WO2004014882A2 - Inhibiteurs du proteasome : derives peptidiques comprenant des groupes heteroaryle c-terminaux - Google Patents

Inhibiteurs du proteasome : derives peptidiques comprenant des groupes heteroaryle c-terminaux Download PDF

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WO2004014882A2
WO2004014882A2 PCT/US2003/024960 US0324960W WO2004014882A2 WO 2004014882 A2 WO2004014882 A2 WO 2004014882A2 US 0324960 W US0324960 W US 0324960W WO 2004014882 A2 WO2004014882 A2 WO 2004014882A2
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methyl
ethyl
oxadiazol
alkyl
ylcarbonyl
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WO2004014882A3 (fr
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Leland C. Burrill, Iii
Rohan V. Mendonca
James T. Palmer
Robert M. Rydzewski
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Axys Pharmaceuticals Inc
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Axys Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is directed to compounds that are proteasome inhibitors, pharmaceutical composition comprising such compounds and methods of treating diseases mediated by unregulated proteasome activity.
  • the proteasome is the main nonlysosomal proteolytic system in the cell and resides in the cytoplasm as well as in the nucleus. It possesses up to five different peptidase activities, in different catalytic domains and the best characterized ones are chymotrypsin-like, trypsin-like, and peptidylglutamyl-peptide hydrolyzing activities. Proteasome plays an active role in regulating different cellular functions. It participates in the rapid elimination and post-translational processing of proteins involved in cellular regulation. For example, the degradation of several important regulators of cell proliferation such as cyclin 2, cyclin 3, cyclin B, p53 and p27 k ⁇ pl are mediated by proteasome.
  • proteasome The activities of several important regulators involved in cell activation are also controlled by proteasome. For example I ⁇ B and I ⁇ B ⁇ are degraded via the proteasome pathway and the p50 component of a transacting nuclear factor NF- ⁇ matures after cotranslational processing of its precursor peptide by proteasome. In addition, proteasome activity is essential for the induction of nitric oxide synthase.
  • proteasome inhibitors can reduce the cellular content and activity of NF- ⁇ which is required for the expression of a number of genes involved in the inflammatory response such as TNF- ⁇ gene and genes encoding the cell adhesion molecules E-selectin, P-selectin, ICAM, and VCAM (see Palombella et al. WO 95/25533).
  • Proteasome inhibitors can also inhibit induction of nitric oxide synthase, and hence production of nitric oxide which is implicated in initiating and exacerbating symptoms of acute and chronic inflammation (see Lundberg et al., Nature Medicine, 3:30-31, 1997).
  • inhibitors of proteasome can treat conditions mediated by proteolytic function of the proteasome such as rapid elimination and post-translational processing of proteins involved in cellular regulation, intercellular communication, and immune response.
  • the present invention provides novel compounds that are proteasome inhibitors and accordingly provide a means for the treatment of diseases mediated by proteolytic function of the proteasome such as inflammatory diseases, autoimmune diseases and proliferative diseases such as cancer.
  • this invention is directed to a compound of Formula I:
  • n is O or l
  • R la is hydrogen or alkyl
  • R 1 is alkyl, haloalkyl, hydroxyalkyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylthioalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, alkoxyalkyl, aminoalkyl, or aralkyl; or R 1 and R la together with the carbon atom to which they are attached form cycloalkyl or heterocycloalkyl;
  • R 2 is alkyl, hydroxyalkyl, alkylthioalkyl, or alkoxyalkyl;
  • R 3 is -(C ⁇ -3 )-CONH-CHR 6 R 7 (where R 6 is hydrogen or alkyl and R 7 is branched (C 4- ⁇ o)alkyl or cycloalkyl), -(C ⁇ -3 )-COOR 8 (where R 8 is branched (C - ⁇ o)alkyl or cycloalkyl), or -(C 1-3 )-Y-(C ⁇ -3 ) n ⁇ Ar (where Y is -O-, -NH-, or -S(O) n2 - where n2 is 0 to 2, nl is 0 or 1, and Ar is aryl);
  • R 4 is alkyl or haloalkyl;
  • X is -CO-, -OCO-, -SO 2 -, -NR 9 CO-, -NR 9 CS-, or -NR 9 SO 2 - where R 9 is hydrogen or alkyl; R 10 is alkyl, aryl, aralkyl, or heteroaryl; or R 9 and R 10 together with the nitrogen atom to which they are attached form heterocycloamino; and
  • Het is a heteroaryl ring; or a pharmaceutically acceptable salt thereof.
  • this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
  • this invention is directed to a method of treating a disorder mediated by the proteolytic function of the proteasome in an animal suffering said disorder, comprising administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the disorder is a cancer, autoimmune disease such as asthma and multiple sclerosis, graft rejection, inflammatory diseases, and septic shock.
  • the disorder is haemotological malignancies such as multiple myeloma and solid tumors such as lung, prostate, pancreatic, breast, and colon cancers.
  • this invention is directed to a method of treating cancer in an animal which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more chemotherapeutic compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, or an angiogenesis inhibitor.
  • chemotherapeutic compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcript
  • the chemotherapeutic compound(s) is independently selected from Taxol ® , Taxotere ® , epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); epidophyllotoxin; procarbazine; mitoxantrone; the mitomycins, discodermolide, podophyllotoxins, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, Herceptin ® , Rituxan ® , 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, colchicines, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms unless otherwise specified, e.g., methyl, ethyl, propyl, 2- propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms unless otherwise specified, e.g., methylene, ethylene, propylene, 2-propylene, butylene (including all isomeric forms), pentylene (including all isomeric forms), and the like.
