WO2004113301A1 - 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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WO2004113301A1
WO2004113301A1 PCT/EP2004/006593 EP2004006593W WO2004113301A1 WO 2004113301 A1 WO2004113301 A1 WO 2004113301A1 EP 2004006593 W EP2004006593 W EP 2004006593W WO 2004113301 A1 WO2004113301 A1 WO 2004113301A1
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optionally substituted
compound
alkyl
independently selected
nitrogen atom
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PCT/EP2004/006593
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English (en)
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Clive Leslie Branch
Steven Coulton
Roderick Alan Porter
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates

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.
  • GlyTl 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 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 three variants of GlyTl , termed GlyT-la, GlyT-1 b and GlyT-1c (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which 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).
  • GlyT2 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 GlyTl
  • 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 GlyTl 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 GlyTl or GlyT2 transporters.
  • R 1 and R 2 is independently selected from hydrogen, optionally substituted C ⁇ galkyl, optionally substituted C3_6cycloalkyl, optionally substituted aryl, optionally substituted arylC-
  • R 1 and R 2 together with the nitrogen atom to which they are attached, are linked to form an optionally substituted 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;
  • R 3 is an optionally substituted group of formula (a):
  • m and n are independently 0, 1 , 2 or 3 and m+n is 2, 3 or 4; each Z is independently -CH2-, -NH-, -O- or -S-; and each Y is independently CH or N;
  • R 4 and R 5 are independently selected from hydrogen, optionally substituted C 1 -C- 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl and optionally substituted arylC 1 -C 4 alkyl; and R 6 , R 7 , R 8 and R 9 are independently selected from hydrogen, optionally substituted C ⁇ -C 6 alkyl and optionally substituted arylC 1 -C 4 alkyl, or R 6 and R 7 together form an optionally substituted C 3 -C 6 cycloalkyl group, or R 8 and R 9 together form an optionally substituted C 3 -C 6 cycloalkyl group.
  • Cx-y and “Cx-Cy” are equivalent.
  • C ⁇ galkyl is the same as “Ci-C ⁇ alkyl”.
  • C ⁇ .C 6 alkyl refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 6, carbon atoms.
  • Examples of "C C 6 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 ⁇ G* alkyl refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 4, carbon atoms.
  • Examples of “C ⁇ -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 C 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 monocyclic aromatic ring or a 6- to 11- membered bicyclic aromatic ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S.
  • Examples of monocyclic aryl groups include: phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyrazolinyl, isothiazolyl, thiazolyl, isoxazolyl, furazanyl, oxazolyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepinyl and pyranyl.
  • bicyclic aromatic ring includes bicyclic ring systems in which both rings are aromatic, as well as bicyclic ring systems in which one of the rings is partially or fully saturated.
  • bicyclic aryl groups in which both rings are aromatic include: naphthyl, indenyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzofuranyl, naphthridinyl, quinolyl, quinoxalinyl, quinazolinyl and isoquinolyl.
  • bicyclic aryl groups in which one of the rings is partially or fully saturated includes dihydrobenzofuranyl, indanyl, tetrahydronaphthyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxazinyl and benzoazepinyl.
  • aryl C C 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 C C 4 alkyl include, but are not limited to, benzyl, phenethyl, pyridylmethyl and phenylpropyl.
  • C ⁇ .C 2 alkylene As used herein, the terms "C ⁇ .C 2 alkylene”, “Ci.Cs alkylene” and “C-i.C ⁇ alkylene” refer to a straight or branched chain divalent hydrocarbon radical, which contains at least 1 , and at most 2, 3 or 4, carbon atoms respectively.
  • Examples of "C- ⁇ -C 2 alkylene”, “C-i.Cs alkylene” and “C 1- 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.
  • 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
  • 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 30 SO 2 NR 31 (CH 2 ) r (where each of R 30 and R 31 independently represents a hydrogen atom or a C ⁇
  • 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 C3_ ⁇ azacycloalkane fused to the first C3_ 6 azac y c ' oa " ⁇ ane.
