WO1996013266A1 - Boronic ester and acid compounds, synthesis and uses - Google Patents
Boronic ester and acid compounds, synthesis and uses Download PDFInfo
- Publication number
- WO1996013266A1 WO1996013266A1 PCT/US1995/014117 US9514117W WO9613266A1 WO 1996013266 A1 WO1996013266 A1 WO 1996013266A1 US 9514117 W US9514117 W US 9514117W WO 9613266 A1 WO9613266 A1 WO 9613266A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- compound
- aralkyl
- independently
- Prior art date
Links
- 0 CC(C)CC(C(N[C@](*)CC(C)C)=O)NC([C@@](C1)(C1C(C)C)NC(OCc1ccccc1)=O)=O Chemical compound CC(C)CC(C(N[C@](*)CC(C)C)=O)NC([C@@](C1)(C1C(C)C)NC(OCc1ccccc1)=O)=O 0.000 description 2
Classifications
-
- 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
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-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
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- 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
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- 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 relates to boronic ester and acid compounds, their synthesis and uses.
- Kettner et ⁇ l. J. Biol. Chem. 259(24):15106-15114 (1984)).
- These compounds have been shown to be inhibitors of certain proteolytic enzymes (Shenvi et ⁇ l. USPN 4,499,082 issued February 12, 1985; Shenvi et ⁇ l. USPN 4,537,773; Siman et ⁇ l. WO 91/13904 published September 19, 1991; Kettner et al, J. Biol. Chem. 259(24):15106-151 14 (1984)).
- a class of N-terminal tri-peptide boronic ester and acid compounds has been shown to inhibit the growth of cancer cells (Kinder et ⁇ l.
- conjugated proteins are hydrolyzed by a 26S proteolytic complex containing a 20S degradative particle called the proteasome (Goldberg, Eur. J. Biochem. 203:9-23 (1992); Goldberg et al, Nature 357:375-379 (1992)).
- This multicomponent system is known to catalyze the selective degradation of highly abnormal proteins and short-lived regulatory proteins.
- the 20S proteasome is composed of about 15 distinct 20-30 kDa subunits.
- NF- ⁇ B The transcription factor NF- ⁇ B and other members of the rel family of protein complexes play a central role in the regulation of a remarkably diverse set of genes involved in the immune and inflammatory responses (Grilli et ⁇ l, International Review of Cytology 143:1-62 (1993)).
- NF- ⁇ B exists in an inactive form in the cytoplasm complexed with an inhibitor protein, I ⁇ B.
- I ⁇ B an inhibitor protein
- NF- ⁇ B is essential for the expression of the human immunodeficiency virus (HIV). Accordingly, a process that would prevent the activation of the NF- ⁇ B in patients suffering from such diseases could be therapeutically beneficial.
- proteasome inhibitors to inhibit MHC-I antigen presentation.
- the ubiquitination/proteolysis pathway is shown to be involved in the processing of internalized cellular or viral antigens into antigenic peptides that bind to MHC-I molecules on an antigen presenting cell. Accordingly, inhibitors of this pathway would be useful for the treatment of diseases that result from undesired response to antigen presentation, including autoimmune diseases and transplant rejection.
- Cyclins are proteins that are involved in cell cycle control in eukaryotes. Cyclins presumably act by regulating the activity of protein kinases, and their programmed degradation at specific stages of the cell cycle is required for the transition from one stage to the next.
- Experiments utilizing modified ubiquitin (Glotzer et al, Nature 349:132-138 (1991); Hershko et al, J. Biol. Chem. 266:376 (1991)) have established that the ubiquitination/proteolysis pathway is involved in cyclin degradation. Accordingly, compounds that inhibit this pathway would cause cell cycle arrest and would be useful in the treatment of cancer, psoriasis, restenosis, and other cell proliferative diseases.
- the present invention provides previously unknown peptidyl boronic acid ester and acid compounds.
- the present invention also provides methods of using amino acid or peptidyl boronic ester and acid compounds, in general, as inhibitors of proteasome function.
- the present invention provides novel boronic acid and ester compounds having formula (1a) or (2a), as set forth below.
- An additional aspect of the present invention is related to the discovery that amino acid and peptidyl boronic acids and esters, in general, are potent and highly selective proteasome inhibitors and can be employed to inhibit proteasome function. Inhibition of proteasome function has a number of practical therapeutic and prophylactic applications.
- the present invention provides a method for reducing the rate of muscle protein degradation in a cell comprising contacting said cell with a proteasome inhibitor having formula (1b) or (2b) as defined below.
- This aspect of the present invention finds practical utility in inhibiting (reducing or preventing) the accelerated breakdown of muscle proteins that accompanies various physiological and pathological states and is responsible to a large extent for the loss of muscle mass (atrophy) that follows nerve injury, fasting, fever, acidosis, and certain endocrinopathies.
- the present invention provides a method for reducing the activity of NF- ⁇ B in a cell comprising contacting the cell with a proteasome inhibitor of the formula (1b) or (2b), as set forth below.
- inhibitors employed in the practice of the present invention are capable of preventing this activation.
- blocking NF- ⁇ B activity is contemplated as possessing important practical application in various areas of medicine, e.g., inflammation, sepsis, AIDS, and the like.
- the present invention provides a method of reducing the rate of degradation of p53 protein in a cell comprising administering to the cell a proteasome inhibitor of the formula (1b) or (2b), as set forth below.
- the present invention provides a method for inhibiting cyclin degradation in a cell comprising contacting said cells with a proteasome inhibitor of the formula (1b) or (2b), as set forth below.
- Inhibiting cyclin degradation is contemplated as possessing important practical application in treating cell proliferative diseases, such as cancer, restenosis and psoriasis.
- the present invention provides a method for inhibiting the growth of a cancer cell, comprising contacting said cell with a proteasome inhibitor of the formula (1a) or (2a), as set forth below.
- the present invention provides a method for inhibiting antigen presentation in a cell comprising administering to the cell a proteasome inhibitor of the formula (1b) or (2b), as set forth below.
- the present invention provides a method for inhibiting inducible NF- ⁇ B dependent cell adhesion in an animal comprising administering to said animal a proteasome inhibitor of the formula (1b) or (2b), as set forth below.
- the present invention provides a method for inhibiting HIV replication in an animal comprising administering to said animal a proteasome inhibitor of the formula (1b) or (2b), as set forth below.
- the present invention provides an approach for inhibiting cytolytic immune responses.
- the proteasome inhibitors of formula (1b) or (2b) can be used to inhibit the processing of internalized cellular or viral antigens into antigenic peptides that bind to MHC-I molecules in an animal, and are therefore useful for treating autoimmune diseases and preventing rejection of foreign tissues, such as transplanted organs or grafts.
- the present invention provides pharmaceutical compositions that comprise compounds of formula (1a), (1b), (2a) or (2b) in an amount effective to inhibit proteasome function in a mammal, and a pharmaceutically acceptable carrier or diluent.
- Figure 2. NF- ⁇ B binding activity.
- Figure 3. Inhibition by MG-273.
- a first aspect of the present invention is directed to novel subsets of boronic acid and ester compounds having formula (1a) or (2a) below.
- Novel compounds of formula (1a) include the following:
- P is hydrogen or an amino-group-protecting moiety as further defined herein;
- B 1 at each occurrence, is independently one of N or CH;
- X 2 is one of -C(O)-NH-, -CH(OH)-CH 2 - -CH(OH)-CH(OH)-,
- R is hydrogen or alkyl, or R forms together with the adjacent R 1 , or when
- A is zero, forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
- R 1 at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -CH 2 -R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
- R 2 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -CH 2 -R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
- R 3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -CH 2 -R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
- R 5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -W-R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
- Z 1 and Z 2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N. S, or O; and A is 0, 1, or 2.
- novel boronic acid and ester derivatives include compounds having a single amino acid side-chain. These compounds have the following formula:
- Y is one of R 8 -C(O)-, R 8 -SO 2 -, R 8 -NH-C(O)- or R 8 -O-C(O)-, where
- R 8 is one of alkyl, aryl, alkaryl, aralkyl, any of which can be optionally substituted, or when Y is R 8 -C(O)- or R 8 -SO 2 -, then R 8 can also be an optionally substituted 5-10 membered, saturated, partially unsaturated or aromatic heterocycle;
- X 3 is a covalent bond or -C(O)-CH 2 -;
- R 3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -CH 2 -R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
- R 5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -W-R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; and
- Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form a moiety derived from dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O;
- R 8 is other than phenyl, benzyl or C 1 - C 3 alkyl.
- P is one of R 7 -C(O)-, R 7 -SO 2 -, R 7 -NH-C(O)- or R 7 -O-C(O)-;
- R 7 is one of alkyl, aryl, alkaryl, aralkyl, any of which can be optionally substituted, or when Y is R 7 -C(O)- or R 7 -SO 2 -, R 7 can also be an optionally substituted 5-10 membered saturated, partially unsaturated or aromatic heterocycle; and
- R 1 is defined above as for formula (1a).
- compositions that comprise compounds of formula (1a) or (2a) in an amount effective to inhibit proteasome function in a mammal, and a pharmaceutically acceptable carrier or diluent are within the scope of the present invention.
- a second aspect of the present invention lies in the discovery that boronic acid and ester derivatives of amino acids and peptides, in general, as well as isosteric variations thereof, inhibit proteasome function.
- the present invention also relates to the use of proteasome inhibitors having formula (1 b) or
- proteasome inhibitors having formula (1b) or (2b) for treating specific conditions in animals that are mediated or exacerbated, directly or indirectly, by proteasome functions.
- These conditions include inflammatory conditions, such as tissue rejection, organ rejection, arthritis, infection, dermatoses, inflammatory bowel disease, asthma, osteoporosis, osteoarthritis and autoimmune disease such as lupus and multiple sclerosis: cell proliferative diseases, such as cancer, psoriasis and restenosis; and accelerated muscle protein breakdown that accompanies various physiological and pathological states and is responsible to a large extent for the loss of muscle mass (atrophy) that follows nerve injury, fasting, fever, acidosis, and certain endocrinopathies.
- inflammatory conditions such as tissue rejection, organ rejection, arthritis, infection, dermatoses, inflammatory bowel disease, asthma, osteoporosis, osteoarthritis and autoimmune disease such as lupus and multiple sclerosis
- cell proliferative diseases such as cancer, psoria
- Proteasome inhibitors of formula (1b) include: i
- P 10 is hydrogen or an amino-group-protecting moiety
- B 11 is independently one of N or CH
- X 12 is one of -C(O)-NH- -CH(OH)-CH 2 -, -CH(OH)-CH(OH)-, -C(O)-CH 2 -, -SO 2 -NH- -SO 2 -CH 2 - or -CH(OH)-CH 2 -C(O)-NH-;
- R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
- R n at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -CH 2 -R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycl e can be optionally substituted;
- R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5- 10 membered saturated, partially unsaturated or aromatic heterocycle or
- ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted
- R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted
- Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and
- Z 12 together form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
- a 10 is 0, 1, or 2
- Proteasome inhibitors of formula (2b) include:
- Y 10 is one of R 8 -C(O)-, R 8 -SO 2 - R 8 -NH-C(O)- or R 8 -O-C(O)-, where
- R 8 is one of alkyl, aryl, alkaryl, aralkyl, any of which can be optionally substituted, or when Y is R 8 -C(O)- or R 8 -SO 2 -, then R 8 can also be an optionally substituted 5-10 membered, saturated, partially unsaturated or aromatic heterocycle;
- X 13 is a covalent bond or -C(O)-CH 2 -;
- R 13 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or-CH 2 -R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
- R 15 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or -W-R 16 , where W is a chalcogen and R 16 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; and
- Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy. or together form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O.
- P is one of R 7 -C(OX, R 7 -SO 2 -, R 7 -NH-C(O)- or R 7 -O-C(O)-;
- R 7 is one of alkyl, aryl, alkaryl, aralkyl, any of which can be optionally substituted, or when Y is R 7 -C(O)- or R 7 -SO 2 -, R 7 can also be an optionally substituted 5-10 membered saturated, partially unsaturated or aromatic heterocycle; and
- R 1 is as defined for formula (1a) above.
- Preferred embodiments of the aforementioned methods of use employ compounds of formula (1a) and formula (2a) as defined above.
- compositions comprising an effective amount of the proteasome inhibitors of formula (2a) or (2b), in combination with any conventional pharmaceutically acceptable carrier or diluent, are included in the present invention.
- amino-group-protecting moiety refers to terminal amino protecting groups that are typically employed in organic synthesis, especially peptide synthesis. Any of the known categories of protecting groups can be employed, including acyl protecting groups, such as acetyl, and benzoyl; aromatic urethane protecting groups, such as benzyloxycarbonyl; and aliphatic urethane protecting groups, such as tert-butoxycarbonyl. See, for example, The Peptides, Gross and Mienhoffer, eds., Academic Press, New York (1981), Vol. 3, pp. 3-88; and Green, T.W. & Wuts,
- Preferred protecting groups include aryl-, aralkyl-, heteroaryl- and heteroarylalkyl- carbonyl and sulfonyl moieties.
- heterocycle is intended to mean a stable 5- to 7- membered monocyclic or 7- to 10-membered bicyclic heterocyclic moieties that are either saturated or unsaturated, and which consist of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms can optionally be oxidized, the nitrogen can optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable formula.
- heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
- heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thi
- substituted means that one or more hydrogens of the designated moiety are replaced with a selection from the indicated group, provided that no atom's normal valency is exceeded, and that the substitution results in a stable compound.
- 2 hydrogens attached to an atom of the moiety are replaced.
- stable compound or “stable formula” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
- heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4
- substituted heteroaryl or “optionally substituted heteroaryl,” used in reference to R 1 , refer to heteroaryl groups, as defined above, having one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, carboxy, amino, C 1-6 alkylamino and/or di(C 1-6 )alkylamino.
- aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
- substituted aryl as employed herein includes aryl groups, as defined above, that include one or two substituents on either the phenyl or naphthyl group selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl,
- alkyl as employed herein includes both straight and branched chain radicals of up to 12 carbons, preferably 1-8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
- substituted alkyl as employed herein includes alkyl groups as defined above that have one, two or three halo substituents, or one C 1-6 alkyl(C 6-10 )aryl, halo(C 6-10 )aryl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, hydroxy and/or carboxy.
- cycloalkyl as employed herein includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups can be substituted with substituents such as halogen, C 1-6 alkyl, alkoxy and/or hydroxy group.
- aralkyl or "arylalkyl” as used herein by itself or as part of another group refers to C 1-6 alkyl groups as discussed above having an aryl substituent, such as benzyl.
- halogen or "halo” as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
- the pharmaceutically acceptable acid and base addition salts those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred.
- Basic salts are formed by mixing a solution of a boronic acid (Z 1 and Z 2 are both OH) of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or an amino compound, such as choline hydroxide, Tris, bis-Tris, N-methylglucamine or arginine. Water-soluble salts are preferable.
- suitable salts include: alkaline metal salts (sodium, potassium etc.), alkaline earth metal salts (magnesium, calcium etc.), ammonium salts and salts of pharmaceutically acceptable amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine and N-methyl-D-glucamine).
- alkaline metal salts sodium, potassium etc.
- alkaline earth metal salts magnesium, calcium etc.
- ammonium salts and salts of pharmaceutically acceptable amines tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine
- the acid addition salts are obtained either by reaction of an organic base of formula (1a) or (2a) with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art.
- useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalide acids such as HCl, HBr, HI; sulfuric acid; phosphoric acid and the like.
- Preferred acids for forming acid addition salts include HCl and acetic acid.
- the boronate esters of boronic acid compounds of the present invention are also preferred. These esters are formed by reacting the acid groups of the boronic acid with a hydroxy compound.
- Preferred hydroxy compounds are dihydroxy compounds, especially pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
- the P moiety of the proteasome inhibitor of formula (1a) is preferably one of R 7 -C(O)-, R 7 -SO 2 -, R 7 -NH-C(O)- or R 7 -O-C(O)-, and R 7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, the ring portion of any of which can be optionally substituted, or if Y is R 7 -C(O)- or R 7 -SO 2 -, then R 7 can also be a saturated or partially unsaturated heterocycle.
- P is one of R 7 -C(O)- or R 7 -SO 2 -
- R 7 is one of aryl, aralkyl, heteroaryl or heteroarylalkyl, any of which can be optionally substituted, or a saturated or partially unsaturated heterocycle.
- R 7 is alkyl, it is preferably straight chained or branched alkyl of from 1 to 6 carbon atoms, more preferably 1-4 carbon atoms.
- Useful values include methyl, ethyl, propyl, butyl, isopropyl, isobutyl and tert-butyl, with methyl being most preferred.
- R 7 is alkaryl, aralkyl or heteroarylalkyl
- the alkyl moiety thereof is also preferably one having from 1 to
- R 7 is aryl, it is preferably aryl of from 5 to 10 carbon atoms, more preferably 6 to 10 carbon atoms.
- R 7 is heteroaryl, one or more of the carbon atoms of the aforementioned aryl is replaced by one to three of O, N, or S.
- the aryl and heteroaryl moieties may, if desired, be ring substituted.
- Useful ring substituents include one or two of hydroxy, nitro, trifluoromethyl, halogen, alkyl, alkoxy, cyano, C 6-10 aryl, benzyl, carboxyalkoxy, amino, and guanidino.
- Preferred substituents include halogen, C 1-6 alkyl, C 1-6 alkoxy, phenyl and benzyl. Additionally, where R 7 is alkaryl, aralkyl or heteroarylalkyl, the above statements equally apply.
- R 7 aryl and aralkyl groups include phenyl, 4-tolyl, benzyl, phenethyl, naphthyl, and naphthylmethyl.
- Preferred heteroaryl groups are quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl or pyrrolyl.
- Useful values of R 7 heteroaryl include 8-quinolinyl, 2-quinoxalinyl, 2-pyrazinyl, 3-furanyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
- Preferred saturated or partially saturated heterocycle moieties are 5-, 6-, 9- and 10- membered heterocycles having one, two or three ring heteroatoms selected from O, S or N.
- a useful value is N-morpholinyl.
- Preferred cycloalkyl moieties include C 3-10 cycloalkyl. Useful values include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
- P are 2-pyrazinecarbonyl, 8-quinolinesulfonyl and N-morpholinoyl.
- a in formula (1a) and (1b) can be either 0, 1 or 2.
- a in formula (1a) and (1b) can be either 0, 1 or 2.
- a is 1 the residue within the brackets is not present and the inhibitor is a dipeptide.
- a is 1 the amino acid or isosteric residue within the brackets is present and the inhibitor is a tripeptide.
- a is 2 the inhibitor is a tetrapeptide.
- A is zero.
- R 1 , R 2 , and R 3 in formula (1a) and (1b) are each independently one of hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, a 5-, 6-, 9- or 10- membered heteroaryl group, or -CH 2 -R 5 , and more preferably C 1-8 alkyl or— CH 2 —R 5 wherein R 1 , R 2 , R 3 and R 5 are optionally substituted.
- R 1 , R 2 and R 3 are each independently one of C 1-6 alkyl, e.g., methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and t-butyl, or—CH 2 —R 5 , where R 5 is one of cycloalkyl, aryl or heterocycle.
- R 5 is preferably one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, C 1-6 alk(C 6-10 )aryl, C 3-10 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio or a 5-, 6-, 9- or 10- membered heteroaryl group.
- the ring portion of any of said aryl, aralkyl, alkaryl or 5-, 6-, 9- or 10- membered heteroaryl groups of R 1 , R 2 , R 3 and R 5 can be optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, C 1-10 aryl(C 1-6 )alkoxy, hydroxy, C 1-6 alkylthio, C
- R 1 and R 2 are isobutyl or —CH 2 —R 5 , and most preferred that R 2 is—CH 2 —R 5 . It is preferred that R 5 is C 6-10 aryl, a 5-, 6-, 9- or 10- membered heteroaryl group having one to three heteroatoms independently selected from O, N and S.
- R 2 is isobutyl, 6-quinolinylmethyl, 3-indolylmethyl, 4-pyridylmethyl, 3-pyridylmethyl, 2-pyridylmethyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-fluorobenzyl, 4-benzyloxybenzyl, 4-(2'-pyridylmethoxy)benzyl or benzylnaphthylmethyl.
- R 3 is C 1-12 alkyl, more preferably C 1-6 alkyl, most preferably C 4 alkyl, such as isobutyl.
- R 1 , R 2 or R 3 is a substituted alkyl, it is preferably C 1-6 alkyl substituted with at least one cycloalkyl group, preferably a C 1-6 cycloalkyl group.
- R 1 , R 2 , R 3 , or R 5 is substituted aryl or substituted heterocycle, it is preferably substituted with at least one C 1-6 alkyl group.
- R 1 , R 2 , R 3 or R 5 is cycloalkyl, it is preferably C 5-6 cycloalkyl, e.g., cyclopentyl or cyclohexyl, and can be optionally substituted with at least one C 6-10 aryl group or at least one alkyl group, preferably a C 1-6 alkyl group.
- R 5 is -W-R 6
- W is a chalcogen, preferably oxygen or sulfur, more preferably sulfur
- R 6 is alkyl, preferably C 1-6 alkyl, e.g., methyl, ethyl, propyl, butyl, or isomers thereof.
- R include hydrogen or C 1-8 alkyl, more preferably C 1-6 alkyl.
- Useful values of R include methyl, ethyl, isopropyl, isobutyl and n-butyl.
- R can form together with the adjacent R 1 , or when A is zero, form together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and can be optionally substituted by one or two of keto, hydroxy, aryl, alkoxy or aryloxy. It is preferred that the ring system be chosen from one of:
- Z 1 and Z 2 are each independently one of C 1-6 alkyl, hydroxy, C 1-6 alkoxy, and C 6-10 aryloxy; or together Z 1 and Z 2 preferably form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1 ,2- cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine, or other equivalents apparent to those skilled in the art.
- Useful values include methyl, ethyl, propyl and n-butyl.
- Z 1 and Z 2 are hydroxy.
- a preferred embodiment of the invention is directed to a subgenus of compounds having formula (1a) above, where P is R 7 -C(O)- or R 7 -SO 2 -. and R 7 is one of quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl or pyrrolyl, and when P is R 7 -C(O)-, R 7 can also be N-morpholinyl.
- a preferred group of compounds of this embodiment are compounds of formula (1a) wherein P is one of quinolinecarbonyl, pyridinecarbonyl, quinolinesulfonyl, quinoxalinecarbonyl, quinoxalinesulfonyl, pyrazinecarbonyl, pyrazinesulfonyl, furancarbonyl, furansulfonyl or N-morpholinylcarbonyl; A is zero; X 2 is -C(O)-NH-; R is hydrogen or C 1-8 alkyl; R 2 and R 3 are each independently one of hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6- 10 ar(C 1- 6 )alkyl, pyridylmethyl, or quinoliny lmethyl; and Z 1 and Z 2 are both hydroxy, C 1-6 alkoxy, or C 6-10 aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consist
- Another preferred embodiment of the present invention is directed to compounds of formula (1a) where A is zero. These compounds possess unexpectedly high potency and selectivity as inhibitors of proteasome function.
- a third preferred subgenus of compounds are compounds of formula (1a) where one of R 1 , R 2 or R 3 corresponds to an amino acid side-chain corresponding to tyrosine or an O-substituted tyrosine derivative, formed by reacting the hydroxyl group of the tyrosine side-chain with a compound having a reactive functional group.
- This subgenus includes compounds having the formula (1a), wherein at least one R 1 , R 2 or R 3 is:
- R 9 is one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, wherein the alkyl is optionally substituted with one of C 1-6 alkyl, halogen, monohalo (C 1-6 ) alkyl, and trifluoromethyl; and wherein said cycloalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups can be optionally substituted with one or two of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alky lamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alk
- C 6-10 arylsulfonyl C 6-10 aryl, C 1-6 alkyl(C 6-10 )aryl, and halo(C 6-10 )aryl
- a 1 and A 2 are independently one of hydrogen, C 1-6 alkyl, halogen, monohalo(C 1-6 )alkyl, or trifluoromethyl.
- the group -O-R 9 is in either the ortho- or para- position, with parabeing preferred.
- the groups A 1 and A 2 can be at any remaining positions on the phenyl ring.
- R 9 is one of C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 ar (C 1-6 )alkyl, 5- to 10- membered heteroaryl or 5- to 10-membered heteroaryl(C 1- 6 )alkyl.
- R 9 Useful values of R 9 include benzyl, phenethyl, pyridyl, pyridy lmethyl, furanylmethyl pyrrolymethyl, pyrrolidylmethyl, oxazolylmethyl and imidazoly lmethyl.
- the ring portion of any of said aryl, aralkyl, alkaryl or 5-, 6-, 9- or 10- membered heteroaryl groups of R 1 , R 2 , R 3 and R 5 can be optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alky lamino, benzylamino, dibenzy lamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, hydroxy, C 1-6 alkylthio, C
- a preferred class of compounds of this embodiment are compounds of formula (1a) wherein: A is zero; P is one of R 7 -C(O)-, R 7 -SO 2 - R 7 -NH-C(O)- or R 7 -O-C(O)-; R 7 is one of quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl or pyrrolyl, or when P is R 7 -C(O)-, R 7 can also be N-morpholinyl; X 2 is -C(O)-NH-; R 3 is C 1-6 alkyl; R 2 is:
- a 1 and A 2 are independently one of hydrogen, C 1-6 alkyl, halogen, monohalo(C 1-6 )alkyl or trifluoromethyl; and R 9 is one of hydrogen, C 1-6 alkyl, phenyl, benzyl, phenethyl or pyridylmethyl; and
- Z 1 and Z 2 are both hydroxy, C 1-6 alkoxy, or C 6-10 aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
- a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
- N-morpholinecarbonyl X 2 is -C(O)-NH-; R 3 is isobutyl; R 2 is:
- a 1 and A 2 are independently one of hydrogen, methyl, ethyl, chloro, fluoro, or trifluoromethyl; and R 9 is one of hydrogen, methyl, ethyl, butyl, phenyl, benzyl, phenethyl or pyridylmethyl; and
- Z 1 and Z 2 are both hydroxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol,
- a fourth preferred subgenus of compounds includes compounds of formula (1a) wherein one of the amino acid side-chains, preferably the side-chain defined by R 2 , is an unnatural amino acid selected from naphthy lmethyl, pyridylmethyl and quinolinylmethyl, with quinolinylmethyl being most preferred.
- this subgenus includes compounds of formula (1a), wherein at least one R 1 , R 2 or R 3 is naphthylmethyl, pyridylmethyl or quinolinylmethyl; provided that the compound is other than isovaleryl-phenylalanine-norvaline-[(naphthylmethyl),
- a fifth preferred subgenus includes compounds of formula (1a) where R, together with R 1 , or with R 2 when A is zero, forms a nitrogen containing heterocycle.
- This subgenus includes compounds having formula (1a), wherein:
- R forms together with the adjacent R', or when A is zero, forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and one or two optional substituents selected from the group consisting of keto, hydroxy, aryl, alkoxy and aryloxy;
- R 1 that is not adjacent to N-R is one of hydrogen, alkyl, cycloalkyl, aryl, heterocycle or -CH 2 -R 5 ; and when A is 1 or 2, R 2 is one of hydrogen, alkyl, cycloalkyl, aryl, heterocycle or -CH 2 -R 5 , where R 5 is defined as above.
- a preferred class of compounds of this embodiment of the invention are those wherein: A is zero; P is hydrogen; X 2 is -C(O ⁇ -NH-; and R forms together with the adjacent R 2 , one of the nitrogen-containing ring systems shown in the above structures; R 3 is C 1-6 alkyl; and Z 1 and Z 2 are both hydroxy, C 1-6 alkoxy, or C 6-10 aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
- the hydrochloride salts of these compounds are also especially preferred.
- R forms together with the adjacent R 2 , a nitrogen-containing ring system having one of the structures shown above; R 3 is isobutyl; and Z 1 and Z 2 are both hydroxy, or together Z 1 and
- Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
- a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
- proteasome inhibitors include without limitation the following compounds, as well as pharmaceutically acceptable salts and boronate esters thereof:
- N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid
- N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.
- Preferred compounds having formula (2a) include compounds where Y is one of R 8 -C(O)-, R 8 -SO 2 -, R 8 - ⁇ H-C(O)- or R 8 -O-C(O)-, and
- R 8 is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, or a 5-10 membered heteroaryl, any of which can be optionally substituted, or when P is R 8 -C(O)-, R 8 can also be N-morpholinyl; provided that when Y is R 8 -C(O)-, then R 8 is other than phenyl, benzyl or C 1-3 alkyl.
- R 8 is alkyl, it is preferably alkyl of from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl, butyl, or isomers thereof. Additionally, where R 8 is alkaryl or aralkyl, the alkyl moiety thereof is also preferably one having from 1 to 4 carbon atoms.
- R 8 is aryl, it is preferably aryl of from 6 to 10 carbon atoms, e.g., phenyl or naphthyl, which may, if desired, be ring substituted. Additionally, where R 8 is alkaryl, aralkyl, aryloxy, alkaryloxy, or aralkoxy, the aryl moiety thereof is also preferably one having from 5 to 10 carbon atoms, most preferably 6 to 10 carbon atoms. Preferably, the R 8 moiety is a saturated, partially unsaturated or aromatic heterocycle, more preferably an isomeric pyridine ring or morpholine ring.
- Y is most preferably one of:
- R 4 is C 6-10 alkyl
- the Y moiety of the proteasome inhibitor of formula (2a) is an isosteric amino acid replacement of formula (3a):
- R 1 is as defined for formula (1a) above. Useful and preferred values of R 1 are the same as those defined for formula (1a) above; and
- P is one of R 7 -C(O)-, R 7 -SO 2 -, R 7 -NH-C(O)- or R1-O—C(O)-, and R 7 is one of alkyl, aryl, alkaryl, aralkyl, any of which can be optionally substituted, or when Y is R 7 -C(O)- or R 7 -SO 2 -, R 7 can also be an optionally substituted 5-10 membered saturated, partially unsaturated or aromatic heterocycle.
- R 7 when R 7 is one of alkyl, aryl, alkaryl, aralkyl, any of which are optionally substituted are as defined for formula (1a) above.
- R 7 is optionally substituted 5-10 membered saturated, partially unsaturated or aromatic heterocycle, preferred and useful values are as defined for heteroaryl, unsaturated and partially saturated heterocycle of the R 7 of formula (1a).
- Y is most preferably:
- X 1 represents a peptide bond or an isostere that can be used as a peptide bond replacement in the proteasome inhibitors to increase bioavailability and reduce hydrolytic metabolism.
- X 1 is—C(O>—NH—.
- R x and R y have the same definitions as R 1 and R 2 , above and P, Z 1 , Z 2 and R 3 are defined as above for formula (1a).
- Another group of compounds of the present invention are aza-peptide isosteres. This is the result of the replacement of the ⁇ -carbon atom of an amino acid with a nitrogen atom, e.g.,
- R x represents R 1
- R y represents R 2
- P, Z 1 , Z 2 and R 3 are defined as above for formula (1a) and (1b).
- boronic ester and acid compounds include both D and L peptidyl configurations. However, L configurations are preferred.
- the present invention relates to a method for reducing the rate of muscle protein degradation in a cell comprising contacting the cell with a proteasome inhibitor described above. More specifically, the present invention relates to a method for reducing the rate of loss of muscle mass in an animal comprising contacting cells of the muscle with a proteasome inhibitor described above.
- the present invention also relates to a method for reducing the activity of NF- ⁇ B in a cell comprising contacting the cell with a proteasome inhibitor described above. More specifically, the present invention also relates to a method for reducing the activity of NF- ⁇ B in an animal comprising contacting cells of the animal with a proteasome inhibitor described above.
- the present invention also relates to a method for reducing the rate of proteasome-dependent intracellular protein breakdown comprising contacting cells with a proteasome inhibitor described above. More specifically, the present invention also relates to a method for reducing the rate of intracellular protein breakdown in an animal comprising contacting cells of the animal with the proteasome inhibitor described above.
- the present invention further relates to a method of reducing the rate of degradation of p53 protein in a cell comprising administering to the cell a proteasome inhibitor described above. More specifically, the present invention further provides a method of reducing the rate of degradation of p53 protein in an animal (preferably, an animal subjected to DNA damaging drugs or radiation) comprising administering to said animal a proteasome inhibitor described above.
- the present invention further relates to a method for inhibiting cyclin degradation in a cell comprising contacting said cells with a proteasome inhibitor described above. More specifically, the present invention relates to a method for inhibiting cyclin degradation in an animal comprising contacting cells of said animal with a proteasome inhibitor described above.
- the present invention also provides a method for treating cancer, psoriasis, restenosis, or other cell proliferative diseases in a patient comprising administering to the patient a proteasome inhibitor described above.
- the present invention also relates to a method for inhibiting antigen presentation in a cell comprising administering to the cell a proteasome inhibitor described above. More specifically, the present invention relates to a method for inhibiting antigen presentation in animal comprising administering to the animal a proteasome inhibitor described above.
- the present invention further provides a method for inhibiting inducible NF- ⁇ B dependent cell adhesion in an animal comprising administering to said animal a proteasome inhibitor described above.
- the present invention also provides a method for inhibiting HIV infection in an animal comprising administering to said animal a proteasome inhibitor described above.
- mammals are preferably mammals. Both terms are intended to include humans.
- the methods described above deliver the proteasome inhibitor by either contacting cells of the animal with a proteasome inhibitor described above or by administering to the animal a proteasome inhibitor described above.
- the compounds of the present invention inhibit the functioning of the proteasome.
- This proteasome-inhibition activity results in the inhibition or blocking of a variety of intracellular functions.
- inhibition of proteasome function inhibits the activation or processing of transcription factor NF- ⁇ B.
- NF- ⁇ B plays a central role in the regulation of a diverse set of genes involved in the immune and inflammatory responses.
- Inhibition of proteasome function also inhibit the ubiquitination/proteolysis pathway. This pathway catalyzes selective degradation of highly abnormal proteins and short-lived regulatory proteins.
- the ubiquitination proteolysis pathway also is involved in the processing of internalized cellular or viral antigens into antigenic peptides that bind to MHC-I molecules.
- the proteasome inhibitors of the present invention can be used in reducing the activity of the cytosolic ATP-ubiquitin- dependent proteolytic system in a number of cell types.
- the inhibitors can be used in vitro or in vivo. They can be administered by any number of known routes, including orally, intravenously, intramuscularly, subcutaneously, intrathecally, topically, and by infusion (Platt et ⁇ l, U.S. Patent No. 4,510, 130; Badalêt et ⁇ l, Proc. Natl Acad. Sci. U.S.A. 86:5983-5987 (1989); Staubli et ⁇ l, Brain Research 444:153-158 (1988)) and will generally be administered in combination with a physiologically acceptable carrier (e.g., physiological saline).
- a physiologically acceptable carrier e.g., physiological saline
- the effective quantity of inhibitor given will be determined empirically and will be based on such considerations as the particular inhibitor used, the condition of the individual, and the size and weight of the individual. It is to be expected that the general end-use application dose range will be about
- the present invention relates to a method of inhibiting (reducing or preventing) the accelerated or enhanced proteolysis that occurs in atrophying muscles and is known to be due to activation of a nonlysosomal ATP-requiring process in which ubiquitin plays a critical role.
- Inhibition of the ATP-ubiquitin-dependent pathway is a new approach for treating the negative nitrogen balance in catabolic states. This can be effected through use of an inhibitor of the present invention, resulting in reduction of loss of muscle mass in conditions in which it occurs. Excessive protein loss is common in many types of patients, including individuals with sepsis, burns, trauma, many cancers, chronic or systemic infections, neuromotor degenerative disease, such as muscular dystrophy, acidosis, or spinal or nerve injuries. It also occurs in individuals receiving corticosteroids, and those in whom food intake is reduced and/or absorption is compromised. Moreover, inhibitors of the protein breakdown pathway could possibly be valuable in animals, e.g., for combating "shipping fever", which often leads to a major weight loss in cattle or pigs.
- this pathway is responsible for the accelerated proteolysis in these catabolic states is based on studies in which different proteolytic pathways were blocked or measured selectively in incubated muscles, and the finding of increased mRNA for components of this pathway (e.g., for ubiquitin and proteasome subunits) and increased levels of ubiquitin-protein conjugates in the atrophying muscles.
- the nonlysosomal ATP-ubiquitin-dependent proteolytic process increases in muscle in these conditions and is responsible for most of the accelerated proteolysis that occurs in atrophying muscles.
- the inhibitors of the present invention can be used to reduce (totally or partially) the nonlysosomal ATP-dependent protein degradation shown to be responsible for most of the increased protein degradation that occurs during fasting, denervation, or disuse (inactivity), steroid therapy, febrile infection, and other conditions.
- One approach to testing drug candidates for their ability to inhibit the ATP-ubiquitin-dependent degradative process is to measure proteolysis in cultured cells (Rock, et ⁇ l, Cell 78:761 (1994)).
- the degradation of long-lived intracellular proteins can be measured in mouse C2C12 myoblast cells. Cells are incubated with 35 S-methionine for 48 hours to label long-lived proteins and then chased for 2 hours with medium containing unlabeled methionine. After the chase period, the cells are incubated for 4 hours in the presence or absence of the test compound.
- the amount of protein degradation in the cell can be measured by quantitating the trichloroacetic acid soluble radioactivity released from the pre-labeled proteins into the growth medium (an indicator of intracellular proteolysis).
- Inhibitors can also be tested for their ability to reduce muscle wasting in vivo.
- Urinary excretion of the modified amino acid 3-methyl histidine (3-MH) is probably the most well characterized method for studying myofibrillar protein degradation in vivo (see Young and Munro, Federation Proc. 37.229-2300 (1978)).
- 3-Methylhistidine is a post-translationally modified amino acid which cannot be reutilized for protein synthesis, and it is only known to occur in actin and myosin. It occurs in actin isolated from all sources, including cytoplasmic actin from many different cell types.
- myosin heavy chain of fast-twitch (white, type II) muscle fibers, but it is absent from myosin of cardiac muscle and myosin of slow-twitch (red, type I) muscle fibers. Due to its presence in actin of other tissues than skeletal muscle, other tissues will contribute to urinary 3-MH. Skeletal muscle has been estimated to contribute 38-74% of the urinary 3-MH in normal rats and 79-86% of the urinary 3-MH in rats treated with corticosterone (100 mg/kg/day subcutaneously) for 2-4 days (Millward and Bates, Biochem. J. 214:607-615 (1983); Kayali, et ⁇ l, Am. J.
- glucocorticoid treatment is used to induce a state of muscle wasting in rats. Treating rats with daily subcutaneous injections of corticosterone (100 mg/kg) causes an increase of approximately 2-fold in urinary 3-MH. The increase in excretion of 3-MH is transient, with a peak increase after 2-4 days of treatment and a return to basal values after 6-7 days of treatment (Odedra, et ⁇ l,
- proteasome inhibitors are therefore expected to inhibit the muscle wasting that occurs after glucocorticoid treatment.
- proteasome inhibitors can be administered alone or in combination with another inhibitor or an inhibitor of another pathway (e.g., a lysosomal or Ca ++ -dependent pathway) responsible for loss of muscle mass.
- another inhibitor or an inhibitor of another pathway e.g., a lysosomal or Ca ++ -dependent pathway
- the inhibitors of the present invention will block the degradation of the tumor suppressor protein p53. This protein is degraded by the ATP ubiquitin dependent proteolysis by the proteasome (see Scheffner et ⁇ l, Cell 75:495-505 (1993)).
- p53 knockout mice indicate an important role for p53 in reducing incidence of tumors (Donehower et ⁇ l, Nature 356:215-221 (1992)).
- the basal levels of p53 are very low due to very rapid degradation of p53 protein.
- expression of p53 protein in normal cells is stimulated in response to radiation and drugs that induce DNA damage (Kastan et ⁇ l, Cancer Res. 51:6304-631 1 (1991)).
- proteasome inhibitors provides a method for augmenting the expression of p53 in normal cells by preventing its degradation by the proteasome.
- An example of this would be the systemic administration of proteasome inhibitor at a sufficient dose to inhibit p53 degradation by the proteasome during the treatment of the tumor with cytotoxic drugs or radiation. This will prolong and increase the levels of p53 expression in normal cells and will enhance the arrest of normal cell proliferation, reducing their sensitivity to higher doses of radiation or cytotoxic drugs. Administration of proteasome inhibitors would therefore permit exposing the tumor to higher doses of radiation, enhancing the killing of tumor cells.
- proteasome inhibitors can be used as adjuvants to therapy with tumoricidal agents, such as radiation and cytotoxic drugs.
- Topical application of proteasome inhibitors to enhance p53 expression in skin The expression of p53 in normal skin is induced by exposure of the skin to UV irradiation, which inhibits DNA replication that is needed for cell division (Maltzman et ⁇ l. Mol. Cell. Biol. 4:1689 (1984); Hall et ⁇ l., Oncogene 5.203-207 (1993)). This protects normal skin from chromosomal DNA damage by allowing time for DNA repair before DNA replication.
- Telangiectasia result in increased susceptibility to ionizing radiation-induced skin tumors (Kastan et ⁇ l, Cell 71:587-597 (1992)). It is well established that exposure of normal individuals increases the risk for many kinds of skin cancers.
- Another approach would be to promote the resistance of the DNA in skin cells to UV damage by the topical application of agents that enhance the skin's expression of p53 in response to UV light. Inhibiting p53 degradation by the topical application of proteasome inhibitors provides a method to enhance the p53 response.
- One preferred embodiment of the present invention is the topical application of proteasome inhibitors to reduce the acknowledged risk of skin cancers that results from the treatment of psoriasis using UV light, which is often combined with psoralens or coal tar. Each of these agents can induce DNA damage.
- NF- ⁇ B exists in an inactive form in the cytoplasm complexed with an inhibitor protein, I ⁇ B.
- I ⁇ B an inhibitor protein
- the NF- ⁇ B In order for the NF- ⁇ B to become active and perform its function, it must enter the cell nucleus. It cannot do this, however, until the I ⁇ B portion of the complex is removed, a process referred to by those skilled in the art as the activation of, or processing of, NF- ⁇ B.
- the normal performance of its function by the NF- ⁇ B can be detrimental to the health of the patient.
- NF- ⁇ B is essential for the expression of the human immunodeficiency virus (HIV). Accordingly, a process that would prevent the activation of the NF- ⁇ B in patients suffering from such diseases could be therapeutically beneficial.
- HAV human immunodeficiency virus
- the inhibitors employed in the practice of the present invention are capable of preventing this activation.
- blocking NF- KB activity could have important application in various areas of medicine, e.g., inflammation, through the inhibition of expression of inflammatory cytokines and cell adhesion molecules, (ref. Grilli et ⁇ l, International Review of Cytology 143: 1-62 ( 1993)) sepsis, AIDS, and the like.
- NF-KB is highly regulated (Grilli et ⁇ l, International Review of Cytology 143: 1-62 (1993); Beg et al, Genes and Development 7:2064-2070 (1993)).
- NF- ⁇ B comprises two subunits, p50 and an additional member of the rel gene family, e.g., p65 (also known as Rel A).
- p65 also known as Rel A
- the p50 and p65 are present in an inactive precursor form in the cytoplasm, bound to I ⁇ B.
- the p50 subunit of NF- ⁇ B is generated by the proteolytic processing of a 105 kD precursor protein NF- ⁇ B, (p105), and this processing is also regulated.
- the sequence of the N-terminal 50 kD portion of pi 05 is similar to that of p65 and other members of the rel gene family (the rel homology domain).
- the C-terminal 55 kD of pi 05 bears a striking resemblance to I ⁇ B- ⁇ (also known as MAD3).
- unprocessed pi 05 can associate with p65 and other members of the rel family to form a p65/p105 heterodimer.
- Processing of pi 05 results in the production of p50, which can form the transcriptionally active p50/p65 heterodimer.
- the C-terminal I ⁇ B- ⁇ -homologous sequence of p105 is rapidly degraded upon processing.
- NF- ⁇ B 2 NF- ⁇ B 2
- pi 00 NF- ⁇ B 2
- the transcriptional activity of heterodimers consisting of p50 and one of the many rel family proteins, such as p65, can be regulated by at least two mechanisms.
- the heterodimers associate with I ⁇ B- ⁇ to form an inactive ternary cytoplasmic complex.
- the rel family members associate with p105 and p100 to form inactive complexes.
- the ternary complex can be activated by the dissociation and destruction of I ⁇ B- ⁇ , while the p65/p105 and p65/p100 heterodimer can be activated by processing pi 05 and pi 00, respectively.
- I ⁇ B- ⁇ The dissociation of I ⁇ B- ⁇ can be induced by a remarkably large number of extracellular signals, such as lipopolysaccharides, phorbol esters, TNF- ⁇ , and a variety of cytokines.
- the I ⁇ B- ⁇ is then rapidly degraded.
- Recent studies suggest that p105 and p100 processing can also be induced by at least some of these extracellular signals.
- p105 or a truncated form of p 105 can be processed to p50 in vitro (Fan et ⁇ l, Nature 354:395-398 (1991)).
- Certain of the requirements and characteristics of this in vitro processing reaction e.g., ATP/Mg ++ dependency
- implicated the involvement of the ubiquitin-mediated protein degradation pathway Goldberg, Eur. J. Biochem. 203:9-23 (1992)
- the proteasome is required for the processing of p105 to p50.
- p105/p60Tth proteins are not processed in mammalian cell cytoplasmic extracts depleted of proteasome activity. However, addition of purified 26S proteasomes to these depleted extracts restores the processing activity. Additionally, specific inhibitors of the proteasome block the formation of p50 in mammalian cell extracts and in vivo.
- mammalian pi 05 is processed to p50 in Saccharomyces cerevisiae in vivo, and a mutant deficient in the chymotrypsin-like activity of the proteasome showed a significant decrease in p105 processing.
- p60Tth is ubiquitinated in vitro and this ubiquitination is a pre-requisite for pi 05 processing.
- I ⁇ B- ⁇ degradation and the activation of NF- ⁇ B are also blocked by inhibitors of proteasome function or ubiquitin conjugation (Palombella et ⁇ l. , Cell 78:773-785 (1994)).
- proteasome plays an essential role in the regulation of
- the proteasome is required for the processing of pi 05 and possibly pi 00.
- the degradation of the inhibitory C-terminus can also require the proteasome.
- the proteasome appears to be required for the degradation of I ⁇ B- ⁇ in response to extracellular inducers.
- the present invention relates to a method for reducing the activity of NF- KB in an animal comprising contacting cells of the animal with inhibitors of proteasome function.
- Whole-cell extracts are prepared from untreated or TNF- ⁇ treated cells that have been pretreated for 1 hour with the test compound.
- the DNA binding activity of NF- ⁇ B is measured by an electrophoretic mobility shift assay using the PRDII probe from the human IFN- ⁇ gene promoter.
- NF- ⁇ B activation As an indirect measure of NF- ⁇ B activation, the cell-surface expression of E-selectin, I-CAM-1, and V-CAM-1 on primary human umbilical vein endothelial cells (HUVECs) can be determined by means of a cell surface fluorescent immuno-binding assay. Because E-selectin, I-CAM- 1 , and V-C AM-1 are under the regulatory control of NF- ⁇ B, inhibition of NF- ⁇ B activation results in reduced levels of these adhesion molecules on the cell surface.
- Compounds can also be tested for their ability to inhibit a delayed-type hypersensitivity response in mice.
- Contact hypersensitivity is a manifestation of an in vivo T-cell mediated immune response (Friedmann, Curr. Opinion
- NF- ⁇ B by mediating events such as the production of cytokines and the induction and utilization of cell-surface adhesion molecules, is a central and coordinating regulator involved in immune responses.
- the compounds of formula (1b) or (2b) can be used to treat chronic or acute inflammation that is the result of transplantation rejection, arthritis, rheumatoid arthritis, infection, dermatosis, inflammatory bowel disease, asthma, osteoporosis, osteoarthritis and autoimmune disease. Additionally, inflammation associated with psoriasis and restenosis can also be treated.
- treatment of inflammation or "treating inflammation” is intended to include the administration of compounds of the present invention to a subject for purposes which can include prophylaxis, amelioration, prevention or cure of an inflammatory response. Such treatment need not necessarily completely ameliorate the inflammatory response. Further, such treatment can be used in conjunction with other traditional treatments for reducing the inflammatory condition known to those of skill in the art.
- proteasome inhibitors of the invention can be provided as a "preventive" treatment before detection of an inflammatory state, so as to prevent the same from developing in patients at high risk for the same, such as, for example, transplant patients.
- efficacious levels of the proteasome inhibitors of the invention are administered so as to provide therapeutic benefits against the secondary harmful inflammatory effects of inflammation.
- an "efficacious level” of a composition of the invention is meant a level at which some relief is afforded to the patient who is the recipient of the treatment.
- an "abnormal" host inflammatory condition is meant an level of inflammation in the subject at a site which exceeds the norm for the healthy medical state of the subject, or exceeds a desired level.
- secondary tissue damage or toxic effects is meant the tissue damage or toxic effects which occur to otherwise healthy tissues, organs, and the cells therein, due to the presence of an inflammatory response, including as a result of a "primary "inflammatory response elsewhere in the body.
- Amounts and regimens for the administration of proteasome inhibitors and compositions of the invention can be determined readily by those with ordinary skill in the clinical art of treating inflammation-related disorders such as arthritis, tissue injury and tissue rejection.
- the dosage of the composition of the invention will vary depending upon considerations such as: type of pharmaceutical composition employed; age; health; medical conditions being treated; kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired; extent of tissue damage; gender; duration of the symptoms; and, counter indications, if any, and other variables to be adjusted by the individual physician.
- a desired dosage can be administered in one or more applications to obtain the desired results.
- Pharmaceutical compositions containing the proteasome inhibitors of the invention can be provided in unit dosage forms.
- proteasome inhibitors are useful for treating such conditions as tissue rejection, arthritis, local infections, dermatoses, inflammatory bowel diseases, autoimmune diseases, etc.
- the proteasome inhibitors of the present invention can be employed to prevent the rejection or inflammation of transplanted tissue or organs of any type, for example, heart, lung, kidney, liver, skin grafts, and tissue grafts.
- Compounds of the present invention inhibit the growth of cancer cells.
- the compounds can be employed to treat cancer, psoriasis, restenosis or other cell proliferative diseases in a patient in need thereof.
- cancer refers to the spectrum of pathological symptoms associated with the initiation or progression, as well as metastasis, of malignant tumors.
- tumor refers to the spectrum of pathological symptoms associated with the initiation or progression, as well as metastasis, of malignant tumors.
- tumor is intended, for the purpose of the present invention, a new growth of tissue in which the multiplication of cells is uncontrolled and progressive.
- the tumor that is particularly relevant to the invention is the malignant tumor, one in which the primary tumor has the properties of invasion or metastasis or which shows a greater degree of anaplasia than do benign tumors.
- treatment of cancer refers to an activity that prevents, alleviates or ameliorates any of the primary phenomena (initiation, progression, metastasis) or secondary symptoms associated with the disease.
- Cancers that are treatable are broadly divided into the categories of carcinoma, lymphoma and sarcoma.
- Sarcomas that can be treated by the composition of the present invention include, but are not limited to: amelioblastic sarcoma, angiolithic sarcoma, botryoid sarcoma, endometrial stroma sarcoma, ewing sarcoma, fascicular sarcoma, giant cell sarcoma, granulositic sarcoma, immunoblastic sarcoma, juxaccordial osteogenic sarcoma, coppices sarcoma, leukocytic sarcoma (leukemia), lymphatic sarcoma (lympho sarcoma), medullary sarcoma, myeloid sarcoma (granulocitic sarcoma), austiogenci sarcoma, periosteal sarcoma, reticulum cell sarcoma (histiocytic lymphoma), round cell sar
- Lymphomas that can be treated by the composition of the present invention include, but are not limited to: Hodgkin's disease and lymphocytic lymphomas, such as Burkitt's lymphoma, NPDL, NML, NH and diffuse lymphomas.
- the compounds of formulae (1b) and (2b) appear to be particularly useful in treating metastases.
- Amounts and regimens for the administration of proteasome inhibitors and compositions of the invention can be determined readily by those with ordinary skill in the clinical art of treating cancer-related disorders such as the primary phenomena (initiation, progression, metastasis) or secondary symptoms associated with the disease.
- the dosage of the composition of the invention will vary depending upon considerations such as: type of composition employed; age; health; medical conditions being treated; kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired; extent of tissue damage; gender; duration of the symptoms; and, counter indications, if any, and other variables to be adjusted by the individual physician.
- a desired dosage can be administered in one or more applications to obtain the desired results.
- Pharmaceutical compositions containing the proteasome inhibitors of the invention can be provided in unit dosage forms.
- N-Protected (Boc-, Cbz-, or Fmoc-) amino acids were commercially available or were prepared from the corresponding free amino acid by standard protection methods, unless otherwise described in the Examples.
- 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), or O-(1H-benzotriazol-1-yl)-NNN'N'-tetramethyluronium tetrafluoroborate (TBTU) were employed as coupling reagents (Sheehan, J.C. et ⁇ l, J. Am. Chem. Soc. 87:2492 (1965); Castro, B., et ⁇ l, Synthesis 11:751 (1976); Tetrahedron Lett. 30:1927 ( 1989)).
- Example 2 N-Cbz-L-Leucine-L-leucine boronic acid [MG-274] A. (1S,2S,3R,5S)-Pinanediol N-Cbz-L-leucine-L-leucine boronate
- BOP reagent 827 mg, 1.87 mmol
- (1S,2S,3 R,5S)-pinanediol leucine boronate trifluoroacetate salt 595 mg, 1.58 mmol
- N-Cbz-L-leucine 500 mg, 1.87 mmol
- acetonitrile 30 mL
- Example 3 ⁇ -(1-Naphthyl)-L-alanine-L-leucine boronic acid
- Example 3 A To the product of Example 3 A (290 mg, 0.58 mmol) in a mixture of hexane (4 mL), MeOH (4 mL), and 1 ⁇ HCl (1.3 mL) was added i-BuB(OH) 2 (71 mg, 0.70 mmol). The reaction mixture was stirred for 72 h at room temperature.
- the aqueous solution was made basic with ⁇ aOH and washed with ether-EtOAc
- Example 4B The product of Example 4B (4.47 g, 7.23 mmol) was dissolved in CH 2 Cl 2 (40 mL) and cooled to 0°C. A solution of 4N H Cl in dioxane (40 mL, 0.16 mol) was added and the reaction mixture was stirred at room temperature for 1.5 h. Concentration afforded a yellow solid, which was triturated with hexane-ether (1 :1, 100 mL). Filtration afforded the title compound (3.65 g) as a pale yellow solid.
- Example 4C By a procedure analogous to that described in Example 1C, the product of Example 4C (2.53 g, 4.56 mmol) was treated with 4-morpholinecarbonyl chloride (0.75 mL, 6.43 mmol) to provide the title compound (2.35 g) as a pale yellow solid.
- 4-morpholinecarbonyl chloride (0.75 mL, 6.43 mmol)
- Example 5 N-Methyl-N-Cbz-L-leucine-L-leucine boronic acid [MG-268]
- Example 5A By a procedure analogous to that described in Example 1 A, the product of Example 5A (85.1 mg, 0.30 mmol) was coupled with (1S,2S,3R,5S)-pinanediol leucine boronate trifluoroacetate salt (105 mg, 0.28 mmol) in the presence of EDC (64 mg, 0.33 mmol), HOBT (45 mg, 0.33 mmol), and ⁇ MM (37 mg, 0.37 mmol) to provide, after purification by flash chromatography (elution with 3:2 hexanes/acetone), the title compound (85 mg).
- EDC 64 mg, 0.33 mmol
- HOBT 45 mg, 0.33 mmol
- ⁇ MM 37 mg, 0.37 mmol
- Example 5B By a procedure analogous to that described in Example 1D, the product of Example 5B (85 mg, 0.16 mmol) was deprotected by treatment with ⁇ aIO 4 (104 mg, 0.485 mmol) and aqueous NH 4 OAc (0.1N, 5 mL, 0.5 mmol) in 10 mL of acetone to provide, after purification by flash chromatography (elution with
- N-Acetyl ⁇ -(6-quinolinyl)-D,L-alanine ethyl ester (728 mg, 2.55 mmol) was heated at reflux in 6N HCl (20 mL). After 20 h, the reaction mixture was concentrated to dryness and the residue was dried in vacuo to provide the title compound, which was used directly in the next reaction.
- Example 6B By a procedure analogous to that described in Example 2A, the product of Example 6B was coupled with (1S,2S,3 R,5S)-pinanediol leucine boronate trifluoroacetate salt (943 mg, 2.5 mmol) in the presence of BOP reagent (1.33 g,
- Example 6C The product of Example 6C (343 mg, 0.61 mmol) was treated with trifluoroacetic acid (7 mL) and thioanisole (1 mL) in CH 2 Cl 2 (15 mL) at 0°C, as described in Example 1B, to provide the title compound.
- Example 6D The product of Example 6D was coupled with 4-morpholinecarbonyl chloride (0.14 mL, 1.22 mmol) by a procedure analogous to that described in Example 1C to produce the title compound (112 mg).
- F. N-(4-Morpholine)carbonyl- ⁇ -(6-quinolinyl)-D, L-alanine-L-leucine boronate
- Example 6E Deprotection of the product of Example 6E (153 mg, 0.27 mmol) was effected according to the procedure described in Example 3B. Purification by silica gel chromatography (elution with 50:50:10 hexanes/acetone/methanol) afforded the title compound (87 mg). The product was further purified by reverse phase HPLC; 5 mg of the title compound was recovered.
- Example 7 N-(4-Morpholine)carbonyl- ⁇ -(1-naphthyl)-L-alanine-L-leucine methylboronic acid [MG-317]; and N-(4-Morpholine) carbonyl- ⁇ -(1-naphthyl)-L-alanine-L-leucine dimethylborane [MG-318]
- 1,3-propanedioI (20.0 mL, 0.28 mmol).
- the resultant clear solution was stirred for 30 min at room temperature, and then anhydrous MgSO 4 was added. Stirring was continued for an additional 30 min. and then the mixture was filtered through a cotton plug and then through a 0.2 mm PTFE filter. The solution was concentrated, toluene (2 mL) was added, and the mixture was again concentrated to produce a white solid. Anhydrous THF (3 mL) was added, and the resultant solution was cooled to 0°C. MeLi (0.8 mL, 1.12 mmol) was added. After 10 min, the mixture was warmed to room temperature.
- Example 8C N-Benzyl-(3R)-3-dioxyboryl-5-methylhexanamide
- the product of Example 8C (223 mg, 0.56 mmol) was deprotected according to the procedure described in Example 3B. Purification by flash chromatography (elution with 5% MeOH/CHCl 3 ) provided a pale yellow oil, which was dissolved in acetonitrile/MeOH. Water was added and the mixture was lyophilized overnight to produce the title compound (108 mg) as a fluffy white solid.
- Example 9 N-Acetyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-L-leucine boronic acid [MG-310]
- Example 9B The product of Example 9B (755 mg) was dissolved in CH 2 Cl 2 (10 mL) and cooled to 0°C. A solution of 4N H Cl in dioxane (8 mL, 0.03 mol) was added and the reaction mixture was stirred at room temperature. Concentration and trituration with ether-hexanes afforded the title compound (565 mg) as an off-white solid.
- Example 10 N-(4-Morpholine)carbonyl- ⁇ -(2-quinolyl)-L-alanine-L-leucine boronic acid [MG-315]
- Example 10A To a solution of the product of Example 10A (8 g, 22.3 mmol) in EtOH (180 mL) was added 6.1N ⁇ aOH (6.5 mL, 40 mmol). After 2 h, 1 1.1N HCl (3.6 mL, 40 mmol) was added, and the reaction mixture was concentrated to dryness. The residue was suspended in 1,4-dioxane (200 mL) and the mixture was heated at reflux for 90 min. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (elution with 30-50% acetone-hexanes) to provide to title compound (4.3 g).
- Example 10B The product of Example 10B (4.3 g, 15 mmol) was treated with Subtilisin Carlsberg (Sigma, 1 1.9 units/mg, 30 mg, 357 units) at room temperature in aqueous ⁇ aHCO 3 (0.2M, 120 mL). After 2 h. the reaction mixture was extracted with CHCl 3 (6 ⁇ 100 mL). The aqueous layer was concentrated to dryness to provide the title compound (3.5 g), which contained salts.
- Subtilisin Carlsberg Sigma, 1 1.9 units/mg, 30 mg, 357 units
- Example 10D By a procedure analogous to that described in Example 2A, the product of Example 10D (0.6 g, 1.9 mmol) was coupled with (1S,2S,3R,5S)-pinanediol leucine boronate trifluoroacetate salt (716 mg, 1.9 mmol) in the presence of BOP reagent (0.84 g, 1.9 mmol) and triethylamine (0.27 mL, 1.9 mmol). Purification by silica gel chromatography (elution with 10-30% acetone-hexanes) afforded the title compound (194 mg). F. (1S,2S,3R,5S)-Pinanediol N-(4-morpholine)carbonyl- ⁇ - (2-quinolyl)-L-alanine-L-leucine boronate
- Example 10E The product of Example 10E (194 mg) was treated with trifluoroacetic acid (7 mL) and thioanisole (1 mL) as described in Example 1B. The resultant product was condensed with 4-morpholinecarbonyl chloride (568 mg, 3.8 mmol) as described in Example 2C. Purification by silica gel chromatography (elution with 20-50% acetone-hexanes) afforded the title compound (367 mg). G.
- Example 10F N-(4-Morpholine)carbonyl- ⁇ -(2-quinolyl)-L-alanine-L-leucine boronic acid
- the product of Example 10F (367 mg, 0.64 mmol) was deprotected according to the procedure described in Example 3B to provide the title compound (222 mg).
- Example 1 1B The product of Example 1 1B (762 mg, 4.3 mmol) was treated with di-tert-butyl pyrocarbonate (1.13 g, 5.17 mmol) according to the procedure described in Example 6B to afford the title compound (886 mg), as a foamy white solid.
- Example 12 Diethanolamine N-(4-morpholine)carbonyl- ⁇ -(1-naphthyl)-L- alanine-L-leucine boronate [MG-286]
- Example 12A To a solution of the product of Example 12A (9.7 g, 62 mmol) in CH 2 Cl 2 (150 mL) was added at room temperature (carbethoxymethylene) triphenylphosphorane (25 g, 71 mmol). The resultant mixture was stirred for 1.5 h, and the homogeneous yellow solution was then concentrated to dryness.
- Example 12B The product of Example 12B (15.3 g, 68 mmol) was dissolved in a mixture of EtOAc ( 100 mL) and MeOH ( 10 mL) and hydrogenated at 1 atm. over
- Example 12K By a procedure analogous to that described in Example 3B, the product of Example 12K (300 mg, 0.522 mmol) was deprotected to provide the title compound (150 mg).
- trans-4-hydroxy-L-proline (5.12 g, 0.039 mol) was treated with benzyl chloroformate (8.5 mL, 0.06 mol) to provide the title compound (6.0 g) as a white solid.
- Example 13D By a procedure analogous to that described in Example 12K, the product of Example 13D (250 mg, 0.72 mmol) was coupled with (1S,2S,3 R,5S)-pinanediol leucine boronate trifluoroacetate salt (300 mg, 0.79 mmol) in the presence of TBTU (302 mg, 0.79 mmol) to provide the title compound (355 mg) as a white solid.
- Example 13F By a procedure analogous to that described in Example 3B, the product of Example 13F (270 mg, 0.6 mmol) was deprotected to provide the title compound (130 mg) as a white solid.
- Example 14B The product of Example 14B (1.24 g, 3.64 mmol) was dissolved in acetone (15 mL) and aqueous NaOH (1M, 4 mL, 4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified with 10% HCl and extracted with EtOAc (3 ⁇ 60 mL). The combined organic extract was washed with water, dried (anhydrous MgSO 4 ), filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 30-50% acetone-hexanes and 70:30: 10 hexane:acetone:methanol) to give the title compound (0.61 g). C.
- Example 14B By a procedure analogous to that described in Example 2, the product of Example 14B (395 mg, 1.1 mmol) was coupled with (1S,2S,3R,5S)-pinanediol leucine boronate trifluoroacetate salt (415 mg, 1.1 mol) in the presence of BOP reagent (487 mg, 1.1 mmol) to afford the title compound (261 mg).
- Example 14C The product of Example 14C (261 mg, 0.43 mmol) was dissolved in CH 2 Cl 2 (10 mL) and treated at 0°C with trifluoroacetic acid (5 mL) and thioanisole (1 mL). After 2 h, solvents were evaporated. The residue was dissolved in CH 2 Cl 2 (10 mL) and cooled to 0°C. 8-Quinolinesulfonyl chloride (98 mg, 0.43 mmol) and triethylamine (0.12 mL, 0.86 mmol) were added. The reaction mixture was stirred at 0°C for 1 h and at room temperature for 15 h. The solvents were removed, water was added, and the product was extracted with EtOAc (3 ⁇ 50 mL).
- Example 14D 152 mg, 0.22 mmol was deprotected according to the procedure described in Example 3B to provide the title compound (12.7 mg).
- Example 16 cis-3-Phenyl-D,L-prrline-L-leucine boronic acid hydrochloride salt[MG-359]
- Trifluoroacetic acid (15.4 mL) was added slowly over 15 min to a solution of the product of Example 15A (7.0 g, 20.1 mmol) and triethylsilane (4.9 mL,
- Example 15B The product of Example 15B (5.9 g) was dissolved in 0.5N NaOH (200 mL) and the resultant solution was stirred at room temperature for 21 h. The solution was washed with EtOAc (75 mL) and then acidified to pH 2 with 3N HCl. The precipitated solids were extracted with CHCl 3 . The organic layer was concentrated to give a gummy residue, which was dissolved in toluene (70 mL) and heated at 75°C for 1 h. The solvent was evaporated to provide the title compound (4.2 g) as a light yellow oil.
- Example 15D The ester obtained in Example 15D (375 mg) was hydrolyzed by heating at reflux in 6N HCl (5 mL) for 17 h. The cooled reaction mixture was washed with EtOAc and the aqueous layer was concentrated to dryness. Recrystallization (MeOH-ether) afforded the title compound (201 mg).
- Example 15F By a procedure analogous to that described in Example 4B, the product of Example 15F (192 mg, 0.66 mmol) was coupled with (1S,2S,3R,5S)pinanediol leucine boronate trifluoroacetate salt (274 mg, 0.73 mmol) in the presence of TBTU (277 mg, 0.73 mmol) to provide the title compound (286 mg).
- Example 15G The product of Example 15G (262 mg) was dissolved in CH 2 Cl 2 (5 mL) and treated at 0°C with 4N HCl-dioxane (4 mL). After 2 h, the reaction mixture was concentrated to dryness, and the residue was treated with isobutylboronic acid (66 mg, 0.64 mmol) according to the procedure described in Example 3B to provide the title compound (71 mg) as a white solid.
- the oil (900 mg, 2.68 mmol) was dissolved in a mixture of HOAc (7 mL) and 8N HCl and the mixture was heated at reflux for 18 h. The mixture was concentrated to dryness. The residue was dissolved in water (30 mL), washed with EtOAc, and again concentrated to dryness.
- Table II summarizes results from kinetic experiments that measured the inhibition of the 20S proteasome by compounds having the formula of compound
- Table III demonstrates that dipeptide boronic acids have lower K i values than the corresponding dipeptide aldehydes.
- Table IV demonstrates the markedly superior selectivity for the 20S proteasome over other proteases, e.g. Cathepsin B, exhibited by the boronic esters/acids as compared to the peptide aldehydes.
- C2Cl2 cells (a mouse myoblast line) were labelled for 48 hrs with 3 5 S-methionine. The cells were then washed and preincubated for 2 hrs in the same media supplemented with 2mM unlabelled methionine. The media was removed and replaced with a fresh aliquot of the preincubation media containing 50% serum, and a concentration of the compound to be tested. The media was then removed and made up to 10% TCA and centrifuged. The TCA soluble radioactivity was counted. Inhibition of proteolysis was calculated as the percent decrease in TCA soluble radioactivity. From this data, an EC 50 for each compound was calculated.
- Rats were stabilized on a diet free from 3-methylhistidine and then placed in metabolic cages for collection of 24-hour urine samples. After two days of urine collections to determine basal 3-methylhistidine output, the rats were treated with daily subcutaneous injections of corticosterone (100 mg/kg).
- Example 21 MG-273 Inhibits the Activation of NF- ⁇ B
- Example 22 MG-273 Inhibits Expression of Cell Adhesion Molecules on
- HUVECs in microtiter plates were exposed to the indicated concentrations of inhibitor for 1 hour, prior to the addition of 100 U/mL TNF- ⁇ .
- Cell surface binding assays were performed at 4°C, using saturating concentrations of monoclonal antibodies specific for the cell adhesion molecules (Becton Dickenson) and fluorescent-conjugated F(ab') 2 goat anti-murine IgG (Caltag Labs, San Francisco, CA). Fluorescent immunoassays for E-selectin and I-CAM were performed at 4 hours, those for V-CAM at 16 hours.
- Figure 3 shows that cell -surface expression I-CAM, V-CAM, and E-selectin on TNF- ⁇ stimulated HUVECs is significantly inhibited by MG-273 at concentrations of 0.5 ⁇ M or above.
- Example 23 Boronic Acid Compounds Block the DTH Response in Mice
- Naive mice were sensitized by the application of 20 ⁇ L of a 0.5% (v/v) solution of 2,4-dinitrofluorobenzene in 4:1 acetone/olive oil to both of the rear limb footpads. This procedure is performed on two consecutive days, which are referred to as days 0 and 1.
- mice were lightly anaesthetized for this procedure by the intraperitoneal (i.p.) injection of a mixture of ketamine (80 mg/kg, Henry Schein) and xylazine (16 mg/kg, Henry Schein).
- Test compounds were administered orally as a suspension in 0.5% methylcellulose (4000 centipoises Fisher Scientific) 30 minutes prior to the application of the challenge dose of 2,4-dinitrofluorobenzene to the ears.
- the dose was delivered in a final volume of 0.5 mL using a 24 gauge 1 inch malleable feeding needle with a 1.25 mm ball tip (Roboz Surgical).
- ear swelling was determined by measuring both the control and the experimental ear using a Mitutoyo Digital micrometer. The absolute difference in thickness of the experimental (left) ears vs. the control (right) ears was determined for each treatment group. Efficacy was determined by comparing this difference in thickness to the difference calculated for the vehicle control group. Test results are provided in Table VII.
Abstract
Description
Claims
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002203936A CA2203936C (en) | 1994-10-28 | 1995-10-27 | Boronic ester and acid compounds, synthesis and uses |
AT95939670T ATE241631T1 (en) | 1994-10-28 | 1995-10-27 | BORONIC ACID AND ESTER COMPOUNDS, THEIR SYSTHESIS AND USES |
NZ296717A NZ296717A (en) | 1994-10-28 | 1995-10-27 | Boronic ester compound which reduces degradation of proteins |
EP95939670A EP0788360B3 (en) | 1994-10-28 | 1995-10-27 | Boronic ester and acid compounds, synthesis and uses |
DE69530936T DE69530936T3 (en) | 1994-10-28 | 1995-10-27 | BORONIC ACID AND ESTER COMPOUNDS, THEIR SYSTHESIS AND USES |
DE200412000025 DE122004000025I1 (en) | 1994-10-28 | 1995-10-27 | Boronic acid and ester compounds, their system and uses. |
JP51483496A JP3717934B2 (en) | 1994-10-28 | 1995-10-27 | Boronic esters and boronic acid compounds, synthesis and use |
DK05023462T DK1627880T3 (en) | 1994-10-28 | 1995-10-27 | Boron ester and acid compounds as well as synthesis and applications |
DE1995630936 DE122004000025I2 (en) | 1994-10-28 | 1995-10-27 | Boronic acid and ester compounds, their systheses and uses |
CH95939670T CH0788360H1 (en) | 1994-10-28 | 1995-10-27 | BORONIC ACID AND ESTER COMPOUNDS, THEIR SYNTHESIS AND USES. |
DK95939670.6T DK0788360T5 (en) | 1994-10-28 | 1995-10-27 | Boronic acid ester and acid compounds, their synthesis and applications |
AU41398/96A AU710564B2 (en) | 1994-10-28 | 1995-10-27 | Boronic ester and acid compounds, synthesis and uses |
FI971746A FI114801B (en) | 1994-10-28 | 1997-04-23 | Borester and acid compounds and their synthesis and use |
NO19971929A NO310558B1 (en) | 1994-10-28 | 1997-04-25 | Boric ester and acid compounds, pharmaceutical compositions and the use of boron compound for the manufacture of medicaments |
HK98100951A HK1002059A1 (en) | 1994-10-28 | 1998-02-07 | Boronic ester and acid compounds, synthesis and uses |
NL300151C NL300151I2 (en) | 1994-10-28 | 2004-05-14 | Boronic acid ester and boronic acid compounds, synthetic applications. |
FR04C0014C FR04C0014I2 (en) | 1994-10-28 | 2004-05-19 | |
LU91083C LU91083I2 (en) | 1994-10-28 | 2004-06-09 | Bortezomib or one of the pharmaceutically acceptable esters, optionally in the form of a pharmaceutically acceptable salt-Velcade. |
NO2004004C NO2004004I2 (en) | 1994-10-28 | 2004-08-06 | Bortezomib or a pharmaceutically acceptable ester thereof, optionally in the form of a pharmaceutically acceptable salt thereof |
FI20041415A FI120974B (en) | 1994-10-28 | 2004-11-03 | Boron ester and acid compounds and their use |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33052594A | 1994-10-28 | 1994-10-28 | |
US08/330,525 | 1994-10-28 | ||
US08/442,581 | 1995-05-16 | ||
US08/442,581 US6083903A (en) | 1994-10-28 | 1995-05-16 | Boronic ester and acid compounds, synthesis and uses |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996013266A1 true WO1996013266A1 (en) | 1996-05-09 |
Family
ID=26987313
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/014117 WO1996013266A1 (en) | 1994-10-28 | 1995-10-27 | Boronic ester and acid compounds, synthesis and uses |
Country Status (25)
Country | Link |
---|---|
US (16) | US6083903A (en) |
EP (4) | EP0788360B3 (en) |
JP (1) | JP3717934B2 (en) |
KR (1) | KR100398944B1 (en) |
CN (2) | CN1305475C (en) |
AT (3) | ATE411324T1 (en) |
AU (1) | AU710564B2 (en) |
CA (2) | CA2496538C (en) |
CH (1) | CH0788360H1 (en) |
CY (1) | CY2484B1 (en) |
DE (5) | DE69535866D1 (en) |
DK (3) | DK1627880T3 (en) |
ES (3) | ES2254803T3 (en) |
FI (2) | FI114801B (en) |
FR (1) | FR04C0014I2 (en) |
HK (2) | HK1002059A1 (en) |
IL (5) | IL137726A (en) |
LU (1) | LU91083I2 (en) |
MX (1) | MX9703063A (en) |
NL (1) | NL300151I2 (en) |
NO (2) | NO310558B1 (en) |
NZ (2) | NZ296717A (en) |
PT (3) | PT1312609E (en) |
TW (1) | TW318850B (en) |
WO (1) | WO1996013266A1 (en) |
Cited By (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2758329A1 (en) * | 1997-01-16 | 1998-07-17 | Synthelabo | New imidazole-4-butane-boronic acid derivatives |
WO1998035691A1 (en) * | 1997-02-15 | 1998-08-20 | Proscript, Inc. | Treatment of infarcts through inhibition of nf-kappab |
WO1999022729A1 (en) * | 1997-10-31 | 1999-05-14 | Centre De Recherche Du Centre Hospitalier De L'universite De Montreal | The use of proteasome inhibitors for treating cancer, inflammation, autoimmune disease, graft rejection and septic shock |
WO1999037666A1 (en) * | 1998-01-26 | 1999-07-29 | Cv Therapeutics, Inc. | α-KETOAMIDE INHIBITORS OF 20S PROTEASOME |
WO1999063998A1 (en) * | 1998-06-11 | 1999-12-16 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Novel use of hiv protease inhibiting compounds |
EP0982317A1 (en) * | 1998-08-26 | 2000-03-01 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Bivalent inhibitors of the proteasome |
WO2000023614A1 (en) * | 1998-10-20 | 2000-04-27 | Millennium Pharmaceuticals, Inc. | Method for monitoring proteasome inhibitor drug action |
WO2003033507A1 (en) * | 2001-10-12 | 2003-04-24 | Kyorin Pharmaceutical Co., Ltd. | Benzylmalonic acid derivatives and proteasome inhibitors contaiing the same |
WO2003059898A2 (en) * | 2002-01-08 | 2003-07-24 | Eisai Co. Ltd. | Eponemycin and epoxomicin analogs and uses thereof |
US6617171B2 (en) | 1998-02-27 | 2003-09-09 | The General Hospital Corporation | Methods for diagnosing and treating autoimmune disease |
WO2004016253A1 (en) * | 2002-08-14 | 2004-02-26 | Janssen Pharmaceutica N.V. | Use of nf-kappa b inhibitors for the treatment of mastitis |
EP1466917A1 (en) * | 2002-09-09 | 2004-10-13 | Trigen Limited | Method for making peptide boronic acids and acids obtainable thereby |
WO2005097809A3 (en) * | 2004-03-30 | 2006-02-16 | Millennium Pharm Inc | Synthesis of boronic ester and acid compounds |
WO2006077428A1 (en) | 2005-01-21 | 2006-07-27 | Astex Therapeutics Limited | Pharmaceutical compounds |
US7112572B2 (en) | 2002-09-09 | 2006-09-26 | Trigen Limited | Multivalent metal salts of boronic acids |
US7223745B2 (en) | 2003-08-14 | 2007-05-29 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
CN100341880C (en) * | 2003-02-13 | 2007-10-10 | 上海仁虎制药股份有限公司 | Boric acid and boric acid ester compound ,their preparing method and use in pharmacy |
WO2008044045A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
WO2008044041A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
US7442830B1 (en) | 2007-08-06 | 2008-10-28 | Millenium Pharmaceuticals, Inc. | Proteasome inhibitors |
WO2009019504A1 (en) | 2007-08-03 | 2009-02-12 | Summit Corporation Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
WO2009019505A2 (en) | 2007-08-03 | 2009-02-12 | Summit Corporation Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
WO2009020448A1 (en) * | 2007-08-06 | 2009-02-12 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
US7531517B2 (en) | 2005-08-10 | 2009-05-12 | 4Sc Ag | Inhibitors of cancer cell, T-cell and keratinocyte proliferation |
US7576206B2 (en) | 2003-08-14 | 2009-08-18 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
EP2100899A2 (en) | 2004-10-20 | 2009-09-16 | Proteolix, Inc. | Compounds for proteasome enzyme inhibition |
US7700543B2 (en) * | 1997-10-28 | 2010-04-20 | The University Of North Carolina At Chapel Hill | Use NF-κB inhibition in combination therapy for cancer |
WO2010105008A2 (en) | 2009-03-12 | 2010-09-16 | Genentech, Inc. | Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies |
WO2010106135A1 (en) | 2009-03-20 | 2010-09-23 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Combined use for the treatment of ovarian carcinoma |
WO2010145376A1 (en) * | 2009-06-19 | 2010-12-23 | 北京大学 | Tripeptide boronic acid or boronic ester, preparative method and use thereof |
EP2284178A2 (en) | 2005-08-10 | 2011-02-16 | 4Sc Ag | Inhibitors of cancer cell, T-cell and keratinocyte proliferation |
WO2011029802A1 (en) | 2009-09-08 | 2011-03-17 | F. Hoffmann-La Roche Ag | 4-substituted pyridin-3-yl-carboxamide compounds and methods of use |
EP2305285A1 (en) | 2009-09-29 | 2011-04-06 | Julius-Maximilians-Universität Würzburg | Means and methods for treating ischemic conditions |
US8071615B2 (en) | 2002-03-13 | 2011-12-06 | Janssen Pharmaceutica N.V. | Carbonylamino-derivatives as novel inhibitors of histone deacetylase |
US8080545B2 (en) | 2006-06-19 | 2011-12-20 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8088741B2 (en) | 2004-05-10 | 2012-01-03 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8114876B2 (en) | 2006-01-19 | 2012-02-14 | Janssen Pharmaceutica N.V. | Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase |
US8114999B2 (en) | 2002-03-13 | 2012-02-14 | Janssen Pharmaceutica N.V. | Aminocarbonyl-derivatives as novel inhibitors of histone deacetylase |
US8129346B2 (en) | 2004-04-15 | 2012-03-06 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
WO2012048745A1 (en) | 2010-10-14 | 2012-04-19 | Synthon Bv | Process for making bortezomib and intermediates for the process |
US8163733B2 (en) | 2002-03-13 | 2012-04-24 | Janssen Pharmaceutica N.V. | Sulfonylamino-derivatives as novel inhibitors of histone deacetylase |
US8198270B2 (en) | 2004-04-15 | 2012-06-12 | Onyx Therapeutics, Inc. | Compounds for proteasome enzyme inhibition |
WO2012133884A1 (en) | 2011-03-31 | 2012-10-04 | ナノキャリア株式会社 | Pharmaceutical composition containing block copolymer comprising boric acid compound |
US8283367B2 (en) | 2005-02-11 | 2012-10-09 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
US8367617B2 (en) | 2007-10-04 | 2013-02-05 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
US8501737B2 (en) | 2002-03-13 | 2013-08-06 | Janssen Pharmaceutica N.V. | Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase |
US8513218B2 (en) | 2010-03-31 | 2013-08-20 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclopropylethylboronic acid |
US8541590B2 (en) | 2009-12-22 | 2013-09-24 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
US8664200B2 (en) | 2008-09-29 | 2014-03-04 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
WO2014041324A1 (en) * | 2012-09-11 | 2014-03-20 | Cipla Limited | Process for preparing of bortezamib |
EP2733147A1 (en) * | 2008-06-17 | 2014-05-21 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US8853147B2 (en) | 2009-11-13 | 2014-10-07 | Onyx Therapeutics, Inc. | Use of peptide epoxyketones for metastasis suppression |
WO2015051067A1 (en) | 2013-10-03 | 2015-04-09 | Millennium Pharmaceuticals, Inc. | Method for the prophylaxis or treatment of systemic lupus erythematosus and/or lupus nephritis |
US9051353B2 (en) | 2009-03-20 | 2015-06-09 | Onyx Therapeutics, Inc. | Crystalline tripeptide epoxy ketone protease inhibitors |
US9114177B2 (en) | 2011-11-17 | 2015-08-25 | The University Of Tokyo | Block copolymer having phenylboronic acid group introduced therein, and use thereof |
EP2910557A1 (en) * | 2014-02-20 | 2015-08-26 | Ikerchem, S.L. | Enantiopure tetrasubstituted pyrrolidines as scaffolds for proteasome inhibitors and medicinal applications thereof |
US9150543B2 (en) | 2004-07-28 | 2015-10-06 | Janssen Pharmaceutica N. V. | Substituted indolyl alkyl amino derivatives as inhibitors of histone deacetylase |
US9205124B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
EP2251344B1 (en) | 2001-01-25 | 2016-03-30 | THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Formulation of boronic acid compounds |
US9309283B2 (en) | 2012-07-09 | 2016-04-12 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US9359398B2 (en) | 2010-03-01 | 2016-06-07 | Onyx Therapeutics, Inc. | Compounds for immunoproteasome inhibition |
US9511109B2 (en) | 2008-10-21 | 2016-12-06 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
EP3120837A1 (en) | 2015-07-22 | 2017-01-25 | Stada Arzneimittel Ag | Ready-to-use solution of bortezomib |
WO2018038687A1 (en) | 2016-08-22 | 2018-03-01 | Mustafa Nevzat Ilaç Sanayii A.Ş. | Pharmaceutical formulations comprising a bortezomib-cyclodextrin complex |
WO2018150386A1 (en) | 2017-02-17 | 2018-08-23 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of boronic acid esters |
WO2019040680A1 (en) | 2017-08-23 | 2019-02-28 | Krzar Life Sciences | Immunoproteasome inhibitors and immunosuppressive agent in the treatment of autoimmune disorders |
AU2018233007B2 (en) * | 2007-08-06 | 2020-07-23 | Takeda Pharmaceutical Company Limited | Proteasome inhibitors |
US10993960B1 (en) | 2014-05-08 | 2021-05-04 | Kawasaki Institute Of Industrial Promotion | Pharmaceutical composition |
US11241448B2 (en) | 2014-05-20 | 2022-02-08 | Millennium Pharmaceuticals, Inc. | Methods for cancer therapy |
US11267803B2 (en) | 2016-06-21 | 2022-03-08 | Orion Ophthalmology LLC | Carbocyclic prolinamide derivatives |
WO2022123530A1 (en) * | 2020-12-10 | 2022-06-16 | 주식회사 엘지화학 | Boronic acid compound |
US11377439B2 (en) | 2016-06-21 | 2022-07-05 | Orion Ophthalmology LLC | Heterocyclic prolinamide derivatives |
US11827656B2 (en) | 2017-11-16 | 2023-11-28 | Principia Biopharma Inc. | Immunoproteasome inhibitors |
Families Citing this family (231)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6083903A (en) * | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
US6838477B2 (en) * | 1995-04-12 | 2005-01-04 | President And Fellows Of Harvard College | Lactacystin analogs |
US6221888B1 (en) * | 1997-05-29 | 2001-04-24 | Merck & Co., Inc. | Sulfonamides as cell adhesion inhibitors |
JP2001517631A (en) * | 1997-09-25 | 2001-10-09 | ミレニアム・ファーマシューティカルズ・インコーポレイテッド | Proteasome inhibitors, ubiquitin pathway inhibitors, or agents that interfere with NF-κB activation via the ubiquitin proteasome pathway for treating inflammatory and autoimmune diseases |
TR200000815T2 (en) * | 1997-09-29 | 2000-12-21 | Point Therapeutics Inc. | Stimulation of hematopoietic cells in vitro. |
DE19802450A1 (en) * | 1998-01-23 | 1999-07-29 | Hoechst Marion Roussel De Gmbh | New saccharide compounds useful in treating schizophrenia |
US6462019B1 (en) | 1998-07-10 | 2002-10-08 | Osteoscreen, Inc. | Inhibitors of proteasomal activity and production for stimulating bone growth |
US6902721B1 (en) | 1998-07-10 | 2005-06-07 | Osteoscreen, Inc. | Inhibitors of proteasomal activity for stimulating bone growth |
US6838436B1 (en) * | 1998-07-10 | 2005-01-04 | Osteoscreen Inc. | Inhibitors of proteasomal activity for stimulating bone growth |
US6979697B1 (en) * | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
US6492333B1 (en) | 1999-04-09 | 2002-12-10 | Osteoscreen, Inc. | Treatment of myeloma bone disease with proteasomal and NF-κB activity inhibitors |
US6890904B1 (en) * | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
US6649593B1 (en) * | 1999-10-13 | 2003-11-18 | Tularik Inc. | Modulators of SREBP processing |
US20040039129A1 (en) * | 2000-08-16 | 2004-02-26 | Hall Dennis G. | Non-pressurized methods for the preparation of conjugrated solid supports for boronic acids |
US6919382B2 (en) | 2000-08-31 | 2005-07-19 | The Governors Of The University Of Alberta | Preparation and uses of conjugated solid supports for boronic acids |
PT1326632E (en) * | 2000-10-12 | 2007-01-31 | Viromics Gmbh | Proteasome inhibitors for the treatment of hepatitis virus infections |
US7112588B2 (en) * | 2001-05-21 | 2006-09-26 | Alcon, Inc. | Use of proteasome inhibitors to treat dry eye disorders |
CA2447909C (en) | 2001-05-21 | 2011-04-05 | Alcon, Inc. | Use of proteasome inhibitors to treat dry eye disorders |
DE60209227T2 (en) * | 2001-05-30 | 2006-08-17 | Novartis Ag | 2 - ((N- (2-AMINO-3- (HETEROARYL- OR -ARYL) PROPIONYL) AMINOACYL) AMINO) -ALKYLBORONIC ACID DERIVATIVES |
JPWO2003033506A1 (en) * | 2001-10-12 | 2005-02-03 | 杏林製薬株式会社 | Aminoboranoic acid derivatives and proteasome inhibitors containing the same |
WO2003077928A1 (en) * | 2002-03-12 | 2003-09-25 | Ariad Pharmaceuticals, Inc. | Peptide analogues and uses thereof |
US20050203029A1 (en) * | 2002-04-05 | 2005-09-15 | Ulrich Schubert | Agents for treating <I>flaviviridae</I>infections |
WO2003106384A2 (en) * | 2002-06-01 | 2003-12-24 | Johns Hopkins University | Novel boronic chalcone derivatives and uses thereof |
AU2003248921A1 (en) * | 2002-07-09 | 2004-01-23 | Point Therapeutics, Inc. | Boroproline compound combination therapy |
US20050176651A1 (en) * | 2002-09-09 | 2005-08-11 | Trigen Limited | Peptide boronic acids useful in making salts thereof |
US20060084592A1 (en) * | 2002-09-09 | 2006-04-20 | Trigen Limited | Peptide boronic acid inhibitors |
US20050282757A1 (en) * | 2002-09-09 | 2005-12-22 | Trigen Limited | Peptide boronic acid compounds useful in anticoagulation |
US20050119226A1 (en) * | 2003-09-09 | 2005-06-02 | Trigen Limited | Methods for synthesizing organoboronic compounds and products thereof |
CA2497977A1 (en) * | 2002-09-20 | 2004-04-01 | Alcon, Inc. | Use of cytokine synthesis inhibitors for the treatment of dry eye disorders |
MXPA05005923A (en) | 2002-12-06 | 2005-09-21 | Millennium Pharm Inc | Methods for the identification, assessment, and treatment of patients with proteasome inhibition therapy. |
WO2005007211A2 (en) * | 2003-07-03 | 2005-01-27 | Medtronic Vascular Inc. | Medical devices with proteasome inhibitors for the treatment of restenosis |
CA2542886A1 (en) | 2003-11-05 | 2005-05-19 | Neelima M. Bhat | Enhanced b cell cytotoxicity of cdim binding antibody |
US20060052390A1 (en) * | 2003-12-24 | 2006-03-09 | Scios, Inc. | Treatment of multiple myeloma by p38 MAP kinase and proteasome inhibition |
US20050203027A1 (en) * | 2004-02-23 | 2005-09-15 | Trustees Of Tufts College | Inhibitors of dipeptidylpeptidase IV |
GB0405272D0 (en) * | 2004-03-09 | 2004-04-21 | Trigen Ltd | Compounds |
US7371875B2 (en) * | 2004-03-12 | 2008-05-13 | Miikana Therapeutics, Inc. | Cytotoxic agents and methods of use |
AU2016202747B2 (en) * | 2004-03-30 | 2017-11-23 | Millennium Pharmaceuticals, Inc. | Synthesis of boronic ester and acid compounds |
WO2006002422A2 (en) | 2004-06-24 | 2006-01-05 | Novartis Vaccines And Diagnostics Inc. | Compounds for immunopotentiation |
US7842707B2 (en) | 2004-07-23 | 2010-11-30 | Nuada, Llc | Peptidase inhibitors |
BRPI0517057A (en) | 2004-11-05 | 2008-09-30 | Palingen Inc | composition to induce cell membrane injury; composition for increasing cell membrane injury in a lymphoid cell; composition to permeabilize a cell; composition to induce cell membrane injury in b cells; composition for increasing cell membrane injury induced by a cell membrane injury antibody; method of treating a mammal suffering from a distinct condition due to hyperproliferation of cells; method for killing a cancer cell; method for inducing cell membrane injury in a lymphoid cell in a human patient; method for inducing cell membrane injury; method for permeabilizing a cell; method of purging the bone marrow of malignant b cells from a patient with this need; kit for determining the dose limit for a multipurpose agent that induces injury to the cell membrane in a mammal; kit for determining the dose limit for a cell membrane injury antibody in a mammal; use of a polyvalent cell membrane injury agent; and use of a cell membrane injury antibody |
TW200618820A (en) * | 2004-11-05 | 2006-06-16 | Alza Corp | Liposome formulations of boronic acid compounds |
US8017395B2 (en) | 2004-12-17 | 2011-09-13 | Lifescan, Inc. | Seeding cells on porous supports |
US20070098685A1 (en) * | 2005-01-19 | 2007-05-03 | Brand Stephen J | Methods and kits to treat chronic inflammatory immune diseases by administering a proteasome inhibitor and an interleukin 2 receptor agonist |
US20090018146A1 (en) * | 2005-01-27 | 2009-01-15 | Research Development Corporation | Combination Therapy with Triterpenoid Compounds and Proteasome Inhibitors |
ES2872962T3 (en) | 2005-02-16 | 2021-11-03 | Anacor Pharmaceuticals Inc | Boronophthalides for therapeutic use |
EP1863513A2 (en) * | 2005-03-11 | 2007-12-12 | The University of North Carolina at Chapel Hill | Potent and specific immunoproteasome inhibitors |
WO2006119032A1 (en) * | 2005-04-29 | 2006-11-09 | Kosan Biosciences Incorporated | Method of treating multiple myeloma using 17-aag or 17-ag or a prodrug of either in combination with a proteasome inhibitor |
JP5055268B2 (en) | 2005-05-18 | 2012-10-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Substituted aminopropenyl piperidine or morpholine derivatives as novel inhibitors of histone deacetylase |
AU2006202209B2 (en) * | 2005-05-27 | 2011-04-14 | Lifescan, Inc. | Amniotic fluid derived cells |
PL1888123T3 (en) * | 2005-06-08 | 2013-06-28 | Janssen Biotech Inc | A cellular therapy for ocular degeneration |
EP1912664A2 (en) * | 2005-07-06 | 2008-04-23 | Biodevelops Pharma Entwicklung GmbH | Use of a compound for enhancing the expression of membrane proteins on the cell surface |
US20070059382A1 (en) * | 2005-09-09 | 2007-03-15 | Board Of Regents, Univ. And Comm. College System Of Nevada... | Medical treatment of breast cancer with boric acid materials |
WO2007067752A2 (en) * | 2005-12-08 | 2007-06-14 | Cytokinetics, Inc. | Certain compositions and methods of treatment |
CN106008571A (en) | 2005-12-30 | 2016-10-12 | 安纳考尔医药公司 | Boron-containing small molecules |
US8101616B2 (en) * | 2006-01-19 | 2012-01-24 | Janssen Pharmaceutica N.V. | Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase |
CN101370803B (en) * | 2006-01-19 | 2012-12-12 | 詹森药业有限公司 | Substituted indolyl-alkyl-amino-derivatives as inhibitors of histone deacetylase |
PL1981874T3 (en) * | 2006-01-19 | 2009-10-30 | Janssen Pharmaceutica Nv | Aminophenyl derivatives as novel inhibitors of histone deacetylase |
JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | PI-3 Kinase inhibitors and methods of their use |
PE20070978A1 (en) * | 2006-02-14 | 2007-11-15 | Novartis Ag | HETEROCICLIC COMPOUNDS AS INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASES (PI3Ks) |
KR101622870B1 (en) | 2006-02-16 | 2016-05-19 | 아나코르 파마슈티칼스 인코포레이티드 | Boron-containing small molecules as anti-inflammatory agents |
AR060358A1 (en) * | 2006-04-06 | 2008-06-11 | Novartis Vaccines & Diagnostic | QUINAZOLINS FOR THE INHIBITION OF PDK 1 |
US8741643B2 (en) * | 2006-04-28 | 2014-06-03 | Lifescan, Inc. | Differentiation of pluripotent stem cells to definitive endoderm lineage |
DE102006026464A1 (en) | 2006-06-01 | 2007-12-06 | Virologik Gmbh Innovationszentrum Medizintechnik Und Pharma | Pharmaceutical composition for the treatment of viral infections and / or tumors by inhibiting protein folding and protein degradation |
WO2007143600A2 (en) * | 2006-06-05 | 2007-12-13 | Incyte Corporation | Sheddase inhibitors combined with cd30-binding immunotherapeutics for the treatment of cd30 positive diseases |
EA020276B1 (en) * | 2006-09-15 | 2014-10-30 | Янссен Фармацевтика Нв | Histone deacetylase inhibitors with combined activity on class-i and class-iib histone deacetylases in combination with proteasome inhibitors |
CA2662432A1 (en) * | 2006-09-15 | 2008-03-20 | Janssen Pharmaceutica Nv | Combinations of class-i specific histone deacetylase inhibitors with proteasome inhibitors |
AU2007221966A1 (en) * | 2006-12-08 | 2008-06-26 | Centenary Institute Of Cancer Medicine And Cell Biology | Assay for response to proteasome inhibitors |
JO3396B1 (en) | 2007-06-20 | 2019-10-20 | Anacor Pharmaceuticals Inc | Boron-containing small molecules |
US9080145B2 (en) | 2007-07-01 | 2015-07-14 | Lifescan Corporation | Single pluripotent stem cell culture |
WO2009018453A1 (en) | 2007-07-31 | 2009-02-05 | Lifescan, Inc. | Differentiation of human embryonic stem cells |
EA034601B1 (en) * | 2007-08-06 | 2020-02-25 | Милленниум Фармасьютикалз, Инк. | Process for producing boronic acids |
BRPI0816807A2 (en) * | 2007-09-12 | 2017-05-16 | Dr Reddy's Laboratories Inc | bortezomib and process for the production thereof |
US20090076031A1 (en) * | 2007-09-17 | 2009-03-19 | Protia, Llc | Deuterium-enriched bortezomib |
US7838673B2 (en) * | 2007-10-16 | 2010-11-23 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
US20090110688A1 (en) * | 2007-10-24 | 2009-04-30 | Georg Fertig | Combination therapy of type ii anti-cd20 antibody with a proteasome inhibitor |
CN101878298B (en) * | 2007-11-27 | 2017-08-15 | 生命扫描有限公司 | The differentiation of human embryo stem cell |
CN101220048B (en) * | 2007-12-14 | 2012-08-15 | 江苏先声药物研究有限公司 | Method for preparing pinane diol ester under ZnCl2 catalysis |
CN101952282A (en) | 2007-12-20 | 2011-01-19 | 诺瓦提斯公司 | Thiazole derivatives used as PI 3 kinase inhibitors |
KR101731474B1 (en) | 2008-02-21 | 2017-05-11 | 얀센 바이오테크 인코포레이티드 | Methods, surface modified plates and compositions for cell attachment, cultivation and detachment |
