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WO2002078697A1 - Composes et procedes - Google Patents

Composes et procedes Download PDF

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Publication number
WO2002078697A1
WO2002078697A1 PCT/US2002/009954 US0209954W WO02078697A1 WO 2002078697 A1 WO2002078697 A1 WO 2002078697A1 US 0209954 W US0209954 W US 0209954W WO 02078697 A1 WO02078697 A1 WO 02078697A1
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alkyl
optionally substituted
ethyl
triazole
anilino
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PCT/US2002/009954
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English (en)
Inventor
Joseph P. Marino, Jr.
Scott K. Thompson
Daniel F. Veber
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Smithkline Beecham Corporation
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Priority to US10/473,103 priority Critical patent/US20040116490A1/en
Priority to EP02723701A priority patent/EP1381360A4/fr
Priority to JP2002576963A priority patent/JP2005508841A/ja
Publication of WO2002078697A1 publication Critical patent/WO2002078697A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/38—Isothioureas containing any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/14—Nitrogen atoms
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Compounds of this invention are non-peptide, reversible inhibitors of type 2 methionine aminopeptidase, useful in treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity.
  • angiogenesis such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity.
  • angiogenesis a process termed angiogenesis (Folkman J. (1974) Adv Cancer Res. 19; 331).
  • the new blood vessels induced by tumor cells as their life-line of oxygen and nutrients also provide exits for cancer cells to spread to other parts of the body. Inhibition of this process has been shown to effectively stop the proliferation and metastasis of solid tumors.
  • a drug that specifically inhibits this process is known as an angiogenesis inhibitor.
  • the anti- angiogenesis therapy (“indirect attack”) has several advantages over the “direct attack” strategies. All the “direct attack” approaches such as using DNA damaging drugs, antimetabolites, attacking the RAS pathway, restoring p53, activating death programs, using aggressive T-cells, injecting monoclonal antibodies and inhibiting telomerase, etc., inevitably result in the selection of resistant tumor cells. Targeting the endothelial compartment of tumors as in the "indirect attack”, however, should avoid the resistance problem because endothelial cells do not exliibit the same degree of genomic instability as tumor cells.
  • anti-angiogenic therapy generally has low toxicity due to the fact that normal endothelial cells are relatively quiescent in the body and exhibit an extremely long turnover.
  • direct attack target different cell types, there is a great potential for a more effective combination therapy.
  • More than 300 angiogenesis inhibitors have been discovered, of which about 31 agents are currently being tested in human trials in treatment of cancers (Thompson, et al., (1999) J Pathol 187, 503).
  • TNP-470 a semisynthetic derivative of fumagillin of Aspergillus fuigatus, is among the most potent inhibitors of angiogenesis.
  • Fumagillin and TNP-470 have been shown to inhibit type 2 methionine aminopeptidase (hereinafter MetAP2) by irreversibly modifying its active site.
  • MetAP2 type 2 methionine aminopeptidase
  • the biochemical activity of fumagillin analogs has been shown to correlate to their inhibitory effect on the proliferation of human umbillical vein endothelial cells (HUVEC).
  • hMetAP-2-catalyzed cleavage of the initiator methionine of proteins could be essential for releasing many proteins that, after myristoylation, function as important signaling cellular factors involved in cell proliferation.
  • Proteins known to be myristoylated include the src family tyrosine kinases, the small GTPase ARF, the HTV protein nef and the subunit of heterotrimeric G proteins.
  • a recently published study has shown that the myristoylation of nitric oxide synthase, a membrane protein involved in cell apoptosis, was blocked by fumagillin (Yoshida, et al. (1998) Cancer Res. 58(16), 3751).
  • MetAP2-catalyzed release of the glycine-terminal myristoylation substrate is proposed to be an indirect outcome of inhibition of MetAP2-catalyzed release of the glycine-terminal myristoylation substrate.
  • MetAP enzymes are known to be important to the stability of proteins in vivo according to the "N-end rule" which suggests increased stability of methionine-cleaved proteins relative to their N-terminal methionine precursors (Varshavsky, A (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 12142). Inhibition of hMetAP2 could result in abnormal presence or absence of some cellular proteins critical to the cell cycle.
