[go: up one dir, main page]

WO2001092212A1 - Modulateurs de recepteur d'acide amine excitateur - Google Patents

Modulateurs de recepteur d'acide amine excitateur Download PDF

Info

Publication number
WO2001092212A1
WO2001092212A1 PCT/US2001/010831 US0110831W WO0192212A1 WO 2001092212 A1 WO2001092212 A1 WO 2001092212A1 US 0110831 W US0110831 W US 0110831W WO 0192212 A1 WO0192212 A1 WO 0192212A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxy
glycine
compound
cyclopropyl
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2001/010831
Other languages
English (en)
Inventor
Ivan Collado-Cano
Jesus Ezquerra-Carrera
Alicia Marcos-Llorente
Luisa Maria Martin-Cabrejas
James Allen Monn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to US10/275,928 priority Critical patent/US7125871B2/en
Priority to EP01938985A priority patent/EP1289935A1/fr
Priority to AU2001264554A priority patent/AU2001264554A1/en
Publication of WO2001092212A1 publication Critical patent/WO2001092212A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/36—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • EAA receptors excitatory amino acid receptors
  • Excitatory amino acid receptors are classified into two general types . Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed " ionotropic" . This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists iV-methyl-D-aspartate (NMDA) , alpha-amino-3-hydroxy- 5-methylisoxazole-4-propionic acid (AMPA) , and kainic acid (KA) .
  • the second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor.
  • This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D or C, increases or decreases in c-AMP formation, and changes in ion channel function.
  • Schoepp and Conn Trends in Pharmacol . Sci . , 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life.
  • Schoepp, Bockaert, and Sladeczek Trends in Pharmacol . Sci . , 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
  • the metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways . These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation.
  • Compounds which modulate the function of these receptors, in particular agonists and antagonists of glutamate, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents .
  • the paper also describes the synthesis of the sixteen possible stereoisomers of 2- (2 ' -carboxy-3 ' -phenylcyclopropyl) glycine and their evaluation as excitatory amino acid receptor ligands.
  • the compound (2S, l'S, 2'S, 3 'R) -2- (2 ' -carboxy-3 ' - phenylcyclopropyl) glycine, also known as PCCG 4 is reported to be a metabotropic glutamate receptor antagonist.
  • 06179643 discloses MCG and generically discloses (2S, l'S, 2 'R) -2- (2-carboxy-3-alkoxymethyl- and 3-aralkoxymethyl- cyclopropyl) glycines as glutamate receptor agonists.
  • PCCG 4 discloses PCCG 4 and also generically discloses various 2-carboxy-3-arylcyclopropylglycines having affinity for metabotropic glutamate receptors .
  • EP-Al- 0870760 discloses that certain 3-substituted 2- carboxycyclopropyl glycine derivatives are modulators of metabotropic glutamate receptor function.
  • the preferred compounds are said to be those in which the substituents at the 1 and 2 positions are in a trans relationship.
  • the examples illustrate such compounds in which the substituents at the 1 and 3 positions are also in a trans relationship.
  • One such compound is (2S, l'S, 2'S, 3 ' S) -2 ' -carboxy-3 ' - methylcyclopropylglycine .
  • R represents CN, lH-tetrazol-5-yl or a group of formula CONR 1 (X 1 R 2 ) ; ⁇ l represents a bond, NHCO, NH, 0 or (CH 2 ) P -Y- in which Y represents 0, S, NR b , or COO and p is 2 or 3 , and R ⁇ , R 2 and R b each independently represents hydrogen; C ⁇ _ ⁇ o alkyl; C2-10 alkenyl; C2-10 alkynyl; aryl; aryl-Ci-io alkyl; aryl- C2-10 alkenyl; aryl-C2-10 alkynyl; heteroaryl; C3-8 cycloalkyl; C3-8-cycloalkyl-C ⁇ _ ⁇ o alkyl; a group of formula
  • R! and X-R2 together with the nitrogen atom to which they are attached form a 5 to 6-membered saturated heterocyclic ring, which ring may optionally be fused with an aromatic ring; an ester thereof; or a salt of said compound of formula I or said ester thereof.
