WO2001010846A2 - Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers - Google Patents

Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers Download PDF

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WO2001010846A2
WO2001010846A2 PCT/CA2000/000897 CA0000897W WO0110846A2 WO 2001010846 A2 WO2001010846 A2 WO 2001010846A2 CA 0000897 W CA0000897 W CA 0000897W WO 0110846 A2 WO0110846 A2 WO 0110846A2
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group
amino
spirocycle
alkyl
compound
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PCT/CA2000/000897
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WO2001010846A3 (fr
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Kenneth Curry
Hossien Pajouhesh
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Igt Pharma Inc.
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Priority to AU64207/00A priority Critical patent/AU6420700A/en
Priority to MXPA02001340A priority patent/MXPA02001340A/es
Priority to CA002381260A priority patent/CA2381260A1/fr
Priority to EP00951157A priority patent/EP1210338A2/fr
Priority to JP2001515312A priority patent/JP2003506440A/ja
Publication of WO2001010846A2 publication Critical patent/WO2001010846A2/fr
Publication of WO2001010846A3 publication Critical patent/WO2001010846A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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

Definitions

  • This invention pertains to the field of therapeutically active 1,4-benzodiazepine compounds and is particularly concerned with 1,4-benzodiazepine compounds containing a carboxy or an amino group, or both.
  • CNS central nervous system
  • neurons transmit information from cell to cell by releasing chemicals known as neurotransmitters through their cell membranes. Subsequent to their release, the neurotransmitters evoke a response from their target cell by interacting with different classes of receptors on the target cell's membrane.
  • the evoked response can be inhibitory, excitatory or modulatory, and occurs as a result of the controlled movement of ions such as sodium, potassium, chloride and calcium across the cell membrane.
  • Errors in neurotransmission or the uncontrolled movements of ions across the cell membrane can lead to neuropathological conditions and vice versa.
  • Sodium and calcium overload of neurons is thought to be a critical factor in the initiation of the pathological conditions leading to cell death following the cerebral ischemia (anoxia) that occurs during strokes or traumatic head injuries, for example.
  • Ischemia of neurons leads to depolarization, potassium loss, sodium uptake with associated cellular swelling, calcium uptake, calcium accumulation in mitochondria with associated damage, liberation of neurotransmitters and activation of calcium-dependent enzymes.
  • L-Glu acidic amino acid L-glutamic acid
  • Ionotropic glutamate receptors contain integral, cation-specific ion channels, whereas the metabotropic receptors are coupled to G proteins and modulate the production of intracellular messengers.
  • the ionotropic receptors can be subdivided into N-methyl-D- aspartate (NMDA) receptors and the ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate receptors according to their selective agonists.
  • NMDA N-methyl-D- aspartate
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate
  • mGluRs of which there are eight distinct types, were only identified within the last ten years.
  • the receptor subtypes are differentiated by their pharmacological profiles as well as by the intracellular second messenger effects that they evoke. For example, L-Glu 's interaction at the mGluRl and mGluR5 subclass of receptor activates phospholipase C and a subsequent inositol phosphate cascade via a G-protein.
  • mGluRs may be implicated in a number of normal as well as pathological mechanisms in the brain and spinal cord. For example, activation of these receptors on neurons can: influence levels of alertness, attention and cognition; protect nerve cells from excitotoxic damage resulting from ischemia, hypoglycemia and anoxia; modulate the level of neuronal excitation; influence central mechanisms involved in controlling movement; reduce sensitivity to pain; reduce levels of anxiety.
  • An object of the present invention is to provide novel 1,4-benzodiazepine compounds and derivatives thereof, that demonstrate activity at the various metabotropic glutamate receptors.
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9 are same or different and selected from the group comprising H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl or acceptable esters thereof;
  • RIO is selected from group comprising: (Ci-C ⁇ ) alkyl (straight chain or branched); (C 6 - C 10 ) aryl [optionally substituted with (Ci-C ⁇ ) alkyl], aryl alkyl group where aryl group is optionally substituted with (Ci- C 6 ) alkyl, (Ci- C ⁇ ) alkoxy, halogen, carboxy, or nitro group; heteroaromatic group; or -O-C(O)R where R is (Ci- C ⁇ ) alkyl, (C 6 - C 10 ) aryl;
  • R31 is either H or taken together with R32 to form a spirocycle
  • R32 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • R41 is XY or -CRllXY
  • R42 is X or Y or -CR11XY
  • Rll is H, (C ⁇ C ⁇ ) alkyl (straight chain or branched); (C 6 - C 10 ) aryl [optionally substituted with (Ci- C 6 ) alkyl], aryl alkyl group where aryl group is optionally substituted with (Ci- C 6 ) alkyl, (Cr C 6 ) alkoxy, halogen, carboxy, or nitro group; (C 4 - C 9 ) heterocyclic group (aromatic or nonaromatic);
  • X is H or an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, -(CH 2 ) n -carboxy,
  • Y is H or a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea, thiourea, with the proviso that, (i) at least one of X or Y is other than H and (ii) when R32 is -(CH 2 ) m R42, R42 is COOH, then m is 1.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound formula (I):
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9 are same or different and selected from the group comprising H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl or acceptable esters thereof;
  • RIO is selected from group comprising: (Ci-C ⁇ ) alkyl (straight chain or branched); (C 6 - Cio) aryl [optionally substituted with ) alkyl], aryl alkyl group where aryl group is optionally substituted with (Ci- C 6 ) alkyl, (Ci- C 6 ) alkoxy, halogen, carboxy, or nitro group; heteroaromatic group; or -O-C(O)R where R is (d- C ⁇ ) alkyl, (C 6 - Cio) aryl;
  • R31 is either H or taken together with R32 to form a spirocycle
  • R32 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • R31 is XY or -CRllXY
  • R41 is X or Y or -CRllXY
  • Rll is H, (Ci- C ⁇ ) alkyl (straight chain or branched); (C ⁇ - Cio) aryl [optionally substituted with (Ci- C ⁇ ) alkyl], aryl alkyl group where aryl group is optionally substituted with (Ci-
  • X is H or an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, -(CH 2 ) n -carboxy,
  • Y is H or a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea, thiourea.
