WO2001072324A1 - Lactames en tant qu'inhibiteurs de production de proteines a-beta - Google Patents

Lactames en tant qu'inhibiteurs de production de proteines a-beta Download PDF

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WO2001072324A1
WO2001072324A1 PCT/US2001/009703 US0109703W WO0172324A1 WO 2001072324 A1 WO2001072324 A1 WO 2001072324A1 US 0109703 W US0109703 W US 0109703W WO 0172324 A1 WO0172324 A1 WO 0172324A1
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phenyl
substituted
alkyl
ethyl
occurrence
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PCT/US2001/009703
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English (en)
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Lorin Andrew Thompson
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Bristol-Myers Squibb Pharma Company
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Priority to EP01922708A priority Critical patent/EP1267906A1/fr
Priority to AU2001249477A priority patent/AU2001249477A1/en
Priority to JP2001570285A priority patent/JP2003528150A/ja
Priority to CA002401120A priority patent/CA2401120A1/fr
Publication of WO2001072324A1 publication Critical patent/WO2001072324A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of A ⁇ -peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to ⁇ -amyloid production such as Alzheimer's disease and Down's Syndrome.
  • AD Alzheimer's disease
  • AD is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability.
  • AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States.
  • AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta) -protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol, 1994, 10: 373- 403) .
  • a ⁇ is an internal polypeptide derived from a type 1 integral membrane protein, termed ⁇ amyloid precursor protein (APP) .
  • APP amyloid precursor protein
  • ⁇ APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans.
  • a ⁇ is derived from cleavage of ⁇ APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
  • proteolytic activities include ⁇ secretase (s) , generating the N-terminus of A ⁇ , ⁇ secretase (s) cleaving around the 16/17 peptide bond in A ⁇ , and ⁇ secretases, generating C-terminal A ⁇ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides .
  • missense DNA mutations at position 717 in the 770 isoform of ⁇ APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD.
  • ⁇ APP mutations have been described in familiar forms of AD.
  • similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human ⁇ APP.
  • individuals with Down's syndrome have an increased gene dosage of ⁇ APP and develop early-onset AD.
  • a ⁇ will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with A ⁇ production.
  • One method of treatment methods would therefore be based on drugs that inhibit the formation of A ⁇ in vivo. Methods of treatment could target the formation of A ⁇ through the enzymes involved in the proteolytic processing of ⁇ amyloid precursor protein. Compounds that inhibit ⁇ or ⁇ secretase activity, either directly or indirectly, could control the production of A ⁇ .
  • compounds that specifically target ⁇ secretases could control the production of A ⁇ . Such inhibition of ⁇ or ⁇ secretases could thereby reduce production of A ⁇ , which, thereby, could reduce or prevent the neurological disorders associated with A ⁇ protein.
  • the present invention discloses compounds of enhanced activity in inhibiting A ⁇ protein production.
  • One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of A ⁇ protein or pharmaceutically acceptable salts or prodrugs thereof. It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • the present invention provides a novel compound of Formula (I) :
  • R 1 is Ci-C ⁇ alkyl substituted with 0-3 R la ; C 6 -C 10 aryl substituted with 0-3 R lb ;
  • R lb at each occurrence, is independently selected from H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, N 3 , NO 2 , NR 15 R 16 , phenoxy, C 1 -C 4 thioalkoxy and CF 3 ;
  • R 5 is C 1 -C 4 alkyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, or cyclobutylethyl ;
  • R 3 at each occurrence, is independently selected from H, OH, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, N0 , NR 15 R 16 , and CF 3 ;
  • n 0, 1, 2, or 3;
  • Z is C 1 -C 3 alkyl substituted with 0-2 R 12 ; 6 -C 10 aryl substituted with 0-4 R 12b ; C 3 -C 10 carbocycle substituted with 0-2 R 12 ; or
  • R 12 is C ⁇ -Cio aryl substituted with 0-4 R 12b ; or C 3 -C 10 carbocycle substituted with 0-2 R 12 ;
  • R 12b is independently selected from H, OH, C 1 -C 6 alkyl, Ci-C ⁇ thioalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, Cl, F, Br, I, CN, N0 2 , NR 15 R 16 and CF3;
  • R 14 is H, phenyl, benzyl, C 1 -C 6 alkyl, or C 2 -C ⁇ alkoxyalkyl;
  • R 19b is H, Ci-C ⁇ alkyl, C 3 -C 8 cycloalkyl, phenyl, benzyl or phenethyl .