  • Compounds of the invention have been found to be agonists of glutamate at metabotropic glutamate receptors and are therefore useful in the treatment of diseases of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal, antidepressant, anticonvulsant, analgesic and anti-emetic agents.
  • diseases of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal, antidepressant, anticonvulsant, analgesic and anti-emetic agents.
  • the compounds of formula (I) contain at least four asymmetric carbon atoms, three being in the cyclopropane ring and one being at the ⁇ -carbon of the amino acid group. Accordingly, the compounds of the invention may exist in and be isolated in enantiomerically pure form, in racemic form, or in a diastereoisomeric mixture.
  • Preferred compounds of the invention are those of formula la
  • the amino acid moiety preferably has the natural amino configuration. Accordingly, preferred compounds according to the invention are those of the formula:- lb
  • alkyl, alkenyl and alkynyl refer to straight chain or branched groups .
  • Ci-io alkyl includes C ⁇ _8 alkyl, Ci-6 alkyl and Ci- alkyl. Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl , octyl , nonyl and decyl .
  • C2-10 alkenyl includes C3-10 alkenyl. Particular values are vinyl and prop-2-enyl.
  • the term also includes groups containing more than one double bond, for example alkadienyl groups, such as 1, 3-butadienyl.
  • C2-10 alkynyl includes C3-10 alkynyl.
  • a particular value is prop-2-ynyl.
  • the term also includes groups containing more than one triple bond, or one or more double bonds .
  • aryl group refers to an aromatic monocyclic or polycyclic carbocyclic ring that may be unsubstituted or substituted by one or more substituents, said substituents being selected from atoms and groups that, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a metabotropic glutamate receptor agonist.
  • substituents being selected from atoms and groups that, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a metabotropic glutamate receptor agonist.
  • Examples of an aromatic monocyclic or polycyclic carbocyclic ring in an aryl group include phenyl and naphthyl .
  • An aromatic monocyclic or polycyclic carbocyclic ring in an aryl group may be unsubstituted or substituted with, for example, one, two or three substituents selected independently from halogen, cyano, nitro, amino, (1- 4C) alkylamino, di (1-4C) alkylamino, carboxy, and a group of formula - (CH 2 ) m -X a - (CH 2 ) n -R a in which m is 0, 1 or 2, n is 0, 1 or 2, X a represents a bond, 0, S, SO, S0 2 , NH, CO, COO, OCO, CONH, NHCO, NHCONH, NHS0 2 or S0 2 NH and R a represents an Ci- alkyl, C2-4 alkenyl, C2-4 alkynyl, halo Ci-4 alkyl or phenyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen, (1
  • heteroaryl refers to an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen.
  • heteroaromatic groups are furyl, thiophenyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, imidazolyl, pyrimidyl, benzofuryl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzo-thiazolyl and indolyl.
  • C3-8 cycloalkyl as such or in the term C3--8 cycloalkyl-C ⁇ _ ⁇ o alkyl, includes monocyclic and polycyclic groups. It includes C3-6 cycloalkyl. Examples of particular values are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo [2 . 2 . 2 ] octane.
  • halogen includes fluorine, chlorine, bromine and iodine .
  • amino acid residue refers to a group that is bonded to the alpha-carbon atom in an amino acid (the carbon also bearing an amino and carboxyl group) in an amino acid selected from D and L:
  • an amino acid residue is hydrogen (Gly) .
  • the term a 5 to 6-membered saturated heterocyclic ring, which ring may optionally be fused with an aromatic ring refers to a 5- or 6-membered saturated ring that may contain, in addition to the nitrogen atom bearing R ⁇ and
  • X ⁇ R2 a second heteroatom selected from O, N and S, which ring may be fused with an aromatic ring.
  • 5- and ' 6-membered saturated rings are piperidinyl and morpholinyl.
  • An example of an aromatic ring is phenyl.