  • a method of modulating the activity of metabotropic glutamate receptors in mammals which comprises administering to a mammal requiring modulated excitatory amino acid neurotransmission a pharmacologically-effective amount of compound of formula (I).
  • a pharmaceutical composition containing compound of formula (I) in treating diseases of the central nervous system related to the metabotropic glutamate receptor system.
  • amino-protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4- fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3 -chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3 -bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl, 2-(4-xenyl)-isopropoxycarbonyl,
  • amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting group(s).
  • Preferred amino-protecting groups are t-butoxycarbonyl (t-Boc), allyloxycarbonyl and benzyloxycarbonyl (CbZ). Further examples of these groups are found in E. Haslam, Protecting Groups in Organic Chemistry, (J. G. W. McOmie, ed., 1973), at Chapter 2; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, (1991), at Chapter 7.
  • carboxy-protecting groups include methyl, ?-nitrobenzyl, ?-methylbenzyl, 7-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl,
  • the present invention provides a compound of the formula (I):
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9 are same or different and selected from the group comprising H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl or acceptable esters thereof;
  • RIO is selected from group comprising: (Ci-C ⁇ ) alkyl (straight chain or branched); (C ⁇ - Cio) aryl [optionally substituted with (d-C ⁇ ) alkyl], aryl alkyl group where aryl group is optionally substituted with (Ci- C ⁇ ) alkyl, (Ci- C ⁇ ) alkoxy, halogen, carboxy, or nitro group; heteroaromatic group; or -O-C(O)R where R is (Ci- C ⁇ ) alkyl, (C ⁇ - Cio) aryl;
  • R31 is either H or taken together with R32 to form a spirocycle
  • R32 is selected from the group comprising:
  • spirocycle 0,1 or when R31 and R32 are taken together to form a spirocycle, then the spirocycle is selected from the group comprising:
  • R41 is XY or -CRllXY
  • R42 is X or Y or -CRllXY
  • Rll is H, (d- C 6 ) alkyl (straight chain or branched); (C ⁇ - C 10 ) aryl [optionally substituted with (Ci- C 6 ) alkyl], aryl alkyl group where aryl group is optionally substituted with (Ci- C 6 ) alkyl, (Ci- C ⁇ ) alkoxy, halogen, carboxy, or nitro group; (C 4 - C ) heterocyclic group (aromatic or nonaromatic); X is H or an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, -(CH 2 ) n -carboxy, (CH ) ⁇ -phosphono, -(CH 2 ) n -phosphino, -(CH 2 ) n -sulfono,-(CH2) n
  • Y is H or a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea, thiourea, with the proviso that (i) at least one of X or Y is other than H and (ii) when R32 is -(CH 2 ) m R42, R42 is COOH, then m is 1.
  • this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I.
  • a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as //•-toluenesulfonic acid, methanesulfonic acid, oxalic acid, /?-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as //•-toluenesulfonic acid, methanesulfonic acid, oxalic acid, /?-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl
  • Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic 0 acids such as maleic acid and methanesulfonic acid.
  • Salts of amine groups may also comprise quarternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety. 5
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, 10 sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is usually not of a critical nature, as long as the salt as a whole is t5 pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formula I.
  • Many of the Formula I compounds can combine with solvents i0 such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • the compounds of the present invention have multiple asymmetric (chiral) centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • R and S are used herein as commonly used in organic chemistry to denote the absolute configuration of a chiral center, according to the Cahn-Ingold-Prelog system.
  • the stereochemical descriptor R rectus
  • S sinister
  • the stereochemical descriptor S refers to that configuration of a chiral center with a counterclockwise relationship of groups tracing the path from highest to second- lowest priority when viewed from the side opposite to the lowest priority group.
  • the priority of groups is decided using sequence rules as described by Cahn et al, Angew.
  • D-L system In addition to the R,S system used to designate the absolute configuration of a chiral center, the older D-L system is also used in this document to denote relative configuration, especially with reference to amino acids and amino acid derivatives.
  • a Fischer projection of the compound is oriented so that carbon- 1 of the parent chain is at the top.
  • D is used to represent the relative configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • the stereochemistry of the Formula I compounds is critical to their potency as agonists.
