AP767A - Quinoxalinediones - Google Patents

Quinoxalinediones Download PDF

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AP767A
AP767A APAP/P/1997/000947A AP9700947A AP767A AP 767 A AP767 A AP 767A AP 9700947 A AP9700947 A AP 9700947A AP 767 A AP767 A AP 767A
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triazol
aryl
methyl
alkyl
alkoxy
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APAP/P/1997/000947A
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AP9700947A0 (en
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Christopher Lee Carr
Michael Jonathan Fray
Elisabeth Colette Louise Gautier
Charles Eric Mowbray
Alan Stobie
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Pfizer Res & Development Company N V /S A
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein R is a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon or nitrogen atom, or is a 6-membered ring heteroaryl group containing from 1 to 3 nitrogen heteroatomt which is linked to the quinoxalinedione ring by a ring carbon atom, either of said groups being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from Ci-CU alkyl, Cj-C4 alkenyl, Cj-C? cycloalkyl, halo, hydroxy, Ci-CU alkoxy, Ci-Oi cycloalkyloxy, -COOH, Ci-C* alkoxycarbonyl, -CONR3R4. -NR'R4, -S(O)p(Ci-Ct alkyl), -SOiNR3R4, aryl, aryloxy, aryl(Ci-Cx)aIkoxy and net, said Ci-C< alkyl being optionally substituted by Cs-C? cycloalkyl, halo, hydroxy, Ci-O alkoxy, halo(Ci-C«)alkoxy, Cj-C? cycloalkyloxy, Cs-C7 cycloalkyl(Ci-O)alkoxy, -COOH, Ci-C< alkoxycarbonyl, -CONR3R4, -NR3R4, -S(O)p(Ci-C4 alkyl), -SOaCaryl), -SO2NR3R4,morpholino, aryl, aryloxy, aryl(C]-C4)alkoxy or bet, and said C2-C4 alkenyl being optionally substituted by aryl; R1 and R selected fromH Fluoro chloro bromo C1-C4 Arkyl and halo (C1-C4)alkyl R3 and R4 are cither each independently SO2NR3R4,morpholino, aryl, aryloxy, aryl SO2NR3R4,morpholino, aryl, aryloxy, aryl(C]-C4)alkoxy or bet, and said C2-C4 alkenyl being optionally substituted by aryl; R1 and R selected fromH Fluoro chloro bromo C1-C4 Arkyl and halo (C1-C4)alkyl R3 and R4 are either each independently selected from H AND c1-c4 alkyl or when, taken together, are C3-C7 alkylene; p is 0, 1 or 2; together with the preparation of compositions containing the uses of and intermediates used in the synthesis of, such compounds. The compounds are useful as NMDA receptor antagonists for treating acute neurodegenerative and chronic neurological disorders.

Description

QUiNQXALINEDlONES
This invention relates to 2,3(1 H,4H)-quinoxalinedione derivatives which are selective antagonists of N-methyl-D-aspartate receptors. More particularly, this invention relates to 5-heteroaryI-2,3(1H,4H)-quinoxalinedione derivatives and to the preparation of, compositions containing, the uses of and the intermediates used in the synthesis of, such derivatives. L-Glutamic acid is an excitatory amino acid neurotransmitter whose physiological role in the brain involves interaction with four receptors, three of which are named after the selective agonists NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate. The fourth receptor is termed the metabotropic receptor. In addition to a binding site for glutamic acid, the NMDA receptor possesses high affinity binding sites for dissociative anaesthetics (e.g. ketamine), polyamines (e.g. spermine), glycine and certain metal ions (e.g. Mg2+, Zn2+). Since the NMDA receptor has an absolute t requirement to bind glycine for activation to occur, glycine antagonists can act as functional NMDA antagonists.
