WO2001078723A1 - Compounds and methods - Google Patents
Compounds and methods Download PDFInfo
- Publication number
- WO2001078723A1 WO2001078723A1 PCT/US2001/011979 US0111979W WO0178723A1 WO 2001078723 A1 WO2001078723 A1 WO 2001078723A1 US 0111979 W US0111979 W US 0111979W WO 0178723 A1 WO0178723 A1 WO 0178723A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- triazol
- triazole
- phenyl
- amine
- het
- Prior art date
Links
- 0 CC(CC1)(*C1(*)CCC1)CC1(C)c1c[n]nn1 Chemical compound CC(CC1)(*C1(*)CCC1)CC1(C)c1c[n]nn1 0.000 description 1
Classifications
-
- 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
- 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
- A61K31/4192—1,2,3-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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/45—Monoamines
- C07C211/48—N-alkylated amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
- C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- 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
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- 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
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D409/04—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 directly linked by a ring-member-to-ring-member bond
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 exhibit 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 and direct attack target different cell types, there is a great potential for a more effective combination therapy.
- TNP-470 a semisynthetic derivative of fumagillin of Aspergillus fuigatus, is among the most potent inhibitors of angiogenesis. It acts by directly inhibiting endothelial cell growth and migration in vitro and in vivo (Ingber et al. (1990) Nature 348, 555). 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
- Proteins known to be myristoylated include the src family tyrosine kinases, the small GTPase ARF, the HIV 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). This 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 cof actors. 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 terme "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 cof actors.
- 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).
- the present invention is to a novel compound of formula (I), or a pharmaceutically active salt or solvate thereof, and, further, 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:
- Q is a 5- or 6-membered monocyclic ring optionally containing up to two heteroatoms selected from N, O, or S, or an 8- to 11-membered fused bicyclic ring optionally containing up to four heteroatoms selected from N, O, or S; with the proviso that Q is substituted by up to eight of R 1 ; and further, if Q is phenyl ("Ph"), Q must be substituted by at least one of substituent R 2 ;
- R 1 is H-, Ph-C 0 -6alkyl-, Het-Co-6 alkyl-, Chalky!-, Ci.galkoxy-, C ⁇ _ gmercaptyl-, Ph-Co-6alkoxy-, Het-C()-6alkoxy-, HO-, R 4 R 5 N-, Het-S- Co- ⁇ al yl-, Ph-S-Co- 6 alkyl-, HO(CH 2 ) ⁇ _ 6 -, R4R5N(CH 2 ) 2 _ 6 -, R4R5 N (CH 2 ) 2 _ 6 O-, R 6 CO 2 (CH 2 ) 0 _ 6 -, R6CO 2 (CH 2 )I_ 6 O-, R 6 SO 2 (CH 2 )!_6-, -CF 3 , -OCF 3 , or halogen, and Ph or Het are substituted with up to five of C 2 _6alkyl-, C ⁇ al oxy-, R4R5
- R 6 SO 2 (CH 2 )i_6-, -CF3 or -OCF3, and Ph or Het are substituted with up to five of C 2 _6alkyl-, Ci ⁇ alkoxy-, R 4 R5N(CH 2 )I _ 6 -, R4R5N(CH 2 ) _6O-, -CO 2 R 6 , -CF3 or, halogen; provided that the compound of formula (I) is not [(6-(lH-l,2,3-triazol-4-yl)-2- napthalenyl)oxy] -acetic acid; [(6-(lH-l,2,3-triazol-4-yl)-2- napthalenyl)oxy]-acetic acid 1,1-dimethylethyl ester; 4-(lH- 1,2,3- triazol-4-yl)-aniline; 2-chloro-4-(lH- 1 ,2,3-triazol-4-yl)-aniline; l-(
- R , R5, and R ⁇ are independently selected from ⁇ -, C 2 -6alkyl-, C3_6al enyl-,
- 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 (IA), or a pharmaceutically acceptable salt or solvate thereof:
- angiogenesis such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity
- Q is a 5- or 6-membered monocyclic ring containing up to two heteroatoms selected from N, O, or S, or an 8- to 11-membered fused bicyclic ring containing up to four heteroatoms selected from N, O, or S; R!