  • the relative stereochemistry is preferably established early during synthesis, which avoids stereoisomer separation problems later in the process. Subsequent synthetic steps then employ stereospecific procedures so as to maintain the preferred configuration.
  • the preferred methods of this invention are the methods employing those preferred compounds.
  • Non-toxic metabolically labile esters and amides of compounds of Formula I are ester or amide derivatives of compounds of Formula I that are hydrolyzed in vivo to afford said compounds of Formula I and a pharmaceutically acceptable alcohol or amine.
  • metabolically labile esters include esters formed with (Ci.C ⁇ ) alkanols in which the alkanol moiety may be optionally substituted by a (Ci.Cg) alkoxy group, for example methanol, ethanol, propanol and methoxyethanol.
  • metabolically labile amides include amides formed with amines such as methylamine.
  • the present invention provides a process for the preparation of a compound of Formula I, or a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof, which comprises:
  • R1-R10 are as defined above,
  • R33 is H or taken together with R34 to form a spirocycle
  • R34 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • R43 is: R44 is:
  • Rll is as defined above, R12 is an acid ester, Y is as defined above.
  • Preferred values for Y is H or NH 2 ; or
  • R1-R10 are as defined above,
  • R35 is H or taken together with R36 to form a spirocycle
  • R36 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • Rll is as defined above, R13 represents a hydrogen atom or a carboxyl protecting group, or a salt thereof, and R14 represents a hydrogen atom or a nitrogen protecting group;
  • R1-R10 are as defined above
  • R37 is H or taken together with R38 to form a spirocycle
  • R38 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • R47 is:
  • Rll is as defined above, R15 and R16 each independently represent a hydrogen atom, a (C 2 -C ⁇ ) alkanoyl group, a (C ⁇ -C ) alkyl group, a (C 3 -C ) alkenyl group or a phenyl (d-C 4 ) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (Ci-C 4 ) alkyl or (Ci-C 4 ) alkoxy, or a salt thereof; or:
  • R1-R10 are as defined above
  • R39 is H or taken together with R40 to form a spirocycle
  • R40 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • R49 is:
  • R50 is:
  • R17 represents a hydrogen atom or an acyl group.
  • Preferred values for R17 are hydrogen and (C2-C ⁇ ) alkanoyl groups, such as acetyl; whereafter, if necessary and/or desired, the following steps are carried out:
  • carboxy protecting groups include alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aralkyl groups such as benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,
  • amine protecting groups include acyl groups, such as groups of formula -C(O)R14 in which R14 represents (Ci-C ⁇ ) alkyl,
  • a phenyl group may optionally be substituted by one or two substituents independently selected from amino, hydroxy, nitro, halogeno, (Ci-C ⁇ ) alkyl, (Ci-C ⁇ ) alkoxy, carboxy, (Ci-C ⁇ ) alkoxycarbonyl, carbamoyl, (Ci-C ⁇ ) alkanoylamino, (Ci-C ⁇ ) alkylsulphonylamino, phenylsulphonylamino, toluenesulphonylamino, and (Ci-
  • the compounds of Formula II are conveniently hydrolyzed in the presence of an acid, such as hydrochloric acid or sulfuric acid, or a base, such as an alkali metal hydroxide, for example sodium hydroxide.
  • an acid such as hydrochloric acid or sulfuric acid
  • a base such as an alkali metal hydroxide, for example sodium hydroxide.
  • the hydrolysis is conveniently performed in an aqueous solvent such as water and at a temperature in the range from 50 to 200 °C.
  • the compounds of Formula IN may be deprotected by conventional methods.
  • an alkyl carboxyl protecting group may be removed by hydrolysis.
  • the hydrolysis may conveniently be performed by heating the compound of Formula IN in the presence of either a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline metal hydroxide, such as barium hydroxide, or an acid such as hydrochloric acid.
  • the hydrolysis is conveniently performed at a temperature in the range from 10 to 300 °C.
  • An arylalkyl carboxyl-protecting group may conveniently be removed by hydrogenolysis.
  • the hydrogenolysis may conveniently be effected by reacting the compound of Formula IN with hydrogen in the presence of a Group NTfl metal catalyst, for example a palladium catalyst such as palladium on charcoal.
  • a Group NTfl metal catalyst for example a palladium catalyst such as palladium on charcoal.
  • Suitable solvents for the reaction include alcohols such as ethanol.
  • the reaction is conveniently performed at a temperature in the range from 0 to 100 °C.
  • An acyl amine protecting group is also conveniently removed by hydrolysis, for example as described for the removal of an alkyl carboxyl protecting group.
  • the compounds of Formula N are conveniently hydrolyzed in the presence of a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide such as barium hydroxide.
  • Suitable reaction media include water.
  • the temperature is conveniently in the range from 50 to 150 °C.
  • R1-R10, R18, R19, R35 and R36 are as defined above;
  • R46 is:
  • R13 and R14 are as defined above, R15 is as defined above, but other than H can also be prepared from compounds of formula (IX) using standard reaction conditions known to a worker skilled in the art: Rl RIO
  • R1-R10 are as defined above,
  • R51 is H or taken together with R52 to form a spirocycle
  • R52 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • n 0-3, R20 is -CO 2 R13 or OH and R13 is as defined above.