  • Examples of particular values for a 5 to 6-membered saturated heterocyclic ring, which ring may optionally be fused with an aromatic ring include morpholinyl and tetrahydroisoquinolinyl .
  • R 1 examples of particular values for R 1 are hydrogen and methyl . Especially preferred are compounds in which R 1 is hydrogen.
  • R 2 examples of particular values for R 2 are:- hydrogen; for Ci-io alkyl: methyl; for C2-10 alkenyl: allyl; for C2-10 alkynyl: propargyl; for aryl : phenyl; for heteroaryl : pyridyl ; for aryl-Ci-io alkyl: benzyl; for aryl-C2-10 alkenyl: cinnamyl; for aryl-C2-10 alkynyl: phenylethynyl ; for C3-8 cycloalkyl: cyclopentyl; for C3-8-cycloalkyl-Ci-io alkyl: eyelohexylmethyl for a group of formula CH(R 3 )COOH: CH 2 COOH; and for a group that together with X 1 , R 1 and the nitrogen to which they are attached forms a 5 to 6-membered saturated heterocyclic ring, which ring may optionally
  • HOOCCH2 phenylCONH and, together with R 1 and the nitrogen to which they are attached, morpholinyl and tetrahydroisoquinolinyl.
  • Particularly preferred compounds are: (2SR, l'SR, 2'RS, 3 'RS) -2- [2 '-carboxy-3 '-
  • the present invention includes salts of the formula (I) compounds. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula (I) .
  • the alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula (I) .
  • the salts of the compounds of formula I may be pharmaceutically-acceptable salts. However, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically-acceptable, acid addition salts, or are useful for identification, characterisation or purification.
  • Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic , fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid.
  • suitable acids such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids
  • organic acids such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic , fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic
  • the present invention includes esters of the formula (I) compounds.
  • the esters of the compounds of formula I may be pharmaceutically acceptable metabolically labile esters of compounds of formula I. These are ester derivatives of compounds of formula I that are hydrolyzed in vivo to afford said compound of formula I and a pharmaceutically acceptable alcohol.
  • metabolically labile esters include esters formed with (1-6C) alkanols in which the alkanol moiety may be optionally substituted by a (1-8C) alkoxy group, for example methanol, ethanol, propanol and methoxyethanol.
  • the most preferred esters are alkyl esters derived from C ⁇ - 4 alkanols, especially methyl and ethyl esters.
  • the present invention also includes esters of compounds of formula I other than pharmaceutically acceptable metabolically labile esters. Such esters are useful as intermediates in the preparation of compounds of formula I.
  • the present invention also provides a process for preparing a compound of formula I, an ester thereof or a salt of said compound of formula I or said ester thereof, which comprises:
  • R 4 and R 5 each independently represents hydrogen or a carboxyl protecting group, and R s represents hydrogen or an amine protecting group;
  • R 7 represents a hydrogen atom or a carboxyl protecting group
  • R 8 and R 9 each independently represents a hydrogen atom, a C ⁇ - alkyl group or a phenyl Ci-4 alkyl group in which the phenyl group is unsubstituted or substituted by halo, C ⁇ - 4 alkyl, C ⁇ _ 4 alkoxy or C 3 - 4 alkenyl; or
  • carboxy protecting groups include C ⁇ -C6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl(C ⁇ - C 4 ) alkyl groups such as benzyl, 4-nitrobenzyl, 4- methoxybenzyl , 3 , -dimethoxybenzyl , 2 , 4-dimethoxybenzyl , 2,4, 6-trimethoxybenzyl, 2,4, 6-trimethylbenzyl, benzhydryl and trityl; silyl groups such as trimethylsilyl and t- butyldimethylsilyl; and allyl groups such as allyl and 1- (trimethylsilylmethyl) prop-l-en-3-yl .
  • C ⁇ -C6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl
  • aryl(C ⁇ - C 4 ) alkyl groups such as benzyl, 4-nitrobenzy
