WO2002014261A2 - Composes chimiques - Google Patents

Composes chimiques Download PDF

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Publication number
WO2002014261A2
WO2002014261A2 PCT/US2001/022589 US0122589W WO0214261A2 WO 2002014261 A2 WO2002014261 A2 WO 2002014261A2 US 0122589 W US0122589 W US 0122589W WO 0214261 A2 WO0214261 A2 WO 0214261A2
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Prior art keywords
compound
amino
alkyl
nmr
unsubstituted
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PCT/US2001/022589
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English (en)
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WO2002014261A3 (fr
Inventor
Alfonso De Dios
Jesus Ezquerra-Carrera
James Eugene Mcgee
Jose Alfredo Martin
Lourdes Prieto
Almudena Rubio-Esteban
Michele Ceceil Smith
Mark Joseph Tebbe
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Eli Lilly And Company
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Priority to AU2001278945A priority Critical patent/AU2001278945A1/en
Publication of WO2002014261A2 publication Critical patent/WO2002014261A2/fr
Publication of WO2002014261A3 publication Critical patent/WO2002014261A3/fr

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    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • 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
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to chemical compounds . More particularly it relates to novel D-glutamic acid derivatives, to pharmaceutical compositions comprising D- glutamic acid derivatives, to use of D-glutamic acid derivatives as antibiotics and to a process for preparing D- glutamic acid derivatives .
  • D-N-hydroxyglutamate is a competitive inhibitor of glutamate racemase (Murl) , -an enzyme which is involved in the synthesis of the bacterial cell wall.
  • the authors disclose that the compound acts as a substrate for the enzyme, instead of L-glutamate, and is converted by the enzyme into -ketoglutarate and ammonia.
  • Certain 4-substituted glutamic acid derivatives are known in the literature, mostly in racemic or L-form, as glutamate receptor modulators, useful in the treatment of disorders of the central nervous system. References disclosing these compounds include United States patents numbers 5,589,501 and 5,576,323 and European patent application publication number EP-A2-0826663. United States patent number 5,589,501 also discloses 4-substituted glutamic acid derivatives having as the 4-substituent a 3- phenyl-2-propenyl, 3- (4-chlorophenyl) -2-propenyl, 4- fluorobenzyl or 1-naphthylmethyl group.
  • the present invention provides the use of a compound of general formula
  • R 1 represents a (1-lOC) alkyl, (2-10C) alkenyl, (2- 10C)alkynyl, (4-10C) alkadienyl, carboxamido (1-8C) alkyl or aminocarbonyl (1-8C) alkyl group which is unsubstituted or substituted by (3-10C) cycloalkyl or by one or two unsubstituted or substituted aromatic groups, a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use as a glutamate racemase inhibitor.
  • the present invention provides a method of inhibiting glutamate racemase in a patient requiring such treatment, which comprises administering an effective amount of a compound of formula I, a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof as defined hereinabove.
  • a compound of formula I a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof as defined hereinabove.
  • the present invention provides a method of combating a bacterial infection in an animal in need of treatment, which comprises administering to said animal an effective amount of compound of general formula I, a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof as defined hereinabove.
  • the present invention provides a compound of general formula
  • X represents a bond, 0, S, SO or S0 2 ;
  • R 1 represents a (1-lOC) alkyl, (2-10C) alkenyl, (2-
  • Compounds according to the invention have also been found to possess antibiotic activity, in particular against Streptococcus, especially Streptococcus pneumoniae.
  • the compounds of formula I may exist in and be isolated in at least two different stereoisomeric forms, (2R, 4R) and (2R, 4S) , as well as in mixtures of these two forms (2R, 4R/S) .
  • the present invention provides each of these forms.
  • Preferred compounds according to the invention have the configuration shown below.
  • (1-lOC) alkyl signifies an unbranched or branched alkyl group containing from one to ten carbon atoms.
  • the term includes within its scope (1- 8C) alkyl, (1-6C) alkyl and (1-4C) alkyl.
  • Examples of particular values for a (1-lOC) alkyl group are methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, t-butyl, pentyl, hexyl, octyl, nonyl and decyl .
  • (2-10C) alkenyl signifies an unbranched or branched alkenyl group containing from two to ten carbon atoms.
  • the term includes within its scope (2-8C) alkenyl, (2-6C) alkenyl and (2-4C) alkenyl .
