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  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
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  • 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
  • C07D207/06—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 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • 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
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  • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
  • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D215/36—Sulfur atoms
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  • 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
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  • 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
  • C07D217/04—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 hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
  • C07D333/30—Hetero atoms other than halogen
  • C07D333/34—Sulfur atoms
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  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

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 psychoses, 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 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-1 is three variants of GlyT1 , 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).
• 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.. 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry. 52, 998-1007 (1996).
• 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.
• NMDA receptors have 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.
• 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.
• pharmacological agents that increase the activity of GlyT1 will result in decreased glycine-activation of NMDA receptors, which activity can be used to treat these and related disease states.
• drugs that directly block the glycine site of the NMDA receptors can be used to treat these and related disease states.
• 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 GlyT1 or GlyT2 transporters.
• Allelix Corp. disclose classes of compounds which inhibit glycine transport (or reuptake) via the GlyT1 transporter.
• WO01/36423 (Akzo Nobel N.V.) discloses a class of compounds that selectively inhibit glycine transport by the human GlyT1 transporter as compared to the human GlyT2 transporter.
• GlyT1 transporters include those that inhibit GlyT1 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.
• Published European Patent Application EP-A-0076072 (Beecham-Wuelfing GmbH), incorporated herein by reference, discloses inter alia compounds of the following general structure: wherein
• R 1 and R 2 is hydrogen and the other is selected from C 1- alkyl, hydroxyi, C- alkoxy, d- 4 alkanoyloxy, hydrogen, halogen, nitro, cyano and amino optionally substituted by one or two C M alkyl groups or by d ⁇ alkanoyl; R 4 is hydroxy or - alkoxy; and NR 2 is 1-pyrrolidyl, 1-piperidyl, morpholino or 4-methyl-1-piperazyl, optionally substituted by one or two methyl groups; and salts thereof, their use as anti-arrhythmic agents, processes for their preparation and pharmaceutical compositions containing them.
• R' is C 2 -C alkyl and R is methyl, Cl or Br.
• R 1 and R 2 are independently selected from hydrogen, d-C 6 alkyl and C 3 -C 6 cycloalkyl, with the proviso that R 1 and R 2 do not both represent hydrogen, or 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 optionally substituted by one or more groups independently selected from d-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 4 alkyl, aryl and arylC ⁇ -C 4 alkyl, and said saturated ring being further optionally bridged by a d-C 3 alky
• Y is C 1 -C 2 alkylene, C 2 alkenylene or C 2 alkynylene, and n is 0 or 1
• 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, -Ci-6alkylsuIphonyl, -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 C ⁇ -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 4 alkyl, aryl, aryloxy or aryl d-C 4 alkyl, optionally substituted by one or more groups independently selected from hal, d-C 6 alkyl, -OR 11 , -COOR 12 -CN, -NO 2 and -NR 13 R 14 ,
• R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 and R 28 are independently selected from hydrogen and d-C 6 alkyl;
• R 4 and R 19 are independently selected from hydrogen, d-C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aryIC ⁇ -C alkyl, optionally substituted by one or more groups independently selected from hal, C,-C 6 alkyl, -OR 24 , -COOR 25 -CN, -NO 2 and -NR 26 R 27 ;
• R 6 , R 7 , R 8 and R 9 are independently selected from hydrogen, d-C 6 alkyl or arylC-i- C 4 alkyl, or R 6 and R 7 together form a C 3 -C 6 cycloalkyl group, or R 8 and R 9 together form a C 3 -C 6 cycloalkyl group; wherein the d-C 6 alkyl, arylC ⁇ -C 4 alkyl group, the C 3 -C 6 cycloalkyl group formed by R 6 and R 7 , and the C 3 -C 6 cycloalkyl group formed by R 8 and R 9 , are 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 independently selected from hydrogen and d-C 6 alkyl; and R 5 is independently selected from hydrogen
• 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.
• the 5- to 8-membered aromatic monocyclic moiety of Z is selected from the group comprising: furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, benzene, pyran, pyridine, pyridazine, pyrimidine, pyrazine, piperazine, triazine.
• the 6- to 10-membered aromatic bicyclic moiety of Z is selected from the group comprising: thienofuran, indolizine, indole, isoindole, indoline, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine, pteridine, chroman, chromene, isochroman, indene, imidazoleisothiazole, benzothiadiazole, benzofuran, naphthalene, azulene.
• 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 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 C5-C7 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 of more groups independently selected from d-C 6 alkyl and 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.
• R 1 and R 2 are independently selected from d-C 6 alkyl, preferably C 3 -C 6 alkyl.