  • Methionine aminopeptidases are ubiquitously distributed in all living organisms. They catalyze the removal of the initiator methionine from newly translated polypeptides using divalent metal ions as cofactors. Two distantly related MetAP enzymes, type 1 and type 2, are found in eukaryotes, which at least in yeast, are both required for normal growth; whereas only one single MetAP is found in eubacteria (type 1) and archaebacteria (type 2). The N-terminal extension region distinguishes the methionine aminopeptidases in eukaryotes from those in procaryotes.
  • a 64-amino acid sequence insertion (from residues 381 to 444 in hMetAP2) in the catalytic C-terminal domain distinguishes the MetAP-2 family from the MetAP- 1 family.
  • all MetAP enzymes appear to share a highly conserved catalytic scaffold termed "pita-bread" fold (Bazan, et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 2473), which contains six strictly conserved residues implicated in the coordination of the metal cofactors.
  • Mammalian type 2 methionine aminopeptidase has been identified as a bifunctional protein implicated by its ability to catalyze the cleavage of N-terminal methionine from nascent polypeptides (Bradshaw, et al (1998) Trends Biochem. Sci. 23, 263) and to associate with eukaryotic initiation factor 2 ⁇ (eIF-2 ⁇ ) to prevent its phosphorylation (Ray, et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 539). Both the genes of human and rat MetAP2 were cloned and have shown 92% sequence identity (Wu,. et al. (1993) J Biol. Chem.
  • the anti-angiogenic compounds, fumagillin and its analogs, have been shown to specifically block the exo-aminopeptidase activity of hMetAP2 without interfering with the formation of the hMetAP2 : eIF2 ⁇ complex (Griffith, et al., (1997) Chem. Biol. 4, 461; Sin, et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 6099). Fumagillin and its analogs inactivate the enzymatic activity of hMetAP2 with a high specificity, which is underscored by the lack of effect of these compounds on the closely related type 1 methionine aminopeptidase
  • the present invention is to a novel compound of formula (I), or a pharmaceutically active salt or solvate thereof, and its use in treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity:
  • angiogenesis such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity:
  • R! is optionally substituted C j fi alkyl, C 2 alkenyl, C 2 6 alkynyl, optionally substituted Ar-C j 6 alkyl-, optionally substituted Het-C j 6 alkyl-, or optionally substituted C 3 .cycloalkyl-C j 6 alkyl-, provided that when R is optionally substituted Het-C galk l-, and Het is indolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, or pyrrolo[2,3-c]pyridinyl then the optional substituent is not -(CH2) ⁇ .5CHRI]S ⁇ R.IIR 1 I J -, or the optional substituent is not a 4- to
  • R 1 is H or C. ⁇ alkyl
  • R ** - * ** * and R * " * - ***** - are independently H, C g alkyl, or together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from N, O, and S; provided that when R ⁇ is
  • C ⁇ alkyl- the optional substituent cannot be -OR ⁇ , -R4, or -NR ⁇ RS, wherein R ⁇ , R * - * ", and R ⁇ are independently selected from H, C fi alkyl, C 3 alkenyl, C 3 fi alkynyl, Ph-C 0 g alkyl-, Het-C ⁇ alkyl-, or C 3 7 cycloalkyl-C 0 fi alkyl-;
  • R- 2 is optionally substituted C alkyl, C 3 fi alkenyl, C 3 6 alkynyl, optionally substituted Ar-C Q g alkyl-, optionally substituted Het-C Q 6 alkyl-, or optionally substituted
  • R 3 is H, optionally substituted C ⁇ 6 alkyl, C 3 6 alkenyl, C 3 6 alkynyl, optionally substituted Ar-C Q g alkyl-, optionally substituted Het-C Q 6 alkyl-, optionally substituted C 3 7 cycloalkyl-C 0 6 alkyl-, -C Q 6 alkyl-C(0)X'AB, C Q 6 alkyl-S(0) 2 X'AB, or -C all yl-X'AB, wherein X' is O, S, C or N, and wherein A and B are independently absent, H, optionally substituted C ⁇ 6 alkyl, C 3 6 alkenyl, C 3 6 alkynyl, optionally substituted Ar-C Q fi alkyl-, optionally substituted Het-C Q _ 6 alkyl-, or C cycloalkyl-C 0 g alkyl-; provided that the compound is not
  • the present invention is to a method of treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity by administering a compound of formula (LA), or a pha ⁇ naceutically acceptable salt or solvate thereof
  • angiogenesis such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity
  • R! is optionally substituted C ⁇ 6 alkyl, C 2 g alkenyl, C 2 g alkynyl, optionally substituted Ar-C ⁇ -6 alkyl-, optionally substituted Het-C ⁇ -6 alkyl-, or optionally substituted
  • R2 is optionally substituted C ⁇ alkyl, C 3 . 6 alkenyl, C 3 . 6 alkynyl, optionally substituted Ar-Co- ⁇ alkyl, optionally substituted Het-C 0 - 6 alkyl-, or optionally substituted C 3 .
