WO2004113280A1 - Inhibiteurs de transporteurs de glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques - Google Patents

Inhibiteurs de transporteurs de glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques Download PDF

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WO2004113280A1
WO2004113280A1 PCT/EP2004/006595 EP2004006595W WO2004113280A1 WO 2004113280 A1 WO2004113280 A1 WO 2004113280A1 EP 2004006595 W EP2004006595 W EP 2004006595W WO 2004113280 A1 WO2004113280 A1 WO 2004113280A1
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4alkyl
alkyl
group
independently selected
hydrogen
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PCT/EP2004/006595
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Clive Leslie Branch
David John Nash
Roderick Alan Porter
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to glycine transporter inhibiting compounds, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychosis, dementia or attention deficit disorder.
  • the invention further comprises processes to make these compounds and pharmaceutical formulations thereof.
  • Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialised structures in both the pre-and post-synaptic terminal and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1987:1032).
  • Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighbouring synapses, transporters maintain the fidelity of synaptic transmission. Last, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilisation.
  • Neurotransmitter transport is dependent upon extracellular sodium and the voltage difference across the membrane; under conditions of intense neuronal firing, as, for example, during seizure, transporters can function in reverse, releasing neurotransmitter in a calcium-independent non-exocytotic manner (Atwell et al., Neuron, 11 , 1993: 401-407). Pharmacologic modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.
  • the amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are thus referred to as "strychnine-sensitive".
  • Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased.
  • Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
  • Glycine also functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system. See Johnson and Ascher, Nature, 325, 1987: 529-531 ; Fletcher et al., Glycine Transmission, Otterson and Storm-Mathisen, eds., 1990: 193-219.
  • glycine is an obligatory co-agonist at the class of glutamate receptor termed N- methyl-D-aspartate (NMDA) receptor.
  • NMDA N- methyl-D-aspartate
  • Activation of NMDA receptors increases sodium and calcium conductance, which depolarises the neuron, thereby increasing the likelihood that it will fire an action potential.
  • NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
  • GlyT1 is found predominantly in the forebrain and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992: 927-935).
  • GlyT-la,- GlyT-1 b and GlyT-1c displays a unique distribution in the brain and peripheral tissues.
  • GlyT2 in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033).
  • Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT1.
  • NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev.. 19 533-552 (1995); Danysz et al, Behavioral Pharmacol..
  • agents that inhibit GlyT1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes.
  • over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma. Coyle & Puttfarcken, Science.
  • Glycine transport inhibitors are already known in the art, for example as disclosed in published International Applications WO97/45423 (Trophix Pharmaceuticals, Inc.), and WO97/45115 (Trophix Pharmaceuticals Inc.).
  • the classes of compounds disclosed in these applications inhibit glycine transport via the GlyTI or GlyT2 transporters.
  • GlyTI transporters include those that inhibit GlyTI transporters selectively over GlyT2 transporters.
  • Such compounds would thus be suitable for the treatment of certain neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes.
  • neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • drug-induced phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine
  • psychosis psychosis associated with affective disorders
  • brief reactive psychosis schizoaffective psychosis
  • psychosis NOS "schizophrenia-spectrum” disorders such as
  • WO95/24385 discloses certain compounds which are claimed to be aspartyl protease inhibitors useful for inhibiting HIV-1 and HIV-2 protease activity.
  • R 1 and R 2 is independently selected from hydrogen, substituted Chalky!, substituted C3_6cycloalkyl, optionally substituted aryl, optionally substituted arylC-]. 4alkyl and optionally substituted arylC3_6cycloalkyl, wherein R 1 and R 2 are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from:
  • n represents an integer from 1 to 4; wherein when the substituent is R 30 R 31 N(CH 2 )n- or R 30 R 31 N(CH 2 )nO, R 30 with at least one CH 2 of the (CH 2 )n portion of the group may also form a C3_gazacycloalkane and R 31 may represent hydrogen, a C- ⁇ alkyl group or with the nitrogen to which it is attached, may form a second Cs. ⁇ azacycloalkane fused to the first C3_ gazacycloalkane;
  • R 1 and R 2 together with the nitrogen atom to which they are attached, are linked to form a 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said saturated ring being substituted by one or more groups independently selected from:
  • halogen hydroxy, oxo, cyano, nitro, C- ⁇ alkoxy, halo i ⁇ alkyl, haloC ⁇
  • R 30 R 31 NSO 2 (CH 2 ) r or R 30 SO 2 NR 31 (CH 2 ) r (where each of R 30 and R 31 independently represents a hydrogen atom or a Ci ⁇ alkyl group or where appropriate R 30 R 31 forms part of a C3_6azacyloalkane or C3_ ⁇ (2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R 30 R 31 N(CH 2 )n- or R 30 R 31 N(CH 2 )nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R 30 R 31 N(CH 2 )n- or R 30 R 31 N(CH 2 )nO, R 30 with at least one CH 2 of the (CH 2 )n portion of the group may also form a C3_6azacycloalkane and R 31 may represent hydrogen, a C- j _
  • R 3 is wherein
  • Y is Ci-Ca alkylene, C 2 alkenylene or C 2 alkynylene, and n is 0 or 1, and
  • Z is a 5- to 8-membered monocyclic or 6- to 10-membered bicyclic aromatic ring system wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, and said ring system being optionally substituted by one or more groups independently selected from -hal, -R 10 , -CF3, -C-i- ⁇ alkylsulphonyl, -OR 11 , -COOR 12 , -CN, -NO 2 , -NR 13 R 14 , -C(O)NR 15 R 16 , -NR 17 C(O)R 18 , -C(O)R 19 , -C(NR 20 )NR 21 R 22 , -C(NOR 23 )R 28 , wherein hal is F, Cl, Br or l, R 10 is Ci-Ce alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 4 alky
  • R 5 is independently selected from hydrogen, d-C 6 alkyl, C 3 -C 6 cycloalkyl, aryl and arylC ⁇ -C 4 alkyl, optionally substituted by one or more groups independently selected from hal, d-C 6 alkyl, -OR 24 , -COOR 25 -CN, -NO 2 and -NR 26 R 27 , wherein R 24 , R 25 , R 26 and R 27 are as hereinbefore defined.
  • disorders mediated by GlyTI refers to disorders that may be treated by the administration of a medicament that alters the activity of the GlyTI transporter.
  • the action of GlyTI transporters affects the local concentration of glycine around NMDA receptors.
  • any change to that local concentration can affect NMDA-mediated neurotransmission.
  • changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders and autism.
  • alterations in the activity of the GlyTI transporter are expected to influence such disorders.
  • Cx-y and “Cx-Cy” are equivalent.
  • C1-6alkyl is the same as “C1-C6 alkyl”.
  • d.Ce alkyl refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 6, carbon atoms.
  • Examples of "Ci.Ce alkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl.
  • .C 4 alkyl refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 4, carbon atoms.
  • Examples of "d-C 4 alkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-propyl and t-butyl.
  • C 3- C 6 cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to six carbon atoms.
  • Exemplary "C 3 -C 6 cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 3 -C 6 cycloalkylC 1 -C 4 alkyl refers to a C 3- C 6 cycloalkyl group, as hereinbefore defined, attached through a C C 4 alkylene linker, wherein d- C 4 alkylene is as defined herein.
  • Examples of "C 3 -C 6 cycloalkylC 1 -C 4 alkyl” include, but are not limited to, cyclohexylmethyl.
  • aryl refers to a 5- to 7-membered aromatic or heteroaromatic ring system wherein the heteroaromatic ring contains at least one heteroatom selected from N, O and S.
  • aryl groups include, but are not limited to, thienyl, furanyl, phenyl and pyridyl.
  • aryl C C 4 alkyl refers to an aryl group, as hereinbefore defined, attached through a C C 4 alkylene linker, wherein C C 4 alkylene is as defined herein.
  • aryl d-C 4 alkyl include, but are not limited to, benzyl, phenethyl, pyridylmethyl and phenylpropyl.
  • C ⁇ _C 2 alkylene refers to a straight or branched chain divalent hydrocarbon radical, which contains at least
  • d-C 2 alkylene 1, 2, 3 or 4, carbon atoms respectively.
  • d.C 3 alkylene 1, 2, 3 or 4 alkylene groups
  • d.C 4 alkylene groups useful in the present invention include methylene, ethylene, n-propylene and n-butylene.
  • C 2 alkenylene refers to a divalent hydrocarbon radical with a double bond, which contains 2 carbon atoms.
  • C 2 alkynylene refers to a divalent hydrocarbon radical with a triple bond, which contains 2 carbon atoms.
  • hal is an abbreviation for "halogen” and refers to fluorine, chlorine, bromine, or iodine.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur, and event(s) that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution by independently chosen substituents being allowed unless otherwise stated. Where there is more than one substituent, the substituents may be different or the same.
  • 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.
  • Physiologically 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 physiologically acceptable anion or cation.
  • physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesul, in
  • Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or formula (la), or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • physiologically functional derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5 th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
  • R 1 and R 2 may be independently selected from the group defined in the first aspect of the invention.
  • R 1 and/or R 2 are independently substituted C ⁇ _galkyl, substituted C3_6cycloalkyl, substituted aryl, substituted arylC ⁇ alkyl or substituted arylC3_gcycloalkyl
  • the substituent(s) in each case is/are independently selected from the group defined in the first aspect of the invention.
  • the number of substituents is 1 , 2, 3 or 4.
  • R 1 and R 2 together with the nitrogen atom to which they are attached, may be linked to form a 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said saturated ring being substituted by one or more groups independently selected from the group defined in the first aspect of the invention.
  • the number of substituents is 1 , 2, 3 or 4.
  • the 5- to 8-membered aromatic monocyclic moiety of Z is selected from: furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
  • the 6- to 10-membered aromatic bicyclic moiety of Z is selected from: thienofuranyl, indolizinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, chromanyl, chromenyl, isochromanyl, indenyl, imidazoleisothiazolyl benzothiadiazolyl, naphthyl or azulenyl.
  • the compound of formula (I) as hereinbefore described has the following stereochemical configuration:
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the sole heteroatom in the heterocyclic ring is the nitrogen atom to which R 1 and R 2 are attached, said ring being substituted as hereinbefore described.
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a 5- or 6-membered ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said ring being substituted as hereinbefore described .
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a 5- or 6-membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R 1 and R 2 are attached, said ring being substituted as hereinbefore described.
  • the 4-, 5-, 6- or 7-membered saturated ring formed by R 1 and R 2 together with the nitrogen atom to which they are linked is selected from the group comprising: azetidine, azepine, pyrrolidine, imidazolidine, piperidine, morpholine, thiomorpholine, and piperazine.
  • R 1 or R 2 together with the nitrogen atom to which they are attached, may not form any of the following structures:
  • n 0.
  • Z is a 5- to 8-membered monocyclic ring system as hereinbefore described.
  • Z is a 5- or 6-membered monocyclic ring system as hereinbefore described.
  • Z is phenyl optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R 10 , -CF3, -Ci-C ⁇ alkylsulphonyl, -OR 11 , -COOR 12 , -CN, -NO 2 , -NR 13 R 14 as hereinbefore defined, more preferably by one or more groups independently selected from -hal, d-C 6 alkyl, d-C 6 alkoxy, CF3, -CN and C 3 -C 6 cycloalkyl.
  • Z is a 6- to 10-membered bicyclic ring system as hereinbefore described.
  • Z is naphthyl, naphthyridinyl, quinolyl, isoquinolyl, benzothienyl, chromanyl, chromenyl, imidazoleisothiazolyl, benzothiadiazolyl, benzofuryl, optionally substituted as hereinbefore described.
  • Z is quinolinyl (preferably 5-quinolinyl), optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R 10 , -OR 11 , -COOR 12 , -CF3, -C ⁇
  • Z is 5-quinolinyl optionally substituted by one or more groups independently selected from -hal, C ⁇ -C 6 alkyl, Ci-Ce alkoxy, -CF3, -CN and C 3 -C 6 cycloalkyl.
  • R 3 is phenyl or 5-quinolinyl.
  • R 4 is hydrogen or d-C 6 alkyl, preferably hydrogen.
  • R 5 is selected from hydrogen, C ⁇ -C 6 alkyl, aryl and benzyl, optionally substituted by one or more groups independently selected from hal, d-C 6 alkyl and OR 24 .
  • R 5 is hydrogen.
  • R 6 , R 7 , R 8 and R 9 are independently selected from hydrogen and Ci-Ce alkyl, preferably hydrogen.
  • R 1 and R 2 is independently selected from hydrogen, substituted C- ⁇ galkyl, substituted C3_gcycloalkyl, optionally substituted aryl, optionally substituted arylC- ⁇ 4alkyl and optionally substituted arylC3_gcycloalkyl, wherein R 1 and R 2 are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from:
  • halogen hydroxy, oxo, cyano, nitro, C-]_galkyl, C ⁇ alkoxy, haloci-4alkyl, haloC ⁇
  • R 1 and R 2 together with the nitrogen atom to which they are attached, are linked to form a 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said saturated ring being substituted by one or more groups independently selected from:
  • R 30 R 31 NSO 2 (CH 2 )r or R 30 SO 2 NR 31 (CH 2 ) r (where each of R 30 and R 31 independently represents a hydrogen atom or a C ⁇ alkyl group or where appropriate R 30 R 31 forms part of a C3_gazacyloalkane or C3_g(2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R 30 R 31 N(CH 2 )n- or R 30 R 31 N(CH 2 )nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R 30 R 31 N(CH 2 )n- or R 30 R 31 N(CH 2 )nO, R 30 with at least one CH 2 of the (CH 2 )n portion of the group may also form a C3_gazacycloalkane and R 31 may represent hydrogen, a C-
  • Z is a 5- or 6-membered monocyclic or 8- to 10-membered bicyclic aromatic ring system wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, and said ring system being optionally substituted by one or more groups independently selected from -hal, -R 10 , -OR 11 , -
  • R 10 is C ⁇ -C 4 alkyl or phenyl, optionally substituted by one or more hal groups, and R 11 , R 12 , R 13 and R 1 are independently selected from hydrogen and methyl.
  • R 11 , R 12 , R 13 and R 1 are independently selected from hydrogen and methyl.
  • the C 2 alkenylene group may be in the cis or trans configuration, preferably the trans configuration.
  • the compound of formula (la) as hereinbefore described has the following stereochemical configuration:
  • Examples of compounds of the invention include:
  • the compounds of formulae (I) and (la) have the ability to crystallise in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of formulae (I) and (la).
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process.
  • Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • Certain of the compounds described herein may exist in stereoisomeric forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism).
  • the individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention.
  • compounds of formulae (I) and (la) may exist in tautomeric forms other than that shown in the formulae and these are also included within the scope of the present invention.
  • individual enantiomers of compounds of formulae (I) and (la) may be prepared and an indication of the preferred stereochemistry for such enantiomers has been given. In a preferred embodiment, an optically pure enantiomer is desired.
  • optically pure enantiomer means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
  • affinities of the compounds of this invention for the GlyTI transporter can be determined by the following assay:
  • HEK293 cells expressing the Glycine (Type 1) transporter were grown in cell medium (DMEM/NUT mix F12) containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 37°C in 5% CO2.
  • Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.6x10 ⁇ cells/ml in assay buffer [NaCI (140 mM), KCI (5.4 mM), CaCI 2 (1.8 mM), MgSO 4 (0.8 mM), HEPES (20 mM), glucose (5 mM) and alanine (5 mM), pH 7.4].
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by GlyTI which comprises administering an effective amount of a GlyTI inhibiting compound of formula (I) or (la) as hereinbefore defined or a salt, solvate or a physiologically functional derivative thereof.
  • the disorders mediated by GlyTI referred to herein include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes.
  • Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • the disorders mediated by GlyTI to be treated by the use or method as hereinbefore described are psychoses, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
  • different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
  • Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
  • a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt, solvate or a physiologically functional derivative thereof, but not including the compounds excluded from the third aspect of the present invention, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound of formula (la) as hereinbefore described or a salt, solvate or a physiologically functional derivative thereof, but not including the compounds excluded from the third aspect of the present invention, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • compositions may be used in the treatment of clinical conditions for which a GlyTI inhibitor is indicated such as, for example, schizophrenia.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or (la) as hereinbefore described as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • Possible formulations include those suitable for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • parenteral for example, subcutaneous, intramuscular, or intravenous
  • rectal topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • inhalation or insufflation either through the mouth or nose.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • a flavoured base such as sugar and acacia or tragacanth
  • pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intraveneously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • the formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • the compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
  • a proposed dose of the active ingredient for use according to the invention for oral, sub-lingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GlyTI inhibitor, including schizophrenia, may be about 1 to about 1000 mg, preferably about 5 to about 500 mg, more preferably about 10 to about 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • a compound of formula (I) as hereinbefore described and salts, solvates and physiologically functionally derivatives thereof, but not including the compounds excluded from the third aspect of the present invention there is provided a compound of formula (la) as hereinbefore described and salts, solvates and physiologically functionally derivatives thereof but not including the compounds excluded from the third aspect of the present invention.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • a compound When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds of formula (I) may be prepared using methodology similar to that described by Gutcait A. et al., Tetrahedron Asymmetry, 1996, 7(6), 1641-1648.
  • the reduction of the azide may be carried out using all methods known to those skilled in the art, for example, hydrogenation in the presence of catalyst such as palladium on carbon, Pd(OH) 2 and those known in the art, see for example March, Advanced Organic Chemistry, 4 th edition, Wiley Interscience.
  • the reduction of the azide is preferably carried out by hydrogenation in the presence of a catalyst such as palladium on carbon.
  • Schemes 1 , 2 and 3 can be adapted to prepare compounds wherein R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are other than hydrogen.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as hereinbefore defined, with a compound of formula (III): R J SO 2 L (III)
  • R 3 is as hereinbefore defined and L is a suitable leaving group, such as, for example, a halogen, preferably chlorine; or
  • R 3 , R 5 , R 6 and R 7 are as defined for formula (!), with a compound of formula R 1 R 2 N wherein R 1 and R 2 are as defined for formula (I),
  • Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques.
  • possible conversion reactions include acylation with an appropriate acylating agent such as acetyl chloride, alkylation using an appropriate alkylating reagent such as methyl iodide, and sulfonylation using a sulfonylating agent such as methanesulfonic anhydride.
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.

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Abstract

L'invention concerne l'utilisation d'un composé de la formule (I) ou d'un sel, d'un solvate ou d'un dérivé physiologiquement fonctionnel de celui-ci, dans la production d'un médicament de traitement d'un trouble médié par GlyT1 tel que par exemple la schizophrénie, formule dans laquelle R1, R2, R3, R4, R5, R6, R7, R8 et R9 ont la notation figurant dans la description.
PCT/EP2004/006595 2003-06-20 2004-06-17 Inhibiteurs de transporteurs de glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques WO2004113280A1 (fr)

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WO2006123020A1 (fr) * 2005-05-18 2006-11-23 Juvantia Pharma Ltd Oy Peptidomimetiques a haute selectivite pour les sous-types 1 et/ou 4 des recepteurs de la somatostatine
WO2007014762A2 (fr) * 2005-08-02 2007-02-08 Glaxo Group Limited Inhibiteurs de transporteurs glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques
US8039514B2 (en) 2008-06-05 2011-10-18 Asahi Kasei Pharma Corporation Sulfonamide compounds and use thereof
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8563617B2 (en) 2009-02-16 2013-10-22 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8642587B2 (en) 2009-02-16 2014-02-04 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
US8653100B2 (en) 2008-04-01 2014-02-18 Abbvie Inc. Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8846741B2 (en) 2011-11-18 2014-09-30 Abbvie Inc. N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8853196B2 (en) 2011-08-05 2014-10-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8883839B2 (en) 2010-08-13 2014-11-11 Abbott Laboratories Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9045459B2 (en) 2010-08-13 2015-06-02 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
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US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9365512B2 (en) 2012-02-13 2016-06-14 AbbVie Deutschland GmbH & Co. KG Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9550754B2 (en) 2014-09-11 2017-01-24 AbbVie Deutschland GmbH & Co. KG 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586945B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586942B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9650334B2 (en) 2013-03-15 2017-05-16 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9656955B2 (en) 2013-03-15 2017-05-23 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy

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US7429585B2 (en) 2004-12-09 2008-09-30 Hoffmann-La Roche Phenyl-piperazine methanone derivatives, substituted by heterocyclic groups
WO2006061135A1 (fr) * 2004-12-09 2006-06-15 F. Hoffmann-La Roche Ag Derives de la phenyl-piperazine methanone
WO2006123020A1 (fr) * 2005-05-18 2006-11-23 Juvantia Pharma Ltd Oy Peptidomimetiques a haute selectivite pour les sous-types 1 et/ou 4 des recepteurs de la somatostatine
WO2007014762A2 (fr) * 2005-08-02 2007-02-08 Glaxo Group Limited Inhibiteurs de transporteurs glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques
WO2007014762A3 (fr) * 2005-08-02 2007-04-26 Glaxo Group Ltd Inhibiteurs de transporteurs glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8653100B2 (en) 2008-04-01 2014-02-18 Abbvie Inc. Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8957089B2 (en) 2008-04-01 2015-02-17 AbbVie Deutschland GmbH & Co. KG Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8039514B2 (en) 2008-06-05 2011-10-18 Asahi Kasei Pharma Corporation Sulfonamide compounds and use thereof
US8642587B2 (en) 2009-02-16 2014-02-04 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
US9096619B2 (en) 2009-02-16 2015-08-04 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
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US8563617B2 (en) 2009-02-16 2013-10-22 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
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US9238619B2 (en) 2010-08-13 2016-01-19 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9045459B2 (en) 2010-08-13 2015-06-02 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9051280B2 (en) 2010-08-13 2015-06-09 AbbVie Deutschland GmbH & Co. KG Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
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US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
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US9656955B2 (en) 2013-03-15 2017-05-23 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
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US9550754B2 (en) 2014-09-11 2017-01-24 AbbVie Deutschland GmbH & Co. KG 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy

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