  • amine protecting groups include acyl groups, such as groups of formula R 12 CO in which R 12 represents C ⁇ - 6 alkyl, C3-10 cycloalkyl, phenyl C ⁇ _ s alkyl, phenyl, C ⁇ - 6 alkoxy, phenyl C ⁇ - 6 alkoxy, or a C3-10 cycloalkoxy, wherein a phenyl group may be optionally substituted, for example by one or two of halogen, C1-C4 alkyl and C1-C4 alkoxy.
  • Preferred amino protecting groups include t-butoxycarbonyl (Boc) and benzyl.
  • R 4 , R 5 , R 7 and R 10 are hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, benzyl, 4-methoxybenzyl, phenylethyl and phenylpropyl .
  • R 6 and R 11 examples include acetyl and tert-butoxycarbonyl.
  • R 8 and R 9 are hydrogen and benzyl .
  • the compounds of formula (II) 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 (II) 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 of from 0°C to 100°C.
  • Convenient reaction media include aqueous solvents, such as aqueous tetrahydrofuran.
  • An aralkyl carboxyl protecting group may conveniently be removed by hydrogenation.
  • the hydrogenation may be effected by reacting the compound of formula (II) with hydrogen in the presence of a Group VIII metal catalyst, for example a palladium catalyst such as palladium on charcoal.
  • a Group VIII 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 of from 0° C 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.
  • a tert-butoxycarbonyl, amine protecting group may conveniently be removed in the presence of 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 performed in the presence of an aqueous solvent, such as aqueous tetrahydrofuran, at a temperature m • the range of from 0°C to 100°C.
  • protecting groups and reaction conditions should be selected so as not to affect any other functional group in the molecule, such as the group CONR 1 (X ⁇ 2 ) .
  • the compounds of formula III 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.
  • 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.
  • ⁇ I I ° temperature is conveniently m the range of from 0 C to
  • the reaction conditions should be selected so as not to affect the group CONR 1 (X 1 R 2 ) .
  • the compounds of formula IV 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.
  • the hydrolysis is conveniently performed in an aqueous solvent such as water, or in an alkanol such as methanol or ethanol, and at a
  • the reaction is performed in the presence of an alkali metal cyanide, such as potassium cyanide, under irradiation with ultrasound.
  • alkali metal cyanide such as potassium cyanide
  • Convenient solvents include ethers, such as tetrahydrofuran. The reaction is conveniently effected at a temperature of from 0 to 100°C.
  • the reaction is performed in the presence of a Lewis acid, such as aluminium trichloride.
  • a Lewis acid such as aluminium trichloride.
  • Convenient solvents include halogenated hydrocarbons, such as dichloromethane. The reaction is conveniently effected at a temperature of from 0 to 100°C.
  • V may be reacted with ammonia in the presence of trimethylaluminium to afford a compound of formula I in which R is CONH 2 .
  • Convenient solvents include ethers such as tetrahydrofuran.
  • the reaction is conveniently effected at a temperature of from 0 to 100 2 C.
  • Compounds of formula II in which R represents 1H- tetrazol-5-yl may be prepared by reacting a corresponding compound of formula II in which R represents CN with an alkali metal azide, such as sodium azide, or Bu 3 SnN 3 , or TMS-Ns.
  • the reaction is ' conveniently effected at temperature of from 0 to 150 2 C.
  • Convenient solvents include ethers, such as tetrahydrofuran or dioxane, and aprotic solvents such as toluene.
  • the compounds of formula V may be prepared by oxidising a compound of formula
  • the oxidation is conveniently effected by reaction with an oxidising agent, such as Jones reagent (a solution of Na 2 Cr 2 ⁇ 7.2H 2 0 in sulfuric acid).
  • an oxidising agent such as Jones reagent (a solution of Na 2 Cr 2 ⁇ 7.2H 2 0 in sulfuric acid).
  • Convenient solvents include ketones, such as acetone.
  • the reaction is conveniently effected at a temperature of from -25 to 10°C.