  • R 3 is H, optionally substituted C ⁇ _ s alkyl, C 3-6 alkenyl, C 3-6 alkynyl, optionally substituted Ar-Co- ⁇ alkyl-, optionally substituted Het-Co-ealkyl-, optionally substituted -C 3-7 cycloalkyl-C 0 - 6 alkyl-, -C 0 .6alkyl-C(O)X'AB, or -C 0 - 6 alkyl-S(O)2XAB, -Co- ⁇ alkyl-X'AB, wherein X' is O, S, C or N and wherein A and B are independently absent, H, optionally substituted C ⁇ _ 6 alkyl, C 3-6 alkenyl, C 3 .
  • the present invention is to a method of inhibiting MetAP2 in the treatment of angiogenesis-mediated diseases, all in mammals, preferably humans, comprising administering to such mammal in need thereof, a compound of formula (LA), or a pharmaceutically active salt or solvate thereof.
  • the present invention is to a pharmaceutical composition comprising a compound of formula (I) or formula (LA) and a pharmaceutically acceptable carrier therefor.
  • the pharmaceutical compositions of the present invention are used for treating MetAP2-mediated diseases.
  • the present invention is to novel intermediates useful in the preparation of the compounds of this invention.
  • substituted 1,2,4-triazoles of formula (I) and formula (LA) are inhibitors of MetAP2. It has also now been discovered that selective inhibition of MetAP2 enzyme mechanisms by treatment with the inhibitors of formula (I) and formula (LA), or a pharmaceutically acceptable salt or solvate thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity.
  • the term "Ph” represents a phenyl ring.
  • C ⁇ .6alkyl as used herein at all occurrences means a substituted and unsubstituted, straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • any C 1-6 alkyl group may be optionally substituted independently by one or more of -OR , -R4, -NR4R5, -S R .
  • C 0 alkyl means that no alkyl group is present in the moiety.
  • Ph-COalkyl- is equivalent to Ph.
  • C 3-7 cycloalkyl as used herein at all occurrences means substituted or unsubstituted cyclic radicals having 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl radicals.
  • C 2- 6alkenyl as used herein at all occurrences means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C 2 . 6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included within the scope of this invention.
  • any C 2-6 alkenyl group may be independently, optionally substituted by one or more of Ph-C 0 .6alkyl-, Het-Co- ⁇ alkyl-, C ⁇ . 6 alkyl, C ⁇ _ 6 alkoxy-, C ⁇ . 6 alkyl-S-, Ph-C 0- 6alkoxy-, Het-Co- ⁇ alkoxy-, HO-, R 4 R -, Het-S-C 0 . 6 alkyl-, Ph-S-C 0 . 6 alkyl-, HO(CH 2 ) ⁇ -6 -, R4R5 N (CH 2 ) 2- 6-, R4R5N(CH 2 ) 2 .