  • R20 is -CO 2 R13 or OH and R13 is as defined above.
  • Compounds of formula IN may be formed by reacting compound X with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and ammonium carbonate or ammonium carbamate.
  • an alkali metal cyanide such as lithium, sodium or potassium cyanide
  • ammonium carbonate or ammonium carbamate Common solvents include alcohols, such as methanol, aqueous methanol and aqueous ethanol. Conveniently the reaction is performed at a temperature in the range of from 10 to 150 °C.
  • the compounds of Formula IN may then be alkylated, for example using an appropriate alkyl, aryl or acyl chloride.
  • R1-R10 are defined above;
  • R53 is H or taken together with R54 to form a spirocycle
  • R54 is selected from the group comprising:
  • spirocycle 0,1 or when R53 and R54 are taken together to form a spirocycle, then the spirocycle is selected from the group comprising:
  • R62 is:
  • Rll is as defined above.
  • the compounds of formula N may be prepared by reacting a compound of formula X with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and either ammonium carbonate in an aqueous alcohol, such as aqueous ethanol, or with an ammonium halide, such as ammonium chloride, conveniently in the presence of ultrasound. If the reaction is conducted with ammonium carbonate, the reaction is conveniently performed at a temperature in the range from 35 to 150 °C. If desired, the compounds of Formula N may then be alkylated, for example using an appropriate alkyl, aryl or acyl chloride. As described in more detail hereinafter, the alkylated compounds may be readily separated into their diastereomers.
  • an alkali metal cyanide such as lithium, sodium or potassium cyanide
  • an ammonium halide such as ammonium chloride
  • the reaction is conducted with an ammonium halide in the presence of ultrasound, the ammonium halide is mixed with chromatography grade alumina in the presence of a suitable diluent such as acetonitrile.
  • Individual isomers of compounds of Formula N may be made by reacting a compound of the Formula X with the stereoisomers of the chiral agent (S)- and (R)-phenylglycinol and a reactive cyanide such as trimethylsilyl cyanide to form the intermediate compounds of Formula XI.
  • R1-R10 are defined above;
  • R55 is H or taken together with R56 to form a spirocycle
  • R56 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • Rll is as defined above.
  • R12 and Y is as defined above, Rll is as defined above, but other than H, can be prepared from compounds of formula (II), wherein R43 is:
  • R46 is:
  • Rll, R13 and R14 are as defined above, can be prepared from compounds of formula (XII):
  • m' is 0-3, R18, R19 and R20 are as defined above, by:
  • Some compounds of the formula X may be can be prepared by:
  • R1-R10 are defined above;
  • R57 is H or taken together with R58 to form a spirocycle;
  • R58 is selected from the group comprising:
  • the spirocycle is selected from the group comprising:
  • R65 is:
  • R is H, (Ci-C ⁇ ) alkyl, phenyl, benzyl or any other carboxyl protecting group;
  • R1-R10 are defined above;
  • R59 is H or taken together with R60 to form a spirocycle
  • R60 is selected from the group comprising:
  • the spirocycle is selected from the group comprising;
  • Rll is as defined above;
  • R1-R10 are defined above;
  • R71 is H or taken together with R72 to form a spirocycle
  • R72 is selected from the group comprising:
  • spirocycle 0,l or when R71 are R72 taken together to form a spirocycle, then the spirocycle is selected from the group comprising:
  • the pharmacological properties of the compounds of the present invention can be determined via appropriate functional assays using recombinant metabotropic glutamate receptors.
  • adenylate cyclase assays or phosphatidylinositol hydrolysis assays can be used to determine agonist or antagonist activity towards mGluRs.
  • In Vitro Testing General in vitro assay methods include monitoring of adenylate cyclase activity and phosphatidyl inositol hydrolysis in a cell line that expresses the appropriate mGluR. Many in vitro assays exist which can be used to study adenylate cycliase activity and phosphatidyl inositol hydrolysis, a few examples of which are provided below.
  • Adenylate cyclase activity is determined in initial experiments in transfected mammalian cells, using standard techniques. See, e.g., N. Adham, et al., Supra; R. L. Weinshank, et al. Proc. Natl. Acad. Sci. (USA), 89:3630-3634 (1992), and the references cited therein.
  • Mammalian cells (the cell line AV12-664 is especially preferred) are stably transfected with a plasmid comprising a cloned metabotropic glutmate receptor.
  • the cells are maintained in an appropriate medium, for example one consisting of Dulbecco's Modified Eagle's Medium (DMEM) containing 5% dialyzed fetal calf serum, 10 mM HEPES buffer (pH 7.3), 1 mM sodium pyruvate, 1 mM glutamine, and 200 ⁇ .g/mL hygromycin.
  • DMEM Dulbecco's Modified Eagle's Medium
  • the cells are released from stock culture flasks with trypsin, and plated in 24-well plastic tissue culture dishes (15 mm wells) at a density of 500,000-700,000 cells per well using the same culture medium. After a twenty four hour incubation in a humidified CO 2 incubator, the cell monolayers are washed with buffer (for example Dulbecco's phosphate-buffered saline containing 0.5 mM LBMX and 3 mM glucose) and then incubated in the same buffer at 37 °C for 30 minutes. The monolayers are then washed with six exchanges of buffer.
  • buffer for example Dulbecco's phosphate-buffered saline containing 0.5 mM LBMX and 3 mM glucose
  • Test compound(s) and forskolin, or forskolin alone, dissolved in buffer, are added after the final wash. After incubating for 20 minutes at 37 °C, 0.5 mL of 8 mM EDTA is added to each well. The plates are then placed in a boiling water bath for about four minutes. The supernatant fluids are recovered from the wells and lyophilized. Cyclic AMP (cAMP) determinations are carried out on the lyophilized samples using commercially available radioimmunoassay kits, following the manufacturer's instructions. The cAMP levels in wells containing test compound(s) are then compared to the forskolin controls.
  • cAMP Cyclic AMP
  • Phosphatidylinositol hydrolysis is measured in clonal cell lines (for example AV12) harbouring a plasmid expressing the cloned metabotropic glutamate receptor in response to addition of glutamate agonists, as a functional assay for metabotropic glutamate receptor activity according to D. Schoepp, Trends in Pharmaceutical Sciences, 11:508, 1990.
  • MEM in the absence of glutamic acid
  • fetal calf serum 2 mM glutamine and 10% dialyzed fetal calf serum.
  • the media is removed and replaced with fresh media containing four microcuries of [ 3 H]myoinositol per well and the cultures are incubated a further 16 to 20 hours.
  • the media is then removed and the cells in each well are washed with serum free medium containing 10 mM lithium chloride, 10 mM myoinositol, and 10 mM HEPES (2 x 1 mL washes). After the final wash, 0.5 mL of washing solution is added containing the appropriate concentration(s) of test compound(s).
  • a ten minutes incubation is performed prior to antagonist induction.
  • Cells are incubated for about one hour at 37 °C. in 95%:5% O 2 :CO 2 or as appropriate for time course.
  • the reactions are terminated by removing media and adding 1 mL of cooled 1:1 acetone: methanol followed by incubation on ice for a minimum of twenty minutes.
  • SEP-PAK® column which is prewetted and equilibrated by passing 10 mL of water, followed by 8 mL of 1 M triethylammonium hydrogen carbonate (TEAB), followed by 10 mL of water through the column.
  • TEAB triethylammonium hydrogen carbonate
  • the assay supernatants containing the water soluble [ 3 H]inositol phosphate are passed over the columns. This is followed by a 10 mL water wash and a 4 mL wash with 0.02 M TEAB to remove [ 3 H]inositol precursors.
  • [ 3 H]inositol phosphate is eluted with 4 mL of 0.1 M TEAB into scintillation vials and counted in the presence of scintillation cocktail. Total protein in each sample is measured using standard techniques. Measurements are taken as the amount of [ 3 H]inositol phosphate released per milligram of protein.
  • the assays are carried out in the absence and in the presence of the compound being tested.
  • the measurements of [ 3 H]inositol phosphate per milligram of protein are compared in order to confirm agonist and antagonist activity of the compound being tested.
  • These types of assays employing cell lines expressing different subtype of cloned metabotropic receptors, may be used to determine which compounds have selective affinity in that they modulate one subtype of receptor with a greater activity than another subtype.
  • DMEM Eagle Medium
  • proline penicillin (100 U/rnL)
  • streptomycin 100 mg/mL
  • dialyzed fetal calf serum All GTBCO, Paisley
  • Phosphatidylinositol (PI) hydrolysis can be measured as described previously (Hayashi et al, Nature 366, 687-690,1992, and J. Neuroscience 14, 3370-3377, 1994). Briefly, the cells are labeled with [ 3 H]inositol (2 ⁇ Ci/mL) 24 h prior to the assay.
  • the cells are incubated with test compound dissolved in phosphate-buffered saline (PBS)- LiCl for 20 min, and agonist activity is determined from the level of 3 H-labeled mono-, bis- and tris-inositol phosphates generated, as measured following ion-exchange chromatography, compared with the level generated in the absence of the test compound.
  • PBS phosphate-buffered saline
  • agonist activity is determined from the level of 3 H-labeled mono-, bis- and tris-inositol phosphates generated, as measured following ion-exchange chromatography, compared with the level generated in the absence of the test compound.
  • the cells are preincubated with ligand dissolved in PBS-LiCl for 20 min prior to incubation with test compound and 10 ⁇ M (S)-Glu for 20 min. The antagonist activity is then determined as the inhibitory effect of the (S)-Glu mediated response.
  • the assay of cyclic AMP formation can be performed as described previously (Hayashi et al, 1992, 1994). Briefly, the cells are incubated for 10 min in PBS containing test coumpound and 10 ⁇ M forskolin and 1 mM 3-isobutyl-l-methylxanthine (LBMX) (both
  • the agonist activity is then determined as the inhibitory effect on the forskolin-induced cyclic AMP formation.
  • the cells are preincubated with ligand dissolved in PBS containing 1 mM LBMX for 20 min prior to a 10 min incubation in PBS containing test compound, 20 ⁇ M(mGlu2) or 50 ⁇ M (mGlu4a) (S)-Glu, 10 ⁇ M forskolin and 1 mM L3MX.
  • the antagonist activity is then determined as the potentiating effect on the forskolin-induced cyclic AMP formation.
  • tissue that expresses mGluRs may be used as described herein, for Sprague dawley rat tissues.
  • Phosphatidylinositol (PI) hydrolysis can be measured as described below:
  • cross-chopped slices are prepared from neonatal Sprague Dawley rat tissue (age:
  • the slices are pre-labelled with [ 3 H] myo-inositol. Following pre-labelling, the slices are incubated with the test drugs and standard (known Group I agonists i.e. ACPD) for a period of 45 minutes. The incubation is terminated by the addition of chloroform/methanol/HCl (100:200:2). The resulting mixture is separated into two phases by the addition of chloroform and distilled water. The aqueous fraction is applied
  • the assay of cyclic AMP formation can be performed as described previously (Tovey et al, Clinica Chimica Acta, 56, 221-234, 1974).
  • the assay can be modelled on the cyclic AMP assay kit available from Amersham, which in turn, is based on the assay created by Tovey et al. Briefly, samples are prepared from Sprague Dawley rat (225-250g) cortical slices. Slices are incubated with the drug, and then challenged with forskolin to induce
  • the compounds of formula I of the present invention exhibit agonistic or antagonistic activity toward certain metabotropic glutamate receptors (mGluRs). Therefore, another aspect of the present invention provides a method of modulating the activity of mGluRs in mammals, which comprises administering to a mammal requiring modulated excitatory amino acid neurotransmission a pharmacologically-effective amount of a compound of Formula I.
  • pharmacologically-effective amount is used to represent an amount of the compound of the present invention that is capable of affecting the mGluRs.
  • a compound of the present invention acts as an agonist
  • the interaction of the compound with the excitatory amino acid receptor mimics the response for the interaction of this receptor with its natural ligand, (i.e. L-Glutamic acid).
  • the interaction of the compound with the excitatory amino acid receptor blocks or attenuates the response from the interaction of this receptor with its natural ligand, (i.e. L-Glutamic acid).
  • the particular dose of compound administered according to the present invention will, of course, be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
  • the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
  • a typical daily dose will contain from about 0.001 mg/kg to about 100 mg/kg of the active compound of this invention.
  • daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 20 mg/kg.
  • Formula I compounds of the present invention can be used (through their interactions at the mGluRs) to treat a variety of neurological disorders in a warm-blooded mammals associated with abnormal excitatory amino acid transmission, including but not limited to acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (e.g. stroke and cardiac arrest), spinal cord trauma, head trauma, perinatal hypoxia, and hypoglycemic neuronal damage.
  • acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (e.g. stroke and cardiac arrest), spinal cord trauma, head trauma, perinatal hypoxia, and hypoglycemic neuronal damage.
  • the Formula I compounds of the present invention through their modulation of mGluR activity can be used to treat a variety of chronic neurological disorders, such as Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ACDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson's disease.
  • the present invention also provides methods for treating these disorders which comprises administering to a patient, in need thereof, an effective amount of a compound of Formula I.
  • the Formula I compounds of the present invention through their modulation of mGluR activity can be used to treat a variety of other neurological disorders in mammals that are associated with glutamate dysfunction, including muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, drug tolerance, withdrawal, and cessation (i.e. opiates, benzodiazepines, nicotine, cocaine, or ethanol), smoking cessation, anxiety and related disorders (e.g. panic attack), emesis, brain edema, chronic pain, sleep disorders, Tourette's syndrome, attention deficit disorder, and tardive dyskinesia. Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of Formula I.
  • the Formula I compounds of the present invention through their modulation of mGluR activity can be used to treat a variety of psychiatric disorders, such as schizophrenia, anxiety and related disorders (e.g. panic attack), depression, bipolar disorders, psychosis, and obsessive compulsive disorders.
  • the present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of Formula I.
  • the present invention provides a method of modulating one or more mGluR functions in a warm-blooded mammal which comprises administering an effective amount of a compound of Formula I, or a non-toxic metabolically-labile ester or amide thereof, or a pharmaceutically acceptable salt thereof.
  • compositions of the present invention are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active ingredient.
  • the compounds of Formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the present invention also provides pharmaceutical compositions containing compounds as disclosed in the claims in combination with one or more pharmaceutically acceptable, inert or physiologically active, diluents or adjuvants.
  • the compounds of the invention can be freeze dried and, if desired, combined with other pharmaceutically acceptable excipients to prepare formulations for administration.
  • These compositions may be presented in any form appropriate for the administration route envisaged.
  • the parenteral and the intravenous route are the preferential routes for administration.
  • Compounds of the general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any procedure known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents for example, corn starch, or alginic acid: binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethyene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example, le
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl -hydroxy-benzoate, one or more coloring agents, one or more flavoring agents or one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n- propyl -hydroxy-benzoate
  • coloring agents for example ethyl, or n- propyl -hydroxy-benzoate
  • flavoring agents for example sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, ka
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oils phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulation according to known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compound(s) of the general Formula I may be administered, together or separately, in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Compound(s) of general Formula I may be administered, together or separately, parenterally in sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the mode, dosage and schedule of administration of taxol in human cancer patients has been studied extensively (see Ann. Int. Med. 111:273 1989).
  • the dose to be administered whether a single dose, multiple dose, or a daily dose, will vary with the particular compound being used. Factors to consider when deciding upon a dose regimen include potency of the compound, route of administration, size of the recipient and the nature of the patient's condition.
  • the dosage to be administered is not subject to defined limits, but in will usually be an effective amount. It will usually be the equivalent, on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active free drug to achieve its desired pharmacological and physiological effects.
  • the Fmoc amino acid ester (compound 17) was dissolved in 5 mL of dry CH 2 CI2 and 50 ⁇ L of dry pyridine, then 0.66 g of cyanuric fluoride was added and the mixture was refluxed under N 2 for 4 h. A white precipitate separated and the mixture was extracted with water (2 x 10 mL). The organic layer was dried over MgSO and evaporated to give a white solid which was recrystallized to give 2.01 g (70%) of the compound 18.
  • the Fmoc amino acid ester (compound 23) was dissolved in 5 mL of dry CH2CI2 and 50 ⁇ L of dry pyridine. Then, 0.66 g of cyanuric fluoride was added and the mixture refluxed under N 2 for 4 h. A white precipitate separated and the mixture was extracted with water (2 x 10 mL). The organic layer was dried over MgSO 4 and evaporated to give a white solid which was recrystallized from C ⁇ Cyhexanes to give 2.38 g (72%) of the desired compound 24.
  • the Fmoc amino acid fluoride ester (compound 24) was dissolved in 10 mL of dry CH 2 CI 2 with 30 ⁇ L of 4-methyl-2,6-di-tert-butylpyridine and 1.15g of 2-amino-5- chlorobenzophenone. The resulting solution was stirred overnight under N 2 and evaporated to dryness. The residue is taken up into 5 mL of 20% piperidine in DMF and stirred for 30 min to remove the N-protecting group. The mixture was diluted with 50 mL of water and extracted with CH2CI 2 , the organic extract was dried over MgSO and evaporated. The residue was taken up in 5% acetic acid in DMF and stirred for 2 days. The reaction mixture was poured into 50 mL of water to precipitate the product which was collected by filtration. The crude product was purified by recrystallization from methanol/ water to afford 1.56 g (80% )of compound 26.
  • mGluRs metabotropic glutamate receptors
  • the assay has been modeled on the cyclic AMP assay kit available from Amersham. This
  • .0 kit in turn, is based on the assay created by Tovey et al. (1974). Briefly, the samples were prepared from Sprague Dawley rat (225-250g) cortical slices. Slices were incubated with the test compound (drug), and then challenged with forskolin to induce cyclic AMP release. Following termination of the reaction by boiling, the slices were homogenized and centrifuged. Samples of supernatant were then incubated for 2-3 hours with a known test compound (drug), and then challenged with forskolin to induce cyclic AMP release. Following termination of the reaction by boiling, the slices were homogenized and centrifuged. Samples of supernatant were then incubated for 2-3 hours with a known test compound (drug), and then challenged with forskolin to induce cyclic AMP release. Following termination of the reaction by boiling, the slices were homogenized and centrifuged. Samples of supernatant were then incubated for 2-3 hours with a known test compound (drug
  • the drugs tested inhibit forskolin-induced cyclic AMP accumulation, they are considered to be Group Il/i ⁇ agonists. Conversely, if they inhibit the decrease in forskolin-induced cyclic AMP accumulation caused by glutamate, they are considered to be Group ⁇ ⁇ i antagonists.
  • mGluRs Group I metabotropic glutamate receptors
  • ACPD standard agonists
  • Cross-chopped slices were prepared from neonatal Sprague Dawley rat tissue (age: p7- pl4). The slices were pre-labelled with [ 3 H]myo-inositol. Following pre-labelling, the slices were incubated with the test compounds and standard (known Group I agonists t ' .e. ACPD) for a period of 45 minutes. The incubation was terminated by the addition of chloroform/methanol/HCl (100:200:2). The resulting mixture was separated into two phases by the addition of chloroform and distilled water.
  • test compounds and standard known Group I agonists t ' .e. ACPD
  • the aqueous fraction was applied to ion exchange columns, and inositol phosphates were eluted using 800 mM Ammonium Formate/100 mM Formic Acid. The eluent was then analyzed using liquid scintillation counting. The amount of inositol phosphate accumulation was expressed as a percentage of that induced by ACPD.
  • the drugs cause an increase in intracellular free inositol phosphate accumulation, they are considered to be Group I agonists. If they inhibit the increase in intracellular free inositol phosphate accumulation induced by ACPD, they are considered to be Group II antagonists.

Abstract

La présente invention concerne de nouveaux composés de 1,4-benzodiazépine thérapeutiquement actifs et des dérivés de ces derniers, de la formule générale (I), dans laquelle R31 et/ou R32 renferme(nt) au moins un groupe carboxy ou un groupe amino, ou les deux. L'invention se rapporte également à un procédé de préparation de composés de la formule (I), et à des compositions pharmaceutiques renfermant les composés précités. Les nouveaux composés de l'invention agissent comme modulateurs des récepteurs métabotropiques du glutamate et, en tant que tels, ils sont utilisés dans le traitement de maladies du système nerveux central liées au système des récepteurs métabotropiques du glutamate.
PCT/CA2000/000897 1999-08-05 2000-08-04 Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers WO2001010846A2 (fr)

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MXPA02001340A MXPA02001340A (es) 1999-08-05 2000-08-04 Compuestos novedosos 1,4-benzodiazepina y derivados de los mismos.
CA002381260A CA2381260A1 (fr) 1999-08-05 2000-08-04 Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers
EP00951157A EP1210338A2 (fr) 1999-08-05 2000-08-04 Derives de 1,4 benzodiazepine utiles dans le traitement de maladies liees au systeme nerveux central
JP2001515312A JP2003506440A (ja) 1999-08-05 2000-08-04 中枢神経系に関連する疾患の処置のための１，４−ジアゼピン誘導体

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002078745A2 (fr) * 2001-04-02 2002-10-10 Brown University Research Foundation Compositions et utilisations d'antagonistes de mglur5
WO2002083665A1 (fr) * 2001-04-12 2002-10-24 F. Hoffmann-La Roche Ag Derives de dihydro-benzo[b][1,4]diazepine-2-one utilises comme antagonistes i de mglur2
WO2002083652A1 (fr) * 2001-04-12 2002-10-24 F. Hoffmann-La Roche Ag Derives dihydro-benzo[b][1,4]diazepin-2-one utilises comme antagonistes de mglur2(ii)
WO2004058754A1 (fr) * 2002-12-24 2004-07-15 Euro-Celtique S.A. Derives de benzoazolylpiperazine presentant une activite antagoniste vis-a-vis de mglur1 et de mglur5
US6916821B2 (en) 2001-04-02 2005-07-12 Brown University Methods of treating disorders with Group I mGluR antagonists
US7459563B2 (en) 2004-11-05 2008-12-02 Hoffmann-La Roche Inc. Process for the preparation of isonicotinic acid derivatives
US7511033B2 (en) 2007-04-19 2009-03-31 Hoffmann-La Roche Inc. Dihydro-benzo[B][1,4]diazepin-2-one sulfonamide derivatives
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
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CN112851691A (zh) * 2021-01-27 2021-05-28 北京工业大学 一种手性噁二嗪杂环稠合1,4-苯并二氮䓬-2-酮类化合物及制备方法
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US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
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US7648993B2 (en) 2001-04-02 2010-01-19 Brown University Methods of treating disorders with Group I mGluR antagonists
WO2002078745A3 (fr) * 2001-04-02 2002-11-28 Univ Brown Res Found Compositions et utilisations d'antagonistes de mglur5
WO2002078745A2 (fr) * 2001-04-02 2002-10-10 Brown University Research Foundation Compositions et utilisations d'antagonistes de mglur5
US6890931B2 (en) 2001-04-02 2005-05-10 Brown University Methods of treating disorders with group I mGluR antagonists
US6916821B2 (en) 2001-04-02 2005-07-12 Brown University Methods of treating disorders with Group I mGluR antagonists
WO2002083665A1 (fr) * 2001-04-12 2002-10-24 F. Hoffmann-La Roche Ag Derives de dihydro-benzo[b][1,4]diazepine-2-one utilises comme antagonistes i de mglur2
WO2002083652A1 (fr) * 2001-04-12 2002-10-24 F. Hoffmann-La Roche Ag Derives dihydro-benzo[b][1,4]diazepin-2-one utilises comme antagonistes de mglur2(ii)
US6544985B2 (en) 2001-04-12 2003-04-08 Hoffman-La Roche Inc. Dihydro-benzo [b][1,4]diazepin-2-one derivatives
US6548495B2 (en) 2001-04-12 2003-04-15 Hoffmann-La Roche Inc. Dihydro-benzo [B] [1,4] diazepin-2-one derivatives
US8604037B2 (en) 2002-12-24 2013-12-10 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
US9434721B2 (en) 2002-12-24 2016-09-06 Purdue Pharma L.P. Therapeutic agents useful for treating pain
HRP20050666B1 (en) * 2002-12-24 2009-05-31 Euro-Celtique S.A. Benzoazolylpiperazine derivatives having vr1 antagonist activity
US7582635B2 (en) 2002-12-24 2009-09-01 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
WO2004058754A1 (fr) * 2002-12-24 2004-07-15 Euro-Celtique S.A. Derives de benzoazolylpiperazine presentant une activite antagoniste vis-a-vis de mglur1 et de mglur5
US8008300B2 (en) 2002-12-24 2011-08-30 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8536177B2 (en) 2002-12-24 2013-09-17 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7459563B2 (en) 2004-11-05 2008-12-02 Hoffmann-La Roche Inc. Process for the preparation of isonicotinic acid derivatives
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US7511033B2 (en) 2007-04-19 2009-03-31 Hoffmann-La Roche Inc. Dihydro-benzo[B][1,4]diazepin-2-one sulfonamide derivatives
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
CN112574220A (zh) * 2020-12-08 2021-03-30 北京工业大学 一种手性1,4-苯并二氮*-2-酮螺杂环化合物及制备方法
CN112851691A (zh) * 2021-01-27 2021-05-28 北京工业大学 一种手性噁二嗪杂环稠合1,4-苯并二氮䓬-2-酮类化合物及制备方法

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