  • the compounds of formula VII may be prepared by hydrolysing a compound of formula VIII
  • a t- butoxycarbonyl protecting group may be introduced by reaction with di-tert-butyldicarbonate in the presence of sodium bicarbonate and in a reaction medium such as tetrahydrofuran or dioxan.
  • the compounds of formula VII may be prepared by hydrolysing a compound of formula IX
  • R 13 and R 14 are as defined for R 8 and R 9 followed by introducing the carboxyl protecting groups R 4 and R 5 and the amino protecting group R 5 .
  • the hydrolysis is conveniently performed in the presence of a base, such as sodium hydroxide, in an aqueous reaction medium, such as water.
  • Alkyl carboxyl protecting groups may be introduced by reaction with the appropriate alkanol, for example ethanol, in the presence of an acid, such as hydrochloric acid.
  • a t- butoxycarbonyl protecting group may be introduced by reaction with di-tert-butyldicarbonate in the presence of sodium bicarbonate and in a reaction medium such as tetrahydrofuran or dioxan.
  • the compounds of formula VIII may be prepared by reacting a compound of formula X
  • the compounds of formula IX may be prepared by hydrolysing a compound of formula X with an alkali metal hydroxide, for example using sodium hydroxide in aqueous ethanol, followed by treatment with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and ammonium carbonate in an aqueous alcohol, such as aqueous ethanol. Conveniently the reaction is performed at a temperature of from 35°C to 150°C.
  • the compounds of formula X may be prepared by oxidising a compound of formula XI
  • the compounds of formula XI may be prepared by reacting a compound of formula XII
  • R 13 represents a hydrogen atom, a C ⁇ _4 alkyl group or a phenyl group, with HCl or camphorsulfonic acid in an alkanol such as ethanol.
  • the compounds of formula XII may be prepared by reacting a compound of formula XIII
  • N2CHCOOR 4 XIV in the presence of Rh 2 (OAc) .
  • a convenient solvent is pentane .
  • CONR 1 (X 1 R 2 ) may be prepared by reacting a compound of formula XV with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and an ammonium halide, such as ammonium chloride.
  • an alkali metal cyanide such as lithium, sodium or potassium cyanide
  • an ammonium halide such as ammonium chloride.
  • the reaction is advantageously performed in the presence of ultrasound.
  • the ammonium halide and alkali metal cyanide are advantageously mixed with chromatography grade alumina in the presence of a suitable diluent, such as acetonitrile.
  • the mixture is then irradiated with ultrasound, whereafter the compound of formula XV is added, and the mixture is again irradiated.
  • the resultant mixture of diastereoisomeric aminonitriles may then be reacted with an acylating agent, such as acetyl chloride in the presence of a suitable base, for example an amine such as diisopropylamme, and in the presence of a suitable solvent such as dichloromethane, to afford a mixture of diastereomeric acylaminonitriles.
  • an acylating agent such as acetyl chloride
  • a suitable base for example an amine such as diisopropylamme
  • a suitable solvent such as dichloromethane
  • the compounds of formula XV may be prepared by oxidising a compound of formula XI, for example by a Swern oxidation.
  • the compounds of the invention are useful for the treatment of disorders of the central nervous system.
  • the present invention provides a method of treating a patient suffering from or susceptible to a disorder of the central nervous system, which comprises administering an effective amount of a compound of formula I as defined hereinabove, a pharmaceutically acceptable metabolically labile ester thereof or a pharmaceutically acceptable salt of said compound of formula I or said pharmaceutically acceptable metabolically labile ester thereof.
  • a pharmaceutically acceptable metabolically labile ester thereof or a pharmaceutically acceptable salt of said compound of formula I or said pharmaceutically acceptable metabolically labile ester thereof.
  • the particular effective amount or dose of compound administered according to this 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.
  • the compound may be administered by continuous infusion.
  • a typical daily dose will contain from about 0.01 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 25 mg/kg.
  • the formula I compounds of the present invention are believed to have the ability to treat a variety of neurological disorders in patients associated with this condition, including acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage.
  • the formula I compounds are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson's.
  • 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 or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof.
  • the formula I compounds of the present invention are also believed to have the ability to treat a variety of other neurological disorders in patients that are associated with glutamate dysfunction, including muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, (such as schizophrenia) , drug tolerance and withdrawal (such as nicotine, opiates and benzodiazepines) , anxiety and related disorders, emesis, brain edema, chronic pain, and tardive dyskinesia.
  • the formula I compounds are also useful as antidepressant and analgesic agents.
  • 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, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof.
  • treating for purposes of the present invention, includes prophylaxis, amelioration or elimination of a named condition once the condition has been established.
  • patient for purposes of the present invention is defined as any warm blooded animal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human.
  • the present invention provides a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention provides the use of a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder of the central nervous system.
  • a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder of the central nervous system.
  • the ability of compounds to modulate metabotropic glutamate receptor function may be demonstrated by examining their ability to influence either cAMP production (mGluR 2, 3, 4, 6, 7 or 8) or phosphoinositide hydrolysis (mGluR 1 or 5) in cells expressing these individual human metabotropic glutamate receptor (mGluR) subtypes. (D. D. Schoepp, et al . , Neuropharmacol . , 1996, 35, 1661-1672 and 1997, 36, 1- 11) .
  • the compounds exemplified herein have all been found to reverse [3H] LY341495 binding with a Ki of less than 30,000 nM at mGluR2.
  • the compound of Example 1 of the present application was found to reverse [3H] LY341495 binding with a Ki of 3421 nM at mGluR2.
  • LY341495 is described in Ornstein et al., J. Med. Chem., 1998, 41, 346-357 and J. Med. Chem., 1998, 41, 358 to 378).
  • the compounds of the present invention are preferably formulated prior to administration.
  • another aspect of the present invention is a pharmaceutical formulation
  • a pharmaceutical formulation comprising a compound of formula I, a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier, diluent, or excipient.
  • the present pharmaceutical formulations 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 which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders .
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably ' about 25 mg to about 300 mg of the active ingredient.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • suitable pharmaceutical carrier diluent, or excipient.
  • Hard gelatin capsules are prepared using the following ingredients :
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. ' sieve.
  • the granules so produced are dried at 50 2 C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Et 2 0 signifies diethylether
  • AcOEt signifies ethyl acetate
  • EtOH signifies ethanol
  • Et 3 N signifies triethylamine
  • THF signifies tetrahydrofuran
  • Bu 3 SnN 3 signifies tributyl tin azide
  • Jones Reagent signifies a solution of 1.0 g of Na 2 Cr 2 ⁇ 7 - 2H 2 0 , and 1.34 g of sulfuric acid in H 2 0 (total volume 5 mL) .

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des composés représentés par la formule (I) dans laquelle R?1, R2 et X1¿ sont tels que décrits dans les spécifications. Ces composés modulent la fonction de récepteur de glutamate métabotropique et ils conviennent pour le traitement des troubles du système nerveux central.
PCT/US2001/010831 2000-05-31 2001-05-24 Modulateurs de recepteur d'acide amine excitateur Ceased WO2001092212A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US10/275,928 US7125871B2 (en) 2000-05-31 2001-05-24 Excitatory amino acid receptor modulators
EP01938985A EP1289935A1 (fr) 2000-05-31 2001-05-24 Modulateurs de recepteur d'acide amine excitateur
AU2001264554A AU2001264554A1 (en) 2000-05-31 2001-05-24 Excitatory amino acid receptor modulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP00500110.2 2000-05-31
EP00500110 2000-05-31

Publications (1)

Publication Number Publication Date
WO2001092212A1 true WO2001092212A1 (fr) 2001-12-06

Family

ID=8174322

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/010831 Ceased WO2001092212A1 (fr) 2000-05-31 2001-05-24 Modulateurs de recepteur d'acide amine excitateur

Country Status (3)

Country Link
EP (1) EP1289935A1 (fr)
AU (1) AU2001264554A1 (fr)
WO (1) WO2001092212A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7081481B2 (en) 2000-05-31 2006-07-25 Eli Lilly And Company Excitatory amino acid receptor modulators
JP2011519944A (ja) * 2008-05-07 2011-07-14 ヘンケル コーポレイション 嫌気性硬化性組成物のための硬化促進剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0870760A1 (fr) * 1997-04-08 1998-10-14 Lilly S.A. Dérivés de la cyclopropyl glycine ayant des propriétés pharmaceutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0870760A1 (fr) * 1997-04-08 1998-10-14 Lilly S.A. Dérivés de la cyclopropyl glycine ayant des propriétés pharmaceutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PELLICCIARI ET AL: "Synthesis and Pharmacological Characterization of All Sixteen Stereoisomers of 2-(2'-Carboxy-3'-phenylcyclopropyl)glycine. Focus on (2S,1'S,2'S,3'R)-2-(2'-Carboxy-3'-phenylcyclopropyl)glycine, a Novel and Selective Group II Metabotropic Glutamate Receptor Antagonist", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 39, no. 11, 1996, pages 2259 - 2269, XP002122695, ISSN: 0022-2623 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7081481B2 (en) 2000-05-31 2006-07-25 Eli Lilly And Company Excitatory amino acid receptor modulators
JP2011519944A (ja) * 2008-05-07 2011-07-14 ヘンケル コーポレイション 嫌気性硬化性組成物のための硬化促進剤

Also Published As

Publication number Publication date
EP1289935A1 (fr) 2003-03-12
AU2001264554A1 (en) 2001-12-11

Similar Documents

Publication Publication Date Title
EP0870760B1 (fr) Dérivés de la cyclopropyl glycine ayant des propriétés pharmaceutiques
US6498180B1 (en) Excitatory amino acid receptor modulators
US20040102521A1 (en) Excitatory amino acid receptor modulators
EP1000927B1 (fr) Modulateurs de recepteurs d'acides aminés excitateurs
AP1116A (en) Bicyclo [2.2.] heptanes and related compounds.
HUP0001404A2 (hu) Metabotróp aminosav receptor modulátorok és ezeket tartalmazó gyógyászati készítmények
EP2252578A1 (fr) Nouveaux conjugues pour le traitement de maladies et troubles neurodegeneratifs
US20040092553A1 (en) Excitatory amino acid receptor modulators
WO2001092212A1 (fr) Modulateurs de recepteur d'acide amine excitateur
US6504052B1 (en) Excitatory amino acid receptor modulators
KR0184876B1 (ko) 트리플루오로메틸 머캅탄 및 머캅토아실 유도체 및 그의 사용 방법
WO2001092213A2 (fr) Modulateurs de recepteur d'acide amine excitateur
EP0826663B1 (fr) Dérivés d'alkynylaminoacides et leur utilisation comme composés pharmaceutiques
WO2003006489A2 (fr) Promedicaments d'acides amines excitateurs
US5990165A (en) Pharmaceutical compounds
EP1458671A1 (fr) Promedicaments a base d'acides amines excitateurs
US20040176459A1 (en) Prodrugs of excitatory amino acids

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: 2001938985

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2001938985

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10275928

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Ref document number: 2001938985

Country of ref document: EP