  • the optionally substituted 4-, 5-, 6- or 7-membered saturated ring formed by R 1 and R 2 may be additionally optionally bridged by a C 1 -C 3 alkylene group; and the optionally substituted 4-, 5-, 6- or 7-membered saturated ring formed by R 1 and R 2 may be additionally optionally fused to a C 5 -C 7 alicyclic or 5- or 6-membered aromatic or heteroaromatic ring optionally substituted by one or more groups independently selected from C-i- C 6 alkyl and C 3 -C 6 cycloalkyl.
  • substituents may be different or the same. If substituent(s) is/are present, preferably the number of substituent(s) is 1 , 2, 3 or 4.
  • R 3 is an N-linked 9-, 10- or 11- membered bicyclic moiety wherein the ring containing the linking nitrogen atom is saturated, the bicyclic moiety being optionally substituted at any available position by one or more substituents as defined above.
  • R ⁇ is substituted by one or more groups selected from hydrogen, hal, Ci-C-e alkyl, C ⁇ -C 6 alkoxy, -CF3, -CN and C 3 -C 6 cycloalkyl.
  • R 3 is selected from: optionally substituted indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzazepinyl.
  • R 1 and R 2 are independently selected from optionally substituted C- I -C 6 alkyl, preferably C 3 -C 6 alkyl.
  • 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 is the nitrogen atom to which R 1 and R 2 are attached, said ring being optionally substituted as hereinbefore described, and said ring being further optionally fused to a C 5 -C 7 alicyclic or 5- or 6-membered aromatic or heteroaromatic ring 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 optionally substituted as hereinbefore described, and said ring being further optionally fused to a C 5 -C 7 alicyclic or 5- or 6-membered aromatic or heteroaromatic ring 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 optionally substituted as hereinbefore described, preferably by one or more groups independently selected from optionally substituted C ⁇ -C 6 alkyl and optionally substituted C 3 -C 6 cycloalkyl, more preferably by one or more groups independently selected from C 1 -C 4 alkyl, most preferably methyl, ethyl or isopropyl.
  • 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, piperazine.
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a pyrrolidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted C- ⁇ -C 4 alkyl, preferably methyl, ethyl or isopropyl.
  • the pyrrolidinyl ring formed by R 1 and R 2 together with the nitrogen atom to which they are attached is substituted by one or more C 1 -C alkyl groups, preferably methyl, ethyl or isopropyl groups, preferably at the 2- and/or 5-positions, more preferably at the 2-position.
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a piperidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted d-C 4 alkyl, preferably methyl or ethyl.
  • the piperidinyl ring formed by R 1 and R 2 together with the nitrogen atom to which they are attached is substituted by one or more methyl or ethyl groups, preferably at the 2- and 6-positions. More preferably, the piperidinyl ring formed by R 1 and R 2 together with the nitrogen atom to which they are attached is substituted by two methyl groups, preferably at the 2- and 6- positions.
  • R is hydrogen or C- ⁇ -C 6 alkyl, preferably hydrogen.
  • R 5 is selected from hydrogen, alkyl, aryl and benzyl, optionally substituted by one or more groups independently selected from hal, C ⁇ Ce alkyl, hydroxy and C ⁇ galkoxy.
  • R 5 is hydrogen.
  • R 6 , R 7 , R 8 and R 9 are independently selected from hydrogen and Ci-Ce alkyl, preferably hydrogen.
  • the compound of formula (I) as hereinbefore described has the following stereochemical configuration:
  • Examples of compounds of the invention include:
  • the compounds of formula (I) 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 formula (I).
  • 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. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • individual enantiomers of compounds of formula (I) may be prepared and an indication of the preferred stereochemistry for such enantiomers has been given.
  • 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.
  • 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.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • stereochemistry is indicated as being variable at certain positions, a mixture of stereoisomers may be obtained, this mixture having been separated where indicated.
  • Stereoisomers may be separated by high-performance liquid chromatography or other appropriate means.
  • 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- Interscience, 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.
  • R 3 is as hereinbefore defined and L is a suitable leaving group, such as, for example, a halogen, preferably chlorine;
  • 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.
  • the compounds of the present invention inhibit the GlyTl transporter.
  • the compounds may selectively inhibit the GlyTl transporter over the GlyT2 transporter.
  • treatment and “treating” refer to the alleviation and/or cure of established symptoms as well as prophylaxis.
  • the affinity of the compounds of the present invention for the GlyTl transporter may be measured 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 6 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].
  • the example compounds below were found to have a PIC50 at the GlyTl transporter of between 5.4 and 7.1.
  • a disorder mediated by GlyTl refers to a disorder that may be treated by the administration of a medicament that alters the activity of the GlyTl transporter.
  • the action of GlyTl transporters affects the local concentration of glycine around NMDA receptors. As a certain amount of glycine is needed for the efficient functioning of 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 GlyTl transporter are expected to influence such disorders.
  • the disorders mediated by GlyTl 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.
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by GlyTl which comprises administering an effective amount of a GlyTl inhibiting compound of formula (I) as hereinbefore defined or a salt, solvate or a physiologically functional derivative thereof.
  • the disorders mediated by GlyTl 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.
  • 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, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • compositions may be used in the treatment of clinical conditions for which a GlyTl 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) 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.
  • 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, 5HT1D 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.
  • 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 GlyTl 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.
  • Example 1 yV- ⁇ (2/?)-3-[(2R,6S)-2,6-dimethyl-1-piperidinyl]-2-hydroxypropyl ⁇ -3,4- dihydro-1(2H)-quinolinesulfonamide

Abstract

L'invention concerne des composés de la formule (I), des sels, des solvates et des dérivés physiologiquement fonctionnels de ceux-ci, dans laquelle R1 et R2 sont choisis indépendamment entre hydrogène, alkyle C1-6 facultativement substitué, cycloalkyle C3-6 facultativement substitué, aryle facultativement substitué, arylalkyle C1-4 facultativement substitué et arylcycloalkyle C3-6 facultativement substitué, dans laquelle R1 et R2 ne représentent pas l'un et l'autre hydrogène, ou R1 et R2, avec l'atome d'azote auquel ils sont fixés, sont liés pour former un cycle saturé à 4, 5, 6 ou 7 éléments facultativement substitués, dans lequel un ou plusieurs des atomes de carbone est facultativement remplacé par un hétéroatome choisi indépendamment entre N, O et S; R3 représente un groupe facultativement substitué de la formule (a): dans laquelle m et n représente indépendamment 0, 1, 2 ou 3 et m+n représente 2, 3 ou 4; chaque Z représentant indépendamment -CH2-, -NH-, -O- ou -S-; et chaque Y représente indépendamment CH ou N; R4 et R5 sont choisis indépendamment entre hydrogène, alkyle C1-C6 facultativement substitué, cycloalkyle C3-C6 facultativement substitué, aryle facultativement substitué et arylalkyle C1-C4 facultativement substitué; et R6, R7, R8 et R9 sont choisis indépendamment entre hydrogène, alkyle C1-C6 facultativement substitué, et arylalkyle C1-C4 facultativement substitué, ou R6 et R7 forment ensemble un groupe cycloalkyle C3-C6 facultativement substitué, ou R8 et R9 forment ensemble un groupe cycloalkyle C3-C6. L'invention concerne également des procédés de préparation ainsi que des utilisations des composés en médecine dans le traitement d'un trouble médié par GlyT1, par exemple la schizophrénie.
PCT/EP2004/006593 2003-06-20 2004-06-17 Inhibiteurs de transporteurs de glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques WO2004113301A1 (fr)

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066121A2 (fr) * 2004-12-16 2006-06-22 Janssen Pharmaceutica N.V. Combinaison d'un inhibiteur de transporteur glycine (glyt1) et d'un antipsychotique destinee au traitement de symptomes de la schizophrenie ainsi que la preparation et l'utilisation de ce compose
WO2006079467A1 (fr) * 2005-01-26 2006-08-03 F. Hofmann-La Roche Ag Derives methanone phenyliques et leur utilisation en tant qu'inhibiteurs du transporteur 1 de la glycine
JP2008522993A (ja) * 2004-12-09 2008-07-03 エフ．ホフマン−ラ ロシュ アーゲー フェニル−ピペラジンメタノン誘導体
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
CN103209964A (zh) * 2010-08-13 2013-07-17 Abbvie德国有限责任两合公司 苯烷基胺衍生物、含其的药物组合物及其在治疗中的用途
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
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
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
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
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
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0076072A2 (fr) * 1981-09-24 1983-04-06 BEECHAM - WUELFING GmbH & Co. KG Sulfonamides
WO2002022581A1 (fr) * 2000-09-14 2002-03-21 Gliatech, Inc. Composes azotes et leur utilisation comme inhibiteurs de transport de la glycine
WO2003055478A1 (fr) * 2001-12-21 2003-07-10 Smithkline Beecham P.L.C. Inhibiteurs de transporteurs glyt1 et utilisatons de ceux-ci dans le traitement de troubles neurologiques et neuropsychiatriques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0076072A2 (fr) * 1981-09-24 1983-04-06 BEECHAM - WUELFING GmbH & Co. KG Sulfonamides
WO2002022581A1 (fr) * 2000-09-14 2002-03-21 Gliatech, Inc. Composes azotes et leur utilisation comme inhibiteurs de transport de la glycine
WO2003055478A1 (fr) * 2001-12-21 2003-07-10 Smithkline Beecham P.L.C. Inhibiteurs de transporteurs glyt1 et utilisatons de ceux-ci dans le traitement de troubles neurologiques et neuropsychiatriques

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JP4762250B2 (ja) * 2004-12-09 2011-08-31 エフ．ホフマン−ラ ロシュ アーゲー フェニル−ピペラジンメタノン誘導体
JP2008522993A (ja) * 2004-12-09 2008-07-03 エフ．ホフマン−ラ ロシュ アーゲー フェニル−ピペラジンメタノン誘導体
WO2006066121A2 (fr) * 2004-12-16 2006-06-22 Janssen Pharmaceutica N.V. Combinaison d'un inhibiteur de transporteur glycine (glyt1) et d'un antipsychotique destinee au traitement de symptomes de la schizophrenie ainsi que la preparation et l'utilisation de ce compose
WO2006066121A3 (fr) * 2004-12-16 2006-08-10 Janssen Pharmaceutica Nv Combinaison d'un inhibiteur de transporteur glycine (glyt1) et d'un antipsychotique destinee au traitement de symptomes de la schizophrenie ainsi que la preparation et l'utilisation de ce compose
KR100915472B1 (ko) * 2005-01-26 2009-09-03 에프. 호프만-라 로슈 아게 페닐 메탄온 유도체 및 그의 글라이신 트랜스포터 1억제제로서의 용도
US7442710B2 (en) 2005-01-26 2008-10-28 Hoffman-La Roche Inc. Substituted phenyl methanones
AU2006208547B2 (en) * 2005-01-26 2011-02-10 F. Hoffmann-La Roche Ag Phenyl methanone derivatives and their use as glycine transporter 1 inhibitors
JP2008528526A (ja) * 2005-01-26 2008-07-31 エフ．ホフマン−ラ ロシュ アーゲー フェニルメタノン誘導体及びグリシントランスポーター１阻害剤としてのこれらの使用
JP4829900B2 (ja) * 2005-01-26 2011-12-07 エフ．ホフマン−ラ ロシュ アーゲー フェニルメタノン誘導体及びグリシントランスポーター１阻害剤としてのこれらの使用
WO2006079467A1 (fr) * 2005-01-26 2006-08-03 F. Hofmann-La Roche Ag Derives methanone phenyliques et leur utilisation en tant qu'inhibiteurs du transporteur 1 de la glycine
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
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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