  • the present invention provides for a compound of Formula I,
  • R 1 is Ci-C ⁇ alkyl substituted with 0-1 R la ;
  • R la at each occurrence, is independently selected from: H, CF 3 , OR 14 , Cl, F, Br, I; 3 -C 10 carbocycle substituted with 0-3 R lb ; and ⁇ -Cio aryl substituted with 0-3 R lb ;
  • R lb at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, N0 2 , N 3 , SCH 3 ,
  • R 5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, or cyclobutylmethyl;
  • R 3 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, N0 2 , and CF 3 ;
  • n 0, 1, or 2;
  • Z is C 1 -C 3 alkyl substituted with 0-2 R 12 ; or C ⁇ -Cio aryl substituted with 0-4 R 12b ;
  • R 12 is C 6 -C 10 aryl substituted with 0-4 R 12b ; or C 3 -C 6 carbocycle substituted with 0-4 R 12b ;
  • R 1 b at each occurrence, is independently selected from H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, N0 2 , SCH 3 , NR 15 R 16 , and CF 3 ;
  • R 14 is H, phenyl, benzyl, or C 1 -C 6 alkyl
  • R 15 at each occurrence, is independently selected from H, C 1 -C 4 alkyl, benzyl, and phenethyl; and R 16 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, benzyl, and phenethyl.
  • the present invention provides for a compound of Formula I,
  • R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl; methyl substituted with 1 R la ; ethyl substituted with 1 R la ; or phenyl substituted with 1-3 R lb ;
  • R la at each occurrence, is independently selected from: H, CF 3 , OR 14 , Cl, F, Br, I;
  • R lb at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, N0 2 , N 3 , SCH 3 ,
  • R 5 is methyl
  • R 3 at each occurrence, is independently selected from H, OH, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, I, CN, N0 2 , and CF 3 ; n is 0 or 1 ;
  • Y is a bond or -0- ;
  • Z is C 1 -C 3 alkyl substituted with 0-2 R 12 ; or phenyl substituted with 0-3 R 12b ;
  • R 12 is C 3 -C 6 cycloalkyl substituted with 0-3 R 12b ; phenyl substituted with 0-3 R 12b ;
  • R 12b is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, SCH 3 , C ⁇ C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, Cl, F, Br, I, CN, N0 2 , NR 15 R 16 , and CF 3 ;
  • R 14 is H, methyl, ethyl, phenyl, or benzyl
  • R 15 is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
  • R 16 is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
  • the present invention provides for a compound of Formula (la) ,
  • R 1 is methyl substituted with 1 R la ; ethyl substituted with 1 R la ; phenyl substituted with 1-3 R lb ; methyl, ethyl, propyl, butyl, pentyl, hexyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthyl , or pyridyl ;
  • R la is phenyl substituted with 0-3 R lb ; cyclopropyl substituted with 0-1 R lb ; cyclobutyl substituted with 0-1 R lb ; cyclopentyl substituted with 0-1 R lb ; or cyclohexyl substituted with 0-1 R lb ;
  • R lb at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, N0 , N 3 , SCH 3 , phenoxy, and CF 3 ;
  • Z is methyl substituted with R 12 ; or phenyl substituted with 0-2 R 12b ;
  • R 12 is phenyl substituted with 0-2 R 12b ;
  • R 12b at each occurrence, is independently selected from H, OH, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, I, CN, N0 2 , SCH 3 , NR 15 R 16 , OCF 3 , and CF 3 ;
  • R 15 at each occurrence, is independently selected from H, methyl, and ethyl
  • R 16 at each occurrence, is independently selected from H, methyl, and ethyl.