- R 2 are independently selected from H-, Ph-C ⁇ -6 a lkyl-, Het-Co_6 alkyl-, C1 -.galkyl-, C ⁇ _6alkoxy-, C ⁇ _6mercaptyl-, Ph-Co-galkoxy-, Het-C 0 -6alkoxy-, HO-, R 4 R5N-, Het-S-C 0 -6alkyl-, Ph-S-C 0 _6alkyl-,
- R 6 CO R 6 , -CF3 or, halogen
- R3 is H-, halogen, or R3 and Q together form a bicyclic or tricyclic saturated or unsaturated fused ring system wherein R ⁇ is -C-, or
- R4, R5, and R ⁇ are independently selected from H-, C 2 _6alkyl-, C3_6alkenyl-,
- 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 (IA), or a pharmaceutically active salt thereof.
- the present invention is to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or formula (IA) 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 1,2,3-triazoles of formula (I) and formula (IA) 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 (IA), or a pharmaceutically acceptable salt 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.
- Het or
- heterocyclic as used herein interchangeably at all occurrences, mean a stable 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 may optionally be oxidized or quaternized, and including any bicyclic group in which any of the above- defined heterocyclic rings is fused to a benzene ring.
- Ph and Het must be substituted with up to five of C 2 _galkyl-, Ci .galkoxy-, R 4 R5N(CH 2 )I .g-, R 4 R5N(CH2) 2 -6O-, -CO 2 R6, -CF 3 or, halogen.
- Ci- ⁇ alkyl 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 ⁇ _6alkyl group may be optionally substituted independently by one or more of OR 4 , R 4 , NR 4 R5.
- C3_7cycloalkyl 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 _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 _6alkenyl 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 -_6alkenyl group may be optionally substituted independently by one or more of Ph-C ⁇ -6 a lkyl-, Het-C ⁇ - ⁇ alkyl-, C ⁇ _6alkyl-, Ci _galkoxy-, Ci .gmercaptyl-, Ph-C ⁇ -6 a lkoxy-, Het-C ⁇ -6 a lkoxy-, HO-, R 4 R 5 N-, Het-S-C 0 -6alkyl-, Ph-S-C 0 _ 6 alkyl-, HO(CH 2 )i-6-, R 4 R 5 N(CH 2 ) 2 . 6 -, R 4 R5N(CH 2 ) 2 . 6 O-, R6CO 2 (CH 2 ) 0 -6-, R 6 CO 2 (CH 2 ) 1 . 6 O-, R 6 SO 2 (CH 2 )i-6-> - F3, -OCF3, or halogen.
- C 2 -6alkynyl 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 _6alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
- 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.
- mercaptyl 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 a sulfur atom, including, but not limited to, methylthio, ethylthio, n- propylthio, isopropylthio, 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, Cl, Br, and I.
- CQ denotes the absence of the substituent group immediately following; for instance, in the moiety PhCo-6alkyl, when C is 0, the substituent is phenyl.
- the triazole ring can exist in either of two tautomeric forms as shown in Figure 1.
- the hydrogen on the triazole ring can exist on either Nl or N3, thus the name for a compound in figure 1 can be any of the following: 4-(Q)-lH- 1,2,3-triazole, 5-(Q)-lH-l-2,3-triazole, 4-(Q)-3H- 1,2,3-triazole, 5-(Q)-3H- 1,2,3-triazole.
- Q is used herein to represent a 5- or 6-membered monocyclic ring optionally containing up to two heteroatoms selected from N, O, or S, or an 8- to 11-membered fused bicyclic ring optionally containing up to four heteroatoms selected from N, O, or S.
- a bicyclic ring is defined as two rings that are fused together by two adjacent atoms.
- the ring may be saturated or unsaturated, wherein the nitrogen may optionally be oxidized or quaternized. It will be understood that if Q is a heterocyclic ring, it may be attached to the triazole ring through any heteroatom or carbon atom of Q which results in the creation of a stable structure.
- Q examples include, but are not limited to phenyl, napthyl, 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, te
- Q is a 5- or 6-membered unsaturated ring or a 9-membered bicyclic ring.
- Q is thiophene, phenyl, pyridine, benzofuran, or benzo[l,3]dioxole.
- R! is H-, Ph-Co_6alkyl-, Het-C ⁇ -6 alkyl-, Ci.galkyl-, C ⁇ _ galkoxy-, C ⁇ .gmercaptyl-, Ph-Co_6alkoxy-, Het-Co_6alkoxy-, HO-, R 4 R ⁇ N-, Het-S-C 0 _6alkyl-, Ph-S-C 0 _6alkyl-, HO(CH 2 )!. 6 -, R 4 R5N(CH 2 ) 2 _ 6 -, R 4 R5N(CH 2 ) 2 .
- R6CO 2 (CH 2 ) 0 _ 6 -, R6CO 2 (CH 2 )!_ 6 O-, R6sO 2 (CH 2 )i_ g-, -CF3, -OCF3, or halogen, and Ph or Het are substituted with up to five of C 2 . 6 alkyl-, C 1 . 6 alkoxy-, R R5N(CH 2 )!_ 6 -, R 4 R5N(CH 2 ) 2 _ 6 O-, -CO 2 R6, - CF3 or, halogen.
- R is halogen, C ⁇ -.galkyl-, C ⁇ . ⁇ alkoxy-, or -OH. More preferably, R 1 is bromine, chlorine, methyl, ethyl, methoxyl, or hydroxyl.
- R 2 is Ph-Co-6alkyl-, Het-C ⁇ -6 alk yl- > c 5_6alkyl-, C 2 . galkoxy-, C1.gmercaptyl-, Ph-Co- ⁇ alkoxy-, Het-Co. ⁇ alkoxy-, HO-, R 4 R ⁇ N-, Het-S-C 0 . 6 alkyl-, Ph-S-C 0 . 6 alkyl-, HO(CH 2 )!_ 6 -, R 4 R5N(CH 2 ) 2 _ 6 -, R 4 R5N(CH 2 ) 2 .
- R6CO 2 (CH 2 ) 0 .6-, R 6 CO 2 (CH 2 ) 1 . 6 O-, R6SO 2 (CH 2 )!_ 5-, -CF3 or -OCF3, and Ph or Het are substituted with up to five of C 2 _6alkyl-, C ⁇ _ 6 alkoxy-, R 4 R5N(CH 2 )!_ 6 -, R R5N(CH 2 ) 2 .
- R 4 , R ⁇ , and R ⁇ are independently selected from H, C 2 _ 6alkyl, C3_galkenyl, C3_6alkynyl, Ph-Co_6alkyl, Het-Co_6alkyl, or C3. 7cycloalkyl-C 0 _6alkyl.
- R 2 is -NR 4 R 5 , -CF 3 , Ph-S-Co_6alkyl-, Ph-Co-6alkoxy-. More preferably, R 2 is benzylamine, propylamine, furan-3- ylmethylamine, furan-2-ylmethylamine, -CF3, Ph-CH 2 -O-, (4-Cl)Ph-S-.
- R 4 , Rx and R ⁇ are independently selected from H-, C 2 -6alkyl-, C3_6alkenyl-, C3_6alkynyl-, Ph-Co_6alkyl-, Het-Co_6alkyl-, or C3-7cycloalkyl-Co-6alkyl-.
- R 4 , R ⁇ , and R ⁇ are independently selected hydrogen, benzyl, furanyl, and propyl.
- pharmaceutically acceptable salts of formula (I) 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:
- An aldehyde such as 2-thiophenecarboxaldehyde (1-Schemel was treated with l-diazo-2-oxopropylphosphonate and potassium carbonate in dry methanol to provide 2-Schemel.
- Treatment of the acetylene such as 2- ethynylthiophene (2-Schemel) with azidotrimethylsilane in refluxing toluene, followed by addition of water afforded 3-Schemel.
- alkynyl aniline such as 3-ethynylphenylamine
- 5-Scheme2 An alkynyl aniline (such as 3-ethynylphenylamine) was substituted by a reductive animation reaction with an aldehyde to provide 5-Scheme2.
- 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 pharmaceutical 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 carrier employed may be, for example, either a solid or liquid.
- solid carriers are lactose, terra 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 carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
- 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 preferred 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, intraperitoneal 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.
- topical formulations of the present invention comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s).
- the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- 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, transferred 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 .
- 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.
- 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.
- 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 carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier 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 mtraperitoneal administration.
- the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
- 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. It will be recognized by one of skill in the art that 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 2 Preparation of 4-(3 odophenyl)-lfl r -l,2,3-triazole Following the procedure of Example 1, except substituting 1-ethynyl- 3-iodobenzene for 3-ethynylphenol, the title compound was prepared as a white solid (20 %).
- Example 7 Preparation of 3-(lfl r -l,2,3-triazoI-4-yl)-phenyIamine Following the procedure of Example 1, except substituting 3-ethynyl- phenylamine for 3-ethynylphenol, the title compound was prepared as a tan solid (19 %).
- 1H-NMR 400MHz, CD 3 OD: ⁇ 8.05 (s, 1H), 7.12-7.20 (m, 3H), 6.73-6.75 (m, 1H).
- Example 12 Preparation of 4-(4-methoxyphenyl)-lfl r -l,2,3-triazole Following the procedure of Example 1, except substituting 1-ethynyl- 4-methoxybenzene for 3-ethynylphenol, the title compound was prepared as a white solid (34 %).
- Example 17 Preparation of 4-(l//-l,2,3-triazol-4-yl)-phenylamine Following the procedure of Example 1, except substituting 4- ethynylphenylamine for 3-ethynylphenol, the title compound was prepared as an orange solid (9 %).
- Example 23 Preparation of 4-(thiophen-3-yl)-lfl r -l,2,3-triazole Following the procedure of Example 22, except substituting 3- thiophenecarboxaldehyde for 2-thiophenecarboxaldehyde in step a, the title compound was prepared as a white solid (2 steps, 8 %).
- Example 25 Preparation of 4-(l,3-dimethylphenyl)-l#-l,2,3-triazole Following the procedure of Example 22, except substituting 2,4- dimethylbenzaldehyde for 2-thiophenecarboxaldehyde in step a, the title compound was prepared as a white solid (2 steps, 3 %).
- Example 29 Preparation of 4-(2-benzyloxy-phenyl)-lff-l,2,3-triazole Following the procedure of Example 22, except substituting 2- benzyloxybenzaldehyde for 2-thiophenecarboxaldehyde in step a, the title compound was prepared as a white solid (2 steps, 25 %).
- MS (ESI) 252.2 (M+H) + .
- Example 30 Preparation of 2-(l_fl r -l,2,3-triazol-4-yl)-6-methylpyridine Following the procedure of Example 22, except substituting 6-methyl- 2-pyridine carboxaldehyde for 2-thiophenecarboxaldehyde in step a, the title compound was prepared as a clear oil (2 steps, 39 %).
- Example 33 Preparation of 4-(2-methoxyphenyI)-l_fl r -l,2,3-triazole Following the procedure of Example 22, except substituting o- anisaldehyde for 2-thiophenecarboxaldehyde in step a, the title compound was prepared as a white solid (2 steps, 6 %).
- Example 36 Preparation of 2-(li__T-l,2,3-triazol-4-yl)-benzofuran Following the procedure of Example 22, except substituting benzofuran-2-carboxaldehyde for 2-thiophenecarboxaldehyde in step a, the title compound was prepared as a white solid (2 steps, 25 %).
- MS (ESI) 186.0 (M+H) + .
- Example 37 Preparation of 4-benzo[l,3]dioxol-4-yI-Lff-l,2,3-triazole a) 4-ethynyl-benzo[l,3]dioxole Following the procedure of Example 22, except substituting benzo[l,3]dioxole-4-carbaldehyde for 2-thiophenecarboxaldehyde in step a, the title compound was obtained as an oil (98 %). 1H-NMR (400MHz, CDCI3): ⁇ 6.94-6.96 (m, IH), 6.80-6.85 (m, 2H), 6.05 (s, 2H), 3.30 (s, IH). b) 4-benzo[l,3]dioxol-4-yl-lH-l,2,3-triazole
- Example 43 Preparation of napthalene-l-ylmethyl-(3-[li ⁇ -l,2,3-triazol-4- yl]phenyl)amine a) napthalene- 1 -ylmethyl-(3-ethynylphenyl)-amine Following the procedure of Example 39, except substituting 1- napthaldehyde for 3-phenylpropionaldehyde in step a, the title compound was prepared as a clear oil (80 %). MS (ESI) 258.2 (M+H) + . b) napthalene-l-ylmethyl-(3-[lH-l,2,3-triazol-4-yl]phenyl)amine
- Example 49 Preparation of 2-(5-bromo-lH-l,2,3-triazol-4-yl)-4-methyl-pyridine Following the procedure of Example 48, except substituting 2-(lH- l,2,3-triazol-4-yl)-4-methyl-pyridine (Example 21) for 3-(lH-l,2,3-triazol-4- yl)-phenol, the title compound was prepared as an orange solid (16 %).
- 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
- 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+ (pH 7.5), 100 mM NaCl, 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).
- H 2 O 2 hydrogen peroxide
- a typical assay contained 50 mM Hepes-Na+, pH 7.5, 100 mM NaCl, 10 ⁇ M CoCl 2 , 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
- V is the maximum velocity
- K a is the apparent Michaelis constant
- I is the inhibitor concentration
- A is the concentration of variable substrates.
- the nomenclature used in the rate equations for inhibition constants is that of Cleland (1963), in which Kj s and K j i represent the apparent slope and intercept inhibition constants, respectively.
- 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. In the absence of any compound, 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 (A45 ⁇ ). 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.
- IC50 concentration of compound that reduces cell viability to 50% control (untreated) viability.
- 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.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001576023A JP2003530438A (en) | 2000-04-12 | 2001-04-12 | Compounds and methods |
AU2001253418A AU2001253418A1 (en) | 2000-04-12 | 2001-04-12 | Compounds and methods |
EP01926914A EP1274424A4 (en) | 2000-04-12 | 2001-04-12 | Compounds and methods |
US10/257,307 US20030220371A1 (en) | 2000-04-12 | 2001-04-12 | Compounds and methods |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19636000P | 2000-04-12 | 2000-04-12 | |
US60/196,360 | 2000-04-12 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/895,803 Continuation US20050004116A1 (en) | 2000-04-12 | 2004-07-21 | Triazole inhibitors of type 2 methionine aminopeptidase |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001078723A1 true WO2001078723A1 (en) | 2001-10-25 |
Family
ID=22725072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/011979 WO2001078723A1 (en) | 2000-04-12 | 2001-04-12 | Compounds and methods |
Country Status (5)
Country | Link |
---|---|
US (2) | US20030220371A1 (en) |
EP (1) | EP1274424A4 (en) |
JP (1) | JP2003530438A (en) |
AU (1) | AU2001253418A1 (en) |
WO (1) | WO2001078723A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1223932A1 (en) * | 1999-10-01 | 2002-07-24 | SmithKline Beecham Corporation | Compounds and methods |
WO2003042211A1 (en) * | 2001-11-15 | 2003-05-22 | Smithkline Beecham Corporation | Phenyl substituted triazoles and their use as selective inhibors of akl5 kinase |
WO2004013125A1 (en) * | 2002-07-31 | 2004-02-12 | Smithkline Beecham Corporation | Pyridinyl substituted (1,2,3,)triazoles as inhibitors of the tgf-beta signalling pathway |
WO2004037791A1 (en) | 2002-10-21 | 2004-05-06 | Chiron Corporation | Inhibitors of glycogen synthase kinase 3 |
EP1434772A1 (en) * | 2001-10-12 | 2004-07-07 | SmithKline Beecham Corporation | Compounds and methods |
WO2006020156A2 (en) * | 2004-07-15 | 2006-02-23 | The General Hospital Corporation | Heterocyclic dye compounds for in vivo imaging and diagnosis of alzheimer’s disease |
EP1921072A1 (en) * | 2006-11-10 | 2008-05-14 | Laboratorios del Dr. Esteve S.A. | 1,2,3-Triazole derivatives as cannabinoid-receptor modulators |
WO2009127669A2 (en) * | 2008-04-15 | 2009-10-22 | Ludwig Institute For Cancer Research Ltd | Ido inhibitors and therapeutic uses thereof |
EP2430921A3 (en) * | 2007-04-03 | 2012-05-30 | E.I. Du Pont De Nemours And Company | Substituted benzene fungicides |
CN107257794A (en) * | 2015-02-18 | 2017-10-17 | 伊莱利利公司 | Pyrazole compound |
US10858585B2 (en) | 2018-01-03 | 2020-12-08 | Ecolab Usa Inc. | Benzotriazole derivatives as corrosion inhibitors |
US11884648B2 (en) | 2016-04-19 | 2024-01-30 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013055385A2 (en) | 2011-10-03 | 2013-04-18 | Zafgen Corporation | Methods of treating age related disorders |
US8642650B2 (en) * | 2008-12-04 | 2014-02-04 | Zafgen, Inc. | Methods of treating an overweight or obese subject |
WO2011085198A1 (en) | 2010-01-08 | 2011-07-14 | Zafgen Corporation | Metap-2 inhibitor for use in treating benign prostatic hypertrophy (bph) |
WO2011088055A2 (en) | 2010-01-12 | 2011-07-21 | Zafgen Corporation | Methods and compositions for treating cardiovascular disorders |
WO2011127304A2 (en) | 2010-04-07 | 2011-10-13 | Zafgen Corporation | Methods of treating an overweight subject |
WO2012064928A1 (en) | 2010-11-10 | 2012-05-18 | Zafgen Corporation | Methods and compositions for treating thyroid hormone related disorders |
WO2012064943A2 (en) * | 2010-11-13 | 2012-05-18 | Viamet Pharmaceuticals, Inc. | Metalloenzyme inhibitor compounds |
US20130316994A1 (en) | 2010-11-29 | 2013-11-28 | Zafgen, Inc. | Methods of Reducing Risk of Hepatobiliary Dysfunction During Rapid Weight Loss with METAP-2 Inhibitors |
WO2012075020A1 (en) | 2010-11-29 | 2012-06-07 | Zafgen Corporation | Treatment of obesity using non-daily administration of 6 - 0 - (4 - dimethylaminoethoxy) cinnamoyl fumagillol |
US9189078B2 (en) | 2010-12-20 | 2015-11-17 | Apple Inc. | Enhancing keycap legend visibility with optical components |
CN104363905A (en) | 2012-05-08 | 2015-02-18 | 扎夫根股份有限公司 | Treating hypothalamic obesity with metap2 inhibitors |
EP2850079B1 (en) | 2012-05-09 | 2018-05-02 | Zafgen, Inc. | Fumigillol type compounds and methods of making and using same |
EP2968250B1 (en) | 2013-03-14 | 2019-06-19 | Zafgen, Inc. | Methods of treating renal disease and other disorders |
AR105671A1 (en) | 2015-08-11 | 2017-10-25 | Zafgen Inc | HUMEROCYCLIC COMPOUNDS OF FUMAGILLOL AND ITS METHODS OF ELABORATION AND USE |
CN106432255A (en) | 2015-08-11 | 2017-02-22 | 扎夫根公司 | Fumigillol spiro-compound, preparation and use method thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3948930A (en) * | 1973-05-29 | 1976-04-06 | Miles Laboratories, Inc. | Phenyl-and (substituted)-phenyl-1,2,3-triazole-alkanoic and- alkenoic acids |
US5412098A (en) * | 1991-12-27 | 1995-05-02 | Wakunaga Seiyaku Kabushiki Kaisha | Quinolone derivative or salt thereof and antibacterial containing the same |
US5756529A (en) * | 1995-09-29 | 1998-05-26 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides for use in veterinary therapies |
US5935972A (en) * | 1993-08-26 | 1999-08-10 | Glaxo Group Limited | Benzofuran derivatives as tachykinin antagonists |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8714789D0 (en) * | 1987-06-24 | 1987-07-29 | Lundbeck & Co As H | Heterocyclic compounds |
US6207704B1 (en) * | 1997-06-09 | 2001-03-27 | Massachusetts Institute Of Technology | Type 2 methionine aminopeptidase [MetAP2] inhibitors and uses thereof |
PT1068198E (en) * | 1998-03-09 | 2003-10-31 | Lundbeck & Co As H | SUBSTITUTED 5-HETEROARYL INDOORS |
JP2002275157A (en) * | 1998-11-20 | 2002-09-25 | Torii Yakuhin Kk | New naphthalene derivative |
EP1379241A1 (en) * | 2001-03-29 | 2004-01-14 | SmithKline Beecham Corporation | Compounds and methods |
US20040116490A1 (en) * | 2002-03-28 | 2004-06-17 | Marino Jr. Joseph P. | Compounds and methods |
-
2001
- 2001-04-12 JP JP2001576023A patent/JP2003530438A/en not_active Withdrawn
- 2001-04-12 EP EP01926914A patent/EP1274424A4/en not_active Withdrawn
- 2001-04-12 WO PCT/US2001/011979 patent/WO2001078723A1/en not_active Application Discontinuation
- 2001-04-12 US US10/257,307 patent/US20030220371A1/en not_active Abandoned
- 2001-04-12 AU AU2001253418A patent/AU2001253418A1/en not_active Abandoned
-
2004
- 2004-07-21 US US10/895,803 patent/US20050004116A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3948930A (en) * | 1973-05-29 | 1976-04-06 | Miles Laboratories, Inc. | Phenyl-and (substituted)-phenyl-1,2,3-triazole-alkanoic and- alkenoic acids |
US5412098A (en) * | 1991-12-27 | 1995-05-02 | Wakunaga Seiyaku Kabushiki Kaisha | Quinolone derivative or salt thereof and antibacterial containing the same |
US5935972A (en) * | 1993-08-26 | 1999-08-10 | Glaxo Group Limited | Benzofuran derivatives as tachykinin antagonists |
US5756529A (en) * | 1995-09-29 | 1998-05-26 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides for use in veterinary therapies |
Non-Patent Citations (1)
Title |
---|
See also references of EP1274424A4 * |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1223932A1 (en) * | 1999-10-01 | 2002-07-24 | SmithKline Beecham Corporation | Compounds and methods |
EP1223932A4 (en) * | 1999-10-01 | 2003-01-15 | Smithkline Beecham Corp | Compounds and methods |
US7304082B2 (en) | 1999-10-01 | 2007-12-04 | Smithkline Beecham Corporation | 1,2,4-triazole derivatives, compositions, process of making and methods of use |
EP1434772A1 (en) * | 2001-10-12 | 2004-07-07 | SmithKline Beecham Corporation | Compounds and methods |
EP1434772A4 (en) * | 2001-10-12 | 2005-05-04 | Smithkline Beecham Corp | Compounds and methods |
WO2003042211A1 (en) * | 2001-11-15 | 2003-05-22 | Smithkline Beecham Corporation | Phenyl substituted triazoles and their use as selective inhibors of akl5 kinase |
WO2004013125A1 (en) * | 2002-07-31 | 2004-02-12 | Smithkline Beecham Corporation | Pyridinyl substituted (1,2,3,)triazoles as inhibitors of the tgf-beta signalling pathway |
WO2004037791A1 (en) | 2002-10-21 | 2004-05-06 | Chiron Corporation | Inhibitors of glycogen synthase kinase 3 |
US6989382B2 (en) | 2002-10-21 | 2006-01-24 | Chiron Corporation | Carbocycle based inhibitors of glycogen synthase kinase 3 |
WO2006020156A2 (en) * | 2004-07-15 | 2006-02-23 | The General Hospital Corporation | Heterocyclic dye compounds for in vivo imaging and diagnosis of alzheimer’s disease |
WO2006020156A3 (en) * | 2004-07-15 | 2006-04-20 | Gen Hospital Corp | Heterocyclic dye compounds for in vivo imaging and diagnosis of alzheimer’s disease |
EP1921072A1 (en) * | 2006-11-10 | 2008-05-14 | Laboratorios del Dr. Esteve S.A. | 1,2,3-Triazole derivatives as cannabinoid-receptor modulators |
US8822521B2 (en) | 2007-04-03 | 2014-09-02 | E I Du Pont De Nemours And Company | Substituted benzene fungicides |
EP2430921A3 (en) * | 2007-04-03 | 2012-05-30 | E.I. Du Pont De Nemours And Company | Substituted benzene fungicides |
EP2529624A3 (en) * | 2007-04-03 | 2013-03-13 | E. I. du Pont de Nemours and Company | Substituted benzene fungicides |
US9198433B2 (en) | 2007-04-03 | 2015-12-01 | E I Du Pont De Nemours And Company | Substituted benzene fungicides |
US9743667B2 (en) | 2007-04-03 | 2017-08-29 | E I Du Pont De Nemours And Company | Substituted benzene fungicides |
WO2009127669A3 (en) * | 2008-04-15 | 2010-04-08 | Ludwig Institute For Cancer Research Ltd | Ido inhibitors and therapeutic uses thereof |
WO2009127669A2 (en) * | 2008-04-15 | 2009-10-22 | Ludwig Institute For Cancer Research Ltd | Ido inhibitors and therapeutic uses thereof |
CN107257794A (en) * | 2015-02-18 | 2017-10-17 | 伊莱利利公司 | Pyrazole compound |
US11884648B2 (en) | 2016-04-19 | 2024-01-30 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
US10858585B2 (en) | 2018-01-03 | 2020-12-08 | Ecolab Usa Inc. | Benzotriazole derivatives as corrosion inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP1274424A4 (en) | 2003-09-17 |
US20050004116A1 (en) | 2005-01-06 |
AU2001253418A1 (en) | 2001-10-30 |
JP2003530438A (en) | 2003-10-14 |
US20030220371A1 (en) | 2003-11-27 |
EP1274424A1 (en) | 2003-01-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1274424A1 (en) | Compounds and methods | |
US7304082B2 (en) | 1,2,4-triazole derivatives, compositions, process of making and methods of use | |
US20040116495A1 (en) | Compounds and methods | |
US20050143578A1 (en) | Compounds and methods | |
US7317031B2 (en) | Substituted triazole diamine derivatives as kinase inhibitors | |
Suthar et al. | Novel quinolone substituted thiazolidin-4-ones as anti-inflammatory, anticancer agents: Design, synthesis and biological screening | |
KR20080110912A (en) | Indazole compounds and methods for inhibition of cdc7 | |
WO2003051906A2 (en) | Compounds and methods | |
JP4589002B2 (en) | Benzazole derivatives for the treatment of scleroderma | |
US20090192164A1 (en) | Treating agent of inflammatory bowel disease | |
US20060247280A1 (en) | Compounds and methods | |
US20040116490A1 (en) | Compounds and methods | |
TW201033179A (en) | Phenylimidazole compound | |
US9034888B2 (en) | Substituted 2-imidazolidones and analogs | |
JP2005508841A (en) | Compounds and methods | |
US6858617B2 (en) | Substituted imidazole compounds | |
US6486158B1 (en) | [4,5]-fused-3,6-disubstituted-pyridazines with sulfur-containing substituents in position three for the treatment of neoplasia | |
US20050222212A1 (en) | Compounds and methods | |
WO2001036404A1 (en) | Compounds and methods | |
AU2002249872B2 (en) | Substituted triazole diamine derivatives as kinase inhibitors | |
AU2002249872A1 (en) | Substituted triazole diamine derivatives as kinase inhibitors | |
EP1712550A2 (en) | Substituted triazole diamine derivatives as kinase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2001926914 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10257307 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 576023 Kind code of ref document: A Format of ref document f/p: F |
|
WWP | Wipo information: published in national office |
Ref document number: 2001926914 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2001926914 Country of ref document: EP |