl)amine (0.075g, 0.253mmol), triethylamine (0.07ml, 0.506mmol) in dichloromethane (10ml) was stirred in an ice bath under argon . Methanesulfonyl chloride (0.058g, 0.04ml, 0.506mmol) was added dropwise with stirring. The resulting mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was washed with water, the organic layer was separated, dried with sodium sulphate and the solvent was removed by rotary evaporation and the desired product was purified by MDAP to afford the title compound as an off white solid (14mg, 15%).
LC/MS (ES): Found 375 (ES+), retention time 2.84mins. C15H17F3N4O2S requires 374. 1H-NMR (400MHz, CDCI3): 1.82 (4H, m), 2.69-2.75 (4H, m), 2.96 (3H, s), 4.51 (2H, d, J=6Hz), 5.50 (1 H, br s), 7.44 (1 H, d, J=8Hz), 7.90 (1 H, m), 8.74 (1 H, m).
Example 22: 1 -[3-fluoro-4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole
Figure imgf000050_0001
A mixture of copper (I) oxide (85mg, 0.6mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole (113mg, 0.6mmol), cesium carbonate (389mg, 1.2mmol) and dimethylsulfoxide (3ml) was stirred for 1 minute, then 4-[(2-fluoro-4-iodophenyl)carbonyl]morpholine (0.20Og, 0.6mmol) and N,N-dimethylglycine (61 mg, 0.6mmol) were successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 18O0C for 30 minutes. The reaction mixture was diluted with ethyl acetate, the mixture was filtered through kieselguhr to remove catalyst and the filtrate was washed with water and brine, the organic layer was dried with sodium sulphate and solvent was removed by rotary evaporation. The desired product was isolated by column chromatography on silica using 10 to 70% ethyl acetate in n-pentane which was further purified by MDAP to give the title compound as a white solid (104mg, 44%).
LC/MS (ES): Found 398 (ES+), retention time 3.17mins. C19H19F4N3O2 requires 397. 1H-NMR (400MHz, CDCI3): 1.84 (4H, m), 2.68 (2H, m), 2.75 (2H, m), 3.60 (2H, appr s), 3.66 (2H, m), 3.80 (4H, m), 7.38 (2H, m), 7.52 (1 H, m).
Example 23: Λ/-({2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1- yl]phenyl}methyl)methanesulfonamide
Figure imgf000051_0001
A mixture of ({2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 /-/-indazol-1- yl]phenyl}methyl)amine (200mg, 0.64mmol), triethylamine (0.18ml, 1.28mmol) in dichloromethane (10ml) was stirred in an ice bath. Methanesulfonyl chloride (0.1 ml, 1.28mmol) was added dropwise with stirring. The resulting mixture was allowed to stir at room temperature for 5 hours. The reaction mixture was washed with water, the organic layer was separated, dried with sodium sulphate and solvent was removed by rotary evaporation. The desired product was purified by MDAP and triturated with n-pentane to give the title compound as a white solid (0.139g, 56%).
LC/MS (ES): Found 392 (ES+), retention time 3.23mins. C16H17F4N3O2S requires 391. 1H-NMR (400MHz, CDCI3): 1.83 (4H, m), 2.67 (2H, m), 2.74 (2H, m), 2.91 (3H, s), 4.42 (2H, d, J=4Hz), 4.70 (1 H, m), 7.33 (2H, m), 7.51 (1 H, m).
Biological Assays
The ability of the compounds of the invention to potentiate AMPA 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. In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).
a) Calcium Influx Fluorescence Assay 384 well plates were 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 were discarded and the wells were 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 were 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 was then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well was washed three times with buffer (80 μl_) (30 μl_ of buffer remained in each well after washing).
Compounds of the invention (or the reference compound, cyclothiazide) were dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions were further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 μl_) was transferred to another compound plate and buffer (50 μl_) added. An agonist stimulus (glutamate) plate was prepared by dissolving sodium glutamate in water to give a concentration of 100 mM. This solution was 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 was then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)]. A baseline fluorescence reading was 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) was added (to give a final concentration in the range 30 μM to 3 pM). The fluorescence was read over 5 minute period. 500 μM glutamate solution (10μl_) was added (to give a final concentration of 100 μM). The fluoresecence was then read over a 4 minute period. The activities of the compounds of the invention and the reference compound were determined by measuring peak fluorescence after the last addition. The activity was 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 pEC5o 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. For each compound, more than one reading was taken.
All the Example compounds were screened using the assay as described above and the average of the measurable pEC50s were taken. All compounds gave an average PEC50 equal to or greater than 4.0 and/or demonstrated an activity of on average 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 may be 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 contained: 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 contained: 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 were 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 were back-filled with internal recording solution. Positive pressure was 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 was used to apply extracellular solution to the bath. Rapid solution exchange used a fast step perfusion system (Biologic RSC160). Two outlet tubes attached together along their length were positioned close to a chosen cell so that the outflow from only one tube could 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 was removed via a tube positioned at the edge of the chamber connected to a vacuum line.
A prospective cell was positioned in the centre of the microscope field of view. Recording electrode was positioned directly above the cell membrane surface. Using fine manipulator control (Luigs and Neumann, SM-6) the electrode was lowered, while monitoring the change in electrode resistance during delivery of a 5 mV depolarizing pulse, until a high resistance seal (gigaseal) was achieved. Whole cell configuration was achieved by removing by suction a small fragment of cell membrane immediately beneath the recording electrode tip. The cell membrane potential was held at -70 mV (voltage- clamped) via the electrode (Axopatch 200B Integrating patch clamp amplifier, pClamp software, Axon Instruments). Test solutions were applied using the fast application system using the following protocol and changes in inward current were 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. All experiments were 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).
The range of mean responses at 1 OnM increased 30 uM AMPA response by 11 to 79 % and at 1O uM by 42 to 679%.

