WO2006059083A1 - Agents neutralisants pour médicaments de type acides boroniques - Google Patents

Agents neutralisants pour médicaments de type acides boroniques Download PDF

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WO2006059083A1
WO2006059083A1 PCT/GB2005/004565 GB2005004565W WO2006059083A1 WO 2006059083 A1 WO2006059083 A1 WO 2006059083A1 GB 2005004565 W GB2005004565 W GB 2005004565W WO 2006059083 A1 WO2006059083 A1 WO 2006059083A1
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acid
group
formula
moiety
hydroxy
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PCT/GB2005/004565
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English (en)
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Suresh Babubhai Chahwala
Shouming Wang
Patric Russell Russell
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Trigen Limited
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Priority claimed from GBGB0426264.8A external-priority patent/GB0426264D0/en
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Publication of WO2006059083A1 publication Critical patent/WO2006059083A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid

Definitions

  • the present disclosure relates to inhibitors of biologically active organoboronates and more particularly of organoboronate medicaments and enzyme inhibitors; the enzymes are more particularly serine proteases, e.g. serine protease anticoagulants.
  • the disclosure additionally includes compounds having a pharmacophore described herein; it further includes a class of fatty acids and fatty acid derivatives.
  • the disclosure also relates to the use of members of the aforesaid products, to their formulation, and to other subject matter.
  • boronic acid compounds and their derivatives have biological activities, notably as Inhibitors or substrates of proteases.
  • 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 is reported by Phillip et al, Proc. Nat. Acad.
  • Pl, P2, P3, etc. designate substrate or inhibitor residues which are amino-terminal to the scissile peptide bond
  • Sl, S2, S3, etc. designate the corresponding subsites of the cognate protease in accordance with: Schechter, I. and Berger, A.
  • the Sl binding site or "specificity pocket” is a well defined groove 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.
  • Claeson et al (US 5574014 and others) and Kakkar et al (WO 92/07869 and family members including US 5648338) disclose thrombin inhibitors having a neutral C-terminal side chain, for example an alky! or alkoxyalkyl side chain.
  • Metternich discloses variants of Phe-Pro-BoroArg boropeptides in which the P3 Phe is replaced by an unnatural hydrophobic amino acid such as trimethylsilylalanine, p-tertbutyl-diphenyl-silyloxymethyl-phenylalanine or p- hydroxymethylphenylalanine and the Pl side chain may be neutral (alkoxyalkyl, alkylthioalkyl or trimethylsilylalkyl).
  • Amparo (WO 96/20698 and family members including US 5698538) 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 2 ) m CONR- (where m is
  • R is H or certain organic groups) or analogues thereof in which the peptide linkage - CONR- is replaced by -CSNR-, -SO 2 NR-, -CO 2 -, -C(S)O- or -SO 2 O-.
  • 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 2 ) n -CONH-CHR 2 -BY 1 ⁇ 2, where R ⁇ is for example a neutral side chain as described above and n is 0 or 1.
  • 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 (-
  • Boronate enzyme inhibitors have wide application, from detergents to bacterial sporulation inhibitors to pharmaceuticals.
  • 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 from 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.
  • 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.
  • Peptide boronic acid inhibitors of hepatic C virus protease are described in WO 01/02424. Matteson D S Chem. Rev. 89: 1535-1551, 1989 reviews the use of ⁇ -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. 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.
  • proteasome inhibitors including boronic acid compounds, are useful for treating infarcts such as occur during stroke or myocardial infarction.
  • a proteasome inhibitor disclosed in the Adams et al patents is bortezom ⁇ b (Velcade ® ), the compound N-(2-pyrazine)-carbonyl-phenylalanine-leucine-boronic acid.
  • WO 02/059131 discloses boronic acid products which are certain boropeptides and/or boropeptidomimetics in which the boronic acid group has been derivatised with a sugar.
  • the disclosed sugar derivatives, which have hydrophobic amino acid side chains, are of the formula
  • R is hydrogen or alkyl
  • A is 0, 1 or 2
  • R 1 , R2 and R ⁇ are independently hydrogen, alkyl, cycloalkyl, aryl or -CH2-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; where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R 1 , R 2 , R ⁇ or R 5 can be optionally substituted; and
  • 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.
  • Some of the disclosed compounds are sugar derivatives of bortezomib (see above), e.g. its mannitol ester.
  • Hemostasis is the normal physiological condition of blood in which its components exist in dynamic equilibrium. When the equilibrium is disturbed, for instance following injury to a blood vessel, certain biochemical pathways are triggered leading, in this example, to arrest of bleeding via clot formation (coagulation). Coagulation is a dynamic and complex process in which proteolytic enzymes such as thrombin play a key role. Blood coagulation may occur through either of two cascades of zymogen activations, the extrinsic and intrinsic pathways of the coagulation cascade.
  • Factor Vila in the extrinsic pathway, and Factor IXa in the intrinsic pathway are important determinants of the activation of factor X to factor Xa, which itself catalyzes the activation of prothrombin to thrombin, whilst thrombin in turn catalyses the polymerization of fibrinogen monomers to fibrin polymer.
  • the last protease in each pathway is therefore thrombin, which acts to hydrolyze four small peptides (two FpA and two FpB) from each molecule of fibrinogen, thus deprotecting its polymerization sites.
  • the linear fibrin polymers may be cross-linked by factor XIIIa, which is itself activated by thrombin.
  • thrombin is a potent activator of platelets, upon which it acts at specific receptors. Thrombin activation of platelets leads to aggregation of the cells and secretion of additional factors that further accelerate the creation of a hemostatic plug. Thrombin also potentiates its own production by the activation of factors V and VIII (see Hemker and Beguin in: Jolles, et. al., "Biology and Pathology of Platelet Vessel Wall Interactions," pp. 219-26 (1986), Crawford and Scrutton in: Bloom and Thomas, “Haemostas ⁇ s and Thrombosis,” pp. 47-77, (1987), Bevers, et. al., Eur. J. Biochem. 122:429-36, 1982, Mann, Trends Biochem. Sd. 12:229-33, 1987).
  • proteases are enzymes which cleave proteins at specific peptide bonds. Cuypers et al., J. Biol. Chem. 257:7086, 1982, and the references cited therein, classify proteases on a mechanistic basis into five classes: serine, cysteinyl or thiol, acid or aspartyl, threonine and metalloproteases. Members of each class catalyse the hydrolysis of peptide bonds by a similar mechanism, have similar active site amino acid residues and are susceptible to class-specific inhibitors. For example, all serine proteases that have been characterised have an active site serine residue.
  • the coagulation proteases thrombin, factor Xa, factor Vila, and factor IXa are serine proteases having trypsin-like specificity for the cleavage of sequence-specific Arg-Xxx peptide bonds.