  • Acyl means a radical -COR where R is hydrogen, alkyl or haloalkyl, e.g., methylcarbonyl, trifluoromethylcarbonyl, and the like.
  • Acylamino means a radical -NHCOR where R is alkyl or haloalkyl, e.g., methylcarbonylamino, trifluoromethylcarbonylamino, and the like.
  • Alkylamino means a radical -NHR where R is alkyl as defined above, or an N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino, n-, tso-propylamino, n-, iso-, tert-butylamino, methylamino-N-oxide, and the like.
  • Aminosulfonyl means a radical -SO 2 NH 2 .
  • Aminoalkyl means a radical -(alkylene)-NR a R b where R and R b are independently hydrogen or alkyl, e.g., aminomethyl, ammoethyl, aminopropyl, and the like.
  • Alkylaminosulfonyl means a radical -SO 2 NHR where R is alkyl as defined above, e.g, methylaminosulfonyl, ethylaminosulfonyl, and the like.
  • Alkoxy means a radical -OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxycarbonyl means a radical -COOR where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, or 2- propoxycarbonyl, n-, iso-, or tert-butoxycarbonyl, and the like.
  • Alkylthio means a radical -SR where R is alkyl as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like.
  • Alkylthioalkyl means a radical -(alkylene)-SR where R is alkyl as defined above, e.g., methylthioethyl, ethylthiopropyl, (including all isomeric forms), and the like.
  • Alkylsulfinyl means a radical -S(O)R where R is alkyl as defined above, e.g., methylsulfinyl, ethylsulf ⁇ nyl, propylsulfinyl (including all isomeric forms), butylsulfinyl (including all isomeric forms), and the like.
  • Alkylsulfinylalkyl means a radical -(alkylene)-S(O)R where R is alkyl as defined above, e.g., methylsulfinylethyl, ethylsulfinylpropyl, (including all isomeric forms), and the like.
  • Alkylsulfonyl means a radical -S(O) 2 R where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl (including all isomeric forms), butylsulfonyl (including all isomeric forms), and the like.
  • Alkylsulfonylalkyl means a radical -(alkylene)-S(O) 2 R where R is alkyl as defined above, e.g., methylsulfonylethyl, ethylsulfonylpropyl, (including all isomeric forms), and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2- ethoxyethyl, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms e.g., phenyl, naphthyl or anthracenyl.
  • the aryl ring may be optionally fused to a saturated or unsaturated heterocycloalkyl ring and optionally substituted on any of the rings with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, nitro, acyl, acylamino, alkoxycarbonyl, alkoxyalkyl, cyano, hydroxyalkyl, optionally substituted heteroaryl, or when two substituents are adjacent to each other they can combine to form methylenedioxy group or aryl is pentafluorophenyl.
  • Alkyl means a radical -(alkylene)-R where R is aryl as defined above, e.g., benzyl, phenethyl, and the like.
  • Cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to seven carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Dialkylamino means a radical -NRR' where R and R' are independently alkyl as defined above, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, and the like.
  • Dialkylaminosulfonyl means a radical -SO 2 NRR' where R and R' are independently alkyl as defined above, or R and R' together with the nitrogen atom to which they are attached form heterocycloamino, e.g, dimethylaminosulfonyl, methylethylaminosulfonyl, piperazin-1-ylsulfonyl, piperidin-1-ylsulfonyl, and the like.
  • Healo means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl substituted with one or more halogen atoms, preferably one to three halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 C1, -CF , -CHF 2 , and the like.
  • Haloalkoxy means a radical -OR where R is haloalkyl as defined above, e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Hydroalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2- hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3- dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms selected from N, O, or S, the remaining ring atoms being carbon.
  • heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, 1,3,4-oxadiazolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, triazolyl, oxazolyl, tetrazolyl, and thiazolyl, and the derivatives thereof, or N-oxide or a protected derivative thereof.
  • the heteroaryl ring may be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, nitro, acyl, acylamino, alkoxycarbonyl, alkoxyalkyl, cyano, hydroxyalkyl, optionally substituted phenyl, or optionally substituted heteroaryl.
  • Heteroaralkyl means a radical -(alkylene)-R where R is a heteroaryl group as defined above e.g., pyridylmethyl, furanylmethyl, indolylmethyl, pyrimidinylmethyl, and the like.
  • Heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C.
  • the heterocycloalkyl ring may be optionally substituted with one or more substituents, preferably one or two substituents, independently selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, halo, cyano, carboxy, or -COOR where R is alkyl as define above or a protected derivative thereof. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino.
  • Heterocycloamino means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C provided that the at least one of the heteroatom is N.
  • the heterocycloalkyl ring may be optionally substituted with one or more substituents, preferably one or two substituents, independently selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, halo, cyano, carboxy, or -COOR where R is alkyl as define above or a protected derivative thereof. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino.
  • the present invention also includes the prodrugs of compounds of Formula
  • prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula I when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo.
  • Prodrugs of compounds of Formula I include compounds wherein a hydroxy, amidino, guanidino, amino, carboxylic, or a similar group is modified.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula I), amides (e.g, trifluoroacetylamino, acetylamino, and the like), and the like.
  • Prodrugs of compounds of Formula I are also within the scope of this invention.
  • the present invention also includes ⁇ -oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an ⁇ -oxide by methods well known in the art.
  • compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups.
  • suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981, the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of Formula I can be prepared by methods well known in the art.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid
  • the compounds of the present invention may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.
  • heteroaryl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heteroaryl group is mono- or disubstituted with an alkyl group and situations where the heteroaryl group is not substituted with the alkyl group.
  • Optionally substituted phenyl means a phenyl ring optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, alkylthio, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, or carboxy or optionally substituted with five fluorine atoms.