  • Examples of particular values for a (2-10C) alkenyl group include vinyl and propenyl .
  • (2-10C) alkynyl signifies an unbranched or branched alkynyl group containing from two to ten carbon atoms.
  • the term includes within its scope (2-8C) alkynyl, (2-6C) alkynyl and (2-4C) alkynyl .
  • Examples of particular values for a (2-IOC) alkynyl group include propynyl .
  • (4-IOC) alkadienyl signifies an unbranched or branched alkadienyl group containing from four to ten carbon atoms.
  • the term includes within its scope (4-6C) alkadienyl .
  • An example of a particular value for a (4-10C) alkadienyl group is buta-1 , 3-dienyl .
  • carboxamido (1-8C) alkyl signifies an unbranched or branched (1-8C) lkyl group bearing a terminal carboxamido group.
  • the term includes within its scope carboxamido ( 1- 4C) alkyl.
  • An example of a particular value for a carboxamido (1-8C) alkyl group is carboxamidomethy1.
  • aminocarbonyl (1-8C) alkyl signifies an unbranched or branched (1-8C) alkyl group bearing a terminal aminocarbonyl group.
  • the term includes within its scope aminocarbonyl (1-4C) alkyl .
  • An example of a particular value for an aminocarbonyl (1-8C) alkyl group is aminocarbonylmethyl .
  • cycloalkyl includes within its scope (3-7C) cycloalkyl .
  • An example of a particular value for (3- 10C) cycloalkyl group is cyclohexyl .
  • unsubstituted or substituted aromatic group signifies a carbocyclic or heterocyclic aromatic group which is 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 it from functioning as a glutamate racemase inhibitor.
  • carbocyclic aromatic group includes phenyl and naphthyl .
  • heterocyclic aromatic group includes 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 another 5-6 membered ring containing one to four atoms selected from oxygen, sulfur and nitrogen.
  • heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl and quinolyl .
  • any aromatic groups are selected independently from phenyl, naphthyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, benzothiazolyl and indolyl .
  • Examples of particular values for an aromatic group are phenyl, naphth-1-yl, naphth-2-yl, fur-2-yl, thien-2-yl, benzothien-2-yl, benzothien-3-yl, pyrid-4-yl, benzofur-2-yl, benzothiazol-2-yl and indol-2-yl.
  • each unsubstituted or substituted aromatic group is unsubstituted or substituted by methylenedioxy or by one, two or three substituents selected independently from halogen, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylthio, halo (1-4C) alkyl, halo (1-4C) alkoxy, cyano, nitro, amino, (1- 4C) alkylamino, di (1-4C) alkylamino, carboxy, and a group of formula - (CH ⁇ m-X 1 - (CH 2 ) n -R 2 in which m is 0, 1 or 2, n is 0, 1 or 2, X 1 represents a bond, 0, S, SO, S0 2 , NH, CO, COO, OCO, CONH, NHCO, NHCONH, NHS0 2 or S0 2 NH and R 2 represents an aromatic group which is unsubstituted or substituted by one or two substituents selected independently from halogen, (
  • Examples of particular values for the aromatic group represented by R 2 are phenyl, benzothien-2-yl, naphth-1-yl, naphth-2-yl, fur-l-yl, thien-3-yl, benzothien-2-yl and benzofur-2-yl .
  • Examples of particular values for substituents that may be present on an aromatic group represented by R 2 are fluoro, chloro, methoxy, methylthio, 1-chloroethyl, nitro, amino and N, N-dimethy1amino .
  • substituents that may be present on an unsubstituted or substituted aromatic group are fluoro, chloro, bromo, iodo, methyl, methoxy, phenyl, 4- fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4- methoxyphenyl , 4-methylthiophenyl, 4- (1-chloroethyl) phenyl, 3-nitrophenyl, 3-aminophenyl, 4-N,N-diethylaminophenyl, phenoxy, benzyloxy, phenylsulfonylamido, phenylaminocarbonylamido, 2-naphthylphenyl , 5-N,N- dimethylaminonaphth-1-ylsulfonamido, fur-l-yl, thien-3-yl, benzothien-2-yl and benzofur-2-yl .