Claims

Claims
1. A compound of formula (I) or a salt thereof:
Figure imgf000055_0001
(I) wherein
A is a group selected from:
Figure imgf000055_0002
(a) (b) (C)
wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen and C1-6alkyl, wherein R1, R2 and R3 are not all hydrogen;
X is selected from the group consisting of CH2OH, C(O)R4, CH2R4 and CH2C(O)R4;
R4 is selected from the group consisting of OR5 and NR6R7, wherein R5 is C1-6alkyl;
R6 and R7 are:
(i) independently C1-6alkyl, wherein one of the alkyl is optionally substituted by hydroxy; or
(ii) R6 is hydrogen and R7 is C1-6alkylsulfonyl; or
(iii) R6 and R7, together with the nitrogen atom to which they are attached, form a 4, 5 or 6-membered heterocyclic ring, which ring is optionally substituted by one or two groups selected from oxo and hydroxy.
2. A compound as claimed in claim 1 , wherein A is selected from the group consisting of:
Figure imgf000055_0003
(b) (c) (d) (e) (f)
3. A compound as claimed in claim 1 , which is selected from the group consisting of: 1-[6-(1-pyrrolidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole
1-[5-(1-pyrrolidinylcarbonyl)-2-pyridinyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole
1-({6-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-3-pyridinyl}methyl)-2- pyrrolidinone methyl 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-pyridinecarboxylate
{5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-pyridinyl}methanol
1-({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-pyridinyl}methyl)-2- pyrrolidinone
1 -[6-(1-azetidinylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazole N-ethyl-N-methyl-S-p-CtrifluoromethylH.S.ΘJ-tetrahydro-I H-indazol-i-yl]^- pyridinecarboxamide
N-(2-hydroxyethyl)-N-methyl-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1-yl]-2- pyridinecarboxamide i-^S-tS-CtrifluoromethylH.S.ΘJ-tetrahydro-I H-indazol-i-yll^-pyridinyllcarbonyO-S- pyrrolidinol
1-[2-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
1-({3-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]phenyl}methyl)-2- pyrrolidinone 1-({2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]phenyl}methyl)-2- pyrrolidinone
1-({2,6-difluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]phenyl}methyl)-2- pyrrolidinone
1-{3-fluoro-4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1 H-indazole
1-[3-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole i-^-chloro^-^-^rifluoromethylH.δ.θJ-tetrahydro-I H-indazol-i-yOphenylJmethyl)^- pyrrolidinone 1-[3-chloro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
1-[3-methyl-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole
1-{4-[(1 ,1-dioxido-2-isothiazolidinyl)methyl]-3-fluorophenyl}-3-(trifluoromethyl)-4, 5,6,7- tetrahydro-1 H-indazole
N-({5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2- pyridinyl}methyl)methanesulfonamide
1-[3-fluoro-4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazole N-({2-fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 - yl]phenyl}methyl)methanesulfonamide and salts thereof.
4. A compound as claimed in any of claims 1-3 for use in medicine.
5. A compound as claimed in any of claims 1-3 for use in the treatment of a disease or a condition mediated by a reduction or imbalance in glutamate receptor function.
6. A compound as claimed in claim 5, wherein the disease or condition is schizophrenia or impairment of cognition.
7. Use of a compound as claimed in any of claims 1-3 in the manufacture of a medicament for treating or preventing a disease or a condition mediated by a reduction or imbalance in glutamate receptor function.
8. Use as claimed in claim 7 wherein the disease or condition is schizophrenia or impairment of cognition.
9. A method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound as claimed in any of claims 1-3.
10. A method as claimed in claim 9 wherein the disease or condition is schizophrenia or impairment of cognition.
11. A pharmaceutical composition comprising a compound as defined in any of claims 1-3 and at least one carrier, diluent or excipient.
12. A combination product comprising a compound as claimed in any of claims 1-3 with an antipsychotic.
PCT/EP2008/052906 2007-03-14 2008-03-12 Compounds which potentiate ampa receptor and uses thereof in medicine WO2008110566A1 (en)

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