  • the cleavage event begins with an attack of the active site serine on the scissile bond of the substrate, resulting in the formation of a tetrahedral intermediate. This is followed by collapse of the tetrahedral intermediate to form an acyl enzyme and release of the amino terminus of the cleaved sequence. Hydrolysis of the acyl enzyme then releases the carboxy terminus.
  • a thrombus can be considered as an abnormal product of a normal mechanism and can be defined as a mass or deposit formed from blood constituents on a surface of the cardiovascular system, for example of the heart or a blood vessel.
  • Thrombosis can be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation.
  • antiplatelet drugs inhibitors of platelet aggregation
  • thrombolytic agents to lyse the newly formed clot, either or both such agents being used in conjunction or combination with anticoagulants.
  • Anticoagulants are used also preventatively (prophylactically) in the treatment of patients thought susceptible to thrombosis.
  • Claeson et al (US 5574014 and others) and Kakkar et al (WO 92/07869 and family members including US 5648338) disclose lipophilic thrombin inhibitors having a neutral (uncharged) C- terminal (Pl) side chain, for example an alkoxyalkyl side chain.
  • the tripeptide sequence of TRI 50b has three chiral centres.
  • the Phe residue is considered to be of (R)-configuration and the Pro residue of natural (S)-configuration, at least in compounds with commercially useful inhibitor activity; the Mpg residue is believed to be of (Reconfiguration in isomers with commercially useful inhibitor activity.
  • TRI50b acts as a prodrug for corresponding free acid TRI 50c, which is the active principle.
  • the active, or most active, TRI 50c stereoisomer is considered to be of R,S,R configuration and may be represented as:
  • WO 2004/022072 disclose pharmaceutically acceptable base addition salts of boronic acids which have a neutral aminoboronic acid residue capable of binding to the thrombin Sl subsite linked through a peptide linkage to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites.
  • Y comprises a hydrophobic moiety which, together with the aminoboronic acid residue
  • R 9 is a straight chain alkyl group interrupted by one or more ether linkages (e.g. 1 or 2) and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 (e.g. 5) or R 9 is - ⁇ CH2)m-W where m is 2, 3, 4 or 5 (e.g. 4) and W is -OH or halogen (F, Cl, Br or I).
  • R 9 is an alkoxyalkyl group in one subset of compounds, e.g. alkoxyalkyl containing 4 carbon atoms. Salts of TRI 50c are exemplary.
  • WO 2004/022071 disclose salts of a pharmaceutically acceptable multivalent (at least divalent) metal and an organoboronic acid drug.
  • Such salts are described as having an improved level of stability which cannot be explained or predicted on the basis of known chemistry, and as being indicated to have unexpectedly high and consistent oral bioavailability not susceptible of explanation on the basis of known mechanisms.
  • the oral formulations of such salts are therefore also disclosed.
  • One particular class of salts comprises those wherein the organoboronic acid comprises a boropeptide or boropeptidomimetic.
  • Such drugs which may beneficially be prepared as salts include without limitation those of the formula X-(aa) n -B(OH)2, where X is H or an amino- protecting group, n is 2, 3 or 4, (especially 2 or 3) and each aa is independently a hydrophobic amino acid, whether natural or unnatural.
  • the organoboronic acid is of formula (A) above. Salts of TRI 50c are exemplary.
  • WO 2004/022070 disclose and claim inter alia parenteral pharmaceutical formulations that include a pharmaceutically acceptable base addition salt of a boronic acid of, for example, formula (A) above.
  • Such salts are described as having an improved level of stability which cannot be explained or predicted on the basis of known chemistry. Salts of TRI 50c are exemplary.
  • 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 3 ), sulfonamido (-NHSO 2 CH 3 ) and alkylamino.
  • WO 95/12655 teaches that ortho substituted compounds are superior.
  • an anticoagulant When used as a therapeutic agent, there can be a requirement for rapid neutralisation should there be unexpected bleeding.
  • the problem of unwanted bleeding is well recognised in the area of anticoagulant therapy; thus protamine is used to reverse the anticoagulant effect of heparin and vitamin K to reverse the effect of warfarin.
  • the present invention relates amongst other things to products useful for neutralising (reducing or destroying) the activity of biologically active organoboronates.
  • boronate as used herein includes reference to boronic acids as well as derivatised forms thereof, e.g. salts as well as esters and other prodrugs.
  • the present disclosure provides a product that can neutralise the activity of a boropeptidyl serine protease inhibitor and thus terminate or reduce its therapeutic effect if required.
  • neutralise as used herein includes both reduction of activity and destruction of activity. In the pharmaceutical industry, compounds having such activities are known as “antidotes”, “reversal agents” and “neutralisers”, and doubtless by other names also.
  • a medicament for therapeutically neutralising e.g. reducing in activity
  • an organoboronate drug of a compound selected from organic acids comprising an aliphatic moiety substituted by a nucleophilic group and salts and prodrugs of such acids.
  • the acid may contain up to 30 carbon atoms, for example; in one class of organic acids, there are at least 6 carbon atoms, e.g. at least 12 carbon atoms. Aliphatic acids are particularly to be mentioned.
  • Said acid is not a boron acid, e.g. a boronic or borinic acid.
  • the nucleophilic group may be a hydroxy, hydroperoxy or amino group.
  • This aliphatic group may be hydrocarbyl or 1, 2, 3, 4 or more hydrogens of the hydrocarbyl groupmay be replaced by a substituent such as a hydroxy or another nucleophilic group, for example.
  • the aliphatic group may be saturated or it may contain one or more carbon-carbon multiple bonds, particularly carbon-carbon double bonds.
  • the aliphatic group may be entirely open-chain, e.g. a linear or branched group, as in the case of an alkyl group, an alkoxyalkyl group or an alkenyl group containing 1, 2, 3, 4 or more double bonds; in one class of compounds such groups form the entirety of R a .
  • R a may contain for example from 2 to 15 in-chain and/or in-ring atoms (usually these are all aliphatic; often they are all carbon), e.g.
  • R a may be a linear hydrocarbyl group optionally substituted by one or more nucleophilic groups. Please see below under Formula (III) under the heading "DETAILED DESCRIPTION OF SEVERAL EXAMPLES" for further examples of R a groups.
  • the organoboronate neutralised by the above-described compound may be a protease inhibitor; it may be a serine protease inhibitor, e.g. a coagulation serine protease inhibitor, for example TRI 50c, or a proteasome inhibitor, for example bortezomib.
  • a serine protease inhibitor e.g. a coagulation serine protease inhibitor, for example TRI 50c
  • a proteasome inhibitor for example bortezomib.
  • the disclosure is not limited as to whether the organoboronate is administered in the form of its active principle or in the form of a derivative, for example a salt, sugar adduct or prodrug thereof: all such possibilities are included.
  • intravenous formulations comprising a compound containing a pharmacophore (or structural fragment) of Formula (III), or a salt or prodrug thereof:
  • L is a linker containing from 5 to 10 in-chain atoms, e.g. 7 or 8.
  • A is hydroxy in a particular class of compounds. As other possible A groups may be mentioned hydroperoxy and amino.
  • the in-chain atoms of L may by way of example be C, O, N or S, e.g. C or O. Included is a class of formulations in which all the in-chain atoms of L are carbon.
  • the in-chain bonds of L are typically double or single bonds; included is a class of compounds in which all the in-chain bonds are single bonds or are all single except one double bond.
  • the remainder of the molecule to which the fragment of Formula (III) is bonded may be an aliphatic group and is a linear aliphatic group in one class of compounds. Included in the disclosure is a class of compounds in which the remainder of the molecule is an R a moiety as described above.
  • Exemplary are 18C and 2OC fatty acids containing the above pharmacophore.
  • the fatty acids may be substituted by at least one further nucleophilic functional group, for example.
  • the compounds may be in the form of prodrugs or salts thereof.
  • the prodrugs may be esters.
  • References herein to acids should be construed to include salt, protected and prodrug forms unless the context requires otherwise.
  • Salt forms may in principle comprise any pharmaceutically acceptable salt, and may in particular include the sodium salt.
  • Figure 1 is a graph showing the effect on the anti-coagulant activity of TRI 50c (sodium salt) of various cholesterol linoleic acids;
  • Figure 2 is a graph showing the effect on the anti-coagulant activity of TRI 50c (sodium salt) of various cholesterol linoleic acids and of various free linoleic acids; and
  • Figure 3 is a graph showing the effect on the anti-coagulant activity of TRI 50c (sodium salt) of particular linoleic acids and derivatives according to the disclosure.
  • aliphatic refers to an open-chain or cyclic species not having aromatic properties. Such species may contain a combination of open-chain and cyclic parts. They may be saturated or unsaturated. Often "aliphatic” refers to open-chain species, whether linear or branched, linear being more common. Aliphatic species may be hydrocarbyl aliphatic. Aliphatic species are often substituted or unsubstituted alkyl, alkenyl or alkynyl; in many instances aliphatic is unsubstituted alkyl, alkenyl or alkynyl, e.g. is alkyl. The species may be a compound or part of a compound, as the context requires. Some aliphatic species contain from 1 to 15 in-chain or in-ring atoms, e.g. 1 to 10 such as 1 to 6, for example.
  • ⁇ -Aminoboronic acid or Boro(aa) refers to an amino acid in which the CO2 group has been replaced by BO2.
  • amino-group protecting moiety refers to any group used to derivatise an amino group, especially an N-terminal amino group of a peptide or amino acid. Such groups include, without limitation, alkyl, 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.
  • coagulation serine protease refers to a serine protease involved in the coagulation of blood, for example thrombin, Factor IXa or Factor X.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • thrombin inhibitor refers to a product which, within the scope of sound pharmacological judgement, is potentially or actually pharmaceutically useful as an inhibitor of thrombin, and includes reference to substance which comprises a pharmaceutically active species and is described, promoted or authorised as a thrombin inhibitor. Such thrombin inhibitors may be selective, that is they are regarded, within the scope of sound pharmacological judgement, as selective towards thrombin in contrast to other proteases; the term “selective thrombin inhibitor” includes reference to substance which comprises a pharmaceutically active species and is described, promoted or authorised as a selective thrombin inhibitor.
  • heteroaryl refers to a ring system which has at least one (e.g. 1, 2 or 3) in-ring heteroatoms and has a conjugated in-ring double bond system.
  • heteroatom includes oxygen, sulfur and nitrogen, of which sulfur is sometimes less preferred.
  • Natural amino acid means an L-amino acid (or residue thereof) selected from the following group of neutral (hydrophobic or polar), positively charged and negatively charged amino acids:
  • Trp tryptophan
  • Acid addition salt a reaction product made by combining an inorganic acid or an organic acid with a free base of an active principle (e.g. an amino group).
  • Base addition salt a reaction product made by combining an inorganic base or an organic base with a free acid (e.g. a carboxylic or boronic acid) of an active principle.
  • Cbz benzyloxycarbonyl
  • Cha cyclohexylalanine (a hydrophobic unnatural amino acid)
  • Dcha dicyclohexylalanine (a hydrophobic unnatural amino acid)
  • Dpa diphenylalanine (a hydrophobic unnatural amino acid)
  • Mpg 3-methoxypropylglycine (a hydrophobic unnatural amino acid)
  • Neutral as applied to drugs or fragments of drug molecules, e.g. amino acid residues
  • uncharged not carrying a charge at physiological pH
  • Salt a product obtainable by combining an acid and a basel
  • TRI 50b pinacol ester of TRI 50c (a prodrug of TRI 50c).
  • organoboronate medicaments particularly boropeptide medicaments.
  • organoboronates are discussed below in more detail under the heading "Target Compounds”.
  • the disclosure provides the use, for the manufacture of a medicament for therapeutically neutralising (e.g. reducing in activity) an organoboronate drug, of a compound selected from organic acids comprising an aliphatic moiety substituted by a nudeophilic group and salts and prodrugs of such acids.
  • a method for neutralising an organoboronate drug in a subject comprising administering an effective amount of a compound selected from organic acids comprising an aliphatic moiety substituted by a nudeophilic group and salts and prodrugs of such acids.
  • the entire acid may be aliphatic, for example a linear aliphatic compound, though acids containing cyclic moieties, for example alicyclic moieties, are not excluded.
  • the acid may contain up to 30 carbon atoms, for example, as in the case of compounds containing up to 24 carbon atoms; in one class of organic acids, there are at least 6 carbon atoms, e.g. at least 12 carbon atoms.
  • the compounds may contain 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, for example.
  • the acid is not a boron acid.
  • the acids may be mentioned carboxylic, phosphonic, phosphinic and sulphonic acids.
  • the nucleophilic group may be a hydroxy, hydroperoxy or amino group, for example.
  • the aliphatic moiety may contain a fragment -C*(H)A- where C* is a chiral centre of (S)- configuration and A is a nucleophilic group. Also included are compounds containing a fragment
  • R a comprises, e.g. is, an aliphatic moiety.
  • the aliphatic moiety may be substituted or unsubstituted, for example substituted by one or more substituents (e.g. 1, 2 or 3 substituents) selected from A groups, halogen (e.g. F or Cl), alkyl (e.g. 1C to 4C, for example methyl), alkoxy (e.g. 1C to 4C, for example methoxy), haloalkyl (e.g. 1C to 4C, for example trifluoromethyl) and carboxy.