MX2010009765A (en) | 2008-03-06 | 2013-07-12 | Anacor Pharmaceuticals Inc | Boron-containing small molecules as anti-inflammatory agents. |
EP2285384A4 (en) * | 2008-05-12 | 2012-04-25 | Anacor Pharmaceuticals Inc | Boron-containing small molecules |
KR101829310B1 (en) | 2008-06-30 | 2018-02-14 | 얀센 바이오테크 인코포레이티드 | Differentiation of pluripotent stem cells |
CN101638414B (en) * | 2008-07-30 | 2014-01-08 | 江苏先声药物研究有限公司 | Peptidyl boronic acid, ester compound thereof, preparation method of peptidyl boronic acid and ester compound thereof, and use of peptidyl boronic acid and ester compound thereof |
US20100028307A1 (en) * | 2008-07-31 | 2010-02-04 | O'neil John J | Pluripotent stem cell differentiation |
WO2010027975A1 (en) * | 2008-09-04 | 2010-03-11 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
WO2010028005A1 (en) | 2008-09-04 | 2010-03-11 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
WO2010045503A1 (en) * | 2008-10-15 | 2010-04-22 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as anti-protozoal agents |
MX349178B (en) | 2008-10-31 | 2017-07-17 | Centocor Ortho Biotech Inc | Differentiation of human embryonic stem cells to the pancreatic endocrine lineage. |
ES2634445T3 (en) | 2008-10-31 | 2017-09-27 | Janssen Biotech, Inc. | Differentiation of human embryonic stem cells with pancreatic endocrine lineage |
JP5719305B2 (en) * | 2008-11-20 | 2015-05-13 | ヤンセン バイオテツク,インコーポレーテツド | Methods and compositions for cell attachment and culture on a planar support |
MX356756B (en) | 2008-11-20 | 2018-06-11 | Centocor Ortho Biotech Inc | Pluripotent stem cell culture on micro-carriers. |
CN101747354B (en) * | 2008-12-04 | 2014-08-13 | 江苏先声药物研究有限公司 | Dipeptide boronic acids consisting of beta amino acids, ester compounds and preparation methods and uses thereof |
PE20120052A1 (en) * | 2008-12-17 | 2012-02-13 | Anacor Pharmaceuticals Inc | (S) -3-AMINO-METHYL-7- (3-HYDROXY-PROPOXY) -3H-BENZO- [C] [1,2] -OXABOROL-1-OL POLYMORPHES |
CA2748921A1 (en) | 2009-01-09 | 2010-08-12 | Sun Pharma Advanced Research Company Limited | Bortezumib containing pharmaceutical composition |
EP3021120A1 (en) | 2009-02-20 | 2016-05-18 | Michael P. Lisanti | Diagnosis, prognosis, therapeutics and methods for treating neoplastic deiseases comprising determining the level of caveolin-1 in a stromal cell sample |
HUE027639T2 (en) * | 2009-03-24 | 2016-11-28 | Janssen Pharmaceutica Nv | Biomarkers for assessing peripheral neuropathy response to treatment with a proteasome inhibitor |
WO2010114768A1 (en) * | 2009-03-30 | 2010-10-07 | Cerulean Pharma Inc. | Polymer-epothilone conjugates, particles, compositions, and related methods of use |
WO2010117668A1 (en) * | 2009-03-30 | 2010-10-14 | Cerulean Pharma Inc. | Polymer-agent conjugates, particles, compositions, and related methods of use |
WO2010114770A1 (en) * | 2009-03-30 | 2010-10-07 | Cerulean Pharma Inc. | Polymer-agent conjugates, particles, compositions, and related methods of use |
CA2763471A1 (en) * | 2009-05-27 | 2010-12-02 | Cephalon, Inc. | Combination therapy for the treatment of multiple myeloma |
EP2270019A1 (en) | 2009-06-19 | 2011-01-05 | LEK Pharmaceuticals d.d. | New synthetic route for the preparation of alpha-amino boronic esters |
EP2280016A1 (en) | 2009-07-27 | 2011-02-02 | LEK Pharmaceuticals d.d. | New synthetic route for the preparation of alpha-amino boronic esters via substituted alk-1-ynes |
CN102803271B (en) | 2009-06-19 | 2016-03-23 | 力奇制药公司 | Hydrogenation haloolefin and the method for not dehalogenation |
US8293753B2 (en) | 2009-07-02 | 2012-10-23 | Novartis Ag | Substituted 2-carboxamide cycloamino ureas |
DE102009027754A1 (en) | 2009-07-15 | 2011-05-05 | Schubert, Ulrich, Dr. | Method for inhibiting the maturation of dendritic cells |
RU2540021C2 (en) * | 2009-07-20 | 2015-01-27 | Янссен Байотек, Инк. | Differentiating human embryonic stem cells |
CN103952372B (en) | 2009-07-20 | 2016-10-05 | 詹森生物科技公司 | The differentiation of human embryo stem cell |
AU2010276438B2 (en) | 2009-07-20 | 2015-06-11 | Janssen Biotech Inc. | Differentiation of human embryonic stem cells |
EP2458995A1 (en) * | 2009-07-28 | 2012-06-06 | Anacor Pharmaceuticals, Inc. | Trisubstituted boron-containing molecules |
WO2011019618A1 (en) * | 2009-08-14 | 2011-02-17 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as antiprotozoal agents |
WO2011022502A1 (en) | 2009-08-18 | 2011-02-24 | Georgetown University | Boronic acid compositions and methods related to cancer |
WO2011022337A1 (en) * | 2009-08-19 | 2011-02-24 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as antiprotozoal agents |
US20110124597A1 (en) * | 2009-09-25 | 2011-05-26 | Anacor Pharmaceuticals, Inc. | Boron containing small molecules |
HUE032571T2 (en) | 2009-10-01 | 2017-09-28 | Janssen Pharmaceutica Nv | Proteasome inhibitors for treating cancer |
US9346834B2 (en) | 2009-10-20 | 2016-05-24 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as antiprotozoal agents |
US8461134B2 (en) * | 2009-11-11 | 2013-06-11 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
WO2011079017A2 (en) | 2009-12-23 | 2011-06-30 | Centocor Ortho Biotech Inc. | Differentiation of human embryonic stem cells |
WO2011079018A2 (en) | 2009-12-23 | 2011-06-30 | Centocor Ortho Biotech Inc. | Differentiation of human embryonic stem cells |
US20110178287A1 (en) | 2010-01-19 | 2011-07-21 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutic delivery |
WO2011094450A1 (en) | 2010-01-27 | 2011-08-04 | Anacor Pharmaceuticals, Inc | Boron-containing small molecules |
CN102791851B (en) | 2010-03-01 | 2017-07-14 | 詹森生物科技公司 | The method of cell of the purifying derived from multipotential stem cell |
KR101530942B1 (en) * | 2010-03-18 | 2015-06-23 | 이노파르마, 인코포레이티드 | Stable bortezomib formulations |
US8263578B2 (en) | 2010-03-18 | 2012-09-11 | Innopharma, Inc. | Stable bortezomib formulations |
US8623911B2 (en) | 2010-03-19 | 2014-01-07 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as anti-protozoal agent |
CA2793959C (en) | 2010-03-25 | 2019-06-04 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
AU2013204868B2 (en) * | 2010-03-31 | 2016-10-13 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclopropylethylboronic acid |
AU2011245630B2 (en) | 2010-04-07 | 2014-07-03 | Onyx Therapeutics, Inc. | Crystalline peptide epoxyketone immunoproteasome inhibitor |
CN101812026B (en) * | 2010-04-12 | 2013-08-28 | 亚邦医药股份有限公司 | Method for synthesizing bortezomib |
EP2560647B1 (en) | 2010-04-19 | 2016-04-13 | Niiki Pharma Inc. | Combination therapy with a proteasome inhibitor and a gallium complex |
WO2011139379A2 (en) | 2010-05-06 | 2011-11-10 | Duke University | A method of treating patients undergoing protein replacement therapy, gene replacement therapy, or other therapeutic modalities |
EP3498825A1 (en) | 2010-05-12 | 2019-06-19 | Janssen Biotech, Inc. | Differentiation of human embryonic stem cells |
EP2571525A4 (en) | 2010-05-18 | 2016-04-27 | Cerulean Pharma Inc | Compositions and methods for treatment of autoimmune and other diseases |
AR082418A1 (en) | 2010-08-02 | 2012-12-05 | Novartis Ag | CRYSTAL FORMS OF 1- (4-METHYL-5- [2- (2,2,2-TRIFLUORO-1,1-DIMETHYL-Ethyl) -PIRIDIN-4-IL] -TIAZOL-2-IL) -AMIDE OF 2 -AMIDA OF THE ACID (S) -PIRROLIDIN-1,2-DICARBOXILICO |
MX355340B (en) | 2010-08-31 | 2018-04-16 | Janssen Biotech Inc | Differentiation of human embryonic stem cells. |
SG187947A1 (en) | 2010-08-31 | 2013-03-28 | Janssen Biotech Inc | Differentiation of pluripotent stem cells |
WO2012030539A2 (en) | 2010-08-31 | 2012-03-08 | Janssen Biotech, Inc. | Differentiation of human embryonic stem cells |
CN103140228A (en) | 2010-09-07 | 2013-06-05 | 阿纳科制药公司 | Benzoxaborole derivatives for treating bacterial infections |
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 |
EP2624818B1 (en) | 2010-10-05 | 2017-04-05 | Fresenius Kabi USA, LLC | Bortezomib formulations stabilised with boric acid |
TW201309700A (en) | 2011-01-31 | 2013-03-01 | Novartis Ag | Novel heterocyclic derivatives |
TW201309303A (en) * | 2011-03-03 | 2013-03-01 | Cephalon Inc | Proteasome inhibitor for the treatment of lupus |
WO2012135528A2 (en) | 2011-03-29 | 2012-10-04 | Texas Tech University System | Galectin-3c combination therapy for human cancer |
AU2012267786B2 (en) | 2011-06-10 | 2017-08-03 | Oregon Health & Science University | CMV glycoproteins and recombinant vectors |
JP5944986B2 (en) * | 2011-06-22 | 2016-07-05 | セファロン、インク. | Proteasome inhibitors and processes for their preparation, purification, and use |
US8481655B2 (en) | 2011-07-27 | 2013-07-09 | Wacker Chemical Corporation | Copper complexes of amino-functional organosilicon compounds and their use |
AU2012294493B2 (en) | 2011-08-11 | 2017-02-23 | Janssen Pharmaceutica Nv | Predictors for cancer treatment |
WO2013021032A1 (en) | 2011-08-11 | 2013-02-14 | Janssen Pharmaceutica Nv | Histone deacetylase inhibitors in combination with proteasome inhibitors and dexamethasone |
CA2844086A1 (en) | 2011-08-19 | 2013-02-28 | Glaxo Group Limited | Benzofuran compounds for the treatment of hepatitis c virus infections |
HRP20221320T1 (en) | 2011-08-30 | 2023-01-06 | Trustees Of Tufts College | Fap-activated proteasome inhibitors for treating solid tumors |
AU2012216792A1 (en) | 2011-09-12 | 2013-03-28 | International Aids Vaccine Initiative | Immunoselection of recombinant vesicular stomatitis virus expressing HIV-1 proteins by broadly neutralizing antibodies |
US9402894B2 (en) | 2011-10-27 | 2016-08-02 | International Aids Vaccine Initiative | Viral particles derived from an enveloped virus |
JP6238900B2 (en) | 2011-10-28 | 2017-11-29 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | Biomarkers of response to NAE inhibitors |
MX340452B (en) | 2011-10-28 | 2016-07-08 | Novartis Ag | Novel purine derivatives and their use in the treatment of disease. |
EP2776586B1 (en) | 2011-11-11 | 2018-03-07 | Millennium Pharmaceuticals, Inc. | Biomarkers of response to proteasome inhibitors |
EP2776043B1 (en) | 2011-11-11 | 2018-02-21 | Millennium Pharmaceuticals, Inc. | Biomarkers of response to proteasome inhibitors |
RU2705001C2 (en) | 2011-12-22 | 2019-11-01 | Янссен Байотек, Инк. | Differentiation of human embryonic stem cells into single-hormonal insulin-positive cells |
US9732101B2 (en) | 2012-01-18 | 2017-08-15 | Wisconsin Alumni Research Foundation | Bioreversible boronates for delivery of molecules into cells |
US9234048B2 (en) | 2012-01-18 | 2016-01-12 | Wisconsin Alumni Research Foundation | Boronate-mediated delivery of molecules into cells |
JP6215235B2 (en) | 2012-01-24 | 2017-10-18 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | How to treat cancer |
US10085987B2 (en) | 2012-01-27 | 2018-10-02 | Thomas Jefferson University | MCT protein inhibitor-related prognostic and therapeutic methods |
JP6335796B2 (en) | 2012-02-08 | 2018-06-06 | アイジーエム バイオサイエンシズ インク.Igm Biosciences Inc. | CDIM binding protein and use thereof |
AU2013227219A1 (en) | 2012-03-02 | 2014-10-23 | Dr. Reddy's Laboratories Limited | Pharmaceutical compositions comprising boronic acid compounds |
JP6383292B2 (en) | 2012-03-07 | 2018-08-29 | ヤンセン バイオテツク,インコーポレーテツド | Clear media for proliferation and maintenance of pluripotent stem cells |
CA2784240C (en) | 2012-03-27 | 2014-07-08 | Innopharma, Inc. | Stable bortezomib formulations |
AU2013263043B2 (en) | 2012-05-16 | 2016-06-16 | Novartis Ag | Dosage regimen for a PI-3 kinase inhibitor |
JP6469003B2 (en) | 2012-06-08 | 2019-02-13 | ヤンセン バイオテツク,インコーポレーテツド | Differentiation of human embryonic stem cells into pancreatic endocrine cells |
EP2679596B1 (en) | 2012-06-27 | 2017-04-12 | International Aids Vaccine Initiative | HIV-1 env glycoprotein variant |
JP2013006855A (en) * | 2012-09-03 | 2013-01-10 | Millennium Pharmaceuticals Inc | Proteasome inhibitor |
JP6486826B2 (en) | 2012-10-01 | 2019-03-20 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | Biomarkers and methods for predicting response to inhibitors and uses thereof |
WO2014072985A1 (en) | 2012-11-06 | 2014-05-15 | Natco Pharma Limited | Novel boronic acid derivatives as anti cancer agents |
EP2919786A4 (en) | 2012-11-16 | 2016-06-01 | Shilpa Medicare Ltd | Crystalline bortezomib process |
WO2014097306A1 (en) | 2012-12-21 | 2014-06-26 | Natco Pharma Limited | Stable and pure polymorphic form of bortezomib |
BR112015015714A2 (en) | 2012-12-31 | 2017-07-11 | Janssen Biotech Inc | suspension and agglomeration of human pluripotent cells for differentiation into pancreatic endocrine cells |
ES2837763T3 (en) | 2012-12-31 | 2021-07-01 | Janssen Biotech Inc | Culture of human embryonic stem cells in the air-liquid interface for differentiation into pancreatic endocrine cells |
US10370644B2 (en) | 2012-12-31 | 2019-08-06 | Janssen Biotech, Inc. | Method for making human pluripotent suspension cultures and cells derived therefrom |
ES2942484T3 (en) | 2012-12-31 | 2023-06-01 | Janssen Biotech Inc | Differentiation of human embryonic stem cells into pancreatic endocrine cells using HB9 regulators |
CA2905751A1 (en) | 2013-03-13 | 2014-10-09 | Forma Therapeutics, Inc. | Novel compounds and compositions for inhibition of fasn |
EP2986619A1 (en) | 2013-04-16 | 2016-02-24 | Cipla Limited | Process for the preparation of bortezomib mannitol ester |
WO2014172627A1 (en) | 2013-04-19 | 2014-10-23 | Thomas Jefferson University | Caveolin-1 related methods for treating glioblastoma with temozolomide |
US9603775B2 (en) | 2013-04-24 | 2017-03-28 | Corning Incorporated | Delamination resistant pharmaceutical glass containers containing active pharmaceutical ingredients |
WO2015003146A1 (en) | 2013-07-03 | 2015-01-08 | Georgetown University | Boronic acid derivatives of resveratrol for activating deacetylase enzymes |
EP2848937A1 (en) | 2013-09-05 | 2015-03-18 | International Aids Vaccine Initiative | Methods of identifying novel HIV-1 immunogens |
US10058604B2 (en) | 2013-10-07 | 2018-08-28 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
CN104586776B (en) * | 2013-10-30 | 2017-05-17 | 扬子江药业集团上海海尼药业有限公司 | Preparation taking bortezomib as active composition and preparation method thereof |
WO2015076359A1 (en) * | 2013-11-21 | 2015-05-28 | 国立大学法人北海道大学 | Proteasome-inhibiting compound |
EP3077823B1 (en) | 2013-12-05 | 2019-09-04 | The Broad Institute, Inc. | Compositions and methods for identifying and treating cachexia or pre-cachexia |
TN2016000179A1 (en) | 2013-12-06 | 2017-10-06 | Novartis Ag | Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor. |
EP3102585B1 (en) | 2014-02-03 | 2021-05-19 | Ohio State Innovation Foundation | Boronic acid esters and pharmaceutical formulations thereof |
CA2949056A1 (en) | 2014-05-16 | 2015-11-19 | Janssen Biotech, Inc. | Use of small molecules to enhance mafa expression in pancreatic endocrine cells |
EP4180041A1 (en) | 2014-08-07 | 2023-05-17 | Mayo Foundation for Medical Education and Research | Compounds and methods for treating cancer |
WO2016050356A1 (en) * | 2014-10-01 | 2016-04-07 | Merck Patent Gmbh | Boronic acid derivatives |
WO2016110870A1 (en) | 2015-01-07 | 2016-07-14 | Emcure Pharmaceuticals Limited | Pharmaceutical composition of bortezomid |
MA41505A (en) | 2015-02-11 | 2017-12-19 | Millennium Pharm Inc | NEW CRYSTALLINE FORM OF A PROTEASOME INHIBITOR |
JP2018510859A (en) | 2015-03-17 | 2018-04-19 | レオン−ナノドラッグズ ゲーエムベーハー | Nanoparticles containing stabilized boronic acid compounds |
US10174292B2 (en) | 2015-03-20 | 2019-01-08 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
EP3072901A1 (en) | 2015-03-23 | 2016-09-28 | International Aids Vaccine Initiative | Soluble hiv-1 envelope glycoprotein trimers |
WO2016184793A1 (en) | 2015-05-15 | 2016-11-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for treating a patient with vegfr inhibitor-resistant metastatic renal cell carcinoma |
WO2016205790A2 (en) | 2015-06-19 | 2016-12-22 | Hanlin Scientific, Inc. | Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis |
CN106478700B (en) * | 2015-08-26 | 2020-12-29 | 杭州雷索药业有限公司 | Boron-substituted aniline protein kinase inhibitor |
CN106588965A (en) * | 2015-10-15 | 2017-04-26 | 北京大学 | Urea peptidomimetic boric acid compound as well as pharmaceutical composition, preparation method and application thereof |
MX2018005298A (en) | 2015-11-02 | 2018-06-22 | Novartis Ag | Dosage regimen for a phosphatidylinositol 3-kinase inhibitor. |
EP3389715A4 (en) | 2015-12-14 | 2019-06-12 | David K. Thomas | Compositions and methods for treating cardiac dysfunction |
CN107151255A (en) * | 2016-03-06 | 2017-09-12 | 复旦大学 | Boric acid compound and its production and use |
CN107151254A (en) * | 2016-03-06 | 2017-09-12 | 复旦大学 | It is a kind of to be used as boric acid compound of 20S proteasome inhibitors and preparation method thereof |
MA45479A (en) | 2016-04-14 | 2019-02-20 | Janssen Biotech Inc | DIFFERENTIATION OF PLURIPOTENT STEM CELLS IN ENDODERMAL CELLS OF MIDDLE INTESTINE |
US11447506B2 (en) | 2016-05-09 | 2022-09-20 | Anacor Pharmaceuticals, Inc. | Crystal forms of crisaborole in free form and preparation method and use thereof |
CN106008572B (en) * | 2016-05-23 | 2018-08-17 | 成都千禧莱医药科技有限公司 | A kind of dipeptide boronic acid compound and preparation method and purposes |
JP6681284B2 (en) * | 2016-06-23 | 2020-04-15 | 信越化学工業株式会社 | Method for reducing metal of sugar alcohol compound |
JP6223508B2 (en) * | 2016-06-27 | 2017-11-01 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | Proteasome inhibitor |
WO2018060833A1 (en) | 2016-09-27 | 2018-04-05 | Novartis Ag | Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib |
WO2018073790A1 (en) | 2016-10-20 | 2018-04-26 | Pfizer Inc. | Therapeutic particles with peptide boronic acid or boronate ester compounds and methods of making and using same |
US11584733B2 (en) | 2017-01-09 | 2023-02-21 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
WO2018129533A1 (en) | 2017-01-09 | 2018-07-12 | Shuttle Pharmaceuticals, Llc | Selective histone deacetylase inhibitors for the treatment of human disease |
US11596629B2 (en) | 2017-02-28 | 2023-03-07 | Mayo Foundation For Medical Education And Research | Compounds and methods for treating cancer |
JP2020533382A (en) | 2017-09-14 | 2020-11-19 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | Combination treatment of cancer |
JP2018024694A (en) * | 2017-10-03 | 2018-02-15 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | Proteasome inhibitor |
JP7333321B2 (en) * | 2017-11-16 | 2023-08-24 | プリンシピア バイオファーマ インコーポレイテッド | immunoproteasome inhibitor |
US10537585B2 (en) | 2017-12-18 | 2020-01-21 | Dexcel Pharma Technologies Ltd. | Compositions comprising dexamethasone |
US11407723B2 (en) | 2018-01-09 | 2022-08-09 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
EP3746065A4 (en) | 2018-01-29 | 2022-02-16 | Cognos Therapeutics Inc. | Intratumoral delivery of bortezomib |
TW202003553A (en) | 2018-03-15 | 2020-01-16 | 美商艾伯維有限公司 | ABBV-621 in combination with anti-cancer agents for the treatment of cancer |
US11243207B2 (en) | 2018-03-29 | 2022-02-08 | Mayo Foundation For Medical Education And Research | Assessing and treating cancer |
EP3873214A4 (en) | 2018-10-29 | 2022-07-13 | Forma Therapeutics, Inc. | Solid forms of (4-(2-fluoro-4-(1-methyl-1 h-benzo[d]imidazol-5-yl)benzoyl) piperazin-1-yl)(1-hydroxycyclopropyl)methanone |
CN109824756B (en) * | 2019-03-19 | 2022-03-22 | 山东大学 | Phenylalanine derivative containing 4- (benzenesulfonyl) piperazine-2-ketone and preparation method and application thereof |
CN114437119A (en) * | 2020-10-30 | 2022-05-06 | 苏州开拓药业股份有限公司 | C-Myc protein inhibitor and preparation method and application thereof |
CN116783212A (en) * | 2020-12-02 | 2023-09-19 | 霍夫曼技术有限责任公司 | Compositions and methods for modulating cancer in non-human mammals |
US11964993B2 (en) | 2021-07-03 | 2024-04-23 | Shilpa Pharma Lifesciences Limited | Crystalline bortezomib process |
US20230062279A1 (en) | 2021-08-12 | 2023-03-02 | Extrovis Ag | Pharmaceutical compositions of bortezomib |
CN113957441B (en) * | 2021-10-29 | 2024-01-02 | 光华科学技术研究院(广东)有限公司 | Etching solution and preparation method and application thereof |
WO2023220641A2 (en) | 2022-05-11 | 2023-11-16 | Juno Therapeutics, Inc. | Methods and uses related to t cell therapy and production of same |
WO2023220655A1 (en) | 2022-05-11 | 2023-11-16 | Celgene Corporation | Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
US5106948A (en) * | 1988-05-27 | 1992-04-21 | Mao Foundation For Medical Education And Research | Cytotoxic boronic acid peptide analogs |
US5169841A (en) * | 1987-11-05 | 1992-12-08 | Hoechst Aktiengesellschaft | Renin inhibitors |
Family Cites Families (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4261868A (en) * | 1979-08-08 | 1981-04-14 | Lever Brothers Company | Stabilized enzymatic liquid detergent composition containing a polyalkanolamine and a boron compound |
US4369183A (en) * | 1979-09-06 | 1983-01-18 | Merck & Co., Inc. | 2-Pyridyl-1,2-benzisothiazolinone-1,1-dioxides and their use as selective protease inhibitors |
US4510130A (en) | 1983-05-20 | 1985-04-09 | Genetic Diagnostics Corporation | Promoting animal and plant growth with leupeptin |
US4537773A (en) | 1983-12-05 | 1985-08-27 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid derivatives |
US4537707A (en) * | 1984-05-14 | 1985-08-27 | The Procter & Gamble Company | Liquid detergents containing boric acid and formate to stabilize enzymes |
US4842769A (en) * | 1985-07-26 | 1989-06-27 | Colgate-Palmolive Co. | Stabilized fabric softening built detergent composition containing enzymes |
US4759032A (en) | 1987-06-03 | 1988-07-19 | Monsanto Company | Electrode seal assembly |
US5242904A (en) * | 1987-06-05 | 1993-09-07 | The Dupont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
US5250720A (en) * | 1987-06-05 | 1993-10-05 | The Dupont Merck Pharmaceutical Company | Intermediates for preparing peptide boronic acid inhibitors of trypsin-like proteases |
US5187157A (en) * | 1987-06-05 | 1993-02-16 | Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
SE8702550D0 (en) * | 1987-06-18 | 1987-06-18 | Anders Grubb | CYSTEINPROTEASHEMMARE |
EP0374157B1 (en) | 1987-06-19 | 1994-07-06 | The Regents Of The University Of California | A new class of low calorie protein sweeteners |
US4963655A (en) * | 1988-05-27 | 1990-10-16 | Mayo Foundation For Medical Education And Research | Boron analogs of amino acid/peptide protease inhibitors |
DE3827340A1 (en) * | 1988-08-12 | 1990-02-15 | Hoechst Ag | USE OF (ALPHA) -AMINOBORONIC ACID DERIVATIVES FOR THE PROPHYLAXIS AND TREATMENT OF VIRUS DISEASES |
ZA897515B (en) * | 1988-10-07 | 1990-06-27 | Merrell Dow Pharma | Novel peptidase inhibitors |
US4997929A (en) * | 1989-01-05 | 1991-03-05 | Synergen, Inc. | Purified ciliary neurotrophic factor |
US4959179A (en) * | 1989-01-30 | 1990-09-25 | Lever Brothers Company | Stabilized enzymes liquid detergent composition containing lipase and protease |
JP2701932B2 (en) * | 1989-04-10 | 1998-01-21 | サントリー株式会社 | Protease inhibitor |
US5030378A (en) * | 1990-01-02 | 1991-07-09 | The Procter & Gamble Company | Liquid detergents containing anionic surfactant, builder and proteolytic enzyme |
JPH05506777A (en) | 1990-03-05 | 1993-10-07 | セファロン、インコーポレーテッド | Chymotrypsin-like proteases and their inhibitors |
GB9017694D0 (en) * | 1990-08-13 | 1990-09-26 | Sandoz Ltd | Improvements in or relating to organic chemistry |
EP0478050A1 (en) * | 1990-09-24 | 1992-04-01 | Unilever N.V. | Detergent composition |
GB9024129D0 (en) * | 1990-11-06 | 1990-12-19 | Thrombosis Research Trust | Inhibitors and substrates of thrombin |
JP2703408B2 (en) | 1990-12-28 | 1998-01-26 | 麒麟麦酒株式会社 | 1,4-benzothiazepine derivatives |
WO1992011850A2 (en) * | 1990-12-28 | 1992-07-23 | Cortex Pharmaceuticals, Inc. | Use of calpain inhibitors in the inhibition and treatment of neurodegeneration |
JPH06504547A (en) * | 1990-12-28 | 1994-05-26 | ジョージア・テック・リサーチ・コーポレーション | Peptide ketoamides, keto acids and ketoesters |
ES2085024T3 (en) * | 1991-04-30 | 1996-05-16 | Procter & Gamble | LIQUID DETERGENTS REINFORCED WITH BORICO-POLYOL ACID COMPLEX TO INHIBIT THE PROTEOLYTIC ENZYME. |
EP0511456A1 (en) * | 1991-04-30 | 1992-11-04 | The Procter & Gamble Company | Liquid detergents with aromatic borate ester to inhibit proteolytic enzyme |
WO1992019707A1 (en) * | 1991-04-30 | 1992-11-12 | The Procter & Gamble Company | Liquid detergents with an aryl boronic acid |
US5554728A (en) * | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
AU4077193A (en) * | 1992-04-16 | 1993-11-18 | Zeneca Limited | Alpha-aminoboronic acid peptides and their use as elastase inhibitors |
AU3959693A (en) * | 1992-04-16 | 1993-11-18 | Zeneca Limited | Alpha-aminoboronic acid peptides and their use as elastase inhibitors |
ATE149563T1 (en) | 1992-08-14 | 1997-03-15 | Procter & Gamble | LIQUID DETERGENTS CONTAINING ALPHA-AMINOBORIC ACID |
JPH08507754A (en) | 1993-02-10 | 1996-08-20 | ザ・プレジデント・アンド・フェローズ・オブ・ハーバード・カレッジ | Role of ATP-ubiquitin-dependent proteolysis in MHC-1-restricted antigen presentation and its inhibitor |
US5384410A (en) * | 1993-03-24 | 1995-01-24 | The Du Pont Merck Pharmaceutical Company | Removal of boronic acid protecting groups by transesterification |
DE4311835A1 (en) * | 1993-04-07 | 1994-10-13 | Boehringer Ingelheim Int | Method for inhibiting gene transcription |
US5424904A (en) | 1993-10-04 | 1995-06-13 | Taylor, Sr.; Thomas T. | Circuit for electrically controlled intermittent motion |
IL111176A0 (en) * | 1993-10-07 | 1994-12-29 | Du Pont Merck Pharma | Dipeptide boronic acid inhibitors of trypsin-like enzymes and pharmaceutical compositions containing them |
US5693617A (en) * | 1994-03-15 | 1997-12-02 | Proscript, Inc. | Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein |
US6660268B1 (en) * | 1994-03-18 | 2003-12-09 | The President And Fellows Of Harvard College | Proteasome regulation of NF-KB activity |
US5574017A (en) | 1994-07-05 | 1996-11-12 | Gutheil; William G. | Antibacterial agents |
US6083903A (en) * | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
US5550262A (en) * | 1994-11-14 | 1996-08-27 | Cephalon, Inc. | Multicatalytic protease inhibitors |
US5614649A (en) | 1994-11-14 | 1997-03-25 | Cephalon, Inc. | Multicatalytic protease inhibitors |
DK2251344T3 (en) * | 2001-01-25 | 2016-05-09 | Us Of America Represented By The Secretary Dept Of Health And Human Services | Formulation of boronic acid |
RS62738B1 (en) * | 2004-03-30 | 2022-01-31 | Millennium Pharm Inc | Synthesis of boronic ester and acid compounds |
-
1995
- 1995-05-16 US US08/442,581 patent/US6083903A/en not_active Expired - Lifetime
- 1995-10-27 PT PT03004280T patent/PT1312609E/en unknown
- 1995-10-27 NZ NZ296717A patent/NZ296717A/en not_active IP Right Cessation
- 1995-10-27 IL IL13772695A patent/IL137726A/en not_active IP Right Cessation
- 1995-10-27 AU AU41398/96A patent/AU710564B2/en not_active Expired
- 1995-10-27 PT PT95939670T patent/PT788360E/en unknown
- 1995-10-27 DE DE69535866T patent/DE69535866D1/en not_active Expired - Lifetime
- 1995-10-27 IL IL13383195A patent/IL133831A/en not_active IP Right Cessation
- 1995-10-27 CH CH95939670T patent/CH0788360H1/en unknown
- 1995-10-27 US US08/549,318 patent/US5780454A/en not_active Expired - Lifetime
- 1995-10-27 KR KR1019970702789A patent/KR100398944B1/en not_active IP Right Cessation
- 1995-10-27 AT AT05023462T patent/ATE411324T1/en active
- 1995-10-27 AT AT03004280T patent/ATE314378T1/en active
- 1995-10-27 DK DK05023462T patent/DK1627880T3/en active
- 1995-10-27 EP EP95939670A patent/EP0788360B3/en not_active Expired - Lifetime
- 1995-10-27 DK DK03004280T patent/DK1312609T3/en active
- 1995-10-27 DE DE1995630936 patent/DE122004000025I2/en active Active
- 1995-10-27 CN CNB951965905A patent/CN1305475C/en not_active Expired - Lifetime
- 1995-10-27 PT PT05023462T patent/PT1627880E/en unknown
- 1995-10-27 WO PCT/US1995/014117 patent/WO1996013266A1/en active IP Right Grant
- 1995-10-27 IL IL11579095A patent/IL115790A/en active Protection Beyond IP Right Term
- 1995-10-27 DE DE69534727T patent/DE69534727T2/en not_active Expired - Lifetime
- 1995-10-27 AT AT95939670T patent/ATE241631T1/en active
- 1995-10-27 TW TW084111436A patent/TW318850B/zh not_active IP Right Cessation
- 1995-10-27 EP EP08016076A patent/EP1997823A1/en not_active Withdrawn
- 1995-10-27 NZ NZ337211A patent/NZ337211A/en not_active IP Right Cessation
- 1995-10-27 DE DE69530936T patent/DE69530936T3/en not_active Expired - Lifetime
- 1995-10-27 EP EP05023462A patent/EP1627880B1/en not_active Expired - Lifetime
- 1995-10-27 ES ES03004280T patent/ES2254803T3/en not_active Expired - Lifetime
- 1995-10-27 ES ES05023462T patent/ES2314540T3/en not_active Expired - Lifetime
- 1995-10-27 CN CN2007100887250A patent/CN101077875B/en not_active Expired - Lifetime
- 1995-10-27 DK DK95939670.6T patent/DK0788360T5/en active
- 1995-10-27 JP JP51483496A patent/JP3717934B2/en not_active Expired - Lifetime
- 1995-10-27 CA CA2496538A patent/CA2496538C/en not_active Expired - Lifetime
- 1995-10-27 ES ES95939670T patent/ES2199257T7/en active Active
- 1995-10-27 EP EP03004280A patent/EP1312609B1/en not_active Expired - Lifetime
- 1995-10-27 CA CA002203936A patent/CA2203936C/en not_active Expired - Lifetime
- 1995-10-27 DE DE200412000025 patent/DE122004000025I1/en active Pending
-
1997
- 1997-04-23 FI FI971746A patent/FI114801B/en active Protection Beyond IP Right Term
- 1997-04-25 NO NO19971929A patent/NO310558B1/en not_active IP Right Cessation
- 1997-04-25 MX MX9703063A patent/MX9703063A/en unknown
-
1998
- 1998-02-07 HK HK98100951A patent/HK1002059A1/en not_active IP Right Cessation
- 1998-05-26 US US09/085,404 patent/US6066730A/en not_active Expired - Lifetime
-
1999
- 1999-12-30 IL IL13383199A patent/IL133831A0/en unknown
-
2000
- 2000-01-25 US US09/490,511 patent/US6297217B1/en not_active Expired - Lifetime
- 2000-08-07 IL IL13772600A patent/IL137726A0/en unknown
-
2001
- 2001-09-14 US US09/953,540 patent/US6465433B1/en not_active Expired - Lifetime
-
2002
- 2002-03-18 US US10/100,295 patent/US6548668B2/en not_active Expired - Lifetime
- 2002-04-19 US US10/125,997 patent/US6617317B1/en not_active Expired - Lifetime
-
2003
- 2003-03-19 US US10/392,165 patent/US6747150B2/en not_active Expired - Lifetime
- 2003-12-08 US US10/730,231 patent/US7119080B2/en not_active Expired - Fee Related
-
2004
- 2004-05-14 NL NL300151C patent/NL300151I2/en unknown
- 2004-05-19 FR FR04C0014C patent/FR04C0014I2/fr active Active
- 2004-06-09 LU LU91083C patent/LU91083I2/en unknown
- 2004-08-06 NO NO2004004C patent/NO2004004I2/en not_active IP Right Cessation
- 2004-11-03 FI FI20041415A patent/FI120974B/en not_active IP Right Cessation
- 2004-11-19 CY CY0400082A patent/CY2484B1/en unknown
-
2005
- 2005-10-17 US US11/252,291 patent/US20060122390A1/en not_active Abandoned
-
2006
- 2006-07-11 HK HK06107756.3A patent/HK1087714A1/en not_active IP Right Cessation
- 2006-12-20 US US11/642,372 patent/US20070282100A1/en not_active Abandoned
-
2008
- 2008-01-02 US US12/006,422 patent/US7531526B2/en not_active Expired - Lifetime
-
2009
- 2009-04-01 US US12/416,193 patent/US8003791B2/en not_active Expired - Fee Related
-
2011
- 2011-08-19 US US13/213,157 patent/US8378099B2/en not_active Expired - Fee Related
-
2013
- 2013-01-11 US US13/739,223 patent/US20130310320A1/en not_active Abandoned
-
2014
- 2014-04-08 US US14/247,711 patent/US20150072942A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
US5169841A (en) * | 1987-11-05 | 1992-12-08 | Hoechst Aktiengesellschaft | Renin inhibitors |
US5106948A (en) * | 1988-05-27 | 1992-04-21 | Mao Foundation For Medical Education And Research | Cytotoxic boronic acid peptide analogs |
Cited By (169)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2758329A1 (en) * | 1997-01-16 | 1998-07-17 | Synthelabo | New imidazole-4-butane-boronic acid derivatives |
WO1998035691A1 (en) * | 1997-02-15 | 1998-08-20 | Proscript, Inc. | Treatment of infarcts through inhibition of nf-kappab |
US6271199B2 (en) | 1997-02-15 | 2001-08-07 | Millennium Pharmaceuticals, Inc. | Treatment of infarcts |
US7700545B2 (en) * | 1997-10-28 | 2010-04-20 | The University Of North Carolina At Chapel Hill | Use of NF-κB inhibition in combination therapy for cancer |
US7700543B2 (en) * | 1997-10-28 | 2010-04-20 | The University Of North Carolina At Chapel Hill | Use NF-κB inhibition in combination therapy for cancer |
US7700073B2 (en) * | 1997-10-28 | 2010-04-20 | The University Of North Carolina At Chapel Hill | Use of NF-κB inhibition in combination therapy for cancer |
WO1999022729A1 (en) * | 1997-10-31 | 1999-05-14 | Centre De Recherche Du Centre Hospitalier De L'universite De Montreal | The use of proteasome inhibitors for treating cancer, inflammation, autoimmune disease, graft rejection and septic shock |
WO1999037666A1 (en) * | 1998-01-26 | 1999-07-29 | Cv Therapeutics, Inc. | α-KETOAMIDE INHIBITORS OF 20S PROTEASOME |
US6781000B1 (en) | 1998-01-26 | 2004-08-24 | Cv Theurapeutics, Inc. | Alpha-ketoamide inhibitors of 20S proteasome |
US6075150A (en) * | 1998-01-26 | 2000-06-13 | Cv Therapeutics, Inc. | α-ketoamide inhibitors of 20S proteasome |
US6773705B1 (en) * | 1998-02-27 | 2004-08-10 | General Hospital Corporation | Methods for diagnosing and treating autoimmune disease |
US6617171B2 (en) | 1998-02-27 | 2003-09-09 | The General Hospital Corporation | Methods for diagnosing and treating autoimmune disease |
FR2779653A1 (en) * | 1998-06-11 | 1999-12-17 | Inst Nat Sante Rech Med | USE OF PROTEASOME MODULATING COMPOUNDS IN THERAPY |
US6506555B1 (en) | 1998-06-11 | 2003-01-14 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Use of HIV protease inhibiting compounds |
WO1999063998A1 (en) * | 1998-06-11 | 1999-12-16 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Novel use of hiv protease inhibiting compounds |
EP0982317A1 (en) * | 1998-08-26 | 2000-03-01 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Bivalent inhibitors of the proteasome |
WO2000023614A1 (en) * | 1998-10-20 | 2000-04-27 | Millennium Pharmaceuticals, Inc. | Method for monitoring proteasome inhibitor drug action |
EP2251344B1 (en) | 2001-01-25 | 2016-03-30 | THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Formulation of boronic acid compounds |
EP3078667B1 (en) | 2001-01-25 | 2018-11-21 | The United States of America, represented by the Secretary, Department of Health and Human Services | Formulation of boronic acid compounds |
EP3078667A1 (en) * | 2001-01-25 | 2016-10-12 | The United States of America, represented by the Secretary, Department of Health and Human Services | Formulation of boronic acid compounds |
WO2003033507A1 (en) * | 2001-10-12 | 2003-04-24 | Kyorin Pharmaceutical Co., Ltd. | Benzylmalonic acid derivatives and proteasome inhibitors contaiing the same |
WO2003059898A3 (en) * | 2002-01-08 | 2004-02-26 | Eisai Co Ltd | Eponemycin and epoxomicin analogs and uses thereof |
WO2003059898A2 (en) * | 2002-01-08 | 2003-07-24 | Eisai Co. Ltd. | Eponemycin and epoxomicin analogs and uses thereof |
US7524883B2 (en) | 2002-01-08 | 2009-04-28 | Eisai R&D Management Co., Ltd. | Eponemycin and epoxomicin analogs and uses thereof |
US8163733B2 (en) | 2002-03-13 | 2012-04-24 | Janssen Pharmaceutica N.V. | Sulfonylamino-derivatives as novel inhibitors of histone deacetylase |
US8501737B2 (en) | 2002-03-13 | 2013-08-06 | Janssen Pharmaceutica N.V. | Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase |
US8394831B2 (en) | 2002-03-13 | 2013-03-12 | Janssen Pharmaceutica, N.V. | Carbonylamino-derivatives as novel inhibitors of histone deacetylase |
US8513237B2 (en) | 2002-03-13 | 2013-08-20 | Janssen Pharmaceutica N.V. | Sulfonylamino-derivatives as novel inhibitors of histone deacetylase |
US9150560B2 (en) | 2002-03-13 | 2015-10-06 | Janssen Pharmaceutica Nv | Inhibitors of histone deacetylase |
US9533979B2 (en) | 2002-03-13 | 2017-01-03 | Janssen Pharmaceutica Nv | Amino-derivatives as novel inhibitors of histone deacetylase |
US8916554B2 (en) | 2002-03-13 | 2014-12-23 | Janssen Pharmaceutica, N.V. | Amino-derivatives as novel inhibitors of histone deacetylase |
US8071615B2 (en) | 2002-03-13 | 2011-12-06 | Janssen Pharmaceutica N.V. | Carbonylamino-derivatives as novel inhibitors of histone deacetylase |
US9556161B2 (en) | 2002-03-13 | 2017-01-31 | Janssen Pharmaceutica Nv | Inhibitors of histone deacetylase |
US8114999B2 (en) | 2002-03-13 | 2012-02-14 | Janssen Pharmaceutica N.V. | Aminocarbonyl-derivatives as novel inhibitors of histone deacetylase |
WO2004016253A1 (en) * | 2002-08-14 | 2004-02-26 | Janssen Pharmaceutica N.V. | Use of nf-kappa b inhibitors for the treatment of mastitis |
US7371729B2 (en) | 2002-09-09 | 2008-05-13 | Trigen Limited | Boronic acid salts useful in parenteral formulations |
EP1466917A1 (en) * | 2002-09-09 | 2004-10-13 | Trigen Limited | Method for making peptide boronic acids and acids obtainable thereby |
US7112572B2 (en) | 2002-09-09 | 2006-09-26 | Trigen Limited | Multivalent metal salts of boronic acids |
CN100341880C (en) * | 2003-02-13 | 2007-10-10 | 上海仁虎制药股份有限公司 | Boric acid and boric acid ester compound ,their preparing method and use in pharmacy |
US7576206B2 (en) | 2003-08-14 | 2009-08-18 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
US8546608B2 (en) | 2003-08-14 | 2013-10-01 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
KR101093880B1 (en) * | 2003-08-14 | 2011-12-13 | 세파론, 인코포레이티드 | Proteasome inhibitors and methods of using the same |
US7223745B2 (en) | 2003-08-14 | 2007-05-29 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
US9233115B2 (en) | 2003-08-14 | 2016-01-12 | Millennium Pharmaceuticals Inc. | Proteasome inhibitors and methods of using the same |
US8058262B2 (en) | 2003-08-14 | 2011-11-15 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
US7915236B2 (en) | 2003-08-14 | 2011-03-29 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
EP4008721A1 (en) * | 2004-03-30 | 2022-06-08 | Millennium Pharmaceuticals, Inc. | Synthesis of boronic ester and acid compounds |
WO2005097809A3 (en) * | 2004-03-30 | 2006-02-16 | Millennium Pharm Inc | Synthesis of boronic ester and acid compounds |
NO344610B1 (en) * | 2004-03-30 | 2020-02-10 | Millennium Pharm Inc | Large scale process for the preparation synthesis of boronic acid ester and boronic acid compounds |
NO20161350A1 (en) * | 2004-03-30 | 2006-12-22 | Millennium Pharm Inc | Synthesis of Boronic Acid Esters and Acid Compounds |
US10000529B2 (en) | 2004-03-30 | 2018-06-19 | Millennium Pharmaceuticals, Inc. | Synthesis of boronic ester and acid compounds |
EP2377868A1 (en) | 2004-03-30 | 2011-10-19 | Millennium Pharmaceuticals, Inc. | Synthesis of Bortezomib |
EP2377869A1 (en) * | 2004-03-30 | 2011-10-19 | Millennium Pharmaceuticals, Inc. | Synthesis of Bortezomib |
NO338905B1 (en) * | 2004-03-30 | 2016-10-31 | Millennium Pharm Inc | Process for the preparation of boronic acid esters - compounds and preparations containing the same |
US9862745B2 (en) | 2004-03-30 | 2018-01-09 | Millennium Pharmaceuticals, Inc. | Synthesis of boronic ester and acid compounds |
EA012927B1 (en) * | 2004-03-30 | 2010-02-26 | Миллениум Фармасьютикалз, Инк. | Synthesis of boronic ester and acid compounds |
US8324174B2 (en) | 2004-04-15 | 2012-12-04 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8207124B2 (en) | 2004-04-15 | 2012-06-26 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8207125B2 (en) | 2004-04-15 | 2012-06-26 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8129346B2 (en) | 2004-04-15 | 2012-03-06 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8207297B2 (en) | 2004-04-15 | 2012-06-26 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8198270B2 (en) | 2004-04-15 | 2012-06-12 | Onyx Therapeutics, Inc. | Compounds for proteasome enzyme inhibition |
US8207127B2 (en) | 2004-04-15 | 2012-06-26 | Onyx Technologies, Inc. | Compounds for enzyme inhibition |
US8207126B2 (en) | 2004-04-15 | 2012-06-26 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8088741B2 (en) | 2004-05-10 | 2012-01-03 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9636341B2 (en) | 2004-07-28 | 2017-05-02 | Janssen Pharmaceutica N.V. | Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase |
US9150543B2 (en) | 2004-07-28 | 2015-10-06 | Janssen Pharmaceutica N. V. | Substituted indolyl alkyl amino derivatives as inhibitors of histone deacetylase |
EP2100899A2 (en) | 2004-10-20 | 2009-09-16 | Proteolix, Inc. | Compounds for proteasome enzyme inhibition |
WO2006077428A1 (en) | 2005-01-21 | 2006-07-27 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8283367B2 (en) | 2005-02-11 | 2012-10-09 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
US7531517B2 (en) | 2005-08-10 | 2009-05-12 | 4Sc Ag | Inhibitors of cancer cell, T-cell and keratinocyte proliferation |
EP2284179A2 (en) | 2005-08-10 | 2011-02-16 | 4Sc Ag | Inhibitors of cancer cell, T-cell and keratinocyte proliferation |
EP2284178A2 (en) | 2005-08-10 | 2011-02-16 | 4Sc Ag | Inhibitors of cancer cell, T-cell and keratinocyte proliferation |
US10150794B2 (en) | 2005-11-09 | 2018-12-11 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9205124B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9205126B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9205125B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8114876B2 (en) | 2006-01-19 | 2012-02-14 | Janssen Pharmaceutica N.V. | Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase |
US9078896B2 (en) | 2006-01-19 | 2015-07-14 | Janssen Pharmaceutica, N.V. | Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase |
US8080576B2 (en) | 2006-06-19 | 2011-12-20 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9657058B2 (en) | 2006-06-19 | 2017-05-23 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8431571B2 (en) | 2006-06-19 | 2013-04-30 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8357683B2 (en) | 2006-06-19 | 2013-01-22 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8080545B2 (en) | 2006-06-19 | 2011-12-20 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8765745B2 (en) | 2006-06-19 | 2014-07-01 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
WO2008044045A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
WO2008044041A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
WO2009019505A2 (en) | 2007-08-03 | 2009-02-12 | Summit Corporation Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
EP3251694A1 (en) | 2007-08-03 | 2017-12-06 | Summit (Oxford) Limited | Drug combinations for the treatment of duchenne muscular dystrophy |
WO2009019504A1 (en) | 2007-08-03 | 2009-02-12 | Summit Corporation Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
US8003819B2 (en) | 2007-08-06 | 2011-08-23 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
WO2009020448A1 (en) * | 2007-08-06 | 2009-02-12 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
AU2007357338B2 (en) * | 2007-08-06 | 2014-03-20 | Takeda Pharmaceutical Company Limited | Proteasome inhibitors |
US8530694B2 (en) | 2007-08-06 | 2013-09-10 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
US8871745B2 (en) | 2007-08-06 | 2014-10-28 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
US7442830B1 (en) | 2007-08-06 | 2008-10-28 | Millenium Pharmaceuticals, Inc. | Proteasome inhibitors |
KR101831674B1 (en) * | 2007-08-06 | 2018-02-23 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | Proteasome inhibitors |
EP2527347A1 (en) * | 2007-08-06 | 2012-11-28 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
EA028622B1 (en) * | 2007-08-06 | 2017-12-29 | Милленниум Фармасьютикалз, Инк. | Proteasome inhibitors |
US8772536B2 (en) | 2007-08-06 | 2014-07-08 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
US7687662B2 (en) | 2007-08-06 | 2010-03-30 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
AU2018233007B2 (en) * | 2007-08-06 | 2020-07-23 | Takeda Pharmaceutical Company Limited | Proteasome inhibitors |
TWI511972B (en) * | 2007-08-06 | 2015-12-11 | Millennium Pharm Inc | Proteasome inhibitors |
US8367617B2 (en) | 2007-10-04 | 2013-02-05 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
US8921324B2 (en) | 2007-10-04 | 2014-12-30 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
US8921583B2 (en) | 2007-10-04 | 2014-12-30 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
EP2318419B1 (en) | 2008-06-17 | 2015-04-08 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
EP2730581B1 (en) | 2008-06-17 | 2016-04-27 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
CN107266480A (en) * | 2008-06-17 | 2017-10-20 | 米伦纽姆医药公司 | Boric acid ester compound and its medical composition |
US9175017B2 (en) | 2008-06-17 | 2015-11-03 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US9175018B2 (en) | 2008-06-17 | 2015-11-03 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
EP2733147A1 (en) * | 2008-06-17 | 2014-05-21 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US8859504B2 (en) | 2008-06-17 | 2014-10-14 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US10526351B2 (en) | 2008-06-17 | 2020-01-07 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
CN107253966A (en) * | 2008-06-17 | 2017-10-17 | 米伦纽姆医药公司 | Boric acid ester compound and its medical composition |
US10604538B2 (en) | 2008-06-17 | 2020-03-31 | Millenium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
CN107253975A (en) * | 2008-06-17 | 2017-10-17 | 米伦纽姆医药公司 | Boric acid ester compound and its medical composition |
US11485746B2 (en) | 2008-06-17 | 2022-11-01 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
CN107266482A (en) * | 2008-06-17 | 2017-10-20 | 米伦纽姆医药公司 | Boric acid ester compound and its medical composition |
US9771381B2 (en) | 2008-09-29 | 2017-09-26 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
US10035811B2 (en) | 2008-09-29 | 2018-07-31 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
KR101739470B1 (en) | 2008-09-29 | 2017-05-24 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
US8664200B2 (en) | 2008-09-29 | 2014-03-04 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
US9511109B2 (en) | 2008-10-21 | 2016-12-06 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
USRE47954E1 (en) | 2008-10-21 | 2020-04-21 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
US10596222B2 (en) | 2008-10-21 | 2020-03-24 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
WO2010105008A2 (en) | 2009-03-12 | 2010-09-16 | Genentech, Inc. | Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies |
US9051353B2 (en) | 2009-03-20 | 2015-06-09 | Onyx Therapeutics, Inc. | Crystalline tripeptide epoxy ketone protease inhibitors |
US9403868B2 (en) | 2009-03-20 | 2016-08-02 | Onyx Therapeutics, Inc. | Crystalline tripeptide epoxy ketone protease inhibitors |
WO2010106135A1 (en) | 2009-03-20 | 2010-09-23 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Combined use for the treatment of ovarian carcinoma |
WO2010145376A1 (en) * | 2009-06-19 | 2010-12-23 | 北京大学 | Tripeptide boronic acid or boronic ester, preparative method and use thereof |
US9421237B2 (en) | 2009-06-19 | 2016-08-23 | Peking University | Tripeptide boronic acid or boronic ester, preparative method and use thereof |
WO2011029802A1 (en) | 2009-09-08 | 2011-03-17 | F. Hoffmann-La Roche Ag | 4-substituted pyridin-3-yl-carboxamide compounds and methods of use |
EP2305285A1 (en) | 2009-09-29 | 2011-04-06 | Julius-Maximilians-Universität Würzburg | Means and methods for treating ischemic conditions |
WO2011039282A1 (en) | 2009-09-29 | 2011-04-07 | Julius-Maximilians-Universität Würzburg | Means and methods for treating ischemic conditions |
US8853147B2 (en) | 2009-11-13 | 2014-10-07 | Onyx Therapeutics, Inc. | Use of peptide epoxyketones for metastasis suppression |
US8541590B2 (en) | 2009-12-22 | 2013-09-24 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
US9359398B2 (en) | 2010-03-01 | 2016-06-07 | Onyx Therapeutics, Inc. | Compounds for immunoproteasome inhibition |
US9023832B2 (en) | 2010-03-31 | 2015-05-05 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclopropylethylboronic acid |
US8513218B2 (en) | 2010-03-31 | 2013-08-20 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclopropylethylboronic acid |
US8703743B2 (en) | 2010-03-31 | 2014-04-22 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclopropylethylboronic acid |
WO2012048745A1 (en) | 2010-10-14 | 2012-04-19 | Synthon Bv | Process for making bortezomib and intermediates for the process |
US8884009B2 (en) | 2010-10-14 | 2014-11-11 | Synthon Bv | Process for making bortezomib and intermediates for the process |
US9561284B2 (en) | 2011-03-31 | 2017-02-07 | Nanocarrier Co., Ltd. | Pharmaceutical composition containing a block copolymer bound to a boronic acid compound |
WO2012133884A1 (en) | 2011-03-31 | 2012-10-04 | ナノキャリア株式会社 | Pharmaceutical composition containing block copolymer comprising boric acid compound |
KR20140038376A (en) | 2011-03-31 | 2014-03-28 | 나노캬리아 가부시키가이샤 | Pharmaceutical composition containing block copolymer comprising boric acid compound |
US9114177B2 (en) | 2011-11-17 | 2015-08-25 | The University Of Tokyo | Block copolymer having phenylboronic acid group introduced therein, and use thereof |
US9878047B2 (en) | 2012-07-09 | 2018-01-30 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US9309283B2 (en) | 2012-07-09 | 2016-04-12 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US10682419B2 (en) | 2012-07-09 | 2020-06-16 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US9315542B2 (en) | 2012-07-09 | 2016-04-19 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US9505787B2 (en) | 2012-09-11 | 2016-11-29 | Cipla Limited | Process for preparing of bortezomib |
WO2014041324A1 (en) * | 2012-09-11 | 2014-03-20 | Cipla Limited | Process for preparing of bortezamib |
WO2015051067A1 (en) | 2013-10-03 | 2015-04-09 | Millennium Pharmaceuticals, Inc. | Method for the prophylaxis or treatment of systemic lupus erythematosus and/or lupus nephritis |
EP2910557A1 (en) * | 2014-02-20 | 2015-08-26 | Ikerchem, S.L. | Enantiopure tetrasubstituted pyrrolidines as scaffolds for proteasome inhibitors and medicinal applications thereof |
WO2015124663A1 (en) * | 2014-02-20 | 2015-08-27 | Ikerchem, S.L. | Enantiopure tetrasubstituted pyrrolidines as scaffolds for proteasome inhibitors and medicinal applications thereof |
US10993960B1 (en) | 2014-05-08 | 2021-05-04 | Kawasaki Institute Of Industrial Promotion | Pharmaceutical composition |
US11241448B2 (en) | 2014-05-20 | 2022-02-08 | Millennium Pharmaceuticals, Inc. | Methods for cancer therapy |
EP3120837A1 (en) | 2015-07-22 | 2017-01-25 | Stada Arzneimittel Ag | Ready-to-use solution of bortezomib |
EP4134069A1 (en) | 2015-07-22 | 2023-02-15 | STADA Arzneimittel AG | Process for the preparation of a bortezomib ester solution |
US11267803B2 (en) | 2016-06-21 | 2022-03-08 | Orion Ophthalmology LLC | Carbocyclic prolinamide derivatives |
US11377439B2 (en) | 2016-06-21 | 2022-07-05 | Orion Ophthalmology LLC | Heterocyclic prolinamide derivatives |
US11866422B2 (en) | 2016-06-21 | 2024-01-09 | Orion Ophthalmology LLC | Carbocyclic prolinamide derivatives |
WO2018038687A1 (en) | 2016-08-22 | 2018-03-01 | Mustafa Nevzat Ilaç Sanayii A.Ş. | Pharmaceutical formulations comprising a bortezomib-cyclodextrin complex |
WO2018150386A1 (en) | 2017-02-17 | 2018-08-23 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of boronic acid esters |
US11667654B2 (en) | 2017-02-17 | 2023-06-06 | Fresenius Kabi Oncology Ltd. | Process for the preparation of boronic acid esters |
WO2019040680A1 (en) | 2017-08-23 | 2019-02-28 | Krzar Life Sciences | Immunoproteasome inhibitors and immunosuppressive agent in the treatment of autoimmune disorders |
US11827656B2 (en) | 2017-11-16 | 2023-11-28 | Principia Biopharma Inc. | Immunoproteasome inhibitors |
WO2022123530A1 (en) * | 2020-12-10 | 2022-06-16 | 주식회사 엘지화학 | Boronic acid compound |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU710564C (en) | Boronic ester and acid compounds, synthesis and uses |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 95196590.5 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TT UA UG UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 296717 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 971746 Country of ref document: FI |
|
ENP | Entry into the national phase |
Ref document number: 2203936 Country of ref document: CA Ref document number: 2203936 Country of ref document: CA Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1019970702789 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1995939670 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1995939670 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1019970702789 Country of ref document: KR |
|
WWG | Wipo information: grant in national office |
Ref document number: 1995939670 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 1019970702789 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 20041415 Country of ref document: FI |
|
WWG | Wipo information: grant in national office |
Ref document number: 971746 Country of ref document: FI |