US20050282742A1 - Formulation of boronic acid compounds - Google Patents

Formulation of boronic acid compounds Download PDF

Info

Publication number
US20050282742A1
US20050282742A1 US11/184,622 US18462205A US2005282742A1 US 20050282742 A1 US20050282742 A1 US 20050282742A1 US 18462205 A US18462205 A US 18462205A US 2005282742 A1 US2005282742 A1 US 2005282742A1
Authority
US
United States
Prior art keywords
boronic acid
carbonyl
compound
aryl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/184,622
Inventor
Louis Plamondon
Louis Grenier
Julian Adams
Shanker Gupta
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Department of Health and Human Services
Millennium Pharmaceuticals Inc
Original Assignee
US Department of Health and Human Services
Millennium Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23004871&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20050282742(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by US Department of Health and Human Services, Millennium Pharmaceuticals Inc filed Critical US Department of Health and Human Services
Priority to US11/184,622 priority Critical patent/US20050282742A1/en
Publication of US20050282742A1 publication Critical patent/US20050282742A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0827Tripeptides containing heteroatoms different from O, S, or N
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02Boron compounds
    • C07F5/025Boronic and borinic acid compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02Boron compounds
    • C07F5/04Esters of boric acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06191Dipeptides containing heteroatoms different from O, S, or N
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02Linear peptides containing at least one abnormal peptide link
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • This invention relates to the formulation of pharmaceutical compounds. More particularly, the invention relates to stable, pharmaceutically acceptable compositions prepared from boronic acid compounds. The invention also relates to methods for preparing such compositions.
  • boronic acid and ester compounds have displayed particular promise as inhibitors of the proteasome, a multicatalytic protease responsible for the majority of intracellular protein turnover.
  • Ciechanover, Cell, 79: 13-21 (1994) teaches that the proteasome is the proteolytic component of the ubiquitin-proteasome pathway, in which proteins are targeted for degradation by conjugation to multiple molecules of ubiquitin.
  • Ciechanover also teaches that the ubiquitin-proteasome pathway plays a key role in a variety of important physiological processes.
  • the references also describe the use of boronic ester and acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF- ⁇ B in a cell, to reduce the rate of degradation of p53 protein in a cell, to inhibit cyclin degradation in a cell, to inhibit the growth of a cancer cell, to inhibit antigen presentation in a cell, to inhibit NF- ⁇ B dependent cell adhesion, and to inhibit HIV replication.
  • Brand et al., WO 98/35691 teaches that proteasome inhibitors, including boronic acid compounds, are useful for treating infarcts such as occur during stroke or myocardial infarction.
  • Elliott et al., WO 99/15183 teaches that proteasome inhibitors are useful for treating inflammatory and autoimmune diseases.
  • alkylboronic acids are relatively difficult to obtain in analytically pure form.
  • Snyder et al., J. Am. Chem. Soc. 80: 3611 (1958) teaches that arylboronic acid compounds readily form cyclic trimeric anhydrides under dehydrating conditions.
  • alkylboronic acids and their boroxines are often air-sensitive.
  • Korcek et al., J. Chem. Soc., Perkin Trans. 2 242 (1972) teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid.
  • the present invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds.
  • the invention also provides methods for preparing such compositions.
  • the invention provides the discovery that lyophilization of an aqueous mixture comprising a boronic acid compound and a compound having at least two hydroxyl groups produces a stable composition that readily releases the boronic acid compound upon dissolution in aqueous media.
  • the invention provides boronate ester compounds having formula (1):
  • P is hydrogen or an amino-group protecting moiety
  • R is hydrogen or alkyl
  • A is 0, 1, or 2;
  • R 1 , R 2 , and R 3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH 2 —R 5 ;
  • R 5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocydyl, heteroaryl, or -W-R 6 , where W is a chalcogen and R 6 is alkyl;
  • Z 1 and Z 2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.
  • the invention provides a composition comprising a compound of formula (2): wherein:
  • P is hydrogen or an amino-group-protecting moiety
  • R is hydrogen or alkyl
  • A is 0, 1, or 2;
  • R 1 , R 2 , and R 3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH 2 —R 5 ;
  • R 5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R 6 , where W is a chalcogen and R 6 is alkyl;
  • Z 3 and Z 4 together form a moiety derived from a compound having at least two hydroxyl 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;
  • the invention provides a method for formulating a boronic acid compound, the method comprising:
  • the invention provides a method for formulating a boronic acid compound, the method comprising:
  • the invention provides compositions prepared by the methods of the invention.
  • the invention provides boronic acid anhydride compounds useful in the methods of the invention.
  • the invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds and methods for preparing the compositions.
  • the invention also provides novel boronate ester compounds.
  • the invention further provides boronic acid anhydride compounds useful in the methods of the invention.
  • formulation of the boronic acid compound refers to the preparation of a boronic acid compound in a form suitable for administration to a mammalian subject, preferably a human.
  • formulation of the boronic acid compound comprises addition of pharmaceutically acceptable excipients, diluents, or carriers.
  • formulation of the boronic acid compound comprises formation of a chemical derivative of the boronic acid compound, preferably formation of a boronate ester.
  • formulation refers to any form commonly used for pharmaceutical administration, including solids, liquids, suspensions, creams, and gels.
  • the formulation is preferably a lyophilized powder.
  • lyophilized powder refers to any solid material obtained by lyophilization of an aqueous mixture.
  • stable formulation any formulation having sufficient stability to have utility as a pharmaceutical agent.
  • the formulation has sufficient stability to allow storage at a convenient temperature, preferably between 0° C. and 40° C., for a reasonable period of time, preferably longer than one month, more preferably longer than three months, even more preferably longer than six months, and most preferably longer than one year.
  • boronic acid refers to any chemical compound comprising a —B(OH) 2 moiety. Snyder et al., J. Am. Chem. Soc. 80: 3611 (1958), teaches that arylboronic acid compounds readily form oligomeric anhydrides by dehydration of the boronic acid moiety. Thus, unless otherwise apparent from context, the term “boronic acid” is expressly intended to encompass free boronic acids, oligomeric anhydrides, including, but not limited to, dimers, trimers, and tetramers, and mixtures thereof.
  • the term “compound having at least two hydroxyl groups” refers to any compound having two or more hydroxyl groups.
  • the two hydroxyl groups are preferably separated by at least two connecting atoms, preferably from about 2 to about 5 connecting atoms, more preferably 2 or 3 connecting atoms.
  • the connecting atoms may be in a chain or a ring, the chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O.
  • the term “dihydroxy compound” may be used to refer to a compound having at least two hydroxyl groups, as defined above.
  • the term “dihydroxy compound” is not intended to be limited to compounds having only two hydroxyl groups.
  • amino-group protecting moiety refers to any group used to derivatize an amino group, especially an N-terminal amino group of a peptide or amino acid. Such groups include, without limitation, allyl acyl, alkoxycarbonyl, aminocarbonyl, and sulfonyl moieties. However, the term “amino-group protecting moiety” is not intended to be limited to those particular protecting groups that are commonly employed in organic synthesis, nor is it intended to be limited to groups that are readily cleavable.
  • chalcogen refers to the elements oxygen or sulfur.
  • alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and still more preferably 1-4 carbon atoms, which may be optionally substituted with one, two or three substituents. Unless otherwise explicitly stated, the term “alkyl” is meant to include saturated, unsaturated, and partially unsaturated aliphatic groups. When unsaturated groups are particularly intended, the terms “alkenyl” or “alkynyl” will be used. When only saturated groups are intended, the term “saturated alkyl” will be used.
  • Preferred saturated alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally may be optionally substituted.
  • Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • aryl is a C 6 -C 14 aromatic moiety comprising one to three aromatic rings, which may be optionally substituted.
  • the aryl group is a C 6 -C 10 aryl group.
  • Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted.
  • the aralkyl group is (C 1 -C 6 )alk(C 6 -C 10 )aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • An “alkaryl” or “alkylaryl” group is an aryl group having one or more alkyl substituents. Examples of alkaryl groups include, without limitation, tolyl, xylyl, mesityl, ethylphenyl, tert-butylphenyl, and methylnaphthyl.
  • heterocycle refers to any stable ring structure having from about 3 to about 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S.
  • the nitrogen and sulfur heteroatoms of the heterocyclic moiety may be optionally oxidized, and the nitrogen atoms may be optionally quaternized.
  • the heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable formula.
  • stable compound or “stable formula” is meant to refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
  • the heterocyclic group may be optionally substituted on carbon at one or more positions with any of the substituents recited above.
  • the heterocyclic group may also independently be substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, oxo, or hydroxy, or on sulfur with oxo or lower alkyl.
  • Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholinyl.
  • the heterocyclic group may also be fused to an aryl, heteroaryl, or heterocyclic group. Examples of such fused heterocyles include, without limitation, tetrahydroquinoline and dihydrobenzofuran.
  • heteroaryl and “aromatic heterocyle” refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to about four, preferably from one to about three, heteroatoms selected from the group consisting of N, O, and S.
  • the heteroaryl group may be optionally substituted on carbon at one or more positions with any of the substituents recited above.
  • Preferred heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.
  • a “substituted” alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is one having from one and to about four, preferably from one to about three, more preferably one or two, non-hydrogen substituents.
  • Suitable substituents include, without limitation, halo, hydroxy, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
  • the substituents are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, cyano, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1 -C 6 )alkoxy, trifluoromethyl, halogen, C 1 -C 6 alkoxy, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy, hydroxy, C 1 -C 6 alkylthio, C 1 -C 6
  • halogen or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.
  • oxo refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
  • acyl refers to an alkylcarbonyl or arylcarbonyl substituent.
  • acylamino refers to an amide group attached at the nitrogen atom.
  • carbamoyl refers to an amide group attached at the carbonyl carbon atom.
  • the nitrogen atom of an acylamino or carbamoyl substituent may be additionally substituted.
  • sulfonamido refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom.
  • amino is meant to include NH 2 alkylamino, arylamino, and cyclic amino groups.
  • ureido refers to a substituted or unsubstituted urea moiety.
  • the invention provides boronate ester compounds having formula (1): wherein
  • P is hydrogen or an amino-group protecting moiety
  • R is hydrogen or alkyl
  • A is 0, 1, or 2;
  • R 1 , R 2 , and R 3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH 2 —R 5 ;
  • R 5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R 6 , where W is a chalcogen and R 6 is alkyl;
  • Z 1 and Z 2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.
  • the term “moiety derived from a sugar” refers to a moiety formed by removing the hydrogen atoms from two hydroxyl groups of any sugar moiety.
  • the moiety derived from a sugar may be attached to boron by any two of the hydroxyl groups of the sugar.
  • the boronate ester forms a 5-, 6-, 7-, 8-, or 9-membered ring. In some preferred embodiments, the boronate ester forms a 5- or 6-membered ring.
  • the sugar is preferably a monosaccharide or disaccharide.
  • suitable sugars include, glucose, sucrose, fructose, trehalose, mannitol, and sorbitol.
  • the sugar is a reduced sugar, more preferably mannitol or sorbitol.
  • Z 1 and Z 2 together form a moiety of formula C 6 H 12 O 6 , wherein the oxygen atoms of the two deprotonated hydroxyl groups form covalent attachments with boron to form a boronate ester compound.
  • the mannitol or sorbitol boronate ester compound has one of the following structures: However, structures with larger boronate ester ring sizes are also possible.
  • the mannitol or sorbitol boronate ester forms a symmetrical 5-membered ring having the following structure:
  • the mannitol or sorbitol is of the D-configuration, although the L-configuration may also be used.
  • Z 1 and Z 2 together form a moiety derived from D-mannitol.
  • the boronate ester compound preferably has one of the following structures: However, structures with larger boronate ester ring sizes are also possible.
  • the boronate ester compound has the following structure:
  • the P moiety of the compound of formula (1) is preferably hydrogen or one of R 7 —C(O)—, R 7 —S(O) 2 —, R 7 —NH—(O)—, or R 7 —O—C(O)—, where R 7 is one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when Y is R 7 —C(O)— or R 7 —S(O) 2 —, R 7 can also be an optionally substituted 5- to 10-membered saturated, partially unsaturated, or aromatic heterocycle.
  • P is one of R 7 —C(O)— or R 7 —S(O) 2 —, and R 7 is an optionally substituted 5- to 10-membered saturated, partially unsaturated, or aromatic heterocycle.
  • R 7 is an aromatic heterocycle, more preferably pyrazinyl, pyridyl, quinolyl, or quinoxalinyl, or a saturated heterocycle, preferably morpholinyl.
  • P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
  • R is hydrogen. In some other preferred embodiments, R is alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 4 alkyl, and most preferably methyl or ethyl.
  • variable A in formula (1) can be 0, 1, or 2.
  • the residue within the brackets is not present and the boronate ester compound is a dipeptide.
  • A is 1, the residue within the brackets is present and the compound is a tripeptide.
  • A is 2, the compound is a tetrapeptide.
  • A is zero.
  • the terms “peptide”, “dipeptide”, and “tripeptide” are intended to encompass compounds comprising natural amino acid residues, unnatural amino acid residues, or a combination of natural and unnatural amino acid residues.
  • peptide “dipeptide”, and “tripeptide” are used herein to refer to compounds in which the carboxylic acid functionality of the C-terminal amino acid residue is replaced by a boronic acid or boronate ester functionality.
  • R 1 , R 2 , and R 3 in formula (1) are each independently one of hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, or C 6 -C 10 aryl, or —CH 2 —R 5 , wherein each of R 1 , R 2 , R 3 , and R 5 may be optionally substituted. More preferably, R 1 , R 2 , and R 3 are each independently one of C 1 -C 4 alkyl or —CH 2 —R 5 , and R 5 is one of cycloalkyl, aryl, heterocyclyl, heteroaryl, or -W-R 6 where W is chalcogen and R 6 is alkyl.
  • R 5 is one of C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, (C 1 -C 6 )alk(C 6 -C 10 )aryl, C 3 -C 10 cycloalkyl, C 1 -C 8 alkoxy, or C 1 -C 8 alkylthio or a 5 to 10-membered heteroaryl ring.
  • the compound of formula (1) is one of:
  • the compound of formula (1) is D-Mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate, preferably having the following structure:
  • the invention provides a composition comprising a compound of formula (2): wherein
  • P is hydrogen or an amino-group-protecting moiety
  • R is hydrogen or alkyl
  • A is 0, 1, or 2;
  • R 1 , R 2 , and R 3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH 2 —R 5 ;
  • R 5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R 6 , where W is a chalcogen and R 6 is alkyl;
  • Z 3 and Z 4 together form a moiety derived from a compound having at least two hydroxyl 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, wherein the atom attached to boron in each case is an oxygen atom;
  • moiety derived from a compound having at least two hydroxyl groups is used analogously to the term “moiety derived from a sugar” described above, and thus refers to a moiety formed by removing the hydrogen atoms from two hydroxyl groups of a compound having at least two hydroxyl groups.
  • the moiety derived from a compound having at least two hydroxyl groups may be attached to boron by the oxygen atoms of any two of its hydroxyl groups.
  • the boron atom, the oxygen atoms attached to boron, and the atoms connecting the two oxygen atoms together form a 5- or 6-membered ring.
  • Suitable compounds having at least two hydroxyl groups include, without limitation, pinanediol, pinacol, perfluoropinacol, ethylene glycol, diethylene glycol, catechol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, 1,2-butanediol, 1,4-butanediol, glycerol, and diethanolamine.
  • the dihydroxy compound is preferably pharmaceutically acceptable and is preferably miscible or soluble in water or an alcoholic solvent.
  • the dihydroxy compound is a sugar, as described above, preferably a monosaccharide or disaccharide, more preferably a reduced sugar, and most preferably sorbitol or mannitol.
  • the dihydroxy compound is mannitol, most preferably D-mannitol.
  • composition according to this aspect of the invention is in the form of a lyophilized powder.
  • the composition also comprises the free dihydroxy compound.
  • the dihydroxy compound and the compound of formula (1) are present in the mixture in a molar ratio ranging from about 0.5:1 to about 100:1, more preferably from about 5:1 to about 100:1.
  • the dihydroxy compound and the compound of formula (1) are present in a ratio ranging from about 10:1 to about 100:1, from about 20:1 to about 100:1, or from about 40:1 to about 100:1.
  • the composition further comprises one or more other pharmaceutically acceptable excipients, carriers, diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • pharmaceutically acceptable formulations containing these materials is described in, e.g., Remington: The Science and Practice of Pharmacy, 20 th Ed ., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
  • the compounds and compositions according to the first and second aspects of the invention may be prepared by the methods described herein, or by any method suitable to produce the compound or composition.
  • the boronate esters of formula (1) can be prepared from the corresponding boronic acids by lyophilization in the presence of mannitol or sorbitol, as described herein, or, alternatively, can be prepared from another boronate ester by transesterification.
  • the boronate esters of formula (1) can be prepared by incorporation of the sugar moiety at an earlier stage in the synthesis.
  • the invention provides a method for formulating a boronic acid compound, the method comprising:
  • the aqueous mixture comprises one or more co-solvents in addition to water.
  • the co-solvent is miscible with water.
  • the co-solvent is an alcohol, including, without limitation, ethanol and tert-butanol.
  • the composition of the solvent mixture may range from about 5% to about 95% v/v alcohol.
  • the aqueous solvent mixture comprises from about 30% to about 50% alcohol, preferably from about 35% to about 45% alcohol.
  • the aqueous solvent mixture comprises about 40% tert-butanol.
  • the aqueous solvent mixture comprises from about 1% to about 15% alcohol, preferably from about 5% to about 10% alcohol. In certain preferred embodiments, the aqueous solvent mixture comprises from about 5% to about 10% ethanol.
  • the compound having at least two hydroxyl groups and the boronic acid compound are present in the mixture in a molar ratio ranging from about 1:1 to about 100:1.
  • the molar ratio of dihydroxy compound to boronic acid compound is about 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, or 100:1.
  • Other ratios are also possible. These ratios are approximate, and may vary somewhat for weighing ease.
  • the aqueous mixture contained dihydroxy compound and boronic acid compound in a 10:1 w/w ratio, which corresponds to a 21:1 molar ratio.
  • the aqueous mixture can be prepared by any order of addition.
  • the dihydroxy compound is added to an aqueous mixture comprising a boronic acid compound.
  • the boronic acid compound is added to an aqueous mixture comprising a dihydroxy compound.
  • the boronic acid compound and dihydroxy compound can be added at the same time, or nearly at the same time.
  • the mixture further comprises one or more pharmaceutically acceptable excipients, carriers, diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • pharmaceutically acceptable formulations containing these materials is described in, e.g., Remington: The Science and Practice of Pharmacy, 20 th Ed. , ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
  • dihydroxy compounds Preferred compounds having at least two hydroxyl groups (“dihydroxy compounds”) according to this aspect of the invention are as described above for the second aspect.
  • the boronic acid compound according to this aspect of the invention has formula (3): wherein
  • P is hydrogen or an amino-group-protecting moiety
  • R is hydrogen or alkyl
  • A is 0, 1, or 2;
  • R 1 , R 2 , and R 3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH 2 —R 5 ,
  • R 5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R 6 , where W is a chalcogen and R 6 is alkyl;
  • Z 5 and Z 6 are each OH.
  • the boronic acid compound is one of:
  • 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.
  • the invention provides a method for formulating a boronic acid compound, the method comprising:
  • boronic acid anhydride refers to a chemical compound formed by combination of two or more molecules of a boronic acid compound of formula (3), with loss of one or more water molecules from the boronic acid moieties. When mixed with water, the boronic acid anhydride compound is hydrated to release a free boronic acid compound of formula (3).
  • the boronic acid anhydride structure can comprise two, three, four, or more boronic acid units and can have a cyclic or linear configuration.
  • the boronic acid anhydride compound exists substantially in a single oligomeric form.
  • the term “boronic acid anhydride compound” also encompasses mixtures of different oligomeric boronic acid anhydrides.
  • Non-limiting examples of such oligomeric boronic acid anhydrides are illustrated below:
  • n is an integer from 0 to about 10, preferably 0, 1, 2, 3, or 4.
  • W at each occurrence, preferably has formula (6): wherein P, R, R 1 , R 2 , R 3 , and A are as defined above for formulae (1)-(3).
  • the boronic acid anhydride compound comprises a cyclic trimer (“boroxine”) of formula (5), wherein n is 1 and W has the meaning given above.
  • the boronic acid anhydride compound exists in a single oligomeric anhydride form. In some embodiments, at least 85%, 90%, 95%, or 99% of the boronic acid present in the boronic acid anhydride compound exists in a single oligomeric anhydride form. In some embodiments, the boronic acid anhydride compound consists essentially of a single oligomeric boronic acid anhydride. In some embodiments, the boronic acid anhydride compound consists of a single oligomeric boronic acid anhydride.
  • the boronic acid anhydride compound consists of, or consists essentially of, a boroxine of formula (5), wherein n is 1, and W has the meaning given above.
  • the boronic acid anhydride compound consists of, or consists essentially of, a boroxine having formula (7):
  • the boronic acid anhydride compound preferably can be prepared from the corresponding boronic acid compound of formula (3) by exposure to dehydrating conditions, including, but not limited to, recrystallization, lyophilization, exposure to heat, and/or exposure to a drying agent.
  • suitable recrystallization solvents include ethyl acetate, dichloromethane, hexanes, ether, acetonitrile, ethanol, and mixtures thereof.
  • the invention provides compositions prepared according to the methods of the third or fourth aspects of the invention.
  • formulation of a boronic acid according to the methods of the invention results in formation of a chemical derivative of the boronic acid compound, preferably formation of a boronate ester.
  • formulation of a boronic acid compound according to the method of the invention produces a composition comprising a boronate ester compound, according to the second aspect of the invention.
  • formulation of a boronic acid compound according to the method of the invention does not result in formation of a chemical derivative of the boronic acid compound.
  • the composition according to the fifth aspect of the invention comprises a boronic acid compound and a compound having at least two hydroxyl groups in a lyophilized powder.
  • compositions according to the second and fifth aspects of the invention can be readily reconstituted by adding an aqueous solvent.
  • the reconstitution solvent is suitable for pharmaceutical administration.
  • suitable reconstitution solvents include, without limitation, water, saline, and phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the compositions according to the second or fifth aspects of the invention are preferably reconstituted with sterile saline (0.9% w/v).
  • the invention provides a boronic acid anhydride compound useful for the methods of the invention.
  • Preferred boronic acid anhydride compounds are as described above for the fourth aspect of the invention.
  • the boronic acid anhydride compound is hydrated to release the free boronic acid.
  • N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was weighed into a container, and 16 mL of tert-butanol was added. The container was closed and the suspension was warmed to approximately 45° C. for 5 minutes to complete dissolution of the compound.
  • Water (24 mL) was added with stirring, followed by 0.4 g of mannitol, added as an excipient, 1% w/v. The mixture was stirred to complete dissolution and then cooled to ambient temperature. The solution was filtered through a 0.45 ⁇ m nylon membrane. One milliliter aliquots were placed in 5 mL serum bottles.
  • Split rubber stoppers were partially inserted into the bottles, and the bottles were placed in a freeze dryer with a shelf temperature of ⁇ 45° C. After approximately 1 hour, the vacuum was applied. The shelf temperature was allowed to rise gradually to ⁇ 35° C. and maintained at ⁇ 35° C. until the ice was gone from the samples (approximately 40 hours). The shelf temperature control was then turned off and the shelf temperature was allowed to gradually rise to 0° C. A secondary drying cycle was carried out by increasing the shelf temperature in 3 increments to 25° C. over a time period of 1.5 hours. The shelf temperature was maintained at 25° C. for 2 hours. The samples were sealed under nitrogen and removed from the freeze dryer.
  • the residual moisture content of the samples was determined by Karl Fischer analysis, using three lyophilized products.
  • the water content was 0.88% by weight.
  • FAB Fast Atom Bombardment
  • a solution of 97% tert-butanol/3% Water for Injection was prepared by warming the required amount of tert-butanol to 35° C. and adding Water for Injection. Approximately 5% of the solution was reserved for use in rinsing. The solution was cooled to 15-30° C., and N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boroxine was added with stirring. The container was rinsed with the reserved tert-butanol/water solution, and the rinses were added to the main vessel. The mixture was stirred until the boronic acid compound was completely dissolved.
  • Mannitol was added, with residual mannitol being rinsed into the reaction vessel with fresh Water for Injection. Sufficient Water for Injection was added to reduce the total alcohol content to 40% v/v. The mixture was stirred until the mannitol was completely dissolved. The mixture was filtered through a 0.22 micron filter. Aliquots of the filtered solution were placed into previously sterilized vials. The vials were sealed with lyophilization stoppers and were placed on lyophilizer chamber shelves maintained at ⁇ 45° C. After two hours, the freeze dryer chamber was evacuated and the chamber pressure was adjusted to 100-200 microns with sterile nitrogen. The lyophilizer chamber shelves were warmed to ⁇ 30° C.
  • the shelf temperature was adjusted to ⁇ 15° C. over 7 hours using an appropriate ramp rate and maintained at that temperature for 5 hours.
  • the shelf was warmed to 0° C. over a period of at least 7 hours using an appropriate ramp rate.
  • the shelf was warmed to 27° C. and maintained at that temperature for 4 hours.
  • the chamber pressure was restored using sterile nitrogen, and the vials were sealed and removed.
  • the mannitol boronate structure was confirmed by mass spectrometry (positive ion or electrospray, acetonitrile solution) and 13 C NMR.
  • the reaction mixture was partitioned with hexanes/methanol and the aqueous methanol layer was concentrated to afford a solid.
  • the solid was reconstituted with aqueous sodium hydroxide. After washing with dichloromethane, the aqueous layer was acidified with aqueous hydrochloric acid.
  • the product was extracted using dichloromethane. After drying with magnesium sulfate, the batch was filtered and the dichloromethane was removed under reduced pressure. Hexanes were added and crude product was isolated by further stripping of solvent.
  • the product was recrystallized from ethyl acetate, collected by filtration and dried under vacuum at 65-70° C. When the material was dry, it was packaged in amber glass bottles with teflon-lined caps, labeled, and stored at ⁇ 20° C.
  • the product has the trimeric boroxine structure shown below, as supported by the results of mass spectrometry, 1 H NMR, and elemental analysis.
  • the lyophilized formulation of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid with D-mannitol was prepared as described in Example 1.
  • One sample was reconstituted with 2 mL of water. Dissolution was complete within 1-2 minutes of shaking. The entire solution was transferred to a volumetric flask, diluted, and analyzed by HPLC for content of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid. The total drug content was 1.09 mg.
  • a second sample was reconstituted with 1 mL of propylene glycol:EtOH:H 2 O, 40:10:50. Dissolution was complete with 1 minute of shaking. The total drug content was 1.11 mg.
  • the lyophilized formulation was also reconstituted with 0.9% w/v saline.
  • the lyophilized material dissolved readily at concentrations up to 6 mg/mL.
  • solid N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was not soluble in 0.9% w/v saline at a concentration of 1 mg/mL.
  • ⁇ T and ⁇ W 1/2 are, respectively, the differences in retention times and the sum of the mid-width of the sample and internal standard peaks. Minor variation of the mobile phase is allowed to achieve results similar to those above.
  • N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was prepared as described in U.S. Pat. No. 5,780,454.
  • the product was obtained as a white amorphous powder.
  • the product was stable for more than 2 years when stored at ⁇ 20° C., as determined by HPLC analysis (purity >97%). When stored at 2-8° C., the product was not stable for longer than 3-6 months.
  • a sterile liquid formulation (0.5 mg/mL) of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was prepared in 0.9% w/v saline, 2% v/v ethanol and 0.1% w/v ascorbic acid. When stored at 2-8° C., the liquid formulation was not stable for longer than 6 months, as determined by HPLC analysis.
  • the lyophilized product was prepared according to Example 1 and stored at 5° C., ambient temperature, 37° C., and 50° C. Stability was monitored for approximately 18 months by periodically reconstituting a sample and analyzing the entire contents of the bottle by HPLC. Over this time period, there was no loss of drug in the lyophilized product stored at any temperature and no evidence of degradation product peaks in the HPLC chromatograms.
  • the lyophilized product was prepared according to Example 1, and samples (2.5 mg/vial) were reconstituted with 2.5 mL of 0.9% w/v sterile saline. Dissolution was complete within 10 seconds and afforded a clear colorless solution containing 1 mg/mL of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid. The solution showed no sign of degradation when stored at ambient temperature (23° C.) for 43 hours. No special care was taken to protect the solution from light.

Abstract

The invention relates to the formulation of pharmaceutical compounds. More particularly, the invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds and methods for preparing the compositions. The invention also provides novel boronate ester compounds. The invention further provides boronic acid anhydride compounds useful in the methods of the invention.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims priority from U.S. Provisional Patent Application Ser. No. 60/264,160.
  • GOVERNMENT FUNDING
  • Work described herein was performed under Collaborative Research and Development Agreement (CRADA) Number 0676. The United States Government has certain rights in the invention.
  • BACKGROUND OF THE INVENTION
  • 1. Field of the Invention
  • This invention relates to the formulation of pharmaceutical compounds. More particularly, the invention relates to stable, pharmaceutically acceptable compositions prepared from boronic acid compounds. The invention also relates to methods for preparing such compositions.
  • 2. Summary of the Related Art
  • Boronic acid and ester compounds display a variety of pharmaceutically useful biological activities. Shenvi et al., U.S. Pat. No. 4,499,082 (1985), discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes. Kettner and Shenvi, U.S. Pat. No. 5,187,157 (1993); U.S. Pat. No. 5,242,904 (1993); and U.S. Pat. No. 5,250,720 (1993), describe a class of peptide boronic acids that inhibit trypsin-like proteases. Kleeman et al., U.S. Pat. No. 5,169,841 (1992), discloses N-terminally modified peptide boronic acids that inhibit the action of renin. Kinder et al., U.S. Pat. No. 5,106,948 (1992), discloses that certain tripeptide boronic acid compounds inhibit the growth of cancer cells.
  • More recently, boronic acid and ester compounds have displayed particular promise as inhibitors of the proteasome, a multicatalytic protease responsible for the majority of intracellular protein turnover. Ciechanover, Cell, 79: 13-21 (1994), teaches that the proteasome is the proteolytic component of the ubiquitin-proteasome pathway, in which proteins are targeted for degradation by conjugation to multiple molecules of ubiquitin. Ciechanover also teaches that the ubiquitin-proteasome pathway plays a key role in a variety of important physiological processes.
  • Adams et al., U.S. Pat. No. 5,780,454 (1998), U.S. Pat. No. 6,066,730 (2000), U.S. Pat. No. 6,083,903 (2000), and U.S. Pat. No. 6,297,217 (2001), hereby incorporated by reference in their entirety, describe peptide boronic ester and acid compounds useful as proteasome inhibitors. The references also describe the use of boronic ester and acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF-κB in a cell, to reduce the rate of degradation of p53 protein in a cell, to inhibit cyclin degradation in a cell, to inhibit the growth of a cancer cell, to inhibit antigen presentation in a cell, to inhibit NF-κB dependent cell adhesion, and to inhibit HIV replication. Brand et al., WO 98/35691, teaches that proteasome inhibitors, including boronic acid compounds, are useful for treating infarcts such as occur during stroke or myocardial infarction. Elliott et al., WO 99/15183, teaches that proteasome inhibitors are useful for treating inflammatory and autoimmune diseases.
  • Unfortunately, alkylboronic acids are relatively difficult to obtain in analytically pure form. For example, Snyder et al., J. Am. Chem. Soc. 80: 3611 (1958), teaches that arylboronic acid compounds readily form cyclic trimeric anhydrides under dehydrating conditions. Also, alkylboronic acids and their boroxines are often air-sensitive. Korcek et al., J. Chem. Soc., Perkin Trans. 2 242 (1972), teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid. These difficulties limit the pharmaceutical utility of boronic acid compounds, complicating the characterization of pharmaceutical agents comprising boronic acid compounds and limiting their shelf-life.
  • There is thus a need in the art for improved formulations of boronic acid compounds. Ideally, such formulations would be conveniently prepared, would exhibit enhanced stability and longer shelf life as compared to the free boronic acid compound, and would readily liberate the bioactive boronic acid compound when administered to a subject in need of boronic acid therapy.
  • SUMMARY OF THE INVENTION
  • The present invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds. The invention also provides methods for preparing such compositions. The invention provides the discovery that lyophilization of an aqueous mixture comprising a boronic acid compound and a compound having at least two hydroxyl groups produces a stable composition that readily releases the boronic acid compound upon dissolution in aqueous media.
  • In a first aspect, the invention provides boronate ester compounds having formula (1):
    Figure US20050282742A1-20051222-C00001
  • P is hydrogen or an amino-group protecting moiety;
  • R is hydrogen or alkyl;
  • A is 0, 1, or 2;
  • R1, R2, and R3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH2—R5;
  • R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocydyl, heteroaryl, or -W-R6, where W is a chalcogen and R6 is alkyl;
  • where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocydyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted; and
  • Z1 and Z2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.
  • In a second aspect, the invention provides a composition comprising a compound of formula (2):
    Figure US20050282742A1-20051222-C00002

    wherein:
  • P is hydrogen or an amino-group-protecting moiety;
  • R is hydrogen or alkyl;
  • A is 0, 1, or 2;
  • R1, R2, and R3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH2—R5;
  • R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R6, where W is a chalcogen and R6 is alkyl;
  • where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted; and
  • Z3 and Z4 together form a moiety derived from a compound having at least two hydroxyl 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;
  • in a lyophilized powder.
  • In a third aspect, the invention provides a method for formulating a boronic acid compound, the method comprising:
  • (a) preparing an aqueous mixture comprising
      • (i) a boronic acid compound; and
      • (ii) a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, the chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
  • (b) lyophilizing the mixture.
  • In a fourth aspect, the invention provides a method for formulating a boronic acid compound, the method comprising:
  • (a) preparing a boronic acid anhydride compound;
  • (b) mixing the boronic acid anhydride compound with water and a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, the chain or ring comprising carbon atoms, and, optionally, a heteroatom or heteroatoms which can be N, S, or O to produce an aqueous mixture; and
  • (c) lyophilizing the mixture.
  • In a fifth aspect, the invention provides compositions prepared by the methods of the invention.
  • In a sixth aspect, the invention provides boronic acid anhydride compounds useful in the methods of the invention.
  • DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds and methods for preparing the compositions. The invention also provides novel boronate ester compounds. The invention further provides boronic acid anhydride compounds useful in the methods of the invention.
  • The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure will prevail.
  • For purposes of the present invention, the following definitions will be used:
  • As used herein, the terms “formulate” and “formulation” refer to the preparation of a boronic acid compound in a form suitable for administration to a mammalian subject, preferably a human. Often, formulation of the boronic acid compound comprises addition of pharmaceutically acceptable excipients, diluents, or carriers. In some embodiments, formulation of the boronic acid compound comprises formation of a chemical derivative of the boronic acid compound, preferably formation of a boronate ester. The term “formulation” refers to any form commonly used for pharmaceutical administration, including solids, liquids, suspensions, creams, and gels. For purposes of the present invention, the formulation is preferably a lyophilized powder.
  • As used herein, the term “lyophilized powder” refers to any solid material obtained by lyophilization of an aqueous mixture.
  • By “stable formulation” is meant any formulation having sufficient stability to have utility as a pharmaceutical agent. Preferably, the formulation has sufficient stability to allow storage at a convenient temperature, preferably between 0° C. and 40° C., for a reasonable period of time, preferably longer than one month, more preferably longer than three months, even more preferably longer than six months, and most preferably longer than one year.
  • As employed herein, the term “boronic acid” refers to any chemical compound comprising a —B(OH)2 moiety. Snyder et al., J. Am. Chem. Soc. 80: 3611 (1958), teaches that arylboronic acid compounds readily form oligomeric anhydrides by dehydration of the boronic acid moiety. Thus, unless otherwise apparent from context, the term “boronic acid” is expressly intended to encompass free boronic acids, oligomeric anhydrides, including, but not limited to, dimers, trimers, and tetramers, and mixtures thereof.
  • As employed herein, the term “compound having at least two hydroxyl groups” refers to any compound having two or more hydroxyl groups. For purposes of the present invention, the two hydroxyl groups are preferably separated by at least two connecting atoms, preferably from about 2 to about 5 connecting atoms, more preferably 2 or 3 connecting atoms. The connecting atoms may be in a chain or a ring, the chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O. For convenience, the term “dihydroxy compound” may be used to refer to a compound having at least two hydroxyl groups, as defined above. Thus, as employed herein, the term “dihydroxy compound” is not intended to be limited to compounds having only two hydroxyl groups.
  • As employed herein, the term “amino-group protecting moiety” refers to any group used to derivatize an amino group, especially an N-terminal amino group of a peptide or amino acid. Such groups include, without limitation, allyl acyl, alkoxycarbonyl, aminocarbonyl, and sulfonyl moieties. However, the term “amino-group protecting moiety” is not intended to be limited to those particular protecting groups that are commonly employed in organic synthesis, nor is it intended to be limited to groups that are readily cleavable.
  • The term “chalcogen” as employed herein refers to the elements oxygen or sulfur.
  • The term “alkyl” as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and still more preferably 1-4 carbon atoms, which may be optionally substituted with one, two or three substituents. Unless otherwise explicitly stated, the term “alkyl” is meant to include saturated, unsaturated, and partially unsaturated aliphatic groups. When unsaturated groups are particularly intended, the terms “alkenyl” or “alkynyl” will be used. When only saturated groups are intended, the term “saturated alkyl” will be used. Preferred saturated alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • The term “cycloalkyl” as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally may be optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • An “aryl” group is a C6-C14 aromatic moiety comprising one to three aromatic rings, which may be optionally substituted. Preferably, the aryl group is a C6-C10 aryl group. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Preferably, the aralkyl group is (C1-C6)alk(C6-C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. An “alkaryl” or “alkylaryl” group is an aryl group having one or more alkyl substituents. Examples of alkaryl groups include, without limitation, tolyl, xylyl, mesityl, ethylphenyl, tert-butylphenyl, and methylnaphthyl.
  • The terms “heterocycle”, “heterocyclic”, and “heterocyclyl” refer to any stable ring structure having from about 3 to about 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S. The nitrogen and sulfur heteroatoms of the heterocyclic moiety may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable formula. The term “stable compound” or “stable formula” is meant to refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
  • The heterocyclic group may be optionally substituted on carbon at one or more positions with any of the substituents recited above. The heterocyclic group may also independently be substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, oxo, or hydroxy, or on sulfur with oxo or lower alkyl. Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholinyl. The heterocyclic group may also be fused to an aryl, heteroaryl, or heterocyclic group. Examples of such fused heterocyles include, without limitation, tetrahydroquinoline and dihydrobenzofuran.
  • As used herein, the terms “heteroaryl” and “aromatic heterocyle” refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to about four, preferably from one to about three, heteroatoms selected from the group consisting of N, O, and S. The heteroaryl group may be optionally substituted on carbon at one or more positions with any of the substituents recited above. Preferred heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.
  • As employed herein, a “substituted” alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is one having from one and to about four, preferably from one to about three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferably the substituents are independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, (C1-C6)alkyl(C3-C8)cycloalkyl, C2-C8alkenyl, C2-C8 alkynyl, cyano, amino, C1-C6alkylamino, di(C1-C6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-C6)alkoxy, trifluoromethyl, halogen, C1-C6 alkoxy, C6-C10 aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy, hydroxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C6-C10arylthio, C6-C10arylsulfinyl, C6-C10 arylsulfonyl, C6-C10 aryl, (C1-C6)alkyl(C6-C10)aryl, and halo(C6-C10)aryl.
  • The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.
  • The term oxo refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
  • As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent.
  • The term “acylamino” refers to an amide group attached at the nitrogen atom. The term “carbamoyl” refers to an amide group attached at the carbonyl carbon atom. The nitrogen atom of an acylamino or carbamoyl substituent may be additionally substituted. The term “sulfonamido” refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term “amino” is meant to include NH2 alkylamino, arylamino, and cyclic amino groups.
  • The term “ureido” as employed herein refers to a substituted or unsubstituted urea moiety.
  • In a first aspect, the invention provides boronate ester compounds having formula (1):
    Figure US20050282742A1-20051222-C00003

    wherein
  • P is hydrogen or an amino-group protecting moiety;
  • R is hydrogen or alkyl;
  • A is 0, 1, or 2;
  • R1, R2, and R3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH2—R5;
  • R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R6, where W is a chalcogen and R6 is alkyl;
  • where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted; and
  • Z1 and Z2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.
  • As used herein, the term “moiety derived from a sugar” refers to a moiety formed by removing the hydrogen atoms from two hydroxyl groups of any sugar moiety. The moiety derived from a sugar may be attached to boron by any two of the hydroxyl groups of the sugar. For example, in various embodiments, the boronate ester forms a 5-, 6-, 7-, 8-, or 9-membered ring. In some preferred embodiments, the boronate ester forms a 5- or 6-membered ring.
  • The sugar is preferably a monosaccharide or disaccharide. Non-limiting examples of suitable sugars include, glucose, sucrose, fructose, trehalose, mannitol, and sorbitol. In certain preferred embodiments, the sugar is a reduced sugar, more preferably mannitol or sorbitol. Thus, in the embodiment wherein the sugar is mannitol or sorbitol, Z1 and Z2 together form a moiety of formula C6H12O6, wherein the oxygen atoms of the two deprotonated hydroxyl groups form covalent attachments with boron to form a boronate ester compound.
  • Preferably, the mannitol or sorbitol boronate ester compound has one of the following structures:
    Figure US20050282742A1-20051222-C00004

    However, structures with larger boronate ester ring sizes are also possible.
  • In certain preferred embodiments, the mannitol or sorbitol boronate ester forms a symmetrical 5-membered ring having the following structure:
    Figure US20050282742A1-20051222-C00005
  • Preferably, the mannitol or sorbitol is of the D-configuration, although the L-configuration may also be used. In certain particularly preferred embodiments, Z1 and Z2 together form a moiety derived from D-mannitol. In these embodiments, the boronate ester compound preferably has one of the following structures:
    Figure US20050282742A1-20051222-C00006

    However, structures with larger boronate ester ring sizes are also possible.
  • In certain particularly preferred embodiments, the boronate ester compound has the following structure:
    Figure US20050282742A1-20051222-C00007
  • The P moiety of the compound of formula (1) is preferably hydrogen or one of R7—C(O)—, R7—S(O)2—, R7—NH—(O)—, or R7—O—C(O)—, where R7 is one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when Y is R7—C(O)— or R7—S(O)2—, R7 can also be an optionally substituted 5- to 10-membered saturated, partially unsaturated, or aromatic heterocycle.
  • In certain preferred embodiments, P is one of R7—C(O)— or R7—S(O)2—, and R7 is an optionally substituted 5- to 10-membered saturated, partially unsaturated, or aromatic heterocycle. Preferably, R7 is an aromatic heterocycle, more preferably pyrazinyl, pyridyl, quinolyl, or quinoxalinyl, or a saturated heterocycle, preferably morpholinyl. In some preferred embodiments, P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
  • In some preferred embodiments, R is hydrogen. In some other preferred embodiments, R is alkyl, preferably C1-C6 alkyl, more preferably C1-C4 alkyl, and most preferably methyl or ethyl.
  • The variable A in formula (1) can be 0, 1, or 2. Thus, when A is zero, the residue within the brackets is not present and the boronate ester compound is a dipeptide. Similarly, where A is 1, the residue within the brackets is present and the compound is a tripeptide. Where A is 2, the compound is a tetrapeptide. In certain particularly preferred embodiments, A is zero. For purposes of the invention, the terms “peptide”, “dipeptide”, and “tripeptide” are intended to encompass compounds comprising natural amino acid residues, unnatural amino acid residues, or a combination of natural and unnatural amino acid residues. It will be apparent from formulae (1)-(3), that the terms “peptide”, “dipeptide”, and “tripeptide” are used herein to refer to compounds in which the carboxylic acid functionality of the C-terminal amino acid residue is replaced by a boronic acid or boronate ester functionality.
  • It is preferred that the substituents R1, R2, and R3 in formula (1) are each independently one of hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl, or —CH2—R5, wherein each of R1, R2, R3, and R5 may be optionally substituted. More preferably, R1, R2, and R3 are each independently one of C1-C4 alkyl or —CH2—R5, and R5 is one of cycloalkyl, aryl, heterocyclyl, heteroaryl, or -W-R6 where W is chalcogen and R6 is alkyl. Preferably, R5 is one of C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6)alk(C6-C10)aryl, C3-C10cycloalkyl, C1-C8alkoxy, or C1-C8 alkylthio or a 5 to 10-membered heteroaryl ring.
  • In certain preferred embodiments, the compound of formula (1) is one of:
  • D-Mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate;
  • D-Mannitol N-(2-uinoline)sulfonyl-L-homophenylalanine-L-leucine boronate;
  • D-Mannitol N-(3pyridine)carbonyl-L-phenylalanine-L-leucine boronate;
  • D-Mannitol N-(4morpholine)carbonyl-L-phenylalanine-L-leucine boronate;
  • D-Mannitol N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronate;
  • D-Mannitol N-(8quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronate;
  • D-Mannitol N-(4morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronate;
  • D-Mannitol N-(4morpholine)carbonyl-L-tyrosine-L-leucine boronate; or
  • D-Mannitol N-(4morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronate.
  • In certain particularly preferred embodiments, the compound of formula (1) is D-Mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate, preferably having the following structure:
    Figure US20050282742A1-20051222-C00008
  • In a second aspect, the invention provides a composition comprising a compound of formula (2):
    Figure US20050282742A1-20051222-C00009

    wherein
  • P is hydrogen or an amino-group-protecting moiety;
  • R is hydrogen or alkyl;
  • A is 0, 1, or 2;
  • R1, R2, and R3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH2—R5;
  • R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R6, where W is a chalcogen and R6 is alkyl;
  • where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3or R5 can be optionally substituted; and
  • Z3 and Z4 together form a moiety derived from a compound having at least two hydroxyl 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, wherein the atom attached to boron in each case is an oxygen atom;
  • in a lyophilized powder.
  • Preferred values for the variables P, R, A, R1, R2, R3, R5, and R6 according to this aspect of the invention are as described above for the first aspect.
  • The term “moiety derived from a compound having at least two hydroxyl groups” according to this aspect of the invention is used analogously to the term “moiety derived from a sugar” described above, and thus refers to a moiety formed by removing the hydrogen atoms from two hydroxyl groups of a compound having at least two hydroxyl groups. The moiety derived from a compound having at least two hydroxyl groups may be attached to boron by the oxygen atoms of any two of its hydroxyl groups. Preferably, the boron atom, the oxygen atoms attached to boron, and the atoms connecting the two oxygen atoms together form a 5- or 6-membered ring. Examples of suitable compounds having at least two hydroxyl groups (“dihydroxy compounds”) include, without limitation, pinanediol, pinacol, perfluoropinacol, ethylene glycol, diethylene glycol, catechol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, 1,2-butanediol, 1,4-butanediol, glycerol, and diethanolamine.
  • For purposes of the present invention, the dihydroxy compound is preferably pharmaceutically acceptable and is preferably miscible or soluble in water or an alcoholic solvent. In some preferred embodiments, the dihydroxy compound is a sugar, as described above, preferably a monosaccharide or disaccharide, more preferably a reduced sugar, and most preferably sorbitol or mannitol. In certain particularly preferred embodiments, the dihydroxy compound is mannitol, most preferably D-mannitol.
  • The composition according to this aspect of the invention is in the form of a lyophilized powder. In some preferred embodiments, the composition also comprises the free dihydroxy compound. Preferably, the dihydroxy compound and the compound of formula (1) are present in the mixture in a molar ratio ranging from about 0.5:1 to about 100:1, more preferably from about 5:1 to about 100:1. In various embodiments, the dihydroxy compound and the compound of formula (1) are present in a ratio ranging from about 10:1 to about 100:1, from about 20:1 to about 100:1, or from about 40:1 to about 100:1.
  • In some preferred embodiments, the composition further comprises one or more other pharmaceutically acceptable excipients, carriers, diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations containing these materials is described in, e.g., Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
  • The compounds and compositions according to the first and second aspects of the invention may be prepared by the methods described herein, or by any method suitable to produce the compound or composition. For example, the boronate esters of formula (1) can be prepared from the corresponding boronic acids by lyophilization in the presence of mannitol or sorbitol, as described herein, or, alternatively, can be prepared from another boronate ester by transesterification. Alternatively, the boronate esters of formula (1) can be prepared by incorporation of the sugar moiety at an earlier stage in the synthesis.
  • In a third aspect, the invention provides a method for formulating a boronic acid compound, the method comprising:
  • (a) preparing an aqueous mixture comprising
      • (i) a boronic acid compound; and
      • (ii) a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, the chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
  • (b) lyophilizing the mixture.
  • In certain preferred embodiments, the aqueous mixture comprises one or more co-solvents in addition to water. Preferably, the co-solvent is miscible with water. More preferably, the co-solvent is an alcohol, including, without limitation, ethanol and tert-butanol. The composition of the solvent mixture may range from about 5% to about 95% v/v alcohol. In some embodiments, the aqueous solvent mixture comprises from about 30% to about 50% alcohol, preferably from about 35% to about 45% alcohol. In certain preferred embodiments, the aqueous solvent mixture comprises about 40% tert-butanol.
  • In some other embodiments, the aqueous solvent mixture comprises from about 1% to about 15% alcohol, preferably from about 5% to about 10% alcohol. In certain preferred embodiments, the aqueous solvent mixture comprises from about 5% to about 10% ethanol.
  • Preferably, the compound having at least two hydroxyl groups and the boronic acid compound are present in the mixture in a molar ratio ranging from about 1:1 to about 100:1. In various embodiments, the molar ratio of dihydroxy compound to boronic acid compound is about 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, or 100:1. Other ratios are also possible. These ratios are approximate, and may vary somewhat for weighing ease. For example, in the formulation described in Example 1 below, the aqueous mixture contained dihydroxy compound and boronic acid compound in a 10:1 w/w ratio, which corresponds to a 21:1 molar ratio.
  • The aqueous mixture can be prepared by any order of addition. For example, in some embodiments, the dihydroxy compound is added to an aqueous mixture comprising a boronic acid compound. In some other embodiments, the boronic acid compound is added to an aqueous mixture comprising a dihydroxy compound. In still yet other embodiments, the boronic acid compound and dihydroxy compound can be added at the same time, or nearly at the same time. In some embodiments, it may be advantageous initially to add the boronic add compound and/or the dihydroxy compound to a solvent mixture containing a higher percentage of co-solvent than is desired for the lyophilization step, and then dilute with water.
  • In some preferred embodiments, the mixture further comprises one or more pharmaceutically acceptable excipients, carriers, diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations containing these materials is described in, e.g., Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
  • Preferred compounds having at least two hydroxyl groups (“dihydroxy compounds”) according to this aspect of the invention are as described above for the second aspect.
  • In certain preferred embodiments, the boronic acid compound according to this aspect of the invention has formula (3):
    Figure US20050282742A1-20051222-C00010