  • Optionally substituted heteroaryl means a heteroaryl ring as defined above which is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, or alkoxycarbonyl.
  • optionally substituted heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, f ranyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, and the derivatives thereof, or N-oxide or a protected derivative thereof.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier/excipient as used in the specification and claims includes both one and more than one such excipient.
  • Treating or “treatment” of a disease includes:
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • a “therapeutically effective amount” means the amount of a compound of Formula I that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • R is alkyl, haloalkyl, alkoxyalkyl, optionally substituted phenyl, or optionally substituted heteroaryl;
  • R 1 is alkyl or aralkyl
  • R 2 is alkyl, hydroxyalkyl, alkylthio, alkylthioalkyl, or alkoxyalkyl;
  • R 3 is -(C ⁇ -3 )-CONHCHR 5 R 6 where R 5 is hydrogen or alkyl and R 6 is branched (C 4-10 )alkyl or cycloalkyl, -(C ⁇ -3 )-COOR 8 (where R 8 is branched (C 4- ⁇ 0 )alkyl or cycloalkyl), or-(C ⁇ -3 )-Y-(C ⁇ -3 ) n ⁇ Ar (where Y is -O-, -NH-, or -S(O) n2 - where n2 is 0 to 2, nl is 0 or 1, and Ar is aryl);
  • X is -CO-, -OC(O)-, -SO 2 -, or -NR 9 SO 2 - where R 9 is alkyl;
  • R 10 is alkyl, aryl, or heteroaryl; or a pharmaceutically acceptable salt thereof.
  • a more preferred group of compound is that wherein X is-CO-.
  • Another more preferred group of compound is that wherein X is -SO 2 -.
  • Another more preferred group of compound is that wherein X is -OC(O)-.
  • X is -NR 9 SO 2 -, preferably -N(CH 3 )SO 2 -.
  • a more preferred group of compound is that wherein:
  • R is methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, optionally substituted phenyl, or optionally substituted heteroaryl, more preferably methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, 4-dimethylaminophenyl, pyridin-4-yl, furan-2-yl, 4-methylphenyl, 4- ⁇ rifluoromethylphenyl, or phenyl, most preferably phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, benzyl, more preferably 1-methylpropyl or 2-methylpropyl;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1- hydroxyethyl, methylthiomethyl; preferably methyl or methoxymethyl, most preferably methyl;
  • R 3 is -CH 2 CONHCH 2 C(CH 3 ) 3 or-(CH 2 ) 2 CONHC(CH 3 ) 3 ; more preferably -CH 2 CONHCH 2 C(CH 3 ) 3; or
  • R 3 is -(C ⁇ -3 )-Y-(C ⁇ -3 )niAr (where Y is -O-, NH-, or -S(O) n2 - where n2 is 0 to 2, nl is 1, and Ar is aryl), preferably R 3 is -(CH 2 )-O-(CH 2 )-Ar, more preferably -(CH 2 )-O-(CH 2 )-(3,5-dimethylphenyl), -(CH 2 )-O-(CH 2 )-(2-methylphenyl) or - (CH 2 )-O-(CH 2 )-(2-chlorophenyl); or
  • R 3 is -(CH 2 ) 2 COO-tert-butyl; and R 10 is aryl, preferably phenyl optionally substituted with alkyl or aminosulfonyl, preferably R 10 is 4-methylphenyl, 3-methylphenyl, or 4- aminosulfonylphenyl, more preferably 4-methylphenyl; or
  • R 10 is alkyl, preferably methyl when X is -NR 9 SO 2 -; or R 10 is alkyl, preferably tert-butyl when X is -OC(O)-; or
  • R 10 is heteroaryl
  • R 1 is alkyl
  • R la is hydrogen
  • R 2 is alkyl, hydroxyalkyl, or alkoxyalkyl
  • R 3 is -(C ⁇ -3 )-CONH-CHR 5 R 6 where R 5 is hydrogen or alkyl and R 6 is branched (C 4- ⁇ o)alkyl or cycloalkyl
  • X is -CO-
  • R 10 is aryl.
  • n 0, Het is 1 ,3,4-oxadiazol-2-yl which is substituted at the 5-position with methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, or optionally substituted phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl;
  • R 3 is -CH 2 CONHCH 2 C(CH 3 ) 3 or- (CH 2 ) 2 CONHC(CH 3 ) 3 ;
  • X is -CO-; and
  • R 10 is aryl.
  • n 0, Het is 1 ,3,4-oxadiazol-2-yl which is substituted at the 5-position with methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, 4-dimethylaminophenyl, pyridin-4- yl, furanyl, 4-methylphenyl, 4-trifluoromethylphenyl, or phenyl;
  • R 1 is methyl, ethyl, 1-methylpro ⁇ yl, 2-methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl;
  • R 3 is -CH 2 CONHCH 2 C(CH 3 ) 3 or -(CH 2 ) 2 CONHC(CH 3 ) 3 ;
  • X is -CO-; and
  • R 10 is phenyl optional
  • R 1 is alkyl;
  • R la is hydrogen;
  • R 2 is alkyl, hydroxyalkyl, or alkoxyalkyl;
  • R 3 is -(C 1-3 )-CONH-CHR 5 R 6 where R 5 is hydrogen or alkyl and R 6 is branched (C 4- ⁇ o)alkyl or cycloalkyl;
  • X is -SO 2 -; and
  • R 10 is aryl.
  • n 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, or optionally substituted phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1 -hydroxyethyl, or methylthiomethyl;
  • R 3 is -CH 2 CONHCH 2 C(CH 3 ) 3 or - (CH 2 ) 2 CONHC(CH 3 ) 3 ;
  • X is -SO 2 -; and
  • R 10 is aryl.
  • n 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, 4-dimethylaminophenyl, pyridin-4- yl, furanyl, 4-methylphenyl, 4-trifluoromethylphenyl, or phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl;
  • R 3 is
  • X is -SO 2 -; and R 10 is phenyl optionally substituted with alkyl.
  • n is 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, 4-dimethylaminophenyl, pyridin-4- yl, furanyl, 4-methylphenyl, 4-trifluoromethylphenyl, or phenyl; R 1 is methyl, ethyl,
  • R la is hydrogen
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl
  • R 3 is
  • X is -S0 2 -; and R 10 is 4- methylphenyl, or 3-methylphenyl.
  • n 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with 4- dimethylaminophenyl, pyridin-4-yl, furanyl, 4-methylphenyl, 4- trifluoromethylphenyl, or phenyl;
  • R 1 is 2-methylpropyl;
  • R la is hydrogen;
  • R 2 is methyl;
  • R 3 is -CH 2 CONHCH 2 C(CH 3 ) 3 ;
  • X is -SO 2 -; and
  • R 10 is 4-methylphenyl.
  • R 3 is -(C ⁇ -3 )-Y-(C ⁇ -3 )nl-Ar; X is -SO 2 -; and R 10 is aryl.
  • n 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, or optionally substituted phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl,
  • R 3 is -CH 2 OCH 2 -Ar where Ar is aryl;
  • X is -
  • R 10 is aryl.
  • (k) n is 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, 4-dimethylaminophenyl, pyridin-4- yl, furanyl, 4-methylphenyl, 4-trifluoromethylphenyl, or phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl;
  • R 3 is
  • Ar is aryl optionally substituted with one, two or three groups independently selected from alkyl, halo, alkoxy, or hydroxy;
  • X is -SO 2 -; and
  • R 10 is phenyl optionally substituted with alkyl.
  • n 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with 4-dimethylamino ⁇ henyl, pyridin-4-yl, furan-2-yl, 4-methylphenyl, 4- trifluoromethylphenyl, or phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2- methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R a is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl;
  • R 3 is -CH 2 OCH 2 -Ar where Ar is phenyl optionally substituted with one, two or three groups independently selected from methyl, chloro, fluoro, methoxy, or hydroxy;
  • X is -SO 2 -; and
  • R 10 is 4-methylphenyl, or
  • n 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with 4-dimethylaminophenyl, pyridin-4-yl, furan-2-yl, 4-methylphenyl, 4- trifluoromethylphenyl, or phenyl;
  • R 1 is 1-methylpropyl;
  • R la is hydrogen;
  • R 2 is methyl;
  • R 3 is -CH 2 OCH 2 -Ar where Ar is phenyl optionally substituted with one, two or three groups independently selected from methyl, chloro, fluoro, methoxy, or hydroxy;
  • X is -SO 2 -; and
  • R 10 is 4-methylphenyl, or 3-methylphenyl.
  • R 1 is alkyl
  • R la is hydrogen
  • R 2 is alkyl, hydroxyalkyl, or alkoxyalkyl
  • R 3 is -(C ⁇ -3 )-CONH-CHR 5 R 6 where R 5 is hydrogen or alkyl and R 6 is branched (C 4 . ⁇ o)alkyl or cycloalkyl
  • X is -NR 9 SO 2 - where R 9 is alkyl
  • R 10 is alkyl.
  • (o) n is 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with 4-dimethylaminophenyl, pyridin-4-yl, furan-2-yl, 4-methylphenyl, 4- trifluoromethylphenyl, or phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2- methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl,
  • R 3 is -CH 2 CONHCH 2 C(CH 3 ) 3 or-(CH 2 ) 2 CONH(CH 3 ) 3 ,
  • X is - NR 9 SO 2 - where R 9 is alkyl; and R 10 is alkyl.
  • (p) n is 0, R
  • R 3 is -(C ⁇ -3 )-Y-(C ⁇ -3 )nl-Ar where Ar is aryl, X is -NR 9 SO 2 - where R 9 is alkyl; and
  • R 10 is alkyl
  • n 0, Het is l,3,4-oxadiazol-2-yl which is substituted at the 5-position with 4-dimethylaminophenyl, pyridin-4-yl, furan-2-yl, 4-methylphenyl, 4- trifluoromethylphenyl, or phenyl;
  • R 1 is methyl, ethyl, 1-methylpropyl, 2- methylpropyl, 2,2-dimethylpropyl, or benzyl;
  • R la is hydrogen;
  • R 2 is methyl, ethyl, methoxymethyl, tert-butoxymethyl, hydroxymethyl, 1-hydroxyethyl, or methylthiomethyl,
  • R 3 is -CH 2 OCH 2 -Ar where Ar is aryl optionally substituted with one, two or three groups independently selected from alkyl, halo, alkoxy, or hydroxy,
  • X is -NR 9 SO 2 - where R 9 is alkyl; and R 10 is alkyl.
  • R 1 is alkyl
  • R la is hydrogen
  • R 2 is alkyl, hydroxyalkyl, or alkoxyalkyl
  • R 3 is -(C ⁇ -3 )-CONH-CHR 5 R 6 where R 5 is hydrogen or alkyl and R 6 is branched (C 4- ⁇ o)alkyl or cycloalkyl; X is -OC(O)-; and R 10 is alkyl.
  • R 5 is hydrogen or alkyl and R 6 is branched (C 4- ⁇ o)alkyl or cycloalkyl; X is -OC(O)-; and R 10 is alkyl.
  • R 4 is alkyl or haloalkyl and other groups are as defined in compounds of Formula II above.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C and most preferably at about room (or ambient) temperature, e.g., about 20 ° C.
  • a compound of Formula I where n is 0 and other groups are as defined in the Summary of the Invention can be prepared by the procedure illustrated and described in Scheme A below.
  • the reaction is carried out by first preparing the Grignard reagent by treating the heteroaryl with /j-butyllithium at approximately -78 °C in an ethereal solvent such as tetrahydrofuran, and the like, followed by treatment of the resulting lithiated compound with magnesium bromide diethyl etherate and then reacting the resulting Grignard reagent with the alpha amino aldehyde.
  • the aldehyde of formula 1 is prepared by the synthetic procedure described in Falkiewicz, B., et al, Nucleosides and Nucleotides, 20, 1393, 2001.
  • Deprotection of the amino group in 3 provides the alpha amino alcohol compound of formula 4.
  • the reaction conditions employed for the removal of the amino protecting group depend on the nature of the amino protecting group. For example, removal of the tert-butoxycarbonyl group can be carried out using a strong acid such as trifluoroacetic acid or hydrochloric acid with or without the presence of a cosolvent such as dichloromethane, methanol, and the like.
  • Benzyloxycarbonyl group can be removed by a number of methods including, catalytic hydrogenation with hydrogen in the presence of a palladium or platinum catalyst in a protic solvent such as methanol, ethanol, and the like.
  • Other suitable reaction conditions for their removal can be found in T.W.
  • reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, dimethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, and the like.
  • halogenated organic solvents e.g., methylene chloride, chloroform, and the like
  • acetonitrile e.g., acetonitrile
  • dimethylformamide ethereal solvents
  • ethereal solvents such as tetrahydrofuran, dioxane, and the like.
  • Oxidation of the hydroxy group in 9 then provides a compound of Formula I.
  • the reaction is carried out at room temperature.
  • Suitable solvents are halogenated organic solvent such as methylene chloride, chloroform, carbon tetrachloride, and the like.
  • Suitable oxidizing agent are Dess-Martin Periodinane (DMP) (supplier Lancaster), and the like.
  • the compounds of the invention are inhibitors of proteasome and hence are useful in the treatment of diseases mediated by the proteolytic function of the proteasome.
  • the compounds of the invention are useful in treating cancer such as multiple myeloma, leukemia, colorectal, prostate, breast and lung cancers, allergic disorders, including, but not limited to asthma; allogeneic immune reponses, including, but not limited to, organ transplants or tissue grafts, autoimmune disorders, including, but not limited to multiple sclerosis, inflammatory diseases, and septic shock.
  • proteasome inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Details of assays for measuring proteasome inhibitory activity in vitro, are set forth in Biological Examples 1 and 2, infra.
  • compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight ( ⁇ g/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 1 ⁇ g/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 8 ⁇ g/day to 800 mg/day.
  • a therapeutically effective amount of a compound of Formula I for treating a given disease.
  • compositions can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like.
  • Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, or the like).
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • a composition of a compound of Formula I for treating a given disease will comprise from 0.0 l%w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients.
  • the pharmaceutical compositions are administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
  • the compounds of this invention can be administered in combination with known anti-cancer agents.
  • known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • the compound of the present invention compounds are particularly useful when administered in combination with radiation therapy.
  • Preferred angiogenesis inhibitors are selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl- carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF.
  • a tyrosine kinase inhibitor an inhibitor of epidermal-derived growth factor
  • an inhibitor of fibroblast-derived growth factor an inhibitor of platelet derived growth factor
  • MMP matrix metalloprotease
  • an integrin blocker interferon-
  • estrogen receptor modulators are tamoxifen and raloxifene.
  • Estrogen receptor modulators refers to compounds that interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2- dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(l-piperidinyl)ethoxy]phenyl]-2H-l- benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone- 2,4-dinitrophenyl-hydrazone, and SH646.
  • Androgen receptor modulators refers to compounds, which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5 ⁇ - reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds, which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylomithine, ILX23-7553, trans-N-(4'- hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Cytotoxic agents refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu- (hexane- 1 ,6-d
  • microtubulin inhibitors include paclitaxel, vindesine sulfate, 3 ' ,4 ' -didehydro-4 ' -deoxy- 8 ' -norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881 ,
  • BMS184476 vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4- methoxyphenyl)benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl- L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, and BMS188797.
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, 9- methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, 1- amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- 1 H, 12H- benzo[de]pyrano[3 ' ,4 ' :b,7]-indolizino[ 1 ,2b]quinoline- 10, 13 (9H, 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin, BNP1350,
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carrnofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabme, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)-sulfonyl]- N'-(3,4-dichlorophenyl
  • Antiproliferative agents also includes monoclonal antibodies to growth factors, other than those listed under “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example).
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col.
  • HMG-CoA reductase inhibitor and “inhibitor of HMG-CoA reductase” have the same meaning when used herein. It has been reported that (Int. J. Cancer, 20;97(6):746-50, 2002) combination therapy with lovastatin, a HMG-CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis lung carcinoma model in mice showed potentiating antitumor effects
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEVACOR ® ; see U.S. Pat. Nos. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR ® ; see U.S. Pat. Nos. 4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL ® ; see U.S. Pat. Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589), fluvastatin
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and Dolchicin the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • HMG-CoA reductase inhibitors where an open-acid form can exist
  • salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein.
  • the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin.
  • the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyrrolidine-l '-yl- methylbenzimidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
  • a suitable organic or inorganic base particularly those formed from
  • salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamao
  • Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibiting compounds examples include (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5- yl)methyl] -4-(3 -chlorophenyl)- 1 -methyl-2( 1 H)-quinolinone, (-)-6- [amino(4- chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chloro phenyl)-l-methyl- 2(lH)-quinolinone, (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5- yl)methyl]-4-(3-chloro phenyl)- l-methyl-2(lH)-quinolinone, 5(S)-n-butyl-l-(2,3- dimethylphenyl)-4-[ 1 -(4-cyanobenzyl)
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0675 112, European Patent Publ. 0 604 181, European Patent Publ.
  • HIV protease inhibitors examples include amprenavir, abacavir, CGP- 73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632.
  • reverse transcriptase inhibitors examples include delaviridine, efavirenz, GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl. It has been reported (Nat. Med.;8(3):225-32, 2002) that HIV protease inhibitors, such as indinavir or saquinavir, have potent anti-angiogenic activities and promote regression of Kaposi sarcoma
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR20), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-oc, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NS AIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib, valdecoxib, and rofecoxib (PNAS, Vol.
  • tyrosine kinase inhibitors such as inhibitor
  • NS AID 's which are potent COX-2 inhibiting agents.
  • an NSAID is potent if it possess an IC 50 for the inhibition of COX-2 of 1 ⁇ M or less as measured by the cell or microsomal assay known in the art.
  • NSAID 's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of ICs 0 for COX-2 over IC 50 for COX-1 evaluated by the cell or microsomal assay disclosed herein under.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2- butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6 -yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-methyl]- lH-l,2,3-triazo le-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentose phosphate, 7,7-(carbonyl-bis[imino-N-methyl- 4,2-pyrrolocarbonyl-imino [N-methyl-4,2-pyrrole] -carbonylimino] -
  • integrated circuit blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counter-act binding of a physiological ligand to the cc v ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ v ⁇ 3 integrin and the ⁇ v ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ v ⁇ 6; ⁇ v ⁇ 8 , i ⁇ i, ⁇ 2 ⁇ , ⁇ , 5 ⁇ , ⁇ 6 ⁇ and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3 , ⁇ v ⁇ s, ⁇ v ⁇ 6 , o. v ⁇ 8 , i ⁇ i, ⁇ ⁇ , s ⁇ ⁇ , ⁇ 6 ⁇ and ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N- (trifluoromethyl-phenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4- dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-(allylamino)- 17- demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4- mo holinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,1 l,12-hexahydro-10- (hydroxymethyl)- 10-hydroxy-9-methyl-9, 12-epoxy -1 H-diindolo [1,2,3- fg:3',2',l'-kl]pyrrolo[3,
  • the instant compounds are also useful, alone or in combination with platelet fibrinogen receptor (GP Ilb/IIIa) antagonists, such as tirofiban, to inhibit metastasis of cancerous cells.
  • Tumor cells can activate platelets largely via thrombin generation. This activation is associated with the release of VEGF.
  • the release of VEGF enhances metastasis by increasing extravasation at points of adhesion to vascular endothelium (Amirl hosravi, Platelets 10, 285-292, 1999). Therefore, the present compounds can serve to inhibit metastasis, alone or in combination with GP Ilb/IIIa) antagonists.
  • fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352.
  • such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range.
  • administration and variants thereof in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents .
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the farnesyl-protein transferase inhibitors disclosed in US Patent 6,313,138 and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
  • antineoplastic agent examples include, in general, microtubule- stabilizing agents (such as paclitaxel (also known as Taxol ® ), docetaxel (also known as Taxotere ® epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule-disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti- hormonal therapeutic agents and haematopoietic growth factors.
  • microtubule- stabilizing agents such as paclitaxel (also known as Taxol ® ), docetaxel (also known as Taxotere ® epothilone A, epothilone B, desoxyepothilone A, desoxye
  • Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins.
  • Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, Herceptin ® , Rituxan ® , 5-fluorouracil, 6- mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phyllotoxin derivatives such as colchicines, etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.
  • antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • the preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
  • Radiation therapy including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the compounds of this invention alone to treat cancer.
  • N- ⁇ -Boc-O-methyl-L-serine (2.19g, 10.0 mmol), HOBt (1.62g, 12.0 mmol), l-ethyl-3-(3'-dimethylamino-propyl)carbodiimide hydrochloride (EDC, 2.01g, 10.5 mmol), and N-methylmorpholine (1.4 mL, 12.5 mmol) were stirred in 150 mL anhydrous dichloromethane.
  • Step 8 (l- ⁇ l-[Hydroxy-(5-phenyl-[l,3,4]oxadiazol-2-yl)methyl]-3- methylbutylcarbamoyl ⁇ -2-methoxyethyl)carbamic acid tert-butyl ester (3.55g, 7.68 mmol) was dissolved in 4. ON HC1 (36 mL, 144 mmol) in 1,4-dioxane and stirred at ambient temperature. After 97 min, the volatiles were removed by rotary evaporation and the residue was triturated with diethyl ether (15 mL).
  • N-(2,2-Dimethylpropyl)-2-(toluene-4-sulfonylamino)succinamic acid (2.68g, 7.52 mmol) and hydroxybenzotriazole (HOBt, 3.00g, 7.52 mmol) were stirred at ambient temperature in dichloromethane (130 mL) .
  • 1 -Ethyl-3 -(3 ' -dimethylamino- propyl)carbodiimide hydrochloride (EDC, 1.51g, 7.90 mmol) and ⁇ - methylmorpholine (1.65g, 15.0 mmol) were added.
  • N-4-(2,2-Dimethylpropyl)-Nl-(l- ⁇ l-[hydroxy-(5-phenyl-[l,3,4]oxadiazol-2- yl)-methyl]-3-methylbutylcarbamoyl ⁇ -2-methoxyethyl)-2-(toluene-4- sulfonylamino)succinamide (2.20g, 3.14 mmol) was dissolved in 50 mL water- saturated dichloromethane and was vigorously stirred at ambient temperature under an atmosphere of nitrogen. Dess Martin periodinane (2.00g, 4.71 mmol) was added in one portion and stirring was continued.
  • the reaction was quenched by the addition of 1.0 N HC1 (150 mL) and transfe ⁇ ed to a separatory funnel.
  • the turbid solution was extracted three times, each with 20 mL of ethyl acetate.
  • the total volume of ethyl acetate was washed once with 1.0 N HC1 (10 mL) and once with brine (10 mL).
  • the organic solution was dried over magnesium sulfate and filtered over sintered glass. The filtrate was concentrated in vacuo.
  • Analytical LCMS of the residual syrup indicated the presence of 2-tert- butoxycarbonylamino-3-(2-methyl-benzyloxy)propionic acid in 60% yield.
  • the crude material was used as is.
  • Step 2 2-tert-Butoxycarbonylamino-3-(2-methylbenzyloxy)propionic acid was mixed with 4.0 N HC1 (20 mL) in dioxane with vigorous agitation. The solution was stirred for 20 minutes after which time LCMS indicated the reaction was complete. The solution was concentrated in vacuo to give 2-amino-3-(2-methylbenzyloxy)propionic acid hydrochloride which was used without purification.
  • Step 3 The thick syrup described above was taken up with vigorous stirring in 20 mL tetrahydrofuran (20 mL) and water (40 mL). Pellets of sodium hydroxide (1.2 g, 30 mmol) were added to the clear, colorless solution with vigorous stirring.
  • p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was added batchwise over thirty minutes with continued stirring. More tetrahydrofuran was added as needed to maintain a homogeneous solution. NaOH pellets were added one at a time to keep the pH 9 or higher. After stirring for two hours, the reaction was quenched by the addition of 4.0 N HCl(aq) (200 mL). The reaction mixture was transferred to a separatory funnel. The turbid solution was extracted three times, each with 30 mL of ethyl acetate.
  • Step l Carbobenzyloxy-L-isoleucine succinate ester (2.17 g, 6.0 mmol), L-glutamic acid ⁇ -t-butyl ester (1.22 g, 6.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) were stirred at ambient temperature in a mixture of THF (98 mL) and water (9 mL) for 16 hr. The reaction mixture was poured into 0.2N aqueous HC1 (200 mL) and extracted twice with dichloromethane. The combined organic phase was washed with water and brine, then dried over anhydrous magnesium sulfate.
  • Step 2 2-(2-Benzyloxycarbonylamino-3-methylpentanoylamino)pentanedioic acid 5- tert-butyl ester (1.73 g, 3.84 mmol) and N-hydroxysuccinimide (442 mg, 3.84 mmol) were dissolved in dry THF (30 mL). Dicyclohexylcarbodiimide (792 mg, 3.84 mmol) was added at ambient temperature. After 30 min., the reaction mixture was cooled to 0-5 °C and left for 14 hr. The precipitate was filtered and rinsed with 5 ml THF. The combined filtrate was rotary evaporated and the resulting sticky white foam was triturated with diethyl ether.
  • 5-tert-butyl ester 5-(2,5-dioxopyrrolidin-l-yl) ester (2.01g, 3.67 mmol) was dissolved in THF (40 L) at ambient temperature. Triethylamine (0.51 mL, 7.34 mmol) was added. A suspension of L-alanine (327 mg, 3.67 mmol) in 50% aqueous THF (10 mL) was then added with stirring. The pH of the reaction mixture was adjusted to 8 by occasional addition of more triethylamine. The reaction mixture was stirred at ambient temperature for 14.5 hr, then poured into 200 mL 0.2N aqueous HC1. The product was extracted twice with 100 mL portions of dichloromethane.
  • the efficacy of the compounds of this invention was evaluated by dete ⁇ nining their effect on human tumor cell proliferation. Then, a cell-associated p21 accumulation assay was carried out to demonstrate that the effects on cell proliferation were mediated by the inhibition of the 26S proteasome.
  • a. Cell proliferation assay The effects of the compounds of this invention on human tumor cell proliferation were monitored in an alamar BlueTM fluorometric assay as described by de Fries and Mitsuhashi (see., "Quantification of mitrogen induced lymphocyte proliferation: comparison of alamar BlueTM assay to 3 H-thymidine incorporation assay" J. Clin. Invest., 9:89-95).
  • cells were cultured in 24-well plates to 80% confluence. Media was changed and replaced with media containing increasing concentrations of the compounds of the invention and the cells were cultured in the presence of compound for 16 hr. At the end of the 16 hr incubation period, cells were washed with PBS, lysed with lysis buffer (IX SDS- PAGE/BME) and boiled for 5 min. Samples were electrophoresed through 12% Tris- glycine SDS-PAGE gels (NO VEX). Proteins in the gel were transferred to nitrocellulose membranes and probed with mouse monoclonal antibodies against p21 (Pharmingen).
  • the blots were washed and incubated with a peroxidase-conjugated aff ipure donkey anti-mouse secondary antibody (Jackson ImmunoResearch Laboratories, Inc., PA). Antigen-antibody complexes were visualized by chemiluminescence with the Pierce SuperSignal West Pico Kit (Rockford, IL) and imaged by autoradiography. Compounds of the invention tested by the above- described assay demonstrated that the effects on cell proliferation were mediated by the inhibition of the 26S proteasome.
  • the following ingredients are mixed to form a suspension for oral administration.
  • Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
  • Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml Injectable Formulation
  • Ingredient Amount compound of this invention 1.2 g sodium acetate buffer solution, 0.4 M 2.0 ml
  • Suppository Formulation A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol ® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg Witepsol ® H- 15 balance

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Abstract

L'invention concerne des composés qui sont des inhibiteurs du protéasome, une composition pharmaceutique comprenant lesdits composés et des méthodes de traitement des maladies médiées par une activité du protéasome non régulée. D'une manière plus spécifique, l'invention concerne des dérivés peptidiques représentés par la formule (I), dans laquelle Het représente un noyau hétéroaryle et R3 représente (C1-3)-CONH-CHR6R7, où R6 représente hydrogène ou alkyle et R7 représente (C4-10)alkyle ou cycloalkyle), (C1-3)-COOR8, où R8 représente (C4-10)alkyle ou cycloalkyle), ou (C1-3)-Y-(C1-3)-n1, Ar, où Y représente O-,-NH- ou S(O)n2-, où n2 vaut de 0 à 2, n1 vaut 0 ou 1 et Ar représente aryle. Ces dérivés peptidiques inhibent les protéasomes 205 et/ou 265.
PCT/US2003/024960 2002-08-09 2003-08-08 Inhibiteurs du proteasome : derives peptidiques comprenant des groupes heteroaryle c-terminaux Ceased WO2004014882A2 (fr)

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EP1637529A1 (fr) * 2004-09-20 2006-03-22 4Sc Ag Nouveaux analogues de piperidin-4-yl-thiazole-carboxamide en tant qu'inhibiteurs de proliferation de lymphocytes T er leurs utilisations
WO2006032322A1 (fr) * 2004-09-20 2006-03-30 4Sc Ag NOUVEAUX INHIBITEURS HÉTÉROCYCLIQUES DU NF-κB
US7531517B2 (en) 2005-08-10 2009-05-12 4Sc Ag Inhibitors of cancer cell, T-cell and keratinocyte proliferation
EP2088205A1 (fr) 2008-02-11 2009-08-12 Institut National De La Sante Et De La Recherche Medicale (Inserm) PSMB10 : marqueur de diagnostic et cible thérapeutique de rejet chronique
US7601745B2 (en) 2004-09-27 2009-10-13 4Sc Ag Heterocyclic NF-kB inhibitors
EP2284179A2 (fr) 2005-08-10 2011-02-16 4Sc Ag Inhibiteurs de la proliferation de céllules cancéreuses, de céllules T, et de kératinocytes
US9126997B1 (en) 2010-09-07 2015-09-08 Northwestern University Synergistic effect of glucocorticoid receptor agonists in combination with proteosome inhibitors for treating leukemia and myeloma

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ADAMS JULIAN ET AL: "Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, 1998, pages 333-338, XP002209920 ISSN: 0960-894X *
BASS KATHRYN E ET AL: "Differential response of endothelial cells to proteasome inhibitors" PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL, vol. 43, March 2002 (2002-03), page 24, XP001156474 93rd Annual Meeting of the American Association for Cancer Research;San Francisco, California, USA; April 06-10, 2002, March, 2002 ISSN: 0197-016X *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101987847A (zh) * 2004-09-20 2011-03-23 4Sc股份有限公司 新型杂环NF-κB抑制剂
EP2343293A1 (fr) * 2004-09-20 2011-07-13 4Sc Ag Nouveaux analogues de piperidin-4-yl-thiazole-carboxamide en tant qu'inhibiteurs de proliferation de lymphocytes t et leurs utilisations
CN101031567B (zh) * 2004-09-20 2011-12-21 4Sc股份有限公司 新型杂环NF-κB抑制剂
US7812041B2 (en) 2004-09-20 2010-10-12 4Sc Ag Heterocyclic NF-κB inhibitors
EP1637529A1 (fr) * 2004-09-20 2006-03-22 4Sc Ag Nouveaux analogues de piperidin-4-yl-thiazole-carboxamide en tant qu'inhibiteurs de proliferation de lymphocytes T er leurs utilisations
EA012607B1 (ru) * 2004-09-20 2009-10-30 4Сц Аг НОВЫЕ ГЕТЕРОЦИКЛИЧЕСКИЕ ИНГИБИТОРЫ NF-κB
WO2006032322A1 (fr) * 2004-09-20 2006-03-30 4Sc Ag NOUVEAUX INHIBITEURS HÉTÉROCYCLIQUES DU NF-κB
US8106048B2 (en) 2004-09-20 2012-01-31 4Sc Ag Heterocyclic NF-κB inhibitors
US7601745B2 (en) 2004-09-27 2009-10-13 4Sc Ag Heterocyclic NF-kB inhibitors
EP2284178A2 (fr) 2005-08-10 2011-02-16 4Sc Ag Inhibiteurs de la proliferation de céllules cancéreuses, de céllules T, et de kératinocytes
US7531517B2 (en) 2005-08-10 2009-05-12 4Sc Ag Inhibitors of cancer cell, T-cell and keratinocyte proliferation
EP2284179A2 (fr) 2005-08-10 2011-02-16 4Sc Ag Inhibiteurs de la proliferation de céllules cancéreuses, de céllules T, et de kératinocytes
EP2088205A1 (fr) 2008-02-11 2009-08-12 Institut National De La Sante Et De La Recherche Medicale (Inserm) PSMB10 : marqueur de diagnostic et cible thérapeutique de rejet chronique
US9126997B1 (en) 2010-09-07 2015-09-08 Northwestern University Synergistic effect of glucocorticoid receptor agonists in combination with proteosome inhibitors for treating leukemia and myeloma

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