In the region of a cerebral infarct, anoxia, for example, causes abnormally high concentrations of glutamic acid to be released. This leads to an over-stimulation of NMDA receptors resulting in the degeneration and death of neurones. Thus, NMDA receptor antagonists, which have been shown to block the neurotoxic effects of glutamic acid in vitro and in vivo, may be useful in the treatment and/or prevention of any pathological condition in which NMDA receptor activation is thought to be important. Examples of such conditions include acute neurodegenerative disorders arising from events such as stroke, transient ischaemic attack, peri-operative ischaemia, global ischaemia (following cardiac arrest) and traumatic head injury to the brain or spinal cord. In addition, NMDA antagonists may be of use in treating certain chronic neurological disorders such as senile dementia, Parkinson’s disease and Alzheimer’s disease. They may also have utility in conditions in which peripheral nerve function has been impaired such as retinal and macular degeneration.
Furthermore, NMDA antagonists have been shown to possess anticonvulsant and anxiolytic activity and may therefore be used to treat epilepsy and anxiety. NMDA antagonists may also attenuate the effects of alcohol withdrawal from physically dependent animals (K.A. Grant etal., J. Pharm.Exp.Ther., 260. 1017 (1992)) and thus NMDA antagonists may be of use in the treatment of alcohol addiction and pain. NMDA antagonists may also be useful in the treatment of hearing disorders (e.g. tinnitus), migraine and psychiatric disorders. EP-A-0572852 describes pyrrol-1-yl-substituted 2,3(1 H,4H)-quinoxalinedione derivatives useful for the treatment of neurodegenerative illnesses and neurotoxic disorders of the central nervous system. EP-A-0556393 discloses, inter alia, imidazolyl- or triazolyl-substituted 2,3(1 H,4H)-quinoxalinedione derivatives with glutamate receptor antagonising activity, particularly NMDA-glycine receptor and AMPA receptor antagonising activities. However, no 5-triazolyl-substituted compounds are specifically described therein.
The present compounds are potent antagonists of the NMDA (glycine site) receptor. In addition, they are highly selective antagonists for the NMDA (glycine site) receptor in comparison to the AMPA receptor to which they have little, if any, affinity.
The present invention relates to a compound of the formula:-
or a pharmaceutically acceptable salt thereof, wherein R is a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms which is linked to the quinoxaiinedione ring by a ring carbon or nitrogen atom, or is a 6-membered ring heteroaryl group containing from 1 to 3 nitrogen heteroatoms which is linked to the quinoxaiinedione ring by a ring carbon atom, either of said
groups being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C·,-C4 alkyl, C2-C4 alkenyl, C3-C- cycloalkyl, halo, hydroxy, C--CA alkoxy, C3-C7 cycloalkyloxy, -COOH, C5-C4 alkoxycarbonyl, -CONR3R4, -NR3R4, -S(O)p(C1-C4 alkyl), -SO2NR3R4, aryl, aryloxy, ary^C^CJalkoxy and het, said CrC4 alkyl being optionally substituted by C3-C7 cycloalkyl, halo, hydroxy, C^C,, alkoxy, halofC^ C4)alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkyl(C1-C4)alkoxy, -COOH, CyCA alkoxycarbonyl, -CONR3R4, -NR3R4, -S(O)P(C1-C4 alkyl), -SO2(aryI), -SO2NR3R4, morpholino, aryl, aryloxy, aryl(C.,-C4)alkoxy or het, and said C2-C4 alkenyl being optionally substituted by aryl; R1 and R2 are each independently selected from H, fluoro, chloro, bromo, CrC4 alkyl and halo(CrC4)alkyl; R3 and R4 are either each independently selected from H and CrC4 alkyl or, when taken together, are C5-C7 alkylene; p is 0, 1 or 2; “aryl”, used in the definition of R and “het”, means phenyl'or naphthyl, each optionally substituted by 1 or 2 substituents each independently selected from C·,-C4 alkyl, CrC4 alkoxy, hydroxy, halo, halo(C.,-C4)alkyl and -NR3R4; “het”, used in the definition of R, means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from CrC4 alkyl, C3-C7 cycloalkyl, CrC4 alkoxy, halo, hydroxy, -COOH, CrC4 alkoxycarbonyl, allyloxycarbonyl, -CONR3R4, -NR3R4, -S(O)P(C.,-C4 alkyl), -SO2NR3R4, halo(C1-C4)alkyl, hydroxy(C.rC4)alkyl, CrC4 alkoxy(C.,-C4)alkyl, R3R4NCO(C1-C4)alkyl, aryl, arylalkyl, het1 and het1(C-,-C4)aIkyl, and/or by an oxido substituent on a ring nitrogen heteroatom when “het” includes a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group; and “het1”, used in the definition of “het", means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isotniazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl. pyrimidinyl or pyrazinyl, each optionally substituted by 1 or 2 Ο,-Ο4 alkyl substituents.
Inthe above definitions, “halo” means fluoro, chloro, bromo or iodo and alkyl, alkoxy and alkylene groups having three or more carbon atoms and alkenyl groups having 4 or more'carbon atoms can be straight- or branched-chain.
The definition “0,-04 alkyl” covers methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl groups. The definition “C1-C4 alkoxy” covers the corresponding alkoxy groups.
Where R is a 5-membered ring heteroaryl group, this definition covers 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl.
Where R is a 6-membered ring heteroaryl group, this definition includes, in particular, 2-, 3- and 4-pyridinyl, 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl and 2-pyrazinyl.
Where “het” is a benzo-fused heteroaryl group, this may be attached to the remainder of the molecule via the heteroaryl or benzo-fused portion of the “het” group.
Preferably, R is triazolyl or tetrazolyl, each substituted by 1 or 2 substituents each independently selected from CA-CA alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C,-C4 alkoxycarbonyl, aryl and het, said C,-C4 alkyl being optionally substituted by halo, hydroxy, C,-C4 alkoxy, halo(C,-C4)aikoxy, C3-C7 cycloalkyl(C1-C4)alkoxy, -COOH, C,-C4 alkoxycarbonyl, -NR3R4, -SO2(aryl), morpholino, aryl, aryloxy, aryl(C,-C4)alkoxy or het; or is pyridinyl or pyrimidinyl.
More preferably, R is 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl or tetrazol-5-yl, each substituted by 1 or 2 substituents each independently selected from C,-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C,-C4 alkoxycarbonyl, aryl and het, said 0,-04 alkyl being optionally substituted by halo, hydroxy, C,-C4 alkoxy, haio(C,-C4)alkoxy, C3-C7 cycloalkyl(C,-C4)alkoxy, -COOH, C,-C4 alkoxycarbonyl, -NR3R4, -SO2(aryl), morpholino, aryl, aryloxy, aryl(C,-C4)alkoxy or het; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl.
Yet more preferably, R is 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl or tetrazol-5-yl, each substituted by 1 or 2 substituents each independently selected from methyl, ethyl, propyl, allyl, cyclopropyl, cyclohexyl, bromo, hydroxy, ethoxycarbonyl, 2-chlorophenyI, 3-chlorophenyl, 4-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl, 4-trifluoromethylphenyl, 2-amino-1,3,4-oxadiazol-5-yl, 2-carboxypyridin-5-yI, 1,5-dimethyl-1 H-pyrazol-3-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yI, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 3-methylisothiazol-4-yl, 4-methyl-1 H-imidazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 5-methyl-1 H-pyrazol-3-yl, 1 -methyl-1 H-pyrazol-5-yl, 1-oxidopyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-5-yl, 1-phenylimidazol-4-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yI, 1-methylpyrrol-2-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 2-methylthiazol-4-yl, 1 -methyl-1 H-1,2,4-triazol-5-yl, 3-(prop-1-yl)-1H-pyrazol-5-yl, pyrazin-2-yl, 1 H-pyrazol-4-yl, pyridazin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, thien-2-yl, 1 H-1,2,4-triazol-5-yl, 1 H-1,2,3-triazol-5-yI, quinolin-3-yl and quinolin-6-yl, said methyl, ethyl or propyl being optionally substituted by fluoro, hydroxy, methoxy, ethoxy, 2,2,2-trifluoroethoxy, cyclohexylmethoxy, cyclopentylmethoxy, -COOH, methoxycarbonyl, dimethylamino, 4-chlorophenylsulphonyl, morpholino, phenyl, phenoxy, benzyloxy, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl.
Examples of R include: 1- (2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl, 1 -(2-hydroxyethyi)-4-phenyl-1,2,3-triazol-5-y I, 2- (2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl, 1 -methyl-5-phenyl-1,2,3-triazol-4-y I, 1 -methyl-4-phenyI-1,2,3-triazol-5-y I, 2-methyI-5-phenyl-1,2,3-triazol-4-yl, 5-phenyl-1 H-1,2,3-triazol-4-yl, 1- methyl-1 H-1.2,4-triazol-3-yl, 2- methyI-2H-1,2,4-triazol-3-yl, 4-(2-hydroxyethyi)-4H-1,2,4-triazol-3-yl, 4-methyl-4H-1,2,4-triazol-3-yl, 3- (2-amino-1,3,4-oxadiazol-5-yl)-5-methyl-4H-1,2,4-triazol-4-yI, 3-benzyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-benzyloxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazoI-4-yl, 3-bromo-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-(3-carboxyprop-1 -y l)-5-(py rid ίη-3-y l)-4H-1,2,4-triazol~4-y I, 3-(2-carboxypyridin-5-yl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl, 3-(2-chlorophenyl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl, 3-(2-chlorophenyl)-5-methyI-4H-1,2,4-triazol-4-yl, 3-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(4-chlorophenylsulphonylmethyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-cyclohexylmethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-cyclopentyimethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-cyclopropyl-5-methyl-4H-1,2,4-triazol-4-yl, 3.5- di(methoxymethyl)-4H-1,2,4-triazol-4-yl, 3-(N,N-dimethylaminomethyl)-5-ethyl-4H-1,2,4-triazol-4-yl, 3-(N,N-dimethylaminornethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazoI-4-yl, 3-(4-dimethylaminophenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(1,5-dimethyl-1 H-pyrazol-3-yl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl, 3-(1,5-dimethyl-1 H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-4-yl, 3.5- dimethyl-4H-1,2,4-triazol-4-yl, 3.5- diphenyl-4H-1,2,4-triazol-4-yl, 3-(2-ethoxyethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-ethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-ethoxycarbonyl-4H-1,2,4-triazol-4-yl, 3-ethyl-5-(2-chlorophenyl)-4H-1,2,4-triazol-4-yl, 3-ethyl-5-(2-methoxyphenyl)-4H-1,2,4-triazol-4-yl, 3-ethyl-5-(1-methylpyrazol-5-yl)-4H-1.2,4-triazol-4-yl, 3-ethyl-5-methyl-4H-1,2,4-triazol-4-yl, 3-ethyl-5-morpholinomethyl-4H-1,2,4-triazol-4-yl, 3-ethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-ethyl-4H-1,2,4-tria'zol-4-yl, 3-(2-hydroxyethyl)-5-methyl-4H-1I2,4-triazol-4-yl, 3-hydroxymethyl-5-methyl-4H-1,2,4-triazol-4-yl, 3-hydroxymethyl-5-phenyl-4H-1,2,4-triazol-4-yl, 3-hydroxymethyl-5-(pyridin-3-yI)-4H-1,2,4-triazol-4-yl, 3-hydroxymethyl-4H-1,2,4-triazoI-4-yl, 3-hydroxy-5-methyl-4H-1,2,4-triazol-4-yl, 3-(2-hydroxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(1 H-imidazol-1 -yl)-5-methyl-4H-1,2,4-triazo l-4-y I, 3-(2-methoxyethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(1 -methyl-1 H-pyrazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(2-methylpyridin-5-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyI-5-(2-methylthiazol-4-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(1-oxidopyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(1-phenylimidazol-4-yl)-4H-1,2,4-triazo!-4-yl, 3-methoxymethyl-5-(5-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yll 3-methoxymethyl-5-(2-phenylpyridin-5-yl)-4H-1,2,4-triazol-4-yll 3-methoxymethy!-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethy!-5-(pyridin-3-ylmethyI)-4H-1,2,4-triazol-4-yl, S-methoxyrnethyi-S-fauinolin-S-ylHH-VAtriazoM-yl, 3-methoxymethyl-5-(quino!in-6-yl)-4H-1,2,4-triazol-4-yl, 3-(2-methoxyphenyl)-5-methyl-4H-1,2,4-triazo!-4-yl, 3-(3-methoxyphenyI)-5-methyl-4H-1,2,4-triazoI-4-yl, 3-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1-methylimidazol-2-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1 -methylimidazol-4-yl)-4H-1,2,4-triaZoI-4-yl, 3-methyI-5-(1 -methyIimidazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-(3-methylisothiazol-4-yl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-methyl-5-(4-methyl-1 H-imidazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(2-met'hylpyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(2-methylpyridin-5-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1 -methylpyrazol-5-yI)-4H-1,2,4-triazol-4-y I, 3-methyl-5-(5-methyl-1 H-pyrazol-3-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1-methylpyrrol-2-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(2-methylthiazol-4-yi)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1 -methyl-1 H-1,2,4-triazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1-methyl-1 H-pyrazol-4-yl)-4H-1,2,4-triazol-4-yl, 3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-phenyl-4H-1,2,4-triazol-4-yl, 3-methyl-5-(3-[prop-1-yI]-1H-pyrazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1 H-pyrazol-4-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-4-yl, 3-methyI-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyridin-3-yimethyI)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyridin-4-ylmethyl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyrimidin-2-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(thien-2-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1 H-1,2,3-triazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(1 H-1,2,4-triazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-morpholinomsthyl-5-(pyridin-3-yl)-4H-1,2,4-triazo1-4-yl, 3-phenoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-(2-phenylethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-(pyridin-3-yl)-5-(2I2,2-trifluoroethoxy)methyl-4H-1,2>4-triazoi-4-yl, 3-(pyridin-3-y[)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(4-trifIuoromethylphenyl)-4H-1,2,4-triazol-4-yl, 1-ailyltetrazol-5-yl, 1 -benzyItetrazol-5-yl, 1 -carboxymethyltetrazol-5-yl, 1 -cyclohexyltetrazol-5-yl, 1 -ethyltetrazol-5-yl, 1 -(2-hyd roxyethyl)tetrazol-5-yl, 1-(3-hydroxypropyl)tetrazol-5-yi, 1-methoxycarbonylmethyltetrazol-5-yl, 1 -(2-methoxyethyl)tetrazol-5-yl, 1 -methyltetrazoI-5-yl, 1 -(2-phenylethyI)tetrazol-5-yl, 1 -phenyltetrazol-5-yl, 1 -(prop-2-yl)tetrazol-5-yl, 1 -(2,2,2-trifluoroethyi)tetrazol-5-yl, pyridin-2-yl, pyridin-3-yi, pyridin-4-yl, pyrimidin-2-yI and pyrimidin-5-yl.
Most preferably R is 1-(3-hydroxypropyl)tetrazol-5-yl, 4-methyl-4H-1,2,4-triazol-3-yI, 1-(2-hydroxyethyl)-5-phenyl-1,2,3-iriazol-4-yl, 3-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methyl-5-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(quinolin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(quinolin-6-yl)-4H-1,2,4-triazol-4-yl or 3-(1,5-dimethyl-1 H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-4-yl.
Preferably, R1 and R2 are each independently selected from chloro and C,-C4 alkyl, especially methyl or ethyl.
Most preferably, R1 and R2 are each chloro.
Preferably, R3 and R4 are each independently selected from H and C,-C4 alkyl. ' Most preferably, R3 and R4 are each methyl.
Preferably, “aryl” means phenyl optionally substituted by 1 or 2 substituents each independently selected from methyl, methoxy, hydroxy, chloro, trifluoromethyl and dimethylamino.
Examples of “aryl” include 2-chlorophenyi, 3-chlorophenyl, 4-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl and 4-trifluoromethylphenyl.
Preferably, “het” means thienyl, pyrroiyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally benzo-fused and optionally substituted by 1 or 2 substituents each independently selected from C,-C4 alkyl, -COOH, -NR3R4 and phenyl, and/or by an oxido substituent on a ring nitrogen heteroatom of said pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group.
Examples of “het” include thien-2-yl, 1-methylpyrrol-2-yl, 1 H-pyrazol-4-yl, 1-metnyl-1 H-pyrazol-4-yl, 5-methyI-1 H-pyrazol-3-yl, 1 -methyl-1 H-pyrazol-5-yl, 1,5-dimethyi-1H-pyrazol-3-yl, 3-(prop-1-yl)-1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yl, 1-methyIimidazol-4-yl, 1-methylimidazol-5-yl, 4-methyl-1H-imidazol-5-yl, 1-phenylimidazol-4-yl, 1H-1,2,3-triazo!-5-yl, 1 H-1,2,4-triazol-5-yl, 1-methyl-1 H-1,2,4-triazol-5-yi, 2-methylthiazol-4-yl, 3-methylisothiazol-4-yl, 2-amino-1,3,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-methyl-1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-3-yl, 2-methylpyridin-5-yl, 1-oxidopyridin-3-yl, 2-carboxypyridin-5-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, quinolin-3-yl and quin'olin-6-yl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate,’ gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and g-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the calcium, lithium, magnesium, potassium, sodium, zinc, ethanolamine, diethanolamine and triethanolamine salts.
For a review on suitable salts see Berge gi ai, J.Pharm.Sci., 66, 1-19 (1977). A compound of the formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in two or more stereoisomeric forms, or it may exist as tautomers. The present invention includes the individual stereoisomers and tautomers of the compounds of the formula (!) and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base.
Certain compounds of the formula (I) can exist in the form of particular stereoisomers known as atropisomers. Atropisomers are isomers that can be separated only because rotation about single bonds is prevented or greatly slowed (see “Advanced Organic Chemistry”, Third Edition, Jerry March, John Wiley and Sons (1985)). They can be separated by conventional methods such as by those described in the preceding paragraph. The present invention includes the individual atropisomers of the compounds of the formula (I) and mixtures thereof.
Preferred examples of the compounds of the formula (I) are those wherein (i) R is 1-(3-hydroxypropyl)tetrazol-5-yl, R1 is chloro and R2 is chloro; (ii) R is 4-methyl-4H-1,2,4-triazoI-3-yl, R1 is chloro and R2 is chloro; (iii) R is 1-(2-hydroxyethyl)-5-pheny!-1,2,3-triazol-4-yl, R1 is chloro and R2 is chloro; (iv) R is 3-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro; (v) R is 3-methyl-5-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro; (vi) R is 3-methoxymethyl-5-(pyridin-3-yI)-4H-1,2,4-triazol-4-yI, R1 is chloro and R2 is chloro; (vii) R is 3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro; (viii) R is 3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is methyl; (ix) R is 3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is methyl and R2 is chloro; (x) R is 3-methoxymethyl-5-(quinolin-3-yl)-4H-1,2,4-iriazol-4-yl, R1 is chloro and R·" is chloro; or (xi) R is 3-methoxymethyl-5-(quinolin-6-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro: or an individual stereoisomer or a pharmaceutically acceptable salt of any thereof.
Particularly preferred compounds of the formula (I) are (i) R-(-)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazoI-4-yl]- 2,3(1 H,4H)-quinoxalinedione or a pharmaceutically acceptable salt thereof and (ii) R-(-)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]- 2,3(1 H,4H)-quinoxalinedione sodium salt.
All the compounds of the formula (I) can be prepared by acidic or basic hydrolysis of a compound of the formula: £
wherein R, R1 and R2 are as previously defined for a compound of the formula (I) and R5 and R6, either when taken alone or together, represent a group or groups that can be hydrolytically cleaved under acidic or basic conditions to provide a quinoxalinedione of the formula (I). Such group or groups are conventional and suitable examples will be well-known to the skilled person.
Preferably R5 and R6 are either each independently selected from CrC4 alkyl (preferably methyl or ethyl) and benzyl, optionally ring-substituted by from 1 to 3 substituents each independently selected from Ci-C4 alkyl, CrC4 alkoxy, halo, nitro and trifluoromethyl, or, when taken together, represent CrC6 alkylene, CH(phenyl), CH(4-methoxyphenyl) or CH(3,4-dimethoxyphenyl). • Preferably, the reaction is carried out by acidic hydrolysis of a compound of the formula (II).

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