  • the present invention provides for a compound Formula (lb) ;
  • R 1 is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,
  • 2-fluoro-6-chlorophenylmethyl 2, 5-dimethylphenylmethyl, 2-fluoro-3-trifluoromethylphenylmethyl, 3- (trifluoromethyl) -4-chloro-phenylmethyl, 3-chloro-4-cyano-phenylmethyl, 3-chloro-4-iodo-phenylmethyl, 3,4, 5-trichlorophenylmethyl, 3,4, 5-trifluorophenylmethyl, 3,4, 5-trimethoxyphenylmethyl, 3,4, 5-tri (trifluoromethyl) phenylmethyl, 2 , 4 , 6-trifluorophenylmethyl, 2,4, 6-trimethylphenylmethyl, 2,4, 6-tri- (trifluoromethyl) phenylmethyl, 2,3, 5-trifluorophenylmethyl, 2,4, 5-trifluorophenylmethyl, 2-phenylethyl, 2- (4-nitrophenyl) ethyl,
  • Z is is phenyl, 2-F-phenyl, 3 -F-phenyl, 4-F-phenyl,
  • the present invention provides for pharmaceutical composition
  • a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the present invention provides for a method for the treatment of neurological disorders associated with ⁇ -amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I) •
  • the present invention provides for a method for inhibiting ⁇ -secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits ⁇ -secretase activity.
  • a ⁇ denotes the protein designated A ⁇ , ⁇ -amyloid peptide, and sometimes ⁇ /A4, in the art.
  • a ⁇ is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules .
  • the isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829.
  • the 43 amino acid sequence is:
  • APP refers to the protein known in the art as ⁇ amyloid precursor protein. This protein is the precursor for A ⁇ and through the activity of "secretase” enzymes, as used herein, it is processed into A ⁇ . Differing secretase enzymes, known in the art, have been designated ⁇ secretase, generating the N-terminus of A ⁇ , ⁇ secretase cleaving around the 16/17 peptide bond in A ⁇ , and " ⁇ secretases”, as used herein, generating C- terminal A ⁇ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides
  • the compounds herein described may have asymmetric centers.
  • any variable e.g. R 12
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 12 at each occurrence is selected independently from the definition of R 12 .
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "C ⁇ -Cs alkyl” denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl .
  • Preferred "alkyl” group unless otherwise specified, is "C 1 -C 4 alkyl".
  • propyl denotes n-propyl or i-propyl
  • butyl denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
  • alkenyl or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain.
  • C -C 6 alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2- pentenyl, 3-pentenyl, hexenyl, and the like.
  • alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, and the like.
  • Alkoxy or “alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
  • alkylthio or “thioalkoxy” is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo . Unless otherwise specified, preferred halo is fluoro and chloro.
  • Counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2 , 2 , 2-trifluoroethyl , 2 , 2-difluoroethyl, heptafluoropropyl, and heptachloropropyl .
  • Haloalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2- trifluoroethoxy, and the like.
  • Halothioalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge .
  • Cycloalkyl is intended to include saturated ring groups, having the specified number of carbon atoms. For example, "C 3 -C 6 cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Carbocycle is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to
  • heterocyclic ring is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1 , 5 , 2-dithiazinyl , 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl , 4aH-carbazole, 4H-quinolizinyl, 6H-1, 2 , 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl , benzothiophenyl, benzoxazolyl, benzthiazolyl , benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl , chromanyl, chromenyl, cinnoliny
  • Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, lH-indazolyl , oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl , quinolinyl, and isoquinolinyl .
  • Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl .
  • fused ring and spiro compounds containing, for example, the above heterocycles are fused ring and spiro compounds containing, for example, the above heterocycles.
  • aryl C ⁇ -Cio aryl or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl .
  • Preferred "aryl” is phenyl.
  • the compounds herein described may have asymmetric centers.
  • One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer.
  • carbon 3 of lactam ring of Formula (I') may exist in either an S or R configuration.
  • R or ⁇ configurations at carbon 3 in Formula (I'-3R) and (I'-3S) are considered part of the invention. Examples of such configuration include, but are not limited to,
  • the carbon atom to which R 5 is attached may display superior biological activity over the opposite enantiomer.
  • R 5 is C 1 -C 4 alkyl
  • the configuration of the carbon may be described as R or S . All configurations are considered part of the invention; however, the S configuration of the carbon bearing R 5 is more preferred.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, aleic, hydroxymaleic , phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetamide, formamide and benzamide derivatives of amine functional groups in the compounds of Formula (I), and the like.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
  • novel compounds of this invention may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • a variety of compounds of Formula (I) can be prepared by methods described in Scheme 1.
  • the protected ⁇ -amine 2 of the ⁇ -amino- ⁇ -caprolactam 1 can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene's book “Protective Groups in Organic Synthesis", like iV-Boc using di-fc- butyldicarbonate in an appropriate solvent like DMSO.
  • the lactam nitrogen of compound 2 can be alkylated to give compound 3 by generating the anion with bases such as LDA, lithium bis ( trimethylsilyl) amide or sodium hydride in solvents like THF, with or without co-solvents such as DMPU or HMPA and reacting this with a variety of groups, each of which containing a leaving groups (LG) such as a bromide, iodide, mesylate or tosylate .
  • Alkylating agents such as ⁇ - bro o amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available.
  • alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art.
  • precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art.
  • the iV-Boc protecting group of compound 3 can be removed by any number of methods well known in the literature like TFA in methylene chloride to give an amine 4.
  • the amine 4 can be coupled to an appropriately substituted carboxylic acid 5 or acid chloride by methods well described in the literature for making amide bonds, like TBTU in DMF with a base like NMM to give an elaborated compound of Formula (I) .
  • carboxylic acid 5 is available through the chemistry shown in Scheme 2.
  • coupling of an amino acid ester 5b under standard conditions including Schotten- Bowman conditions produces an amide 5a.
  • the carboxylic acid 5 is available through saponification of the ester 5a under standard basic conditions.
  • the amide 5a can be formed using the amino acid ester 5b and a carboxylic acid using any of the standard coupling agents mentioned above or known to one skilled in the art.
  • Step la Di- tert-butyldicarbonate (10.2 g, 46.7 mmoles) was added portion wise to a solution of L- (-) - ⁇ -amino- ⁇ - caprolactam 1 (5.0 g, 39.0 mmoles) in dimethyl sulfoxide (30 mL) . After 5 h at rt, the reaction was partitioned between water (100 mL) and ethyl acetate. The combined organic extracts were washed successively with 1 M HCl (50 mL) , brine, and dried (MgS ⁇ 4 > and concentrated in vacuo .
  • Step lb A I M solution of lithium bis (trimethylsilyl) amide was added dropwise to a solution of caprolactam 2 (0.3 g,
  • Step Id (2S) -2- [2- (3 , 5-Difluoro-phenyl) -acetylamino] - propionic acid (74 mg, 0.30 mmol, prepared according to the chemistry described in Scheme 2 where R 5 is CH 3 and R 1 is -
  • Methods of treatment target formation of A ⁇ production through the enzymes involved in the proteolytic processing of ⁇ amyloid precursor protein.
  • Compounds that inhibit ⁇ or ⁇ secretase activity either directly or indirectly, control the production of A ⁇ .
  • Such inhibition of ⁇ or ⁇ secretases reduces production of A ⁇ , and is expected to reduce or prevent the neurological disorders associated with A ⁇ protein, such as Alzheimer's Disease.
  • the compounds of the present invention have utility for the prevention and treatment of disorders involving A ⁇ production, such as cerebrovascular disorders.
  • Compounds of Formula (I) are expected to possess ⁇ - secretase inhibitory activity.
  • the ⁇ -secretase inhibitory activity of the compound of the present invention is demonstrated using assays for such activity, for example, using the assay described below.
  • the compound of the present invention has been shown to inhibit the activity of ⁇ -secretase, as determined by the A ⁇ immunoprecipitation assay.
  • a compound provided by this invention should also be useful as a standard and reagent in determining the ability of a potential pharmaceutical to inhibit A ⁇ production. These would be provided in commercial kits comprising a compound of this invention.
  • ⁇ g denotes microgram
  • mg denotes milligram
  • g denotes gram
  • ⁇ L denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • nM denotes nanomolar
  • ⁇ M denotes micromolar
  • mM denotes millimolar
  • M denotes molar
  • nm denotes nanometer
  • SDS denotes sodium dodecyl sulfate
  • DMSO denotes dimethyl sulfoxide
  • EDTA denotes ethylenediaminetetraacetic acid.
  • a compound is considered to be active if it has an IC50 or ⁇ i val e of less than about lOO ⁇ M for the inhibition of A ⁇ production.
  • the IC50 or Kj_ value is less than about 10 ⁇ M; more preferrably the IC50 or
  • Kj_ value is less than about O.l ⁇ M.
  • the present invention has been shown to inhibit A ⁇ protein production with an IC50 or Kj_ value of less than lOO ⁇ M.
  • a novel assay to evaluate the accumulation of A ⁇ protein was developed to detect potential inhibitors of secretase.
  • the assay uses the N 9 cell line, characterized for expression of exogenous APP by immunoblotting and immunoprecipitation.
  • test compounds The effect of test compounds on the accumulation of A ⁇ in the conditioned medium is tested by immunoprecipitation. Briefly, N 9 cells are grown to confluency in 6-well plates and washed twice with 1 x Hank's buffered salt solution. The cells are starved in methionine/cysteine deficient media for 30 min, followed by replacement with fresh deficient media containing 150uCi S35 Translabel (Amersham) . Test compounds dissolved in DMSO (final concentration 1%) are added together with the addition of radiolabel. The cells are incubated for 4 h at 37 °C in a tissue culture incubator.
  • the conditioned medium is harvested and pre-cleared by the addition of 5 ⁇ l normal mouse serum and 50ul of protein A Sepharose
  • the samples are washed three times with high salt washing buffer (50mM Tris, pH 7.5, 500mM NaCl, 5mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50mM Tris, pH 7.5, 150mM NaCl, 5mM EDTA, 0.5% Nonidet P-40), and three times with lOmM Tris, pH 7.5.
  • high salt washing buffer 50mM Tris, pH 7.5, 500mM NaCl, 5mM EDTA, 0.5% Nonidet P-40
  • low salt wash buffer 50mM Tris, pH 7.5, 150mM NaCl, 5mM EDTA, 0.5% Nonidet P-40
  • lOmM Tris pH 7.5.
  • the pellet after the last wash is resuspended in SDS sample buffer (Laemmli, 1970) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5% Tris
  • the gels are dried and exposed to X-ray film or analyzed by phosphorimaging. The resulting image is analyzed for the presence of A ⁇ polypeptides.
  • the steady-state level of A ⁇ in the presence of a test compound is compared to wells treated with DMSO (1%) alone.
  • a typical test compound blocks A ⁇ accumulation in the conditioned medium, and is therefore considered active, with an IC 50 less than 100 ⁇ M.
  • C-Terminus ⁇ Amyloid Precursor Protein Accumulation Assay The effect of a test compound on the accumulation of C-terminal fragments is determined by immunoprecipitation of APP and fragments thereof from cell lysates . N 9 cells are metabolically labeled as above in the presence or absence of test compounds . At the end of the incubation period, the conditioned medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150mM NaCl, 0.125% NaN 3 ) .
  • RIPA buffer 10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150mM NaCl, 0.125% NaN 3
  • lysates are precleared with 5ul normal rabbit serum / 50ul protein A Sepharose, followed by the addition of BC-1 antiserum (15 ⁇ l;) and 50 ⁇ l protein A Sepharose for 16 hours at 4°C.
  • the immunoprecipitates are washed as above, bound proteins eluted by boiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager, the resulting images are analyzed for the presence of C- terminal APP fragments.
  • the steady-state level of C- terminal APP fragments is compared to wells treated with DMSO (1%) alone.
  • a typical test compound stimulates C- terminal fragment accumulation in the cell lysates, and is therefore considered active, with an IC 50 less than 100 ⁇ M.
  • a ⁇ Immunoprecipitation Assay This immunoprecipitation assay is specific for ⁇ - secretase (i.e., proteolytic activity required to generate the C-terminal end of A ⁇ either by direct cleavage or generating a C-terminal extended species which is subsequently further proteolyzed) .
  • N 9 cells are pulse labeled in the presence of a reported ⁇ secretase inhibitor (MDL 28170) for 1 h, followed by washing to remove radiolabel and MDL 28170. The media is replaced and test compounds are added. The cells are chased for increasing periods of times and A ⁇ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see above) .
  • MDL 28170 reported ⁇ secretase inhibitor
  • test compound is characterized whether a stabilization of C-terminal fragments is observed and whether A ⁇ is generated from these accumulated precursor.
  • a typical test compound prevents the generation of A ⁇ out of accumulated C-terminal fragments and is considered active with an IC 50 less than 100 ⁇ M.
  • Dosa ⁇ e and Formulation The compound of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration.
  • the active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions.
  • the active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier.
  • a valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
  • the compound of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations) , pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed to prevent or treat neurological disorders related to ⁇ -amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.
  • the compound of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal .
  • the compound can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents .
  • the compound can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compound of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the compound for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
  • the compound herein described in detail can form the active ingredient, and is typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices .
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or ⁇ -lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines .
  • Compound of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels .
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets .
  • Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours.
  • Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

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Abstract

L'invention concerne de nouveaux lactames représentés par la formule générale (I), leurs compositions pharmaceutiques et leurs procédés d'utilisation. Ces nouveaux composés inhibent le traitement de la protéine précurseur amyloïde et, d'une manière plus spécifique, inhibent la production de peptides Aβ, prévenant ainsi la formation de dépôts neurologiques de la protéine amyloïde. Plus particulièrement, l'invention concerne le traitement de troubles neurologiques liés à la production de la protéine β-amyloïde, notamment la maladie d'Alzheimer et le syndrome de Down.
PCT/US2001/009703 2000-03-28 2001-03-27 Lactames en tant qu'inhibiteurs de production de proteines a-beta WO2001072324A1 (fr)

Priority Applications (4)

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EP01922708A EP1267906A1 (fr) 2000-03-28 2001-03-27 Lactames en tant qu'inhibiteurs de production de proteines a-beta
AU2001249477A AU2001249477A1 (en) 2000-03-28 2001-03-27 Lactams as inhibitors of a-beta protein production
JP2001570285A JP2003528150A (ja) 2000-03-28 2001-03-27 Ａβタンパク質産生の阻害剤としてのラクタム
CA002401120A CA2401120A1 (fr) 2000-03-28 2001-03-27 Lactames en tant qu'inhibiteurs de production de proteines a-beta

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Cited By (4)

* Cited by examiner, † Cited by third party
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WO2001087354A2 (fr) * 2000-05-17 2001-11-22 Bristol-Myers Squibb Pharma Company Utilisation de radioligands a petites molecules en vue de rechercher des inhibiteurs de production d'amyloide-beta et destine a l'imagerie diagnostique
WO2004031154A1 (fr) * 2002-10-03 2004-04-15 Astrazeneca Ab Nouvelles lactames et utilisations de ces dernieres
WO2004080983A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Nouveaux lactames et leurs utilisations
WO2006065218A1 (fr) * 2004-12-14 2006-06-22 Astrazeneca Ab Nouvelles sondes moleculaires

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ZA200603165B (en) * 2003-11-03 2007-07-25 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
US7536962B2 (en) 2005-04-19 2009-05-26 Kamterter Ii, L.L.C. Systems for the control and use of fluids and particles

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WO1998028268A2 (fr) * 1996-12-23 1998-07-02 Elan Pharmaceuticals, Inc. CYCLOALKYLE, LACTAME ET COMPOSES ASSOCIES, COMPOSITIONS PHARMACEUTIQUES CONTENANT CES COMPOSES, ET PROCEDES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE AU MOYEN DE TELS COMPOSES
WO1999067221A1 (fr) * 1998-06-22 1999-12-29 Elan Pharmaceuticals, Inc. COMPOSES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE
WO2000007995A1 (fr) * 1998-08-07 2000-02-17 Du Pont Pharmaceuticals Company SUCCINOYLAMINO LACTAMES COMME INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b)

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1998028268A2 (fr) * 1996-12-23 1998-07-02 Elan Pharmaceuticals, Inc. CYCLOALKYLE, LACTAME ET COMPOSES ASSOCIES, COMPOSITIONS PHARMACEUTIQUES CONTENANT CES COMPOSES, ET PROCEDES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE AU MOYEN DE TELS COMPOSES
WO1999067221A1 (fr) * 1998-06-22 1999-12-29 Elan Pharmaceuticals, Inc. COMPOSES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE
WO2000007995A1 (fr) * 1998-08-07 2000-02-17 Du Pont Pharmaceuticals Company SUCCINOYLAMINO LACTAMES COMME INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087354A2 (fr) * 2000-05-17 2001-11-22 Bristol-Myers Squibb Pharma Company Utilisation de radioligands a petites molecules en vue de rechercher des inhibiteurs de production d'amyloide-beta et destine a l'imagerie diagnostique
WO2001087354A3 (fr) * 2000-05-17 2002-08-22 Bristol Myers Squibb Pharma Co Utilisation de radioligands a petites molecules en vue de rechercher des inhibiteurs de production d'amyloide-beta et destine a l'imagerie diagnostique
US6878363B2 (en) 2000-05-17 2005-04-12 Bristol-Myers Squibb Pharma Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
WO2004031154A1 (fr) * 2002-10-03 2004-04-15 Astrazeneca Ab Nouvelles lactames et utilisations de ces dernieres
JP2006503862A (ja) * 2002-10-03 2006-02-02 アストラゼネカ・アクチエボラーグ 新規なラクタムおよびその使用
EP1845089A1 (fr) * 2002-10-03 2007-10-17 AstraZeneca AB Nouvelles lactames et leur utilisations
US7294622B2 (en) 2002-10-03 2007-11-13 Astrazeneca Ab Lactams and uses thereof
JP4637584B2 (ja) * 2002-10-03 2011-02-23 アストラゼネカ・アクチエボラーグ 新規なラクタムおよびその使用
WO2004080983A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Nouveaux lactames et leurs utilisations
JP2006520396A (ja) * 2003-03-14 2006-09-07 アストラゼネカ・アクチエボラーグ 新規なラクタム及びその使用
US7342007B2 (en) 2003-03-14 2008-03-11 Astrazeneca Ab Lactams and uses thereof
WO2006065218A1 (fr) * 2004-12-14 2006-06-22 Astrazeneca Ab Nouvelles sondes moleculaires

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