• 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 or thienyl, optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R 10 , -CF3, -C ⁇ -C6alkylsulphonyl, -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, C ⁇ -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, naphthyridine, quinolyl, isoquinolyl, benzothienyl, chromanyl, chromenyl, imidazoleisothiazolyl, benzothiadiazolyl, benzofuryl, optionally substituted as hereinbefore described.
• Z is naphthyl or quinolyl (preferably 5-quinolyl), optionally substituted as hereinbefore described, preferably by one or more groups independently selected from hal, d-C 6 alkyl, d-C 6 alkoxy, CF3 j -CN and C 3 -C 6 cycloalkyl.
• Z is 1 -naphthyl, optionally substituted by one or more groups independently selected from -hal, d-C 6 alkyl, Ci-Ce alkoxy, CF3, -CN and C 3 -C 6 cycloalkyl.
• R 4 is hydrogen or d-C 6 alkyl, preferably hydrogen.
• R 5 is selected from hydrogen, d-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 d-C 6 alkyl, preferably hydrogen.
• a compound of formula (la) for the manufacture of a medicament for treating disorders mediated by GlyTI , said compound having the formula (la):
• R 1 and R 2 are independently selected from C 3 -C 6 alkyl, or
• R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a 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 by one or more groups independently selected from d-C 4 alkyl and C 3 -C 6 cycloalkyl, and said ring being further optionally fused to a C 6 alicyclic or aromatic ring, and said ring being further optionally bridged by a methylene group;
• n is 0 or 1
• 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 , - COOR 12 , -CN, -NO 2 , -NR 13 R 14 , -CF3, and -C . -C ⁇ alkylsulphonyl, wherein hal is F, Cl, Br or I,
• R 10 is d-C 4 alkyl or phenyl, optionally substituted by one or more hal groups, and
• R 11 , R 12 , R 13 and R 14 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:
• 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 of more groups independently selected from d-C 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 d-C 4 alkyl groups, preferably methyl, ethyl or isopropyl groups, preferably at the 2- and/or 5- positions, more preferably at the 2-position.
• the pyrrolidinyl ring formed by R 1 and R 2 together with the nitrogen atom to which they are attached is substituted by one isopropyl group, 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 of more groups independently selected from C 1 -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 one methyl group, preferably at the 2- position, or by two methyl groups, preferably at the 2- and 6- positions.
• n 0.
• Z is selected from 2- or 3-thiophene, phenyl, 1- or 2- naphthyl, optionally substituted by one or more groups independently selected from - hal, -R 10 . -OR 11 , -COOR 12 , -CN, -NO 2 , -NR 13 R 14 , wherein hal, R 10 , R 11 , R 12 , R 13 and R 14 are as hereinbefore defined.
• Z is 1 -naphthyl, or 5-quinolinyl, optionally substituted by one or more groups independently selected from -hal, -R 10 , -OR 11 , -COOR 12 , -CF3, -C-
• R 3 is 1 -naphthyl or 5-quinolinyl.
• Examples of preferred compounds of the invention include Naphthalene-1 -sulfonic acid [(R)-2-hydroxy-3-piperidin-1 -ylpropylj-amide
• Naphthalene-1 -sulfonic acid ⁇ 3-[(2R,6S)-dimethylpiperidin-1 -yl]-(2R)-hydroxypropyl ⁇ - amide
• Naphthalene-1 -sulfonic acid ⁇ 3-[(2S)-ethylpiperidin-1-yl]-(2R)-hydroxypropyl ⁇ -amide )
• Naphthalene-1 -sulfonic acid [(R)-2-hydroxy-3-(2-isopropylpyrrolidin-1 -yl)propyl]amide trifluoroacetate
• Naphthalene-1 -sulfonic acid [(R)-3-(2,5-dimethylpyrrolidin-1 -yl)-2- hydroxypropyljamide trifluoroacetate
• 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.
• d_C 6 alkyl refers to a straight or branched chain hydrocarbon which contains at least 1, and at most 6, carbon atoms.
• 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.
• d_C 4 alkyl refers to a straight or branched chain hydrocarbon which contains at least 1, and at most 4, carbon atoms.
• 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 cyciohexyl.
• 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 aromatic or heteroaromatic ring system wherein the heteroatomic ring contains at least one heteroatom selected from N, O and S.
• exemplary "aryl” groups include thiophenyl, furanyl and phenyl.
• aryl d-C 4 alkyl refers to an aryl group, as hereinbefore defined, attached through a d-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 1 , and at most 2, 3 or 4, carbon atoms respectively.
• Examples of "C C 2 alkylene”, “d.C 3 alkylene” and “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 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.
• 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. Likewise, it is understood that 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.
• 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.
• 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.
• 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 as active ingredient the compound of formula (I) as hereinbefore described or a salt, solvate or a physiologically functional derivative thereof, but not including N-[3-(2,4-dimethyl-1-pyrrolidinyl)-2-hydroxypropyl]-1 -naphthalenesulfonamide, N-[2-hydroxy-3-(2-methyl-1-piperidinyl)propyl]-1-naphthalenesulfonamide, N-[2-hydroxy-3-(1 -piperidinyl)propyl]-1 -naphthalenesulfonamide, and N-[2-hydroxy-3-(1-pyrrolidinyl)propyl]-1 -naphthalenesulfonamide, and salts thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
• a pharmaceutical composition comprising as active ingredient the compound of formula (la) as hereinbefore described or a salt, solvate or a physiologically functional derivative thereof, but not including N-[3-(2,4-dimethyi-1 -pyrrolidinyl)-2-hydroxypropyl]-1 -naphthalenesulfonamide, N-[2-hydroxy-3-(2-methyl-1-piperidinyl)propyl]-1-naphthalenesulfonamide, N-[2-hydroxy-3-(1 -piperidinyl)propyl]-1 -naphthalenesulfonamide, and N-[2-hydroxy-3-(1-pyrrolidinyl)propyl]-1 -naphthalenesulfonamide, and salts thereof, 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.
• 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 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 and 2 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 3 is as hereinbefore defined and L is a suitable leaving group, such a, for example, a halogen, preferably chlorine.
• M molar
• mM millimolar
• i. v. intravenous
• Hz Hertz
• T r retention time
• RP reverse phase
• TEA triethylamine
• TFA trifluoroacetic acid
• TFAA trifluoroacetic anhydride
• THF tetrahydrofuran
• DCE dichloroethane
• DMF ⁇ /, ⁇ /-dimethylformamide
• DMPU ⁇ /, ⁇ /'-dimethylpropyleneurea
• CDI 1,1-carbonyldiimidazole
• IBCF isobutyl chloroformate
• HOAc acetic acid
• HOSu ⁇ /-hydroxysuccinimide
• HOBT hydroxybenzotriazole
• mCPBA metal-chloroperbenzoic acid
• EDC ethylcarbodiimide hydrochloride
• BOC ferf-butyloxycarbonyl
• FMOC 9-fluorenylmethoxycarbonyl
• DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere);
• TIPS triisopropylsilyl
• TBS -butyldimethylsilyl
• MS mass spectra
• MS and liquid chromatography MS were recorded on a Micromass MS2 Platform LC spectrometer. All mass spectra were taken under electrospray ionisation (ESI), chemical ionisation (Cl), electron impact (El) or by fast atom bombardment (FAB) methods. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualised with UV light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
• the title compound was prepared from ferf-butylpropylamine (D36) (632mg; 5.5mmol) using the method outlined in Description 1 (40mg; 4% over 2 steps).
• Potassium hydride (860mg; 30% in oil) was weighed into an oven dried 3-necked flask and stirred in THF (5ml) under an inert atmosphere during the addition of
• 2,6-Diacetylpyridine (2g) was dissolved in diethyleneglycol (50ml) with hydrazine monohydrate (3.6ml). The reaction mixture was heated at 170°C for 30 min. The reaction mixture was then cooled to room temperature for the addition of potassium hydroxide (3.1g), then heated at 200°C for 2h when the reaction mixtue lost all colour. The reaction mixture was then cooled to room temperature and poured onto water.
• the resulting solution was evaporated at reduced pressure and azeotroped twice from toluene to yield the sodium salt as a white solid. This solid was suspended in phosphorus oxychloride and heated to reflux for 2 hours. After cooling, the reaction mixture was diluted with dichloromethane and added portionwise to saturated sodium hydrogen carbonate solution, with stiring. The resulting two-phase solution was stirred at room temperature for 2 hours until effervescence had ceased.
• the diastereomers were separated using normal-phase preparative chiral HPLC to give faster- and slower- eluting components as their free-bases.
• Example 73 The title compound, prepared by the procedure of Example 73 was obtained as a yellow oil (72mg), m/z 411 [MH + ] Example 80.
• Example 88 The title compound, prepared by the procedure of Example 73 was obtained as a colourless oil (74mg) m/z 378 [MH + j. Example 88.
• Example 101 4-Fluoronaphthalene-1 -sulfonic acid [(R)-3-((2R,6S)-2,6-dimethyl-piperidin-1 -yl)-2- hydroxy-propylj-amide (E101 )

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