  • substituents e.g. 1, 2 or 3 substituents
  • substituents e.g. 1, 2 or 3 substituents
  • substituents e.g. 1, 2 or 3 substituents
  • substituents e.g. 1, 2 or 3 substituents
  • substituents e.g. 1, 2 or 3 substituents
  • substituents e.g. 1, 2 or 3 substituents
  • the compounds substituted by a nucleophilic functional group may for example be aliphatic acids or be capable of releasing aliphatic acids in vivo; thus, they may be salts or esters of aliphatic acids.
  • the acids may be carboxylic acids, e.g. mono- or di-carboxylic acids, but sulphonic acids, for example, are included in the scope of the disclosure.
  • the compounds may be alkanes or alkenes containing 1, 2, 3, 4, 5, 6 or more double bonds (multiple double bonds may be conjugated or unconjugated; acids may include both conjugated and unconjugated double bonds), substituted by nucleophilic and acid moieties (other than boron acids), or of course salt or prodrug forms thereof.
  • the acids may be substituted by a plurality of nucleophilic groups, particularly plural hydroxy groups (e.g. 2, 3, 4 5 or 6 hydroxy groups).
  • the present disclosure provides a product for neutralising a boropeptidyl serine protease inhibitor, the product comprising a compound of the Formula (I) or a salt or prodrug thereof:
  • R is -COOH, -P(O)(OH) 2 , -HPOOH, or -SO 3 H;
  • A is a nucleophilic group; the sum of a and b is an integer from 4 to 9 inclusive and a or b may be 0; the sum of c and d is an integer from 1 to 6 inclusive and c or d may be 0 e and f are independently 0 or 1, the value of each instance of e and f being independent of each other instance, if any; r is an integer from 1 to 6, e.g.
  • p, q, s and t are independently 0 or 1, the value of each instance of s and t being independent of the value of each other instance (if any) and there being at least one -C(H)A- moiety; and at least one -CH 2 - group within the compound may be replaced by an ether linkage -O- or an amine linkage -NH-.
  • the cis double bond is typically not further conjugated to a further double bond but the compound may contain additional double bonds, e.g. a second cis double bond separated from the first one by a single -CH 2 - group.
  • Chiral centre -C(H)A- may be of (S)-configuration.
  • R-(CH 2 ) a -[C(H)A]p-(CH 2 )b- may include an ether linkage -O- or an amine linkage -
  • the amine linkage may be of the formula -N(Q) -, where Q is H or 1C-6C hydrocarbyl, e.g. alkyl, optionally substituted by hydrogen, hydroxy, 1C-6C alkoxy, amino or carboxy, for example.
  • a -CH 2 - group is replaced, then in a class of compounds the replacement is by an ether linkage. Sometimes a single -CH 2 - group is replaced; in other compounds, two -CH 2 - groups are replaced.
  • p+q may particularly be 1.
  • r is 1 or 2.
  • the acid of Formula (I) typically comprises from 6 to 24, particularly from 12 to 24 carbon atoms in total, in particular 14 to 20 carbon atoms, for example 18 or 20 carbon atoms.
  • at least one of the carbon atoms e.g. 1, 2 or 3
  • Typical products of Formula (I) may contain 1 or 2 nucleophilic groups A, for example hydroxy groups and/or hydroperoxy groups.
  • the reversal agent is a fatty acid or a fatty acid derivative such as a fatty acid salt or fatty acid ester, for example a pharmaceutically acceptable salt such as a sodium salt, or a cholesteryl ester or alkyl ester.
  • R is -COOH, or of course the -COOH group may be derivatised to form a salt or prodrug, e.g. an ester.
  • A is -OH, -OOH or -NH 2 , more especially -OH or -OOH.
  • A is -OH.
  • any compound of the disclosure contains plural A groups
  • Any one or more hydrogen atoms of the disclosed compounds may be replaced by halogen, e.g. F or Cl, of which F forms a particular example.
  • halogen e.g. F or Cl
  • those atoms which are indicated to be hydrogens are not replaced by halogen.
  • the neutralising acids may be of the Formula (II), or salts or prodrugs thereof:
  • R is -COOH, -P(O)(OH) 2 , -HPOOH, Or -SO 3 H;
  • A is a nucleophilic group; the sum of a and b is an integer from 4 to 9 inclusive and a or b may be 0; the sum of c and d is an integer from 1 to 6 inclusive and c or d may be 0 z is 1 or 2; and p and q are independently 0 or 1 and p+q is at least 1.
  • the double bond may be of trans configuration and any double bond it is conjugated to may be of cis configuration.
  • Chiral centre - CH(A)- may be of (S)-configuration.
  • the products of Formula (II) will typically comprise from 12 to 24 carbon atoms in total, in particular 14 to 20 carbon atoms, for example 18 carbon atoms.
  • Typical products of Formula II may contain 1 or 2 nucleophilic groups A, for example hydroxy groups and/or hydroperoxy groups.
  • the product of Formula (II) is a fatty acid or a fatty acid derivative such as a fatty acid salt or fatty acid ester, for example a pharmaceutically acceptable salt such as a sodium salt, or a cholesteryl or alkyl ester.
  • the nucleophilic group A may be in the ⁇ , ⁇ or Y position with respect to an unsaturated carbon, in particular in the ⁇ or ⁇ position, notably the ⁇ position.
  • the nucleophilic group may typically be located in a 7, 8, 9, 10, 11, 12, 13 or 14 position, e.g. the 7, 9, or 11 position, such as the 9 position, for example.
  • the or each -CH(A)- chiral centre may be of (S)-configuration, excluding any impurity of (Reconfiguration; in some compounds there is a single -CH(A)- chiral centre of (S) configuration, whether or not there are plural -CH(A)- chiral centres.
  • the compound may be, for example, at least about 95% of (S)-configuration e.g. at least about 96, 97, 98, 99 or 100% of (S)- configuration, at -CH(A)- chiral centre(s) of (S)-configuration. Racemic mixtures are not excluded.
  • the compound may be substantially mono substituted, e.g. at least about 95% mono-substituted, such as at least about 96, 97, 98, 99 or 100% mono substituted, for example.
  • Those compounds having just one -CH(A)- group may be isomerically pure in the sense of the group being at a single position in the molecule, excluding any impurity, for example they may contain at least about 95% of a particular isomer (e.g. 9-HODE), such as at least about 96, 97, 98, 99 or 100% of one isomer.
  • a particular isomer e.g. 9-HODE
  • the disclosed compounds may be in isolated form.
  • the compounds may be substantially pure, e.g. at least about 95% pure, for example at least about 96%, 97%, 98%, 99% or 100% pure.
  • A is a nucleophilic group
  • L is a linker containing from 5 to 10 in-chain atoms, e.g. 5, 6, 7 or 8.
  • A is hydroxy in a particular set of compounds. As other possible A groups may be mentioned hydroperoxy and amino.
  • the in-chain atoms of L may by way of example be C, O, N or S, e.g. C or O. Included is a class of compounds in which all the in-chain atoms of L are carbon. In one class of compounds there are 0, 1 or 2 in-chain atoms which are not carbon, e.g. 1 such non-carbon atom.
  • the in-chain bonds of L are typically double or single bonds; included is a class of compounds in which all the in-chain bonds are single bonds or are all single except one double bond, usually a carbon-carbon double bond.
  • L is unsubstituted (all out-of-chain bonds are to hydrogen); alternatively the linker may be substituted, for example each in-chain atom may have at least one substituent or, more frequently, L contains fewer substituent groups than in-chain atoms. In one class of compounds, no in-chain atom contains more than one substituent. Included are compounds in which L has 1, 2 or 3 substituents, e.g. 1 substituent. As substituents there may be mentioned A groups, halogen (e.g. F or Cl), alkyl (e.g. 1C to 4C, for example methyl), alkoxy (e.g. 1C to 4C, for example methoxy), haloalkyl (e.g. 1C to 4C, for example trifluoromethyl) and carboxy. Included are compounds in which any substituents on L are halogen or an A group; as a particular substituent of this set may be mentioned hydroxy.
  • substituents on L are halogen or an A group; as
  • L groups have 5, 6, 7 or 8 in-chain atoms, e.g. 6 or 7. Suitably all the in- chain atoms are carbon atoms. Included in the disclosure are L groups which are alkylene or alkenylene groups.
  • the remainder of the molecule to which the fragment of Formula (III) is bonded may be an aliphatic group and is an open chain aliphatic group, particularly a linear aliphatic group, in one class of compounds.
  • the aliphatic group may be completely saturated or it may be -unsaturated, e.g. containing 1,. 2, 3, 4 or more carbon-carbon multiple, particularly double, bonds.
  • the aliphatic group may be a hydrocarbyl group.
  • v is from 0 to 6, e.g. is 0, 1, 2, 3 or 4.
  • u is 1, 2 or 3
  • v is 1, 2, 3 or 4.
  • -CH CH-(CH 2 )4-CH 3
  • -CH CH-CH 2 -
  • the compounds have a pharmacophore of Formula (IV):
  • the cis (Z) double bond is not conjugated to a second trans double bond, e.g. the pharmacophore is of formula (V):
  • R 1 is H or 1C-10C alkyl or 2C-10C alkenyl, optionally substituted by one or more substituents selected from A groups, halogen (e.g. F or Cl), alkoxy (e.g. 1C to 4C, for example methoxy), haloalkyl (e.g. 1C to 4C, for example trifluoromethyl) and carboxy.
  • R* is alkyl or alkenyl, it may be branched or, more particularly, linear. Included are compounds in which any substituents on R* are halogen or an A group; as a particular substituent of this set may be mentioned hydroxy.
  • R 1 is unsubstituted; alternatively R* may be substituted, for example each in-chain atom may have at least one substituent or, more frequently, R* contains fewer substituent groups than in-chain atoms. In one class of compounds, no in-chain atom contains more than one substituent. Included are compounds in which R 1 has 1, 2 or 3 substituents, e.g. 1 substituent.
  • R ⁇ is alkyl which has 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. from 4 to 7.
  • R 1 is alkenyl, it may have one or more double bonds; in the case of plural double bonds they may be conjugated or unconjugated, e.g. unconjugated.
  • R* may contain both conjugated and unconjugated double bonds. Included amongst compounds having alkenyl R* groups are those of formula (VII):
  • SfSVHETRE The full name of this compound is 8(S)-hydroxy-9E, HZ, 14Z-eicosatrienoic acid and its structure is shown below.
  • the invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group.
  • prodrug represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood.
  • Prodrugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof.
  • prodrugs are transformed to the active drug by hydrolysis.
  • Carboxylic acid Esters including e.g. acyloxyalkyl esters, amides Alcohol Esters, including e.g. sulfates and phosphates as well as carboxylic acid esters
  • Amine Amides carbamates, imines, enamines,
  • Carhonyl (aldehyde, Imines, oximes, acetals/ketals, enol esters, oxazolidines ketone) and thiazoxolidines
  • esters formed at the carboxy group of the acid are esters formed at the carboxy group of the acid.
  • the invention is not limited as to the identity of the ester forming group: it may be a simple organic moiety, for example an alkyl (e.g. 1C to 8C), alkoxyalkyl (e.g. 2C to 8C) or alkenyl group (e.g. 2C to 8C), such groups being removable by carboxyesterases and often containing 1, 2, 3 or 4 carbon atoms.
  • the esters may be glycerols, e.g. triacylglycerols.
  • esters of terpenes notably steroids such s, for example, steroids
  • the cholesteryl esters of 9(S)-HODE, 8(S)- HETRE and 8(S)-HEPE the former of which has the following structure:
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, and in Stahl et al (Eds), "Handbook of Pharmaceutical Salts Properties Selection and Use" Wiley-VCH, 2002.
  • the invention thus includes pharmaceutically-acceptable salts of the disclosed compounds and their covalent prodrug molecules wherein the parent compound is modified by making acid or base salts thereof, for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • base addition salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • the disclosed compounds may be in the form of a solvate or hydrate thereof.
  • the present invention includes combinations of one or more of the compounds as disclosed herein.
  • the present invention includes combinations of one or more of 9(S)-HODE, 8(S)- HETRE and 8(S)-HEPE. More usually, a single active ingredient is included in a pharmaceutical formulation.
  • the products of the disclosure are useful for reducing or substantially destroying the clinically significant activity of a biologically active boronate species and particularly of organoboronate drugs. Such reduction of substantial destruction of clinically significant activity of drugs are convenience referred to herein as "neutralisation”.
  • the disclosed products find application in neutralising aminoboronates or peptidoboronates as described in more detail below.
  • the boronate group (-B(OH)2 or a salt or prodrug form thereof) of the target compound is bonded to an aliphatic carbon atom and normally to an sp ⁇ carbon atom.
  • the target compound may for example be any boronic acid drug mentioned under the heading "BACKGROUND” or in any document referred to under that heading, e.g.
  • boronic acid drugs are peptide boronic acids, including those having a C-terminal residue which is of an ⁇ -aminoboronic acid having an alkyl or alkoxyalkyl side chain.
  • An exemplary C-terminal residue is of Boro-3-methoxypropylglycine, as for example in the case that the drug comprises a boropeptide which includes the sequence Pro-Mpg- B(OH)2, for example as part of the larger sequence Phe-Pro-Mpg-B(OH)2, whether administered as the free acid, a salt or a prodrug.
  • reference to a boronic acid described in the prior art includes reference to the free acids and salts of boronate esters described in the prior art. It may be any other boronic acid drug.
  • the target compounds for neutralisation by the products of the invention are organoboronates and especially boropeptides.
  • Organoboronates e.g. peptide boronates
  • pharmaceutically useful boronic acids may be administered as the free acid or anhydride, they may also be administered in other forms, e.g. as salts or as esters or other prodrugs.
  • organoboronates include basic groups and may therefore be administered in the form of acid addition salts.
  • exemplary acids include HBr, HCI and HSO2CH3.
  • the organoboronates may be administered in the form of base addition salts thereof as described in WO 2004/022072, USSN 10/659,178 and EP-A-1396270; WO 2004/022071, USSN 10/659,179 and EP-A-1396269; and also in WO 2004/022070, USSN 10/658,971 and EP-A-1400245.
  • Salts of alkali metal and alkaline earth metals, e.g. sodium and calcium are representative of base addition salts as well as salts of organic bases, e.g. N-methyl-D-glucamine.
  • the target organoboronate drugs may be administered as esters, notably esters of diols; exemplary diols in particular are sugars, for example mannitol, as described in WO 02/059131 and US 66998
  • the target compounds of the invention therefore include all variant forms of the substances concerned, for example any tautomer or any pharmaceutically acceptable salt, ester, acid or other variant of the substances and their tautomers as well as substances which, upon administration, are capable of providing directly or indirectly such substances or providing a species which is capable of existing in equilibrium with such a substance.
  • the organoboronic acid is hydrophobic.
  • the organoboronic acid comprises an aminoboronic acid linked through a peptide linkage to an organic moiety, and often a moiety comprising an amino acid (natural or unnatural) or a peptide, which organic moiety may be hydrophobic.
  • the organic moiety can comprise an amino acid whose C-terminal carboxy group forms part of said peptide linkage.
  • the target compound may therefore be of formula (XIII):
  • G is an organic moiety, for example comprising together with -CO- a residue of an optionally N-terminally substituted amino acid or peptide (e.g. dipeptide), a suitable N-terminal substituent being for example an X group as described below.
  • R is a side chain of an amino acid (whether natural or unnatural). G and R may be hydrophobic. R may be an R 1 group as described below.
  • Peptide linkages in formula (XIII) compounds are optionally and independently N-substituted, for example by a C1-C13 hydrocarbyl optionally containing in-chain oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl (an example of such an N-substituent is 1C to 6C alkyl).
  • organoboronic acid comprises a boropeptide or boropeptidomimetic.
  • organoboronic acid is of the formula (VIII):
  • R 1 is H or a non-charged side group
  • R ⁇ is H or Ci ⁇ 43 hydrocarbyl optionally containing in-chain oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl; or R 1 and R 2 together form a Cj-C ⁇ moiety which in combination with N-CH forms a 4-6 membered ring and which is selected from alkylene (whether branched or linear) and alkylene containing an in-chain sulfur or linked to N-CH through a sulfur; R 3 is the same as or different from R 1 provided that no more than one of R 1 and R 2 is H;
  • R ⁇ is H or a C1-C43 hydrocarbyl group optionally containing in-chain oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl; or R 3 and R ⁇ together form a C4-C43 moiety which in combination with N-CH forms a 4-6 membered ring and which is selected from alkylene (whether branched or linear) and alkylene containing an in-chain sulfur or linked to N-CH through a sulfur; and
  • R5 is X-E- wherein E is nothing or a hydrophobic moiety selected from the group consisting of amino acids (natural or unnatural) and peptides of two or more amino acids (natural or unnatural) of which more than half are hydrophobic, in which peptides the nitrogen(s) of the peptide linkage(s) may be substituted by a C ⁇ -CJJ hydrocarbyl optionally containing in-chain oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl (an example of such an N-substituent is 1C to 6C alkyl), and X is H or an amino-protecting group.
  • E is nothing or a hydrophobic moiety selected from the group consisting of amino acids (natural or unnatural) and peptides of two or more amino acids (natural or unnatural) of which more than half are hydrophobic, in which peptides the nitrogen(s) of the peptide linkage(s) may be substituted by a
  • Said C1-C13 hydrocarbyl optionally containing in-chain oxygen or sulfur may be selected from alkyl; alkyl substituted by cycloalkyl, aryl or heterocyclyl; cycloalkyl; aryl; and/or heterocyclyl.
  • Heterocyclyl may be heteroaryl.
  • R 1 may be non polar. In some embodiments, R 1 contains up to 20 carbon atoms. R 1 may have affinity for the Sl subsite of a protease.
  • the acid has a neutral moiety capable of binding to the thrombin Sl subsite linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites.
  • the acid may for example be of formula (III):
  • Y comprises a moiety which, together with the fragment -CH(R ⁇ )-B(OH)2, has affinity for the substrate binding site of thrombin;
  • R9 is a straight chain alkyl group interrupted by one or more ether linkages (e.g. 1 or 2) and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 (e.g. 5) or R ⁇ is -(CH2)m-W where m is 2, 3, 4 or 5 (e.g. 4) and W is -OH or halogen (F, Cl, Br or I).
  • ether linkages e.g. 1 or 2
  • R ⁇ is -(CH2)m-W where m is 2, 3, 4 or 5 (e.g. 4) and W is -OH or halogen (F, Cl, Br or I).
  • straight chain alkyl interrupted by one or more ether linkages (-O-) may be mentioned alkoxyalkyl (one interruption) and alkoxyalkoxyalkyl (two interruptions).
  • R 9 is an alkoxyalkyl group in one subset of compounds, e.g. alkoxyalkyl containing 4 carbon atoms.
  • the neutral aminoboronic acid residue capable of binding to the thrombin Sl subsite may be linked through a peptide linkage to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites.
  • Y ⁇ comprises a hydrophobic moiety which, together with the aminoboronic acid residue
  • R 9 is as defined above.
  • YCO- comprises an amino acid residue (whether natural or unnatural) which binds to the S2 subsite of thrombin, the amino acid residue being N-terminally linked to a moiety which binds the S3 subsite of thrombin.
  • Peptide linkages in the acid of formula (IX) may be substituted or unsubstituted; in one class of embodiments they are unsubstituted.
  • YCO- is an optionally N-terminally protected dipeptide residue which binds to the S3 and S2 binding sites of thrombin and the peptide linkages in the acid are optionally and independently N-substituted by a C1-C13 hydrocarbyl group optionally containing in-chain and/or in-ring nitrogen, oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl.
  • the N-terminal protecting group when present, may be a group X as defined above (other than hydrogen).
  • the acid contains no N- substituted peptide linkages; where there is an N-substituted peptide linkage, the substituent is often 1C to 6C hydrocarbyl, e.g. saturated hydrocarbyl; the N-substituent comprises a ring in some embodiments, e.g. cycloalkyl, and may be cyclopentyl, for example.
  • One class of acids has an N-terminal protecting group (e.g. an X group) and unsubstituted peptide linkages.
  • the S3-binding amino acid residue may be of R configuration and/or the S2-binding residue may of S configuration.
  • the fragment -NHCH(R 9 )-B(OH) may of R configuration.
  • the disclosure is not restricted to chiral centres of these conformations, however.
  • the side chain of P3 (S3-binding) amino acid and/or the P2 (S2- binding) amino acid is a moiety other than hydrogen selected from a group of formula A or B: -(CO) a -(CH 2 ) b -D c -(CH 2 )d-E (A)
  • R 12 CO 2 R 13 and -R 12 O 2 CR 13 wherein R 12 is -(CH 2 ) r and R 13 is -(CH 2 ) g H or by a moiety whose non-hydrogen atoms consist of carbon atoms and in-ring heteroatoms and number from 5 to 14 and which contains a. ring system (e.g.
  • f and g are each independently from 0 to 10, g particularly being at least 1 (although -OH may also be mentioned as a substituent), provided that (f+g) does not exceed 10, more particularly does not exceed 6 and most particularly is 1, 2, 3 or 4, and provided that there is only a single substituent if the substituent is a said moiety containing a ring system, or E is Ci-C 6 trialkylsilyl; and E 1 , E 2 and E 3 are each independently selected from -R 15 and -J-R 15 , where J is a 5-6 membered ring and R 15 is selected from Ci-C 6 trialkylsilyl, -CN, -R 13 , -R 12 OR 13 ,
  • -R 12 COR 13 -R 12 CO 2 R 13 , -R 12 O 2 CR 13 , and one or two halogens (e.g. in the latter case to form a -J-R 15 moiety which is dichlorophenyl), where R 12 and R 13 are, respectively, an R 12 moiety and an R 13 moiety as defined above (in some acids where E 1 , E 2 and E 3 contain an R 13 group, g is 0 or 1); in which moiety of Formula (A) or (B) any ring is carbocyclic or aromatic, or both, and any one or more hydrogen atoms bonded to a carbon atom is optionally replaced by halogen, especially F.
  • R 12 and R 13 are, respectively, an R 12 moiety and an R 13 moiety as defined above (in some acids where E 1 , E 2 and E 3 contain an R 13 group, g is 0 or 1); in which moiety of Formula (A) or (B) any ring is carbocyclic or aromatic, or both,
  • a is 0. If a is 1, c may be 0. In particular examples, (a+b+c+d) and (a+b+c+e) are no more than 4 and are more especially 1, 2 or 3. (a+b+c+d) may be 0.
  • Exemplary groups for E, E 1 , E 2 and E 3 include aromatic rings such as phenyl, naphthyl, pyridyl, quinolinyl and furanyl, for example; non-aromatic unsaturated rings, for example cydohexenyl; saturated rings such as cyclohexyl, for example.
  • E may be a fused ring system containing both aromatic and non-aromatic rings, for example fluorenyl.
  • E, E*, E 2 and E 3 groups are aromatic (including heteroaromatic) rings, especially 6-membered aromatic rings.
  • E 1 is H whilst E 2 and E 3 are not H; in those compounds, examples of E 2 and E 3 groups are phenyl (substituted or unsubstituted) and C 1 -G j alkyl, e.g. methyl.
  • E contains a substituent which is C 1 -Cs alkyl, (C4-C5 alkyl)carbonyl, carboxy C 1 -Cs alkyl, aryl (including heteroaryl), especially 5-membered or preferably 6-membered aryl (e.g. phenyl or pyridyl), or arylalkyl (e.g. arylmethyl or arylethyl where aryl may be heterocyclic and is preferably 6-membered).
  • aryl including heteroaryl
  • 5-membered or preferably 6-membered aryl e.g. phenyl or pyridyl
  • arylalkyl e.g. arylmethyl or arylethyl where aryl may be heterocyclic and is preferably 6-membered.
  • E contains a substituent which is OR 13 , wherein R 13 can be a 6- membered ring, which may be aromatic (e.g. phenyl) or is alkyl (e.g. methyl or ethyl) substituted by such a 6-membered ring.
  • R 13 can be a 6- membered ring, which may be aromatic (e.g. phenyl) or is alkyl (e.g. methyl or ethyl) substituted by such a 6-membered ring.
  • a class of moieties of formula A or B are those in which E is a 6-membered aromatic ring ⁇ optionally substituted, particularly at the,2-position or 4-position, by -R 13 or -OR* 3 . , .
  • boronic aid thrombin inhibitors in which the P3 and/or P2 side chain comprises a cyclic group in which 1 or 2 hydrogens have been replaced by halogen, e.g. F or Cl.
  • halogen e.g. F or Cl.
  • organoboronic acid in which the side chains of formula (A) or (B) are of the following formulae (C), (D) or (E): C q H 2q CHT 2 (C)
  • T is independently hydrogen, one or two halogens (e.g. F or Cl), -SiMe 3 , -CN, -R 13 , -OR 13 , -COR 13 , -CO 2 R 13 or -O 2 CR 13 .
  • T is at the 4-position of the phenyl group(s) and is -R 13 , - OR 13 , -COR 13 , -CO 2 R 13 or -O 2 CR 13
  • R 13 is C 1 -C 10 alkyl and more particularly C 1 -Ce alk y'-
  • T is -R 13 or -OR 13 , for example in which f and g are each independently 0, 1, 2 or 3; in some side chains groups of this sub-class, T is -R 12 OR 13 and R 13 is H.
  • the side chain is of formula (C) and each T is independently R 13 or OR 13 and R 13 is C4-C4 alkyl. In some of these compounds, R 13 is branched alkyl and in others it is straight chain. In some moieties, the number of carbon atoms is from 1 to 4.
  • the P3 amino acid has a side chain of formula (A) or (B) as described above and the P2 residue is of an imino acid.
  • the target compounds may therefore be organoboronic acids which are thrombin inhibitors, particularly selective thrombin inhibitors, having a neutral Pl (Sl-binding) moiety.
  • thrombin inhibitors particularly selective thrombin inhibitors, having a neutral Pl (Sl-binding) moiety.
  • the boronic acids may have a Ki for thrombin of about 100 nM or Iess ⁇ e.g. about 20 nM or less. ⁇ • ⁇ ⁇ • • • - • ⁇ - - - - . • ; • - • •
  • a subset of the Formula (IX) acids comprises the acids of Formula (X):
  • X is a moiety bonded to the N-terminal amino group and may be H to form NH2.
  • X is not critical but may be a particular X moiety described above. In one example there may be mentioned benzyloxycarbonyl.
  • X is R 6 -(CH 2 ) p -C(O>, R 6 -(CH 2 ) p -S(O) 2 -, R 5 -(CH 2 ) p -NH-C(O)- or R 6 -(CH 2 ) p -
  • R 6 is H or a 5 to 13-membered cyclic group optionally substituted by 1, 2 or 3 substituents selected from halogen, amino, nitro, hydroxy, a C5-C5 cyclic group, C1-C4 alkyl and C1-C4 alkyl containing, and/or linked to the 5 to 13-membered cyclic group through, an in-chain O, the aforesaid alkyl groups optionally being substituted by a substituent selected from halogen, amino, nitro, hydroxy and a C5-C5 cyclic group.
  • X is R 6 -(CH2) p -C(O)- or R 6 -(CH2) p -O-C(O)- and p is 0 or 1.
  • Said 5 to 13-membered cyclic group is often aromatic or heteroaromatic, for example is a 6-membered aromatic or heteroaromatic group. In many cases, the group is not substituted.
  • Exemplary X groups are (2-pyrazine) carbonyl, (2-pyrazine) sulfonyl and particularly benzyloxycarbonyl.
  • aa* is an amino acid residue having a hydrocarbyl side chain containing no more than 20 carbon atoms (e.g. up to 15 and optionally up to 13 C atoms) and comprising at least one cyclic group having up to 13 carbon atoms.
  • the cyclic group(s) of aa 1 have/has 5 or 6 ring members.
  • the cyclic group(s) of aa 1 may be aryl groups, particularly phenyl.
  • Certain side chains comprise, or consist of, methyl substituted by one or two 5- or 6- membered rings.
  • aa* is Phe, Dpa or a wholly or partially hydrogenated analogue thereof.
  • the wholly hydrogenated analogues are Cha and Dcha.
  • aa 2 is an imino acid residue having from 4 to 6 ring members.
  • aa 2 is GIy N- substituted by a C3-C43 hydrocarbyl group; e.g. a C3-C8 hydrocarbyl group comprising a C3-C5 hydrocarbyl ring; the hydrocarbyl group may be saturated, for example exemplary N-substituents are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • a hydrocarbyl group containing one or more unsaturated bonds may be mentioned phenyl and methyl or ethyl substituted by phenyl, e.g. 2-phenylethyl, as well as ⁇ , ⁇ -dialkylphenylethyl.
  • An exemplary class of products comprises those in which aa 2 is a residue of an imino acid of formula (XI)
  • R 11 is -CH2-, CH2-CH2-, -S-CH2- or -CH2-CH2-CH2-, which group when the ring is 5 or 6- membered is optionally substituted at one or more -CH2- groups by from 1 to 3 C1-C3 alkyl groups, for example to form the R* 1 group -S-C(CH3)2".
  • imino acids azetidine-2- carboxylic acid, especially (s)-azetidine-2-carboxyIic acid, and more particularly proline are illustrative. It will be appreciated from the above that a particular class of organoboronates consists of those in which aai-aa 2 is Phe-Pro.
  • aai-aa 2 is Dpa-Pro.
  • aa ⁇ -aa 2 is Cha-Pro or Dcha-Pro.
  • Pro is replaced by (s)-azetidine-2-carboxylic acid.
  • R9 is as defined previously and may be a moiety R* of the formula -(CH2) S -Z.
  • Integer s is 2, 3 or 4 and W is -OH, -OMe, -OEt or halogen (F, Cl, I or, preferably, Br).
  • Particularly illustrative Z groups are -OMe and -OEt, especially -OMe. In certain examples s is 3 for all Z groups and, indeed, for all compounds of the disclosure.
  • R 1 groups are 2-bromoethyl, 2-chloroethyl, 2-methoxyethyl, 4-bromobutyl, 4-chlorobutyI, 4-methoxybutyl and, especially, 3-bromopropyl, 3- chloropropyl and 3-methoxypropyl. Most preferably, R 1 is 3-methoxypropyl. 2-Ethoxyethyl is another preferred R 1 group.
  • a specific class of target compounds comprises boropeptides having the amino acid sequence Phe-Pro-BoroMpg, particularly (R)-Phe-(S)-Pro-(R)-BoroMpg.
  • acids of the formula X-Phe-Pro-Mpg-B(OH)2, especially Cbz-Phe-Pro-Mpg-B(OH)2 also included are analogues of these compounds in which Mpg is replaced by a residue with another of the R 1 groups and/or Phe is replaced by Dpa or another aa 1 residue.
  • the aa* moiety is preferably of R configuration.
  • the aa 2 moiety is preferably of (S)- configuration.
  • Particularly preferred target compounds of formula (III) have aa* of (R)- configuration and aa 2 of (S)-configuration.
  • the chiral centre -NH-CH(R ⁇ )-B- is preferably of (R)- configuration. It is considered that commercial formulations will have the chiral centres in (R,S,R) arrangement, as for example in the case of Cbz-Phe-Pro-BoroMpg-OH:
  • the target boronic acids may of course be administered in any form which results in release of the free acid or a corresponding boronate anion, e.g. as salts or prodrugs thereof. All the boronic acids described herein may therefore be administered in the form of prodrugs, or as the reaction product (salt) of combining the boronic acid or a prodrug thereof with a pharmaceutically acceptable acid or base, and the disclosed reversal agents may be used following administration of a boronic acid drug in free form or in salt or prodrug form.
  • esters e.g. with a residue of an alkanol, e.g. a C4-C4 alkanol such as methanol or ethanol, for example. It may be an ester of a diol.
  • diol is not critical.
  • suitable diols may be mentioned aliphatic and aromatic compounds having hydroxy groups that are substituted on adjacent carbon atoms or on carbon atoms substituted by another carbon. That is to say, suitable diols include compounds having at least two hydroxy groups separated by at least two connecting carbon atoms in a chain or ring.
  • One class of diols comprises hydrocarbons substituted by exactly two hydroxy groups.
  • One such diol is pinacol and another is pinanediol and a third is diethanolamine; there may also be mentioned neopentylglycol, 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 2,3-butanediol, 1,2- diisopropylethanediol, 5,6-decanediol and 1,2-dicydohexylethanediol.
  • the prodrug may be a sugar derivative as described in WO 02/059131 (see above).
  • boronate group may be esterified with a sugar such as a monosaccharide or disaccharide, for example.
  • the sugar may be a reduced sugar, e.g. mannitol or sorbitol; it may be any individual sugar or class of sugars taught in WO 02/059131.
  • the boronic acid, sugar (or other diol) and water may be combined and then lyophilised, for example as taught in WO 02/059131.
  • Salts of strongly basic organic nitrogen-containing compounds including:
  • Salts of strongly basic amine examples of which include (i) aminosugars and (ii) other amines.
  • