| Multivalent metal salts of boronic acids -> Monitor Keywords |
|
|
 
Multivalent metal salts of boronic acidsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 2 Peptide Repeating Units In Known Peptide ChainMultivalent metal salts of boronic acids description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060229257, Multivalent metal salts of boronic acids. Brief Patent Description - Full Patent Description - Patent Application Claims
PRIORITY CLAIM [0001] This application is a divisional of U.S. application Ser. No. 10/659,179, filed Sep. 9, 2003, which is incorporated herein by reference, which claims priority to GB 0220764.5, filed Sep. 9, 2002, GB 0220822.1, filed Sep. 9, 2002, GB 0307817.7, filed Apr. 4, 2003, GB 0311237.2, filed May 16, 2003, and GB 0315691.6, filed Jul. 4, 2003, all of which are hereby incorporated by reference. BACKGROUND [0002] The present disclosure relates to pharmaceutically useful products obtainable from organoboronic acids. The disclosure also relates to the use of members of the aforesaid class of products, to their formulation, their preparation, their synthetic intermediates and to other subject matter. [0003] The disclosure further relates to oral pharmaceutical formulations containing the described products. Boronic Acid Compounds [0004] It has been known for some years that boronic acid compounds and their derivatives, e.g. esters, have biological activities, notably as inhibitors or substrates of proteases. For example, Koehler et al. Biochemistry 10:2477, 1971 report that 2-phenylethane boronic acid inhibits the serine protease chymotrypsin at millimolar levels. The inhibition of chymotrypsin and subtilisin by arylboronic acids (phenylboronic acid, m-nitro-phenylboronic acid, m-aminophenylboronic acid, m-bromophenylboronic acid) is reported by Phillip et al, Proc. Nat Acad. Sci. USA 68:478-480, 1971. A study of the inhibition of subtilisin Carlsberg by a variety of boronic acids, especially phenyl boronic acids substituted by Cl, Br, CH.sub.3, H.sub.2N, MeO and others, is described by Seufer-Wasserthal et al, Biorg. Med. Chem. 2(1):35-48, 1994. [0005] In describing inhibitors or substrates of proteases, P1, P2, P3, etc. designate substrate or inhibitor residues which are amino-terminal to the scissile peptide bond, and S1, S2, S3, etc., designate the corresponding subsites of the cognate protease in accordance with: Schechter, I. and Berger, A. On the Size of the Active Site in Proteases, Biochem. Biophys. Res. Comm., 27:157-162, 1967. In thrombin, the S1 binding site or "specificity pocket" is a well defined slit in the enzyme, whilst the S2 and S3 binding subsites (also respectively called the proximal and distal hydrophobic pockets) are hydrophobic and interact strongly with, respectively, Pro and (R)-Phe, amongst others. [0006] Pharmaceutical research into serine protease inhibitors has moved from the simple arylboronic acids to boropeptides, i.e. peptides containing a boronic acid analogue of an .alpha.-amino carboxylic acid. The boronic acid may be derivatised, often to form an ester. Shenvi (EP-A-145441 and U.S. Pat. No. 4,499,082) disclosed that peptides containing an .alpha.-aminoboronic acid with a neutral side chain were effective inhibitors of elastase and has been followed by numerous patent publications relating to boropeptide inhibitors of serine proteases. Specific, tight binding boronic acid inhibitors have been reported for elastase (K.sub.i, 0.25 nM), chymotrypsin (K.sub.i, 0.25 nM), cathepsin G (K.sub.i, 21 nM), .alpha.-lytic protease (K.sub.i, 0.25 nM), dipeptidyl aminopeptidase type IV (K.sub.i, 16 pM) and more recently thrombin (Ac-D-Phe-Pro-boroArg-OH (DuP 714 initial K.sub.i 1.2 nM). [0007] Claeson et al (U.S. Pat. No. 5,574,014 and others) and Kakkar et al (WO 92/07869 and family members including U.S. Pat. No. 5,648,338) disclose thrombin inhibitors having a neutral C-terminal side chain, for example an alkyl or alkoxyalkyl side chain. [0008] Modifications of the compounds described by Kakkar et al are included in WO 96/25427, directed to peptidyl serine protease inhibitors in which the P2-P1 natural peptide linkage is replaced by another linkage. As examples of non-natural peptide linkages may be mentioned --CO.sub.2--, --CH.sub.2O--, --NHCO--, --CHYCH.sub.2--, --CH.dbd.CH--, --CO(CH.sub.2).sub.pCO-- where p is 1, 2 or 3, --COCHY--, --CO.sub.2--CH.sub.2NH--, --CHY--NX--, --N(X)CH.sub.2--N(X)CO--, --CH.dbd.C(CN)CO--, --CH(OH)--NH--, --CH(CN )--NH--, --CH(OH)--CH.sub.2-- or --NH--CHOH--, where X is H or an amino protecting group and Y is H or halogen, especially F. Particular non-natural peptide linkages are --CO.sub.2-- or --CH.sub.2O--. [0009] Metternich (EP 471651 and U.S. Pat. No. 5,288,707, the latter being assigned to Trigen Limited) discloses variants of Phe-Pro-BoroArg boropeptides in which the P3 Phe is replaced by an unnatural hydrophobic amino acid such as trimethylsilylalanine, p-tert.butyl-diphenyl-silyloxymethyl-phenylalanine or p-hydroxymethylphenylalanine and the P1 side chain may be neutral (alkoxyalkyl, alkylthioalkyl or trimethylsilylalkyl). [0010] The replacement of the P2 Pro residue of borotripeptide thrombin inhibitors by an N-substituted glycine is described in Fevig J M et al Bioorg. Med. Chem. 8: 301-306 and Rupin A et al Thromb. Haemost. 78(4):1221-1227, 1997. See also U.S. Pat. No. 5,585,360 (de Nanteuil et al). Amparo (WO 96/20698 and family members including U.S. Pat. No. 5,698,538) discloses peptidomimetics of the structure Aryl-linker-Boro(Aa), where Boro(Aa) may be an aminoboronate residue with a non-basic side chain, for example BoroMpg. The linker is of the formula --CH.sub.2).sub.mCONR-- (where m is 0 to 8 and R is H or certain organic groups) or analogues thereof in which the peptide linkage --CONR-- is replaced by --CSNR--, --SO.sub.2NR--, --CO.sub.2--, --C(S)O-- or --SO.sub.2O--. Aryl is phenyl, naphthyl or biphenyl substituted by one, two or three moieties selected from a specified group. Most typically these compounds are of the structure Aryl-(CH.sub.2).sub.n--CONH--CHR.sup.2--BY.sup.1Y.sup.2, where R.sup.2 is for example a neutral side chain as described above and n is 0 or 1. [0011] Non-peptide boronates have been proposed as inhibitors of proteolytic enzymes in detergent compositions. WO 92/19707 and WO 95/12655 report that arylboronates can be used as inhibitors of proteolytic enzymes in detergent compositions. WO 92/19707 discloses compounds substituted meta to the boronate group by a hydrogen bonding group, especially acetamido (--NHCOCH.sub.3), sufonamido (--NHSO.sub.2CH.sub.3) and alkylamino. WO 95/12655 teaches that ortho-substituted compounds are superior. [0012] Boronate enzyme inhibitors have wide application, from detergents to bacterial sporulation inhibitors to pharmaceuticals. In the pharmaceutical field, there is patent literature describing boronate inhibitors of serine proteases, for example thrombin, factor Xa, kallikrein, elastase, plasmin as well as other serine proteases like prolyl endopeptidase and Ig AI Protease. Thrombin is the last protease in the coagulation pathway and acts to hydrolyse four small peptides form each molecule of fibrinogen, thus deprotecting its polymerisation sites. Once formed, the linear fibrin polymers may be cross-linked by factor XIIIa, which is itself activated by thrombin. In addition, thrombin is a potent activator of platelets, upon which it acts at specific receptors. Thrombin also potentiates its own production by the activation of factors V and VIII. [0013] Other aminoboronate or peptidoboronate inhibitors or substrates of serine proteases are described in: [0014] U.S. Pat. No. 4,935,493 [0015] EP 341661 [0016] WO 94/25049 [0017] WO 95/09859 [0018] WO 96/12499 [0019] WO 96/20689 [0020] Lee S-L et al, Biochemistry 36:13180-13186, 1997 [0021] Dominguez C et al, Bioorg. Med. Chem. Lett. 7:79-84, 1997 [0022] EP 471651 [0023] WO 94/20526 [0024] WO 95/20603 [0025] WO 97/05161 [0026] U.S. Pat. No. 4,450,105 [0027] U.S. Pat. No. 5,106,948 [0028] U.S. Pat. No. 5,169,841. [0029] Peptide boronic acid inhibitors of hepatic C virus protease are described in WO 01/02424. [0030] Matteson D S Chem. Rev. 89: 1535-1551, 1989 reviews the use of .alpha.-halo boronic esters as intermediates for the synthesis of inter alia amino boronic acids and their derivatives. Matteson describes the use of pinacol boronic esters in non-chiral synthesis and the use of pinanediol boronic esters for chiral control, including in the synthesis of amino and amido boronate esters. [0031] Contreras et al J. Organomet. Chem. 246: 213-217, 1983 describe how intramolecular N.fwdarw.B coordination was demonstrated by spectroscopic studies on cyclic boronic esters prepared by reacting Me.sub.2CHCMe.sub.2-BH.sub.2 with diethanolamines. [0032] Boronic acid and ester compounds have displayed 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. [0033] 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 equivalent WO 96/13266, and U.S. Pat. No. 6,297,217 (2001) describe peptide boronic ester and acid compounds useful as proteasome inhibitors. These documents also describe the use of boronic ester and acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF-.kappa.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-.kappa.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. [0034] Unfortunately, organoboronic acids can be relatively difficult to obtain in analytically pure form. Thus, 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. [0035] It is known that derivatisation of boronic acids as cyclic esters provides oxidation resistance. For example, Martichonok V et al J. Am. Chem. Soc. 118: 950-958, 1996 state that diethanolamine derivatisation provides protection against possible boronic acid oxidation. U.S. Pat. No. 5,681,978 (Matteson D S et al) teaches that 1,2-diols and 1,3 diols, for example pinacol, form stable cyclic boronic esters that are not easily oxidised. [0036] Wu et al, J. Pharm. Sci., 89:758-765, 2000, discuss the stability of the compound N-(2-pyrazine) carbonyl-phenylalanine-leucine boronic acid (LDP-341, also known as bortezomib), an anti-cancer agent. It is described how "during an effort to formulate [LDP-341] for parenteral administration, the compound showed erratic stability behaviour". The degradation pathways were investigated and it was concluded that the degradation was oxidative, the initial oxidation being attributed to peroxides or molecular oxygen and its radicals. Continue reading about Multivalent metal salts of boronic acids... Full patent description for Multivalent metal salts of boronic acids Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Multivalent metal salts of boronic acids patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Multivalent metal salts of boronic acids or other areas of interest. ### Previous Patent Application: Identification of n-alkylglycine trimers for induction of apoptosis Next Patent Application: Ai-2 compounds and analogs based on salmonella typhimurium lsrb structure Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Multivalent metal salts of boronic acids patent info. IP-related news and info Results in 0.25349 seconds Other interesting Feshpatents.com categories: Medical: Surgery , Surgery(2) , Surgery(3) , Drug , Drug(2) , Prosthesis , Dentistry 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