  • Examples of particular values for an unsubstituted or substituted aromatic group are phenyl, 3-fluorophenyl, 2,4- difluorophenyl, 3-chlorophenyl, 3-bromophenyl , 3-iodophenyl, 4-iodophenyl, 3-methyIphenyl, 4-methylphenyl, 4-(l- chloroethyl) phenyl, 4-N,N-diethylaminophenyl, 4- phenylphenyl , 4- (4-fluorophenyl) phenyl , 4- (3- chlorophenyl ) phenyl , 4- (4-chlorophenyl) phenyl, 3-(4-(l- chloroethyl) phenyl)phenyl, 4- (4-methoxypheny1)phenyl , 4- (3- nitrophenyl) phenyl, 3- (3-aminophenyl) henyl, 4- (3- aminophenyl)
  • 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.
  • 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, or
  • the present invention includes amides and esters of the compounds of formula I . These amides or esters are useful as intermediates in the preparation of the compounds of formula I or as pro-drugs of the compounds of formula I . Some compounds which are an ester or amide of a compound of formula I have also been found to possess activity as glutamate racemase inhibitors.
  • esters of compounds of formula I include esters formed between the 1-carboxyl, the 5-carboxyl or the 1- and 5-carboxyl groups in the compound of formula I with a (l-8C)alkanol, such as methanol, ethanol, propanol or butanol; a (1-4C) alkoxy (1-4C) alkanol, such as methoxyethanol; a (3-8C) alkenol, such as allyl alcohol; or an aryl ( (1-4C) alkanol, such as benzyl alcohol.
  • a (l-8C)alkanol such as methanol, ethanol, propanol or butanol
  • a (1-4C) alkoxy (1-4C) alkanol such as methoxyethanol
  • a (3-8C) alkenol such as allyl alcohol
  • an aryl ( (1-4C) alkanol such as benzyl alcohol.
  • amides of compounds of formula I include amides formed between the 1-carboxyl, the 5-carboxyl or the 1- and 5-carboxyl groups in the compound of formula I with ammonia; a (1-4C) alkylamine, such as methylamine; or an arylamine, such as aniline.
  • the compounds of formula I may form a monoester, a diester, a monoamide, a diamide or a mixed ester amide.
  • the ester or amide groups in a diester or diamide may be the same or different.
  • Amides and esters of the compounds of formula I which are useful as pro-drugs are pharmaceutically acceptable metabolically labile amides and esters of compounds of formula I . These are amide and ester derivatives of compounds of formula I that are hydrolyzed in vivo to afford said compound of formula I and a pharmaceutically acceptable amine or 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 ⁇ _ alkanols, especially methyl and ethyl esters.
  • X represents a bond, 0 or S .
  • R 1 preferably represents a methyl, ethyl, propyl, vinyl, prop-2-enyl, prop-2-ynyl, buta-1, 3-dienyl or carboxamidomethyl group which is unsubstituted or substituted by (3-10C) cycloalkyl or by an unsubstituted or substituted aromatic group.
  • the present invention provides a process for the preparation of a compound of formula I, an ester or amide thereof, or a salt thereof, which comprises (A) hydrolysing a compound of formula
  • R 2 represents a hydrogen atom or a carboxyl protecting group and R 3 represents a hydrogen atom or an amino protecting group
  • R and R ,5 D each represents a hydrogen atom or a carboxyl protecting group and R ⁇ represents a hydrogen atom or an amino protecting group; or an ester or amide thereof, followed, if desired, by
  • carboxy protecting groups include Ci-Ce alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl(C ⁇ - C 4 ) lkyl groups such as benzyl, 4-nitrobenzyl, 4- methoxybenzyl , 3 , 4-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 .
  • Ci-Ce alkyl groups such as methyl, ethyl, t-butyl and t-amyl
  • aryl(C ⁇ - C 4 ) lkyl groups such as benzyl, 4-
  • Examples of a ine protecting groups include acyl groups, such as groups of formula R 8 C0 in which R 8 represents C ⁇ _ 6 alkyl, C 3 _ ⁇ 0 cycloalkyl, phenyl C ⁇ _ 6 alkyl, phenyl, C ⁇ _6 alkoxy, phenyl C ⁇ _6 alkoxy, or a C 3 _ ⁇ o cycloalkoxy, wherein a phenyl group may be optionally substituted, for example by one or two of halogen, C 1 -C 4 alkyl and C ⁇ -C alkoxy.
  • Preferred amino protecting groups include t-butoxycarbonyl (Boc) and benzyl.
  • R 2 , R 4 and R 5 are hydrogen, methyl, ethyl and benzyl.
  • R 3 and R 6 examples include acetyl and terfc-butoxycarbonyl .
  • the hydrolysis is conveniently conducted in the presence of an acid, such as hydrochloric acid, or a base, such as an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide such as barium hydroxide.
  • an acid such as hydrochloric acid
  • a base such as an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide such as barium hydroxide.
  • Convenient solvents include aqueous ethers, such as tetrahydrofuran.
  • the temperature is conveniently in the range of from 0 to 120°C.
  • the compounds of formula (III) may be deprotected according to step (B) 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 (III) 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 20°C to 300°C.
  • An aryl (C 1 -C 4 ) alkyl carboxyl protecting group may conveniently be removed by hydrogenation.
  • the hydrogenation may be effected by reacting the compound of formula (III) 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 an acid, for example hydrochloric acid or trifluoroacetic acid.
  • the hydrolysis is performed in the presence of a solvent such as water, ethyl acetate or dichloromethane and at a temperature in the range of from 20°C to 100°C.
  • the compounds of formula I may be converted into an ester or amide by a conventional method, for example by reaction of the compound of formula I or a reactive derivative thereof, such as a halide or anhydride, with an appropriate alcohol or amine. Salts of the compounds of formula I, or their esters or amides, may also be formed by a conventional method, such as by reaction with the appropriate acid or base.
  • R 1 -Z 1 V wherein Z 1 represents a leaving atom or group, in the presence of a strong base.
  • Compounds of formula II in which X represents a bond may also be prepared from a compound of formula IV via an aldol condensation reaction with an appropriate aldehyde, followed by dehydration of the resultant carbinol and reduction, or a Mannich reaction with an appropriate N,N- dibenzyl-N-methylene halide followed by catalytic hydrogenation to remove the benzyl groups and acylation with a (1-8C) alkanoic acid or reactive derivative thereof.
  • the process comprising a Mannich reaction affords a compound of formula II in which R 1 represents an aminocarbonyl (1-
  • the leaving atom or group represented by Z 1 may be, for example, a halogen atom such as a bromine atom.
  • the strong base may be, for example, lithium bis (trimethylsilylamide) , LHMDS .
  • Convenient solvents include ethers, such as tetrahydrofuran. The reaction is conveniently conducted at a temperature in the range of from
  • R -OH VII in the presence of a dehydrating agent, such as diethyl azodicarboxylate (DEAD) with triphenylphosphine .
  • a dehydrating agent such as diethyl azodicarboxylate (DEAD) with triphenylphosphine .
  • R 9 represents a hydroxyl protecting group, such as t-butoxycarbonyl .
  • the hydrolysis may conveniently be effected in the presence of an acid, such as trifluoroacetic acid.
  • R ⁇ -SR 1 X in the presence of a strong base, such as lithium bis (trimethylsilyla ide) , LHMDS .
  • Compounds of formula II in which X represents 0 may be prepared by a Mitsunobu type reaction of a compound of formula IX, in which R 9 is hydrogen, and an aromatic alcohol in the presence of a dehydrating agent, such as
  • DEAD and a tertiary phosphine, such as triphenylphosphine .
  • R 1 contains a biaryl group
  • a compound of formula II in which R 1 contains an iodophenyl group may be prepared from a corresponding compound of formula II in which R 1 contains an iodophenyl group by reaction with an arylboronic acid in the presence of a palladium catalyst, such as Pd(Ph 3 P) 4 -
  • a compound of formula II in which R 1 contains an iodophenyl or bromophenyl group may be reacted with an aryl-tri-n- butylstannane in the presence of triphenylphosphine and Pd 2 dba 3 or a similar palladium catalyst, such as Pd(Ph 3 P) 4 .
  • compounds of formula II may be converted into other compounds of formula II by conventional methods.
  • a compound of formula II in which R 1 contains an alkenyl group may be reduced to a compound of formula II in which R 1 contains an alkyl group, for example by catalytic hydrogenation in the presence of a palladium catalyst.
  • Compounds of formula II in which X represents S may be converted into compounds of formula II in which X represents SO or S0 2 by reaction with a perbenzoic acid, such as m-chloroperbenzoic acid.
  • Compounds of formula III and esters and amides thereof may be prepared by reacting a compound of formula II with an alkali metal peroxide, such as lithium peroxide, to afford a compound of formula III in which R 4 represents a hydrogen atom, followed if desired by functionalization of the carboxyl group bearing R 4 .
  • an alkali metal peroxide such as lithium peroxide
  • Glutamate racemase activity was determined by HPLC separation following derivitization with Marfey's reagent. Basically, for a control assay, 6 ⁇ g-ml -1 of glutamate racemase was incubated with L-glutamic acid (10 mM, dissolved in DMSO) for 15 minutes at room temperature (100 ⁇ l final volume) . For the test assay in identical conditions, the inhibitor is dissolved in DMSO and mixed with L-glutamic acid in that manner that the final percentage of DMSO present in both control samples and test samples is the same. The enzyme is then added to start the reaction.
  • L-glutamic acid 10 mM, dissolved in DMSO
  • MHII Mueller Hinton II
  • LHB lysed horse blood
  • Broth microdilution assay 1 Dispense 100 ⁇ l MHII with 5% LHB plus 5% DMSO into wells in rows B through H of a 96 well microtiter plate. Dispense 200 ⁇ l MHII with 5% LHB (no DMSO) into wells in row A. 2. Dissolve compounds to be tested in DMSO to a concentration of 10 mg/ l. 3. Add 10 ⁇ l of the compound solution to the 200 ⁇ l of medium in well A. Perform a twofold serial dilution through well G. Resulting concentration range of compound after dilution with inoculum will be 250 - 4 ⁇ g/ml .
  • the MIC is the lowest concentration of compound that completely inhibits growth as detected by the unaided eye.
  • the animal treated by the compounds according to the invention may be, for example, a warm blooded mammal, such as a mouse, guinea pig, cat, dog, sheep, cow, horse or human, or an avian. Preferably it is a human.
  • 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. Alternatively, 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.
  • treating for purposes of the present invention, includes prophylaxis, amelioration or elimination of a named condition once the condition has been established.
  • the compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I, a pharmaceutically acceptable metabolically labile ester or amide 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. In making the compositions of the present invention, 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 When 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.
  • the 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, annitol, 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.
  • 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 ,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.
  • NBS N-bromosuccinimide
  • AIBN 2 , 2 ' -Azobisisobutyronitrile
  • DMF dimethylformamide
  • Et 2 0, diethyl ether
  • hex hexane
  • DIBAL-H diisobutylaluminium hydride
  • DEAD diethylazodicarboxylate
  • LHMDS lithium bis ( trimethylsilylamide) or lithium hexamethyldisilazide
  • Pd 2 dba 3 palladium bis (dibenzylideneacetone) ;
  • EDCI ethyl-
  • Second step Synthesis of C-2 heterocylcic methyl alcohols.
  • DIBAL-H (1M solution in Hex, 1.05 equiv) is dropwise added and the mixture stirred for lh at -78 °C and then hydrolyzed with saturated NH 4 C1, diluted with Et 2 0 and IN HC1.
  • the organic layer was washed with IN HCl, and the aqueous phase extracted with Et 2 0 and the combined organic layers washed with water and brine.
  • N-Benzenesulfonyl-2-indolylmethyl bromide Prepared in three steps from 1-benzenesulfonyl indol. Brownish solid.
  • ⁇ 2R, AS) -2-Amino-4- (pyridyl) thio pentanedioic acid hydrochloride salt was prepared by refluxing a mixture of the corresponding pyroglutamate (2 mmol) and a 6N aqueous HCl solution (25 ml) for 16 hours. The resulting solution was evaporated to dryness yielding a white solid which was triturated with ethyl ether, filtered off and dried under high vacuum. The compound was obtained as a 2:1 mixture of 4S/4R diastereomers. Cream solid. 78% overall.
  • STEP 15A Ethyl (22?, 42?) and (22?, 45) -1- (tert-butoxy carbonyl) -4- (2-benzo[b] thiazolyl) methyl pyroglutamate.
  • the title compound was prepared as an inseparable mixture of epimers at C-4 in an analogous manner to that described for Example 1, Step IC, using 2- (benzo [b] thiazolyl) ethyl bromide as reagent. NMR data consistent with structure. White solid. 65%. STEP 15B .
  • the slurry mixture is vigorously stirred and placed in a preheated (120 °C) oil bath and heated to reflux for 4 hours (or until TLC of the mixture showed complete conversion of the starting pyroglutamate) .
  • the reaction mixture was then cooled to room temperature, diluted with water (30 ml) and Et0 (40 ml) and the aqueous phase was extracted with Et 2 0 (4 x 10 ml) .
  • the combined organic layers were washed with water (15 ml) and brine (20 ml) , dried over MgS0 4 and evaporated in vacuo.
  • step 33A To a solution of the starting nitro compound (step 33A, 1.30 mmol) in 20 ml of CH 3 CN was added ammonium formate (NH 4 C0 2 H, 8 equiv) followed by 10% Pd/C (20 mol% of catalyst) . The resulting mixture was heated to reflux for 6 hours and then cooled to rt, filtered through a short pad of Celite and the solvents evaporated in vacuo to afford a crude oil. After purification by silica gel chromatography (Hex/EtOAc, 3:1), the N,N-diethylamino derivative was obtained in 88% yield along with a minor amount of the corresponding N-ethylamino compound (17%).
  • Example 35 is fluorescent and is therefore particularly useful as a research tool, for example in high throughput screening for other glutamate racemase inhibitors .
  • EXAMPLE 36 is fluorescent and is therefore particularly useful as a research tool, for example in high throughput screening for other glutamate racemase inhibitors .
  • the reaction mixture was warmed up to rt and the stirred for lh.
  • the solution was diluted with CH 2 C1 2 and H 2 0, and the aqueous phase extracted with CH 2 C1 2 .
  • the combined organic layers were washed with IN HCl, water and brine. After drying over MgS0 4 , evaporation of the solvent afforded a colorless oil which was purified by silica gel chromatography (Hex/EtOAc, 3:1) to afford a pure colorless oil (368 mg) . 76%.
  • the aqueous phase was washed with ethyl acetate (3 x 20 mL) and the combined organic phases were treated with isopropanol (4 ml) for 2 hours.
  • the black precipitate was filtered and the organic solution was washed with water.
  • the organic phase was dried (Na 2 S0 4 ) , filtered and evaporated to dryness.
  • the reaction crude was purified by column chromatography (Hex/EtOAc, 3:1) obtaining a white solid (quantitative yield), mp 105-106 2 C. NMR data consistent with structure.
  • Step 52A (3-benzo [b] thienyl) methyl pyroglutamate (Step 52A, 0.5 mmol) in 12 ml of THF, cooled to 0 °C, was dropwise added a solution of LiOOH (freshly prepared by adding a 0.2 M solution of LiOH, 1.1 equiv, to a mixture of 30% vol H 2 0 2 , 5 equiv, in 4 ml of water) . The resulting mixture was stirred at 0 °C for 1.5h or until TLC showed complete conversion. The reaction was cooled to -78 °C and a solution of NaHS0 3 (40% vol) in 3 ml of water is added.
  • LiOOH freshly prepared by adding a 0.2 M solution of LiOH, 1.1 equiv, to a mixture of 30% vol H 2 0 2 , 5 equiv, in 4 ml of water
  • STEP 53A (22?, 45) -2-Amino-N- (tert-butoxycarbonyl) -4-.(3- benzo [b] thienyl) methyl pentanedioic acid, 1-O-benzyl, 5-O- ethyl ester .
  • a solution of Benzyl (22?, 45) -1- (tert-butoxycarbonyl) -4- (3- benzo [b] thienyl) methyl pyroglutamate (Step 52A, 0.32 mmol) was dissolved in 8 ml of anhydrous THF and cooled at -78 °C under N 2 .
  • lithium ethoxide was prepared at -78 °C under N 2 by adding lithium hexamethyl disilazide (1.0 M soln in THF, 0.8 equiv) to a solution of 0.25 ml of EtOH in 3 ml of THF with stirring.
  • the LiOEt solution was rapidly added via cannula to the pyroglutamate.
  • the mixture was stirred at -78 °C for 1.5h and hydrolyzed by addition of saturated NH 4 C1, extracted with Et 2 0 and the organic layer washed with water and brine. Drying over MgS0 4 and evaporation in vacuo afforded a crude diester which was purified by silica gel chromatography. Colorless oil, 100%. NMR data consistent with structure.
  • EXAMPLE 54 (22?, 42?) -2-Amino-4- (2-benzo [b] thienyl) methyl pentanedioic acid, 1-O-benzyl, 5-O-ethyl ester, hydrochloride salt.
  • STEP 54A (22?, 42?) -2-Amino-N- (tert-butoxycarbonyl) -4- (2- benzo [b] thienyl) methyl pentanedioic acid, 1-O-benzyl, 5-0- ethyl ester.

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Abstract

L'invention concerne des composés représentés par la formule (I), un ester ou un amide ou un sel de ceux-ci, utilisés comme inhibiteurs de glutamate racemase et comme antibiotiques. Dans cette formule, X représente une liaison, O, S, SO ou SO2; et R1 représente un groupe (1-10C)alkyle, un groupe, (2-10C)alcényle, un groupe (2-10C)alcynyle, un groupe (4-10C) alkadiényle, un groupe carboxamido(1-8C)alkyle ou un groupe aminocarbonyl(1-8C)alkyle non substitué ou substitué par (3-10C)cycloalkyle ou par un ou deux groupe(s) aromatique(s) substitué(s) ou non substitué(s).
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WO2004061097A2 (fr) * 2002-12-20 2004-07-22 Astrazeneca Ab Structure cristalline de glutamate racemase (muri)
WO2004061097A3 (fr) * 2002-12-20 2004-09-23 Astrazeneca Ab Structure cristalline de glutamate racemase (muri)
JP2008500981A (ja) * 2004-05-28 2008-01-17 ノバルティス アクチエンゲゼルシャフト 置換ピロリジン−２−オン
EP2316962A1 (fr) 2006-03-07 2011-05-04 Cargill, Incorporated Aldolases, acides nucléiques les codant et leurs procédés de fabrication et d'utilisation
EP2388316A2 (fr) 2006-03-07 2011-11-23 Verenium Corporation Aldolases, acides nucléiques les codant et leurs procédés de fabrication et d'utilisation
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EP3153580A2 (fr) 2006-03-07 2017-04-12 BASF Enzymes LLC Aldolases, acides nucléiques les codant et procédés de fabrication et d'utilisation de celles-ci
EP2112227A1 (fr) 2006-03-07 2009-10-28 Cargill, Incorporated Aldolases, acides nucléiques les codant et procédés de fabrication et d'utilisation de celles-ci
EP2385108A1 (fr) 2006-03-07 2011-11-09 Verenium Corporation Aldolases, acides nucléiques les codant et leurs procédés de fabrication et d'utilisation
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JP2011520931A (ja) * 2008-05-20 2011-07-21 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト ｛ｆ−１９｝標識ｌ−グルタミン酸及びｌ−グルタミン誘導体（ｉｉｉ）、それらの使用並びにそれらを得る方法
JP2011522799A (ja) * 2008-05-20 2011-08-04 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 新規な［ｆ−１８］−ラベル化ｌ−グルタミン酸およびｌ−グルタミン誘導体（ｉｉ）、それらの使用及びその調製法
US9308282B2 (en) 2008-05-20 2016-04-12 Piramal Imaging Sa [F-18]-labelled L-glutamic acid and L-glutamine derivatives (I), their use and processes for their preparation
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JP2013510894A (ja) * 2009-11-17 2013-03-28 バイエル・ファルマ・アクチェンゲゼルシャフト ヨウ素標識のホモグルタミン酸およびグルタミン酸
WO2011061154A1 (fr) * 2009-11-17 2011-05-26 Bayer Schering Pharma Aktiengesellschaft Acide homo-glutamique marqué à l'iode et dérivés d'acide glutamique
EP2520556A1 (fr) * 2011-05-03 2012-11-07 Bayer Pharma Aktiengesellschaft Acides aminés radiomarqués pour imagerie de diagnostic
JP2014519489A (ja) * 2011-05-03 2014-08-14 ピラマル イメージング ソシエテ アノニム 画像診断のための放射性標識アミノ酸
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JP2018524318A (ja) * 2015-06-18 2018-08-30 セファロン、インク． 置換４−ベンジル及び４−ベンゾイルピペリジン誘導体
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JP2021121612A (ja) * 2015-06-18 2021-08-26 エイティナイン バイオ リミテッド 置換４−ベンジル及び４−ベンゾイルピペリジン誘導体
US11702388B2 (en) 2015-06-18 2023-07-18 89Bio Ltd 1,4-substituted piperidine derivatives
JP7334211B2 (ja) 2015-06-18 2023-08-28 エイティナイン バイオ リミテッド 置換４－ベンジル及び４－ベンゾイルピペリジン誘導体
US11878966B2 (en) 2015-06-18 2024-01-23 89Bio Ltd Substituted 4-benzyl and 4-benzoyl piperidine derivates

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