  • C 2 - 6 al ynyl as used herein at all occurrences means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C 2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • any C 2 - 6 alkynyl group may be independently, optionally substituted by one or more of Ph-Co- ⁇ alkyl-, Het-Co- ⁇ alkyl-, C ⁇ aHcyl-, C ⁇ galkoxy-, C ⁇ . 6 alkyl-S-, Ph-C 0 . 6 alkoxy-, Het-C 0 . 6 alkoxy- 5 HO-, R 4 R5N-, Het-S-C 0 . 6 alkyl-, Ph-S-C 0-6 alkyl-, HO(CH 2 )i -6 -, R4 5N(CH 2 ) 2 .6-, R 4 R5N(CH 2 ) 2 . 6 0-, 6C0 2 (CH 2 )O-6-, R 6 C0 2 (CH 2 ) ⁇ -6 ⁇ -, R 6 S ⁇ 2(CH2) ⁇ -6 -, -CF3, -OCF3, or halogen.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • hetero or “heteroatom” as used herein interchangeably at all occurrences mean oxygen, nitrogen and sulfur.
  • halo or halogen as used herein interchangeably at all occurrences mean F, CI, Br, and I.
  • C 0 denotes the absence of the substituent group immediately following; for instance, in the moiety PhCo- ⁇ alkyl-, when C is 0, the substituent is phenyl.
  • Ar or "aryl” as used herein interchangeably at all occurrences mean phenyl and naphthyl, optionally substituted by one or more of Ph-C Q 6 alkyl-, Hef-C 0 6 alkyl-, C j 6 alkyl, C. _ g alkoxy-, C ⁇ alkyl-S-, Ph-C o g alkoxy-, Het'-Co- 6 alkoxy-, -OH, -NR 4 R5,
  • Het or "heterocyclic” as used herein interchangeably at all occurrences, mean a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocyclic ring, all of which are either saturated or unsaturated, and consist of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • Het may be optionally substituted with one or more of Ph-C 0 - 6 alkyl-, Hetf- w alkyl-, C 1-6 alkyl, C ⁇ alkoxy-, C ⁇ . 6 alkyl-S-, Ph-C 0 . 6 alkoxy-, Hef-Co- ⁇ alkoxy-, -OH, -NR 4 R5, Hef-S-Co.
  • Preferred optional substituents on Het are C ⁇ -6 alkyl, C w alkoxy-, C w al yl-S-, halogen, -CF3, -OCF3, -CN, or -NR 4 R5.
  • Het' is defined as for Het and may be optionally substituted by one or more of C 1-6 alkyl, Q ⁇ alkoxy-, -OH, -(CH2) 1-6 NR R5, -0(CH 2 ) I . 6 NR 4 R5, -C0 2 R 6 , CF3, or halogen.
  • heterocycles include, but are not limited to piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, t
  • Compounds of this invention of formula (I), do not include compounds wherein R 2 is optionally substituted Het-Cnalkyl-, and Het is indolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiozolylor benzopyrazolyl, and the optional substituent is -(CH 2 ) 2 NR4R5.
  • a moiety when a moiety is “optionally substituted” the moiety may have one or more optional substituents, each optional substituent being independently selected.
  • substituents each optional substituent being independently selected.
  • hetero or “heteroatom” as used herein interchangeably at all occurrences mean oxygen, nitrogen and sulfur.
  • halo or halogen as used herein interchangeably at all occurrences mean F, CI, Br, and I.
  • CO denotes the absence of the substituent group immediately following; for instance, in the moiety ArCo- ⁇ alkyl-, when C is 0, the substituent is Ar, e.g., phenyl.
  • ArCo- ⁇ alkyl- when the moiety ArCo- ⁇ alkyl- is identified as a specific aromatic group, e.g., phenyl, it is understood that C is 0.
  • R* is optionally substituted C 2-6 alkyl, C 3 . 6 alkenyl, C 3-6 alkynyl, optionally substituted Ar-C 0- 6alkyl-, optionally substituted Het-C 0- 6alkyl-, or optionally substituted C 3-7 cycloalkyl-Co. 6 alkyl-.
  • R- * * is Ar-Co ⁇ alkyl- or optionally substituted Het-C 0 - 6 alkyl-. More preferably Rp is Ar-C2alkyl- or optionally substituted Het-C2alkyl-. Most preferably R! is phenethyl, optionally substituted ethylfuran or optionally substituted ethylthiophene. When R! is Ar-C2alk l- or Het-C2alkyl-, the alkyl chain is directly attached to the 5-position of the triazole.
  • R 2 is optionally substituted C 1-6 alkyl, C 3-6 alkenyl, C 3 . 6 alkynyl, optionally substituted Ar-Co- ⁇ alkyl-, optionally substituted Het-C 0 _ 6 alkyl-, or optionally substituted C 3-7 cycloalkyl-C 0 - 6 alkyl-.
  • R 2 is optionally substituted Ar-C 0-6 alkyl-. More preferably R 2 is optionally substituted Ar-C()alkyl-, wherein the optional substituent is either in the ortho position or the para position.
  • R 2 is optionally substituted Ar-C ⁇ alkyl-, wherein the optional substituent is ortho C ⁇ . 6 alkyl, preferably branched C ⁇ -6 alkyl, most preferably isopropyl.
  • R3 is H, optionally substituted C 1-6 alkyl, C 3 . 6 alkenyl, C 3 . 6 alkynyl, optionally substituted Ar-C 0-6 alkyl-, optionally substituted Het-C 0-6 alkyl-, optionally substituted C 3 . 7 cycloalkyl-Co.
  • R3 is hydrogen or -C 0 . 6 allyl-C(O)X'AB. More preferably R ⁇ is hydrogen or
  • R4, R-5, and R ⁇ are independently selected from H-, C 2 - 6 alkyl, C 3 . 6 alkenyl, C 3 . 6 alkynyl, Ph-Co- ⁇ alkyl-, Het-C 0 - 6 alkyl-, or C 3 . 7 cycloalkyl-Co- 6 alkyl-.
  • pharmaceutically acceptable salts of formula (I) and formula (LA) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
  • inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate
  • an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms.
  • the stereocenters may be (R), (S) or any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention.
  • Novel intermediates useful in making compounds of this invention are as follows: 1 -(3 -Cyclohexyl-propanoyl)-2-ethyl-3 -phenyl-isothiourea; l-(3-(2-thienyl)-propanoyl)-2-ethyl-3-(2-isopropylphenyl)-isothiourea; 1 -(2-Methyl-3 -phenyl-propanoy l)-2-ethyl-3 -(2-isopropylphenyl)-isothiourea; 1 -(3 -(2-thienyl)-propanoyl)-2-ethy 1-3 -phenyl-isothiourea; and 1 -(2-pheny lthio-acetyl)-2-ethyl-3 -phenyl-isothiourea.
  • a thiourea (such as l-(2-methylphenyl)thiourea, l-(4-methylphenyl)-thiourea,
  • the S-ethylisothiourea could be acylated with a carboxylic acid (such as 2-methyl-3-phenyl-propanoic acid, 3-cyclohexylpropionic acid, 3-(2-thienyl)propanoic acid, phenylsulfanyl-acetic acid) under standard coupling conditions to afford the amide.
  • a carboxylic acid such as 2-methyl-3-phenyl-propanoic acid, 3-cyclohexylpropionic acid, 3-(2-thienyl)propanoic acid, phenylsulfanyl-acetic acid
  • compositions are administered in conventional dosage forms prepared by combining a compound of this invention of formula (I) or (IA) ("active ingredient”) in an amount sufficient to treat cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization or obesity ("MetAp2-mediated disease states") with standard pha ⁇ naceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical ca ⁇ ier employed may be, for example, either a solid or liquid.
  • solid earners are lactose, te ⁇ a alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the ca ⁇ ier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • a wide variety of pharmaceutical forms can be employed.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of MetAP2-mediated disease states.
  • the amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician.
  • a suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most prefe ⁇ ed dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
  • topical administration non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, inrraperitoneal and intramuscular administration.
  • an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
  • the topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable ca ⁇ ier(s) therefor and optionally any other therapeutic ingredient(s).
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transfe ⁇ ed to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
  • the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol.
  • the formulation may incorporate any suitable surface-active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
  • suitable surface-active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • the active ingredient may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
  • this invention relates to a method of treating cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization or obesity, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a MetAP2 inhibitor, in particular, a compound of this invention.
  • a MetAP2 inhibitor in particular, a compound of this invention.
  • treating is meant either prophylactic or therapeutic therapy.
  • Such compound can be administered to such mammal in a conventional dosage form prepared by combining the compound of this invention with a conventional pharmaceutically acceptable ca ⁇ ier or diluent according to known techniques.
  • the fo ⁇ n and character of the pharmaceutically acceptable ca ⁇ ier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the compound is administered to a mammal in need of treatment for cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization or obesity, in an amount sufficient to decrease symptoms associated with these disease states.
  • the route of administration may be oral or parenteral.
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally prefe ⁇ ed.
  • the daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient.
  • the daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient.
  • the optimal quantity and spacing of individual dosages of a compound of this invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • Example 4 Preparation of 3-(4-methyl-anilino -5-[2-(phenyl ethyl]-1.2.4-triazole Following the procedure of Example 2(a)-2(b) except l-(4-methylphenyl)-thiourea was substituted for l-(2-isopropylphenyl)thiourea in step 2(a) the title compound was prepared as a white solid (18%). MS (ESI) 279.0 (M+H)+. IH-NMR (400MHz, d4-MeOH): ⁇ 2.44 (s, 3H), 2.91-3.09 (m, 4H), 7.07 (m, 2H), 7.12-7.29 (m, 7H).
  • Example 6 Preparation of 3-(4-fluoro-anilino ' )-5-[2-(phenyl)ethyl1-1.2.4-triazole Following the procedure of Example 2(a)-2(b) except 1 -(4-fluoro-phenyl)thiourea was substituted for l-(2-isopropylphenyl)thiourea in step 2(a) the title compound was prepared as a white solid (31%). MS (ESI) 283.2 (M+H)+.
  • Example 8 Preparation of 3-anilino-3-methyl-5-[2-(phenyl)ethyl]-1.2.4-triazole Following the procedure of Example 2(a)-2(b) except 1 -methyl- 1-phenylthiourea was substituted for l-(2-isopropylphenyl)thiourea in step 2(a) the title compound was prepared as a white solid (45%). MS (ESI) 279.0 (M+H)+. IH-NMR (400MHz, d4-MeOH): ⁇ 2.92- 2.94 (m, 2H), 3.00-3.03 (m, 2H), 3.40 (s, 3H), 7.1 3 . 7 .38 (m, 10H).
  • Example 9 Preparation of 1 -(5 -phenethyl-4H- [ 1 ,2,4 " ltriazol-3 -ylV 1.2.3.4-tetrahydro-quinoline Following the procedure of Example 2(a)-2(b) except 3,4-dihydro-2H-quinoline-l- carbothioic acid amide was substituted for l-(2-isopropylphenyl)thiourea in step 2(a) the title compound was prepared as a white solid (32%). MS (ESI) 305.4 (M+H)+.
  • Example 13 Preparation of 3- 2-isopropyl-anilino)-5-r2-(2-thienyl ethyl "
  • S-ethyl-l-(2-isopropylphenyl)- isothiourea hydroiodide was substituted for S-ethyl-1-phenylisothiourea hydroiodide and 3- (2-thienyl)propanoic acid was substituted for 3-cyclohexylpropionic acid in step 12(a) the title compound was prepared as a white solid (3%).
  • Example 14 Preparation of 3-anilino-5-[ 1 -methyl-2-(phenyl ethyl]- 1.2.4-triazole Following the procedure of Example 12(a)-2(b) except 2-methy 1-3 -phenyl-propanoic acid was substituted for 3-cyclohexylpropionic acid in step 12(a) the title compound was prepared as a white solid (32%). MS (ESI) 279.0 (M+H)+.
  • the hMetAP2 activity can be measured by direct spectrophotometric assay methods using alternative substrates, L-methionine-p-nitroanilide (Met-pNA) and L-methionine-7- amido-4-methylcoumarin (Met-AMC).
  • Method-pNA L-methionine-p-nitroanilide
  • Metal-AMC L-methionine-7- amido-4-methylcoumarin
  • the formation of -nitroaniline (pNA) or 7-amido- 4-methylcoumarin (AMC) was continuously monitored by increasing absorbance or fluorescence at 405 nm and 460 nm, respectively, on a corresponding plate reader. All assays were carried out at 30°C.
  • the fluorescence or spectrophotometric plate reader was calibrated using authentic pNA and AMC from Sigma, respectively.
  • each 50 ⁇ L assay solution contained 50 mM Hepes.Na-f- (pH 7.5), 100 mMNaCl, 10-lOOnM purified hMetAP2 enzyme, and varying amounts of Met-AMC (in 3% DMSO aqueous solution) or Met-pNA. Assays were initiated with the addition of substrate and the initial rates were corrected for the background rate determined in the absence of hMetAP2.
  • Coupled Spectrophotometric Assays of hMetAP2 Coupled Spectrophotometric Assays of hMetAP2:
  • the methionine aminopeptidase activity of hMetAP2 can also be measured spectrophotometrically by monitoring the free L-amino acid formation.
  • the release of N- terminal methionine from a tripeptide (Met-Ala-Ser, Sigma) or a tetrapeptide (Met-Gly- Met-Met, Sigma) substrate was assayed using the L-amino acid oxidase (AAO) / horse radish peroxidase (HRP) couple (eq. l-3a,b).
  • H202 hydrogen peroxide
  • a typical assay contained 50 mM Hepes.Na+, pH 7.5, 100 mM NaCl, 10 ⁇ M CoC12, 1 mM o-Dianisidine or 50 ⁇ M Amplex Red, 0.5 units of HRP (Sigma), 0.035 unit of AAO (Sigma), 1 nM hMetAP2, and varying amounts of peptide substrates. Assays were initiated by the addition of hMetAP2 enzyme, and the rates were corrected for the background rate determined in the absence of hMetAP2.
  • v is the initial velocity
  • N is the maximum velocity
  • Ka is the apparent Michaelis constant
  • I is the inhibitor concentration
  • A is the concentration of variable substrates.
  • Kis and Kii represent the apparent slope and intercept inhibition constants, respectively.
  • Cell growth inhibition assays The ability of MetAP2 inhibitors to inhibit cell growth was assessed by the standard XTT microtitre assay. XTT, a dye sensitive to the pH change of mitochondria in eukaryotic cells, is used to quantify the viability of cells in the presence of chemical compounds. Cells seeded at a given number undergo approximately two divisions on average in the 72 hours of incubation.
  • this population of cells is in exponential growth at the end of the incubation period; the mitochondrial activity of these cells is reflected in the spectrophotometric readout (A450). Viability of a similar cell population in the presence of a given concentration of compound is assessed by comparing the A450 reading from the test well with that of the control well.
  • Flat-bottomed 96-well plates are seeded with appropriate numbers df cells (4-6 x 103 cells/well in a volume of 200 ul) from trypsinized exponentially growing cultures, h the case of HUVECs, the wells are coated with matrigel prior to establishing the cultures. To "blank" wells is added growth medium only. Cells are incubated overnight to permit attachment.
  • the compounds of this invention show MetAP2 inhibitor activity having IC50 values in the range of 0.0001 to 100 uM.
  • the full structure/activity relationship has not yet been established for the compounds of this invention.
  • one of ordinary skill in the art can utilize the present assays in order to determine which compounds of this invention are inhibitors of MetAP2 and which bind thereto with an IC50 value in the range of 0.0001 to 100 uM.

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Abstract

L'invention concerne des composés qui constituent des inhibiteurs réversibles non peptidiques de méthionine aminopeptidase de type 2, utiles pour traiter des états pathologiques dépendant de l'angiogenèse, tels que le cancer, l'hémangiome, la rétinopathie proliférative, la polyarthrite rhumatoïde, la néovascularisation athéroscléreuse, le psoriasis, la néovascularisation oculaire et l'obésité.
PCT/US2002/009954 2001-03-29 2002-03-28 Composes et procedes WO2002078697A1 (fr)

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EP02723701A EP1381360A4 (fr) 2001-03-29 2002-03-28 Composes et procedes pour inhiber la metap2 chez les mammiferes
JP2002576963A JP2005508841A (ja) 2001-03-29 2002-03-28 化合物および方法

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