    wherein
  • P is hydrogen or an amino-group-protecting moiety;
  • R is hydrogen or alkyl;
  • A is 0, 1, or 2;
  • R1, R2, and R3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH2—R5,
  • R5 in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R6, where W is a chalcogen and R6 is alkyl;
  • where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocydyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted; and
  • Z5 and Z6 are each OH.
  • Preferred values for the variables P, R, A, R1, R2, R3, R5, and R6 according to this aspect of the invention are as described above for the first aspect.
  • In certain particularly preferred embodiments, the boronic acid compound is one of:
  • N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;
  • N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;
  • N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;
  • N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;
  • N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid;
  • N-(8-quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid;
  • N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;
  • N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid; or
  • N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.
  • In a fourth aspect, the invention provides a method for formulating a boronic acid compound, the method comprising:
  • (a) preparing a boronic acid anhydride compound;
  • (b) mixing the boronic acid anhydride compound with water and a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, the chain or ring comprising carbon atoms, and, optionally, a heteroatom or heteroatoms which can be N, S, or O to produce an aqueous mixture; and
  • (c) lyophilizing the mixture.
  • For purposes of the invention, the term “boronic acid anhydride” refers to a chemical compound formed by combination of two or more molecules of a boronic acid compound of formula (3), with loss of one or more water molecules from the boronic acid moieties. When mixed with water, the boronic acid anhydride compound is hydrated to release a free boronic acid compound of formula (3).
  • In various embodiments, the boronic acid anhydride structure can comprise two, three, four, or more boronic acid units and can have a cyclic or linear configuration. In some embodiments, the boronic acid anhydride compound exists substantially in a single oligomeric form. However, the term “boronic acid anhydride compound” also encompasses mixtures of different oligomeric boronic acid anhydrides.
  • Non-limiting examples of such oligomeric boronic acid anhydrides are illustrated below:
    Figure US20050282742A1-20051222-C00011
  • In formulae (4) and (5), n is an integer from 0 to about 10, preferably 0, 1, 2, 3, or 4. W, at each occurrence, preferably has formula (6):
    Figure US20050282742A1-20051222-C00012

    wherein P, R, R1, R2, R3, and A are as defined above for formulae (1)-(3). In some preferred embodiments, the boronic acid anhydride compound comprises a cyclic trimer (“boroxine”) of formula (5), wherein n is 1 and W has the meaning given above.
  • In some embodiments, at least 80% of the boronic acid present in the boronic acid anhydride compound exists in a single oligomeric anhydride form. In some embodiments, at least 85%, 90%, 95%, or 99% of the boronic acid present in the boronic acid anhydride compound exists in a single oligomeric anhydride form. In some embodiments, the boronic acid anhydride compound consists essentially of a single oligomeric boronic acid anhydride. In some embodiments, the boronic acid anhydride compound consists of a single oligomeric boronic acid anhydride.
  • In some preferred embodiments, the boronic acid anhydride compound consists of, or consists essentially of, a boroxine of formula (5), wherein n is 1, and W has the meaning given above. In certain particularly preferred embodiments, the boronic acid anhydride compound consists of, or consists essentially of, a boroxine having formula (7):
    Figure US20050282742A1-20051222-C00013
  • The boronic acid anhydride compound preferably can be prepared from the corresponding boronic acid compound of formula (3) by exposure to dehydrating conditions, including, but not limited to, recrystallization, lyophilization, exposure to heat, and/or exposure to a drying agent. Nonlimiting examples of suitable recrystallization solvents include ethyl acetate, dichloromethane, hexanes, ether, acetonitrile, ethanol, and mixtures thereof.
  • In a fifth aspect, the invention provides compositions prepared according to the methods of the third or fourth aspects of the invention. In some preferred embodiments, formulation of a boronic acid according to the methods of the invention results in formation of a chemical derivative of the boronic acid compound, preferably formation of a boronate ester. In these embodiments, formulation of a boronic acid compound according to the method of the invention produces a composition comprising a boronate ester compound, according to the second aspect of the invention.
  • In some other embodiments, formulation of a boronic acid compound according to the method of the invention does not result in formation of a chemical derivative of the boronic acid compound. In these embodiments, the composition according to the fifth aspect of the invention comprises a boronic acid compound and a compound having at least two hydroxyl groups in a lyophilized powder.
  • The compositions according to the second and fifth aspects of the invention can be readily reconstituted by adding an aqueous solvent. Preferably, the reconstitution solvent is suitable for pharmaceutical administration. Examples of suitable reconstitution solvents include, without limitation, water, saline, and phosphate buffered saline (PBS). For clinical use, the compositions according to the second or fifth aspects of the invention are preferably reconstituted with sterile saline (0.9% w/v).
  • Upon reconstitution in aqueous medium, an equilibrium is established between any boronate ester present in the composition and the corresponding boronic acid. Typically, equilibrium is reached quickly, e.g., within 10-15 minutes, after the addition of water. The relative concentrations of boronate ester and boronic acid present at equilibrium is dependent upon the pH of the solution, temperature, and the ratio of dihydroxy compound to boronic acid compound.
  • In a sixth aspect, the invention provides a boronic acid anhydride compound useful for the methods of the invention. Preferred boronic acid anhydride compounds are as described above for the fourth aspect of the invention. When mixed with water, the boronic acid anhydride compound is hydrated to release the free boronic acid.
  • The following examples are intended to further illustrate certain preferred embodiments of the invention, and are not intended to limit the scope of the invention.
  • EXAMPLES Example 1 Preparation of a Lyophilized Formulation of N-(2-pyrazine)-carbonyl-L-phenylalanine-L-leucine Boronic Acid with D-mannitol
  • Approximately 40 mg of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was weighed into a container, and 16 mL of tert-butanol was added. The container was closed and the suspension was warmed to approximately 45° C. for 5 minutes to complete dissolution of the compound. Water (24 mL) was added with stirring, followed by 0.4 g of mannitol, added as an excipient, 1% w/v. The mixture was stirred to complete dissolution and then cooled to ambient temperature. The solution was filtered through a 0.45 μm nylon membrane. One milliliter aliquots were placed in 5 mL serum bottles. Split rubber stoppers were partially inserted into the bottles, and the bottles were placed in a freeze dryer with a shelf temperature of −45° C. After approximately 1 hour, the vacuum was applied. The shelf temperature was allowed to rise gradually to −35° C. and maintained at −35° C. until the ice was gone from the samples (approximately 40 hours). The shelf temperature control was then turned off and the shelf temperature was allowed to gradually rise to 0° C. A secondary drying cycle was carried out by increasing the shelf temperature in 3 increments to 25° C. over a time period of 1.5 hours. The shelf temperature was maintained at 25° C. for 2 hours. The samples were sealed under nitrogen and removed from the freeze dryer.
  • The residual moisture content of the samples was determined by Karl Fischer analysis, using three lyophilized products. The water content was 0.88% by weight.
  • Fast Atom Bombardment (FAB) mass spectral analysis of the lyophilized product showed a strong signal at m/z=531 (see Figure), indicative of formation of a covalent boronate ester adduct between N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid and D-mannitol. Glycerol was employed as the matrix, and a signal for the glycerol adduct with N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was observed at m/z=441. However, the intensity of the signal at m/z=441 was very low compared to the signal at m/z=531, possibly indicative of the enhanced stability of the D-mannitol adduct.
  • Example 2 Production-Scale Preparation of a Lyophilized Formulation of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boronic Acid with D-mannitol
  • In a clean compounding vessel, a solution of 97% tert-butanol/3% Water for Injection was prepared by warming the required amount of tert-butanol to 35° C. and adding Water for Injection. Approximately 5% of the solution was reserved for use in rinsing. The solution was cooled to 15-30° C., and N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boroxine was added with stirring. The container was rinsed with the reserved tert-butanol/water solution, and the rinses were added to the main vessel. The mixture was stirred until the boronic acid compound was completely dissolved. Mannitol was added, with residual mannitol being rinsed into the reaction vessel with fresh Water for Injection. Sufficient Water for Injection was added to reduce the total alcohol content to 40% v/v. The mixture was stirred until the mannitol was completely dissolved. The mixture was filtered through a 0.22 micron filter. Aliquots of the filtered solution were placed into previously sterilized vials. The vials were sealed with lyophilization stoppers and were placed on lyophilizer chamber shelves maintained at −45° C. After two hours, the freeze dryer chamber was evacuated and the chamber pressure was adjusted to 100-200 microns with sterile nitrogen. The lyophilizer chamber shelves were warmed to −30° C. using an appropriate ramp rate, and held at that temperature for 10-15 hours. After each of the product thermocouples read −33° C. or warmer, the shelf temperature was adjusted to −15° C. over 7 hours using an appropriate ramp rate and maintained at that temperature for 5 hours. After all product thermocouples recorded the shelf temperature, the shelf was warmed to 0° C. over a period of at least 7 hours using an appropriate ramp rate. When all thermocouples recorded 0° C., the shelf was warmed to 27° C. and maintained at that temperature for 4 hours. At the end of the terminal drying phase, the chamber pressure was restored using sterile nitrogen, and the vials were sealed and removed.
  • The mannitol boronate structure was confirmed by mass spectrometry (positive ion or electrospray, acetonitrile solution) and 13C NMR.
  • The 13C NMR (d6-DMSO) spectrum revealed three new mannitol carbon signals, as compared with the same region of the spectrum for free mannitol. This result indicates formation of a symmetrical mannitol complex as illustrated below:
    Figure US20050282742A1-20051222-C00014
  • Example 3 Preparation of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boroxine
  • (1S,2S,3R,5S)-Pinanediol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate was synthesized according to the procedures described in Adams et al., U.S. Pat. No. 5,780,454 (1998) and dissolved in a mixture of methanol and hexanes at room temperature. Liberation of the terminal boronic add sub-unit from the pinanediol protecting group was effected by treatment with 2-methylpropaneboronic acid and aqueous hydrochloric acid in methanol and hexanes at room temperature. The progress of the reaction was assessed by thin layer chromatography. The reaction mixture was partitioned with hexanes/methanol and the aqueous methanol layer was concentrated to afford a solid. The solid was reconstituted with aqueous sodium hydroxide. After washing with dichloromethane, the aqueous layer was acidified with aqueous hydrochloric acid. The product was extracted using dichloromethane. After drying with magnesium sulfate, the batch was filtered and the dichloromethane was removed under reduced pressure. Hexanes were added and crude product was isolated by further stripping of solvent. The product was recrystallized from ethyl acetate, collected by filtration and dried under vacuum at 65-70° C. When the material was dry, it was packaged in amber glass bottles with teflon-lined caps, labeled, and stored at −20° C.
  • The product has the trimeric boroxine structure shown below, as supported by the results of mass spectrometry, 1H NMR, and elemental analysis.
    Figure US20050282742A1-20051222-C00015
  • Mass spectral analysis (positive ion, electrospray) of an acetonitrile solution of the product exhibited sodium, proton, and potassium adducts of trimeric boroxine at m/z=1121, 1099, and 1137, respectively. No monomeric boronic acid was observed in any adduct form.
  • The 1H NMR (d6-DMSO) spectrum showed no BOH resonance, suggesting the presence of the boroxine structure.
  • X-ray powder diffraction and polarized-light microscopy analysis demonstrated the crystalline nature of the product, and dynamic vapor sorption studies demonstrated its non-hygroscopic nature, consistent with the anhydride structure.
  • Example 3 Reconstitution of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boronic Acid
  • The lyophilized formulation of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid with D-mannitol was prepared as described in Example 1. One sample was reconstituted with 2 mL of water. Dissolution was complete within 1-2 minutes of shaking. The entire solution was transferred to a volumetric flask, diluted, and analyzed by HPLC for content of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid. The total drug content was 1.09 mg. A second sample was reconstituted with 1 mL of propylene glycol:EtOH:H2O, 40:10:50. Dissolution was complete with 1 minute of shaking. The total drug content was 1.11 mg.
  • The lyophilized formulation was also reconstituted with 0.9% w/v saline. The lyophilized material dissolved readily at concentrations up to 6 mg/mL. By contrast, solid N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was not soluble in 0.9% w/v saline at a concentration of 1 mg/mL.
  • To be certain that free N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was rapidly liberated upon reconstitution of the lyophilized formulation in aqueous solution, the lyophilized formulation was dissolved in neat DMSO and assayed for inhibition of the chymotrypsin-like activity of the 20S proteasome as described in U.S. Pat. No. 5,780,454. Proteasome inhibition can only be observed if hydrolysis under the assay conditions is fast. The observed Ki value of 0.3 nM is equivalent to that observed for free N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, indicating complete and rapid hydrolysis of the D-mannitol adduct under the assay conditions.
  • Example 4 HPLC Analysis of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boronic Acid
  • System parameters:
  • Column: Adsorbosphere-HSC18, 5 μ, 250×4.6 mm
  • Mobile Phase: 65/35: methanol/water containing 0.1% TFA
  • Flow Rate: 1.0 mL/min
  • Detection/Sensitivity: PDA and UV at 255 nm, 0.1 aufs
  • Injection volume: 25 μL
  • Internal Standard Solution:
  • 0.18 mg/mL diphenylamine in methanol
  • Sample Preparation:
  • Accurately weighed 0.5-1.5 mg portions of the sample or reference standard were dissolved in 2.00 mL of the internal standard solution.
  • Chromatographic Parameters:
    Sample Internal Standard
    Retention time 8.4 min 18.9 min
    Capacity factor, k′ 2.0 5.8
    Asymmetry (10%) 1.7 1.3
    Rel. Retention, α 0.34
    Resolution, Rs = ΔT/ΣW1/2 15.1
  • ΔT and ΣW1/2 are, respectively, the differences in retention times and the sum of the mid-width of the sample and internal standard peaks. Minor variation of the mobile phase is allowed to achieve results similar to those above.
  • Example 5 Stability of Formulations
  • Solid N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boronic Acid
  • N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was prepared as described in U.S. Pat. No. 5,780,454. The product was obtained as a white amorphous powder. The product was stable for more than 2 years when stored at −20° C., as determined by HPLC analysis (purity >97%). When stored at 2-8° C., the product was not stable for longer than 3-6 months.
  • Liquid N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boronic Acid
  • A sterile liquid formulation (0.5 mg/mL) of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid was prepared in 0.9% w/v saline, 2% v/v ethanol and 0.1% w/v ascorbic acid. When stored at 2-8° C., the liquid formulation was not stable for longer than 6 months, as determined by HPLC analysis.
  • Lyophilized D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boronate
  • The lyophilized product was prepared according to Example 1 and stored at 5° C., ambient temperature, 37° C., and 50° C. Stability was monitored for approximately 18 months by periodically reconstituting a sample and analyzing the entire contents of the bottle by HPLC. Over this time period, there was no loss of drug in the lyophilized product stored at any temperature and no evidence of degradation product peaks in the HPLC chromatograms.
  • Reconstituted Solution of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine Boronic Acid
  • The lyophilized product was prepared according to Example 1, and samples (2.5 mg/vial) were reconstituted with 2.5 mL of 0.9% w/v sterile saline. Dissolution was complete within 10 seconds and afforded a clear colorless solution containing 1 mg/mL of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid. The solution showed no sign of degradation when stored at ambient temperature (23° C.) for 43 hours. No special care was taken to protect the solution from light.

Claims (15)

1-32. (canceled)
33. A method for formulating a boronic acid compound, the method comprising:
(a) preparing an aqueous mixture comprising
(i) a boronic acid compound; and
(ii) a compound selected from the group consisting of pinanediol, pinacol, perfluoropinacol, ethylene glycol, diethylene glycol, catechol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, 1,2-butanediol, 1,4-butanediol, glycerol, and diethanolamine; and
(b) lyophilizing the mixture.
34. The method of claim 33, wherein the boronic acid compound has formula (3):
Figure US20050282742A1-20051222-C00016
wherein:
P is hydrogen or an amino-group-protecting moiety;
R is hydrogen or alkyl;
A is 0, 1, or 2;
R1, R2, and R3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH2—R5;
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or -W-R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted; and
Z5 and Z6 are each OH.
35. The method of claim 34, wherein P is one of R7—C(O)—, R7—S(O)2, R7—NH—C(O)—, or R7—O—C(O)—;
where R7 is one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R7—C(O)— or R7—S(O)2—, R7 can also be an optionally substituted 5- to 10-membered saturated, partially unsaturated, or aromatic heterocycle.
36. The method of claim 35, wherein P is R7—C(O)— or R7—S(O),—, and R7 is an aromatic heterocycle.
37. The method of claim 36, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
38. The method of claim 35, wherein:
A is zero;
R is hydrogen or C1-C8 alkyl; and
R3 is C1-C6 alkyl.
39. The method of claim 38, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
40. The method of claim 35, wherein:
R1, R2 and R3 are each independently one of hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, or C8-C10 aryl, or —CH2—R5;
R5, in each instance, is one of C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6)alk(C6-C10)aryl, C3-C10 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkylthio;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R1, R2, R3 or R5 can be optionally substituted.
41. The method of claim 33, wherein the boronic acid compound is:
N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;
N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(8-quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid; or
N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.
42. The method of claim 33, wherein the boronic acid compound is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid
43-49. (canceled)
50. The method of claim 33, wherein the aqueous mixture further comprises a water-miscible co-solvent.
51. The method of claim 50, wherein the water-miscible co-solvent is an alcohol.
52-92. (canceled)
US11/184,622 2001-01-25 2005-07-19 Formulation of boronic acid compounds Abandoned US20050282742A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/184,622 US20050282742A1 (en) 2001-01-25 2005-07-19 Formulation of boronic acid compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US26416001P 2001-01-25 2001-01-25
US10/056,563 US6699835B2 (en) 2001-01-25 2002-01-25 Formulation of boronic acid compounds
US10/744,843 US7109323B2 (en) 2001-01-25 2003-12-23 Formulation of boronic acid compounds
US11/184,622 US20050282742A1 (en) 2001-01-25 2005-07-19 Formulation of boronic acid compounds

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/744,843 Continuation US7109323B2 (en) 2001-01-25 2003-12-23 Formulation of boronic acid compounds

Publications (1)

Publication Number Publication Date
US20050282742A1 true US20050282742A1 (en) 2005-12-22

Family

ID=23004871

Family Applications (5)

Application Number Title Priority Date Filing Date
US10/056,563 Expired - Lifetime US6699835B2 (en) 2001-01-25 2002-01-25 Formulation of boronic acid compounds
US10/056,567 Expired - Lifetime US6713446B2 (en) 2001-01-25 2002-01-25 Formulation of boronic acid compounds
US10/664,732 Expired - Lifetime US6958319B2 (en) 2001-01-25 2003-09-18 Formulation of boronic acid compounds
US10/744,843 Expired - Lifetime US7109323B2 (en) 2001-01-25 2003-12-23 Formulation of boronic acid compounds
US11/184,622 Abandoned US20050282742A1 (en) 2001-01-25 2005-07-19 Formulation of boronic acid compounds

Family Applications Before (4)

Application Number Title Priority Date Filing Date
US10/056,563 Expired - Lifetime US6699835B2 (en) 2001-01-25 2002-01-25 Formulation of boronic acid compounds
US10/056,567 Expired - Lifetime US6713446B2 (en) 2001-01-25 2002-01-25 Formulation of boronic acid compounds
US10/664,732 Expired - Lifetime US6958319B2 (en) 2001-01-25 2003-09-18 Formulation of boronic acid compounds
US10/744,843 Expired - Lifetime US7109323B2 (en) 2001-01-25 2003-12-23 Formulation of boronic acid compounds

Country Status (14)

Country Link
US (5) US6699835B2 (en)
EP (4) EP2251344B1 (en)
JP (2) JP2004517932A (en)
AT (1) ATE501157T1 (en)
AU (1) AU2002243646B2 (en)
CA (2) CA2435124A1 (en)
CY (2) CY1111488T1 (en)
DE (1) DE60239384D1 (en)
DK (3) DK2251344T3 (en)
ES (3) ES2359391T3 (en)
HK (1) HK1149936A1 (en)
PT (2) PT3078667T (en)
TR (1) TR201819416T4 (en)
WO (2) WO2002059131A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009154737A1 (en) * 2008-06-17 2009-12-23 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
WO2011090940A1 (en) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
US8664200B2 (en) 2008-09-29 2014-03-04 Millennium Pharmaceuticals, Inc. Derivatives of 1-amino-2-cyclobutylethylboronic acid
AU2013203964B2 (en) * 2008-06-17 2015-04-23 Takeda Pharmaceutical Company Limited Boronate ester compounds and pharmaceutical compositions thereof
WO2016130724A1 (en) * 2015-02-11 2016-08-18 Millennium Pharmaceuticals, Inc. Novel crystalline form of a proteasome inhibitor
EP3566719A1 (en) 2010-05-18 2019-11-13 Cerulean Pharma Inc. Compositions and methods for treatment of autoimmune and other diseases
US11241448B2 (en) 2014-05-20 2022-02-08 Millennium Pharmaceuticals, Inc. Methods for cancer therapy

Families Citing this family (139)

* Cited by examiner, † Cited by third party
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
ES2359391T3 (en) 2001-01-25 2011-05-23 The United States Of America, Represented By The Secretary, Department Of Health And Human Services FORMULATION OF BORONIC ACID COMPOUNDS.
US20060084592A1 (en) * 2002-09-09 2006-04-20 Trigen Limited Peptide boronic acid inhibitors
US20050176651A1 (en) * 2002-09-09 2005-08-11 Trigen Limited Peptide boronic acids useful in making salts thereof
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations
US20050119226A1 (en) * 2003-09-09 2005-06-02 Trigen Limited Methods for synthesizing organoboronic compounds and products thereof
PL376535A1 (en) 2002-09-09 2006-01-09 Trigen Limited Boronic acid salts ant their use in the treatment of thrombosis
US20050282757A1 (en) * 2002-09-09 2005-12-22 Trigen Limited Peptide boronic acid compounds useful in anticoagulation
US7576206B2 (en) 2003-08-14 2009-08-18 Cephalon, Inc. 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
US20060052390A1 (en) * 2003-12-24 2006-03-09 Scios, Inc. Treatment of multiple myeloma by p38 MAP kinase and proteasome inhibition
GB0405272D0 (en) * 2004-03-09 2004-04-21 Trigen Ltd Compounds
AU2016202747B2 (en) * 2004-03-30 2017-11-23 Millennium Pharmaceuticals, Inc. Synthesis of boronic ester and acid compounds
CA2560886C (en) * 2004-03-30 2014-08-12 Millennium Pharmaceuticals, Inc. Synthesis of boronic ester and acid compounds
AU2011265442B2 (en) * 2004-03-30 2014-12-04 Millennium Pharmaceuticals, Inc. Synthesis of boronic ester and acid compounds
US7842707B2 (en) 2004-07-23 2010-11-30 Nuada, Llc Peptidase inhibitors
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
US7468383B2 (en) 2005-02-11 2008-12-23 Cephalon, Inc. Proteasome inhibitors and methods of using the same
EP1874297A4 (en) * 2005-04-29 2009-04-22 Kosan Biosciences Inc Method of treating multiple myeloma using 17-aag or 17-ag or a prodrug of either in combination with a proteasome inhibitor
AU2006202209B2 (en) * 2005-05-27 2011-04-14 Lifescan, Inc. Amniotic fluid derived cells
AU2006255183B2 (en) * 2005-06-08 2012-02-02 Centocor, Inc. A cellular therapy for ocular degeneration
EP2623113B1 (en) 2005-11-09 2017-05-31 Onyx Therapeutics, Inc. Compound for enzyme inhibition
US8741643B2 (en) * 2006-04-28 2014-06-03 Lifescan, Inc. Differentiation of pluripotent stem cells to definitive endoderm lineage
JP5226679B2 (en) 2006-06-19 2013-07-03 プロテオリックス, インコーポレイテッド Compounds for enzyme inhibition
AU2007221966A1 (en) * 2006-12-08 2008-06-26 Centenary Institute Of Cancer Medicine And Cell Biology Assay for response to proteasome inhibitors
US9080145B2 (en) 2007-07-01 2015-07-14 Lifescan Corporation Single pluripotent stem cell culture
RU2473685C2 (en) 2007-07-31 2013-01-27 Лайфскен, Инк. Differentiation of human embryo stem cells
EA034601B1 (en) * 2007-08-06 2020-02-25 Милленниум Фармасьютикалз, Инк. Process for producing boronic acids
AU2016253697A1 (en) * 2007-08-06 2016-11-24 Millennium Pharmaceuticals, Inc. Proteasome inhibitors
US7442830B1 (en) 2007-08-06 2008-10-28 Millenium Pharmaceuticals, Inc. Proteasome inhibitors
JP5261488B2 (en) * 2007-08-06 2013-08-14 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 inhibitor
JP2010539183A (en) * 2007-09-12 2010-12-16 ドクター・レディーズ・ラボラトリーズ・リミテッド Bortezomib and process for its production
TWI501773B (en) 2007-10-04 2015-10-01 Onyx Therapeutics Inc Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides
WO2009051581A1 (en) 2007-10-16 2009-04-23 Millennium Pharmaceuticals, Inc. Proteasome inhibitors
US7838673B2 (en) 2007-10-16 2010-11-23 Millennium Pharmaceuticals, Inc. Proteasome inhibitors
WO2009070592A2 (en) * 2007-11-27 2009-06-04 Lifescan, Inc. Differentiation of human embryonic stem cells
BRPI0908033A2 (en) 2008-02-21 2015-08-04 Centocor Ortho Biotech Inc Surface modified plate method and compositions for cell adhesion, culture and detachment
CN102159703B (en) 2008-06-30 2015-11-25 森托科尔奥索生物科技公司 The differentiation of multipotential stem cell
US20100028307A1 (en) * 2008-07-31 2010-02-04 O'neil John J Pluripotent stem cell differentiation
EA201170527A1 (en) * 2008-10-01 2011-10-31 Др. Редди'С Лабораторис Лтд. PHARMACEUTICAL COMPOSITIONS, INCLUDING BORONIC ACID COMPOUNDS
WO2010048298A1 (en) 2008-10-21 2010-04-29 Proteolix, Inc. Combination therapy with peptide epoxyketones
KR101712085B1 (en) 2008-10-31 2017-03-03 얀센 바이오테크 인코포레이티드 Differentiation of human embryonic stem cells to the pancreatic endocrine lineage
CN107435038B (en) * 2008-10-31 2021-07-09 詹森生物科技公司 Differentiation of human embryonic stem cells into the pancreatic endocrine lineage
AU2009316580B2 (en) 2008-11-20 2016-04-14 Janssen Biotech, Inc. Pluripotent stem cell culture on micro-carriers
CA2744227C (en) * 2008-11-20 2018-10-02 Centocor Ortho Biotech Inc. Methods and compositions for cell attachment and cultivation on planar substrates
US9095514B2 (en) * 2009-01-09 2015-08-04 Sun Pharma Advanced Research Company Ltd. Pharmaceutical composition
CA2753285A1 (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
TWI504598B (en) 2009-03-20 2015-10-21 Onyx Therapeutics Inc Crystalline tripeptide epoxy ketone protease inhibitors
DK2411535T3 (en) * 2009-03-24 2015-07-13 Janssen Pharmaceutica Nv BIOMAR RUNNING FOR ASSESSMENT OF PERIPHERAL NEUROPATHY RESPONSE TO TREATMENT WITH a proteasome inhibitor
EP2238973A1 (en) * 2009-04-07 2010-10-13 Cephalon France Lyophilized preparations of proteasome inhibitors
CN101928329B (en) * 2009-06-19 2013-07-17 北京大学 Tripeptide boric acid (ester) compound and preparation method and application thereof
WO2011011300A2 (en) 2009-07-20 2011-01-27 Centocor Ortho Biotech Inc. Differentiation of human embryonic stem cells
RU2540016C2 (en) 2009-07-20 2015-01-27 Янссен Байотек, Инк. Differentiating human embryonic stem cells
MX340952B (en) * 2009-07-20 2016-07-29 Janssen Biotech Inc Differentiation of human embryonic stem cells.
JP5567136B2 (en) 2009-09-08 2014-08-06 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト 4-Substituted pyridin-3-yl-carboxamide compounds and methods of use
US20110189204A1 (en) * 2009-10-01 2011-08-04 Roland De Coster Treatment of Disease with Proteasone Inhibitors
EP2498793B1 (en) 2009-11-13 2019-07-10 Onyx Therapeutics, Inc. Oprozomib for use in metastasis suppression
NZ600786A (en) 2009-12-22 2013-12-20 Cephalon Inc Proteasome inhibitors and processes for their preparation, purification and use
RU2586506C2 (en) 2009-12-23 2016-06-10 Янссен Байотек, Инк. Differentiation of human embryonic stem cells
SG10201408552YA (en) 2009-12-23 2015-02-27 Janssen Biotech Inc Differentiation of human embryonic stem cells
RU2607380C2 (en) 2010-03-01 2017-01-10 Янссен Байотек, Инк. Methods of purifying cells, derived from pluripotent stem cells
EP2542238B1 (en) 2010-03-01 2015-08-12 Onyx Therapeutics, Inc. Compounds for immunoproteasome inhibition
US8263578B2 (en) 2010-03-18 2012-09-11 Innopharma, Inc. Stable bortezomib formulations
EP2547333B1 (en) * 2010-03-18 2017-08-23 Innopharma, Inc. Stable bortezomib formulations
CN102892291A (en) 2010-03-31 2013-01-23 米伦纽姆医药公司 Derivatives of 1-amino-2-cyclopropylethylboronic acid
AU2011245630B2 (en) 2010-04-07 2014-07-03 Onyx Therapeutics, Inc. Crystalline peptide epoxyketone immunoproteasome inhibitor
US20110276102A1 (en) * 2010-05-05 2011-11-10 Cohen Todd J Redundant pacing system with leaded and leadless pacing
SG185511A1 (en) 2010-05-12 2012-12-28 Centocor Ortho Biotech Inc Differentiation of human embryonic stem cells
KR101836855B1 (en) 2010-08-31 2018-04-19 얀센 바이오테크 인코포레이티드 Differentiation of pluripotent stem cells
KR101836850B1 (en) 2010-08-31 2018-03-09 얀센 바이오테크 인코포레이티드 Differentiation of human embryonic stem cells
EP3372672A1 (en) 2010-08-31 2018-09-12 Janssen Biotech, Inc. Differentiation of human embryonic stem cells
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
US8962572B2 (en) 2010-10-05 2015-02-24 Fresenius Kabi Usa, Llc Bortezomib formulations
US8884009B2 (en) 2010-10-14 2014-11-11 Synthon Bv Process for making bortezomib and intermediates for the process
ES2586328T3 (en) 2011-08-11 2016-10-13 Janssen Pharmaceutica, N.V. Predisposing factors for cancer treatment
SI2744332T1 (en) 2011-08-19 2017-01-31 Glaxo Group Limited Benzofuran compounds for the treatment of hepatitis c virus infections
EP2776586B1 (en) 2011-11-11 2018-03-07 Millennium Pharmaceuticals, Inc. Biomarkers of response to proteasome inhibitors
WO2013071142A1 (en) 2011-11-11 2013-05-16 Millennium Pharmaceuticals, Inc. Biomarkers of response to proteasome inhibitors
JP6441080B2 (en) 2011-12-22 2018-12-19 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 single hormone insulin-positive cells
JP6215234B2 (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. Method for treating nasopharyngeal cancer
EP2810066B1 (en) 2012-01-24 2019-07-31 Millennium Pharmaceuticals, Inc. Methods of treatment of cancer
CA2866135A1 (en) 2012-03-02 2014-09-06 Dr. Reddy's Laboratories Limited Pharmaceutical compositions comprising boronic acid compounds
US9434920B2 (en) 2012-03-07 2016-09-06 Janssen Biotech, Inc. Defined media for expansion and maintenance of pluripotent stem cells
CA2784240C (en) 2012-03-27 2014-07-08 Innopharma, Inc. Stable bortezomib formulations
CN108103006A (en) 2012-06-08 2018-06-01 詹森生物科技公司 Differentiation of the human embryo stem cell to pancreatic endocrine cell
EA021179B1 (en) * 2012-06-15 2015-04-30 Ощество С Ограниченной Ответственностью "Тева" Lyophilisate of a compound of boronic acid
WO2014011695A2 (en) 2012-07-09 2014-01-16 Onyx Therapeutics, Inc. Prodrugs of peptide epoxy ketone protease inhibitors
CN104822688A (en) 2012-09-11 2015-08-05 西普拉有限公司 Process for preparing of bortezomib
JP2015536342A (en) 2012-11-16 2015-12-21 シルパ・メディケア・リミテッドShilpa Medicare Limited Method of crystalline bortezomib
MX2015008578A (en) 2012-12-31 2015-09-07 Janssen Biotech Inc Differentiation of human embryonic stem cells into pancreatic endocrine cells using hb9 regulators.
AU2013370228B2 (en) 2012-12-31 2018-10-18 Janssen Biotech, Inc. Suspension and clustering of human pluripotent cells for differentiation into pancreatic endocrine cells
AU2013368221B2 (en) 2012-12-31 2018-11-01 Janssen Biotech, Inc. Culturing of human embryonic stem cells at 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
CN103070835B (en) * 2013-01-31 2015-01-07 江苏奥赛康药业股份有限公司 Freeze-dried composition containing bortezomib and preparation method of freeze-dried composition
WO2014170628A1 (en) 2013-04-16 2014-10-23 Cipla Limited Process for the preparation of bortezomib mannitol ester
JP6165986B2 (en) * 2013-08-23 2017-07-19 シントン・ビー.ブイ.Synthon B.V. Pharmaceutical composition comprising bortezomib
EA201690686A1 (en) 2013-10-03 2016-08-31 Милленниум Фармасьютикалз, Инк. Method of prevention or treatment of systemic red lupus and / or lupine jade
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
CN106132970B (en) * 2014-02-03 2020-09-04 俄亥俄州创新基金会 Borate esters and pharmaceutical formulations thereof
EP3954759A1 (en) 2014-05-16 2022-02-16 Janssen Biotech, Inc. Use of small molecules to enhance mafa expression in pancreatic endocrine cells
DE102014010218A1 (en) 2014-07-10 2016-01-14 Immunologik Gmbh Agent for the treatment of retroviral infections
DE102014010220A1 (en) 2014-07-10 2016-01-14 Immunologik Gmbh Agent for the treatment of retroviral infections
US10301273B2 (en) 2014-08-07 2019-05-28 Mayo Foundation For Medical Education And Research Compounds and methods for treating cancer
EP3031811A1 (en) 2014-12-09 2016-06-15 Teva Pharmaceuticals Ltd. Malic acid esters of bortezomib
WO2016110870A1 (en) 2015-01-07 2016-07-14 Emcure Pharmaceuticals Limited Pharmaceutical composition of bortezomid
EP3270891A1 (en) * 2015-03-17 2018-01-24 Leon-Nanodrugs GmbH Nanoparticles comprising a stabilized boronic acid compound
KR101891728B1 (en) * 2015-04-20 2018-08-24 동아에스티 주식회사 Pharmaceutical composition for stabilizing peptide boronic acid compound
US9752093B2 (en) * 2015-06-04 2017-09-05 Chevron Oronite Company Llc Borated polyol ester of hindered phenol antioxidant/friction modifier with enhanced performance
EP3120836A1 (en) 2015-07-22 2017-01-25 Stada Arzneimittel Ag Ready-to-use solution of bortezomib
EP3120837A1 (en) 2015-07-22 2017-01-25 Stada Arzneimittel Ag Ready-to-use solution of bortezomib
MA45479A (en) 2016-04-14 2019-02-20 Janssen Biotech Inc DIFFERENTIATION OF PLURIPOTENT STEM CELLS IN ENDODERMAL CELLS OF MIDDLE INTESTINE
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
WO2018038687A1 (en) 2016-08-22 2018-03-01 Mustafa Nevzat Ilaç Sanayii A.Ş. Pharmaceutical formulations comprising a bortezomib-cyclodextrin complex
US11584733B2 (en) 2017-01-09 2023-02-21 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
CA3049435A1 (en) 2017-01-09 2018-07-12 Scott Grindrod Selective histone deacetylase inhibitors for the treatment of human disease
US20200030463A1 (en) 2017-02-24 2020-01-30 Bayer Aktiengesellschaft Use radium ra-223 dichloride for the treatment of multiple myeloma
CA3054572A1 (en) 2017-02-28 2018-09-07 Mayo Foundation For Medical Education And Research Compounds and methods for treating cancer
CN106916177B (en) * 2017-03-23 2019-04-23 南京陵瑞医药科技有限公司 A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes
JP2018177649A (en) * 2017-04-04 2018-11-15 日本化薬株式会社 Pharmaceutical composition containing bortezomib
CN108794516A (en) * 2017-04-26 2018-11-13 上海时莱生物技术有限公司 Boric acid and boric acid ester compound and its preparation method and application
RU2659160C1 (en) * 2017-07-10 2018-06-28 Акционерное Общество "Фарм-Синтез" Bortezomib lyophilizate production method and the bortezomib containing pharmaceutical composition in the form of stable lyophilizated product produced by said method
EP3694878A1 (en) 2017-09-14 2020-08-19 GlaxoSmithKline Intellectual Property Development Limited Combination treatment for 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
JP7423028B2 (en) 2017-11-01 2024-01-29 日医工岐阜工場株式会社 Lyophilized pharmaceutical composition containing bortezomib
US10537585B2 (en) 2017-12-18 2020-01-21 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone
WO2019139921A1 (en) 2018-01-09 2019-07-18 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
US11243207B2 (en) 2018-03-29 2022-02-08 Mayo Foundation For Medical Education And Research Assessing and treating cancer
CN108451911B (en) * 2018-04-04 2020-05-22 重庆惠源医药有限公司 Preparation method of bortezomib preparation
JP2021521219A (en) 2018-04-18 2021-08-26 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト Combination therapy with BET inhibitors and proteasome inhibitors
CN110540547A (en) * 2018-05-28 2019-12-06 秦艳茹 Synthesis and application of peptide borate compound
WO2020144607A1 (en) * 2019-01-11 2020-07-16 Intas Pharmaceuticals Ltd. A process for preparation of a stable pharmaceutical composition of bortezomib
JP7387330B2 (en) 2019-08-09 2023-11-28 東和薬品株式会社 Bortezomib storage container
US20220133757A1 (en) * 2020-11-02 2022-05-05 Spes Pharmaceuticals Inc. Aqueous compositions of bortezomib
EP4134083A1 (en) 2021-08-12 2023-02-15 Extrovis AG Pharmaceutical compositions of bortezomib
US20230104074A1 (en) 2021-09-24 2023-04-06 MAIA Pharmaceuticals, Inc. Bortezomib compositions
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
WO2023220641A2 (en) 2022-05-11 2023-11-16 Juno Therapeutics, Inc. Methods and uses related to t cell therapy and production of same

Citations (13)

* Cited by examiner, † Cited by third party
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
US5187157A (en) * 1987-06-05 1993-02-16 Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
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
US5492900A (en) * 1993-09-10 1996-02-20 Neutron Technology Corporation Method for enhancing the solubility of the boron delivery drug, boronophenylalanine (BPA)
US5574017A (en) * 1994-07-05 1996-11-12 Gutheil; William G. Antibacterial agents
US5780454A (en) * 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
US5935944A (en) * 1993-09-10 1999-08-10 Neutron Technology Corporation Formulation for I.V. administration of the boron delivery drug, boronophenylalanine (BPA)
US5990083A (en) * 1994-11-14 1999-11-23 Cephalon, Inc. Multicatalytic protease inhibitors
US6619076B2 (en) * 2001-10-12 2003-09-16 David W. Boling Method and apparatus for cooking starch
US6699835B2 (en) * 2001-01-25 2004-03-02 The United States Of America As Represented By The Department Of Health And Human Services Formulation of boronic acid compounds

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5825042B2 (en) * 1979-08-10 1983-05-25 科学技術庁無機材質研究所長 Synthesis method of diamond powder by impact compression
FI60700C (en) 1980-04-09 1982-03-10 Ksv Chemicals Oy FOER FARING FRAMSTAELLNING AV 1,2-DIACYL-SN-GLYCEROLER
US4434188A (en) * 1981-12-17 1984-02-28 National Institute For Researches In Inorganic Materials Method for synthesizing diamond
IT1153974B (en) 1982-09-23 1987-01-21 Erba Farmitalia PHARMACOLOGICAL COMPOSITIONS BASED ON CISPLATIN AND METHOD FOR THEIR OBTAINMENT
DE3502902A1 (en) * 1984-01-31 1985-08-08 Futaba Denshi Kogyo K.K., Mobara, Chiba ION RAY VAPOR DEVICE
US4743522A (en) * 1985-09-13 1988-05-10 Minolta Camera Kabushiki Kaisha Photosensitive member with hydrogen-containing carbon layer
JPS63107898A (en) * 1986-10-23 1988-05-12 Natl Inst For Res In Inorg Mater Method for synthesizing diamond with plasma
US4822466A (en) * 1987-06-25 1989-04-18 University Of Houston - University Park Chemically bonded diamond films and method for producing same
US4816291A (en) * 1987-08-19 1989-03-28 The Regents Of The University Of California Process for making diamond, doped diamond, diamond-cubic boron nitride composite films
JPS6461396A (en) * 1987-09-01 1989-03-08 Idemitsu Petrochemical Co Synthesis of diamond and installation therefor
NZ226170A (en) 1987-09-18 1990-07-26 Ethicon Inc Stable freeze-dried pharmaceutical composition containing epidermal growth factor
US4925701A (en) * 1988-05-27 1990-05-15 Xerox Corporation Processes for the preparation of polycrystalline diamond films
US4928629A (en) * 1988-06-13 1990-05-29 Iowa State University Research Foundation, Inc. Egg inoculation method
US4862529A (en) * 1988-07-13 1989-09-05 Hill-Rom Company, Inc. Hospital bed convertible to chair
US4919974A (en) * 1989-01-12 1990-04-24 Ford Motor Company Making diamond composite coated cutting tools
JP2730145B2 (en) * 1989-03-07 1998-03-25 住友電気工業株式会社 Method of forming single crystal diamond layer
US5082359A (en) * 1989-11-28 1992-01-21 Epion Corporation Diamond films and method of growing diamond films on nondiamond substrates
US4954365A (en) * 1989-12-18 1990-09-04 The United States Of America As Represented By The Secretary Of The Army Method of preparing a thin diamond film
US5071677A (en) * 1990-05-24 1991-12-10 Houston Advanced Research Center Halogen-assisted chemical vapor deposition of diamond
CA2049673A1 (en) * 1990-11-26 1992-05-27 James F. Fleischer Cvd diamond by alternating chemical reactions
US5989511A (en) * 1991-11-25 1999-11-23 The University Of Chicago Smooth diamond films as low friction, long wear surfaces
US5209916A (en) * 1991-11-25 1993-05-11 Gruen Dieter M Conversion of fullerenes to diamond
US5849079A (en) * 1991-11-25 1998-12-15 The University Of Chicago Diamond film growth argon-carbon plasmas
US5620512A (en) * 1993-10-27 1997-04-15 University Of Chicago Diamond film growth from fullerene precursors
US5772760A (en) * 1991-11-25 1998-06-30 The University Of Chicago Method for the preparation of nanocrystalline diamond thin films
US5370855A (en) * 1991-11-25 1994-12-06 Gruen; Dieter M. Conversion of fullerenes to diamond
US6592839B2 (en) * 1991-11-25 2003-07-15 The University Of Chicago Tailoring nanocrystalline diamond film properties
US5360477A (en) * 1992-03-04 1994-11-01 Semiconductor Energy Laboratory Co., Ltd. Method for forming diamond and apparatus for forming the same
US5505953A (en) 1992-05-06 1996-04-09 Alcon Laboratories, Inc. Use of borate-polyol complexes in ophthalmic compositions
US5439492A (en) * 1992-06-11 1995-08-08 General Electric Company Fine grain diamond workpieces
US5273788A (en) * 1992-07-20 1993-12-28 The University Of Utah Preparation of diamond and diamond-like thin films
US5449531A (en) * 1992-11-09 1995-09-12 North Carolina State University Method of fabricating oriented diamond films on nondiamond substrates and related structures
US5308661A (en) * 1993-03-03 1994-05-03 The Regents Of The University Of California Pretreatment process for forming a smooth surface diamond film on a carbon-coated substrate
TW280770B (en) 1993-10-15 1996-07-11 Takeda Pharm Industry Co Ltd
US5897924A (en) * 1995-06-26 1999-04-27 Board Of Trustees Operating Michigan State University Process for depositing adherent diamond thin films
US6271199B2 (en) 1997-02-15 2001-08-07 Millennium Pharmaceuticals, Inc. Treatment of infarcts
US5962049A (en) 1997-03-31 1999-10-05 Miljkovic; Dusan Boron carbohydrate complexes and uses thereof
EP1017398A1 (en) 1997-09-25 2000-07-12 Proscript, Inc. Proteasome inhibitors, ubiquitin pathway inhibitors or agents that interfere with the activation of nf-kb via the ubiquitin proteasome pathway to treat inflammatory and autoimmune diseases
US5985842A (en) 1998-05-14 1999-11-16 Miljkovic; Dusan Boron compounds/complexes to control hair growth, and methods of use
US5935994A (en) 1998-05-29 1999-08-10 Nimni; Marcel E. Nutritionally balanced dermal composition and method
US6169076B1 (en) 1999-03-31 2001-01-02 Glcosyn Pharmaceuticals, Inc. P-Boronophenylalanine complexes with fructose and related carbohydrates and polyols
WO2001002601A2 (en) 1999-07-07 2001-01-11 Du Pont Pharmaceuticals Company Cell-based assay systems for examining hcv ns3 protease activity
US6422077B1 (en) * 2000-04-06 2002-07-23 The University Of Chicago Ultrananocrystalline diamond cantilever wide dynamic range acceleration/vibration/pressure sensor
US6783589B2 (en) * 2001-01-19 2004-08-31 Chevron U.S.A. Inc. Diamondoid-containing materials in microelectronics

Patent Citations (18)

* Cited by examiner, † Cited by third party
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
US5187157A (en) * 1987-06-05 1993-02-16 Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
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
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
US5935944A (en) * 1993-09-10 1999-08-10 Neutron Technology Corporation Formulation for I.V. administration of the boron delivery drug, boronophenylalanine (BPA)
US5492900A (en) * 1993-09-10 1996-02-20 Neutron Technology Corporation Method for enhancing the solubility of the boron delivery drug, boronophenylalanine (BPA)
US5574017A (en) * 1994-07-05 1996-11-12 Gutheil; William G. Antibacterial agents
US5780454A (en) * 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
US6066730A (en) * 1994-10-28 2000-05-23 Proscript, Inc. Boronic ester and acid compounds, synthesis and uses
US6083903A (en) * 1994-10-28 2000-07-04 Leukosite, Inc. Boronic ester and acid compounds, synthesis and uses
US6297217B1 (en) * 1994-10-28 2001-10-02 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US5990083A (en) * 1994-11-14 1999-11-23 Cephalon, Inc. Multicatalytic protease inhibitors
US6699835B2 (en) * 2001-01-25 2004-03-02 The United States Of America As Represented By The Department Of Health And Human Services Formulation of boronic acid compounds
US6713446B2 (en) * 2001-01-25 2004-03-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Formulation of boronic acid compounds
US6958319B2 (en) * 2001-01-25 2005-10-25 The United States Of America As Represented By The Department Of Health And Human Services Formulation of boronic acid compounds
US6619076B2 (en) * 2001-10-12 2003-09-16 David W. Boling Method and apparatus for cooking starch

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9175018B2 (en) 2008-06-17 2015-11-03 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
US9175017B2 (en) 2008-06-17 2015-11-03 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
JP2011524903A (en) * 2008-06-17 2011-09-08 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 Boronic ester compounds and pharmaceutical compositions thereof
CN103435638A (en) * 2008-06-17 2013-12-11 米伦纽姆医药公司 Boronate ester compounds and pharmaceutical compositions thereof
KR101860743B1 (en) 2008-06-17 2018-05-24 밀레니엄 파머슈티컬스 인코퍼레이티드 Boronate ester compounds and pharmaceutical composition thereof
KR20140094663A (en) * 2008-06-17 2014-07-30 밀레니엄 파머슈티컬스 인코퍼레이티드 Boronate ester compounds and pharmaceutical compositions thereof
AU2009260778B2 (en) * 2008-06-17 2014-08-28 Takeda Pharmaceutical Company Limited Boronate ester compounds and pharmaceutical compositions thereof
KR20140107482A (en) * 2008-06-17 2014-09-04 밀레니엄 파머슈티컬스 인코퍼레이티드 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
EP2318419B1 (en) 2008-06-17 2015-04-08 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
AU2013203964B2 (en) * 2008-06-17 2015-04-23 Takeda Pharmaceutical Company Limited Boronate ester compounds and pharmaceutical compositions thereof
TWI498333B (en) * 2008-06-17 2015-09-01 Millennium Pharm 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
US11485746B2 (en) 2008-06-17 2022-11-01 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
US20090325903A1 (en) * 2008-06-17 2009-12-31 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
WO2009154737A1 (en) * 2008-06-17 2009-12-23 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
KR101690571B1 (en) 2008-06-17 2016-12-28 밀레니엄 파머슈티컬스 인코퍼레이티드 Boronate ester compounds and pharmaceutical compositions thereof
KR101704694B1 (en) 2008-06-17 2017-02-08 밀레니엄 파머슈티컬스 인코퍼레이티드 Boronate ester compounds and pharmaceutical compositions thereof
KR101741142B1 (en) 2008-06-17 2017-05-29 밀레니엄 파머슈티컬스 인코퍼레이티드 Boronate ester compounds and pharmaceutical compositions thereof
EA027346B1 (en) * 2008-06-17 2017-07-31 Милленниум Фармасьютикалз, Инк. Boronate ester compounds and pharmaceutical compositions thereof
US10604538B2 (en) 2008-06-17 2020-03-31 Millenium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
US9771381B2 (en) 2008-09-29 2017-09-26 Millennium Pharmaceuticals, Inc. 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
US10035811B2 (en) 2008-09-29 2018-07-31 Millennium Pharmaceuticals, Inc. Derivatives of 1-amino-2-cyclobutylethylboronic acid
WO2011090940A1 (en) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
EP3566719A1 (en) 2010-05-18 2019-11-13 Cerulean Pharma Inc. Compositions and methods for treatment of autoimmune and other diseases
US11241448B2 (en) 2014-05-20 2022-02-08 Millennium Pharmaceuticals, Inc. Methods for cancer therapy
CN107207540A (en) * 2015-02-11 2017-09-26 千年药物公司 The novel crystalline form of proteasome inhibitor
WO2016130724A1 (en) * 2015-02-11 2016-08-18 Millennium Pharmaceuticals, Inc. Novel crystalline form of a proteasome inhibitor

Also Published As

Publication number Publication date
US6958319B2 (en) 2005-10-25
EP2251344B1 (en) 2016-03-30
US20040063623A1 (en) 2004-04-01
US6699835B2 (en) 2004-03-02
EP3078667B1 (en) 2018-11-21
DE60239384D1 (en) 2011-04-21
PT1355910E (en) 2011-03-24
JP4162491B2 (en) 2008-10-08
DK1355910T3 (en) 2011-06-27
JP2004517932A (en) 2004-06-17
TR201819416T4 (en) 2019-01-21
US20020188100A1 (en) 2002-12-12
ES2571219T3 (en) 2016-05-24
WO2002059131A1 (en) 2002-08-01
EP3078667A1 (en) 2016-10-12
US20020169114A1 (en) 2002-11-14
US7109323B2 (en) 2006-09-19
CY1111488T1 (en) 2015-08-05
WO2002059130A1 (en) 2002-08-01
ES2359391T3 (en) 2011-05-23
EP1360189A1 (en) 2003-11-12
EP2251344A1 (en) 2010-11-17
AU2002243646B2 (en) 2006-06-22
ATE501157T1 (en) 2011-03-15
EP1355910B1 (en) 2011-03-09
DK3078667T3 (en) 2019-01-07
HK1149936A1 (en) 2011-10-21
EP1355910A1 (en) 2003-10-29
ES2702732T3 (en) 2019-03-05
JP2004517931A (en) 2004-06-17
CA2435124A1 (en) 2002-08-01
DK2251344T3 (en) 2016-05-09
CA2435146A1 (en) 2002-08-01
PT3078667T (en) 2018-12-28
CA2435146C (en) 2011-03-29
US20040138411A1 (en) 2004-07-15
CY1121142T1 (en) 2020-05-29
US6713446B2 (en) 2004-03-30

Similar Documents

Publication Publication Date Title
US7109323B2 (en) Formulation of boronic acid compounds
AU2002243646A1 (en) Formulation of boronic acid compounds
US9862745B2 (en) Synthesis of boronic ester and acid compounds
CA2376965A1 (en) Peptide boronic acid inhibitors of hepatitis c virus protease
AU2002249979A1 (en) Formulation of boronic acid compounds
AU2013202996A1 (en) Synthesis of boronic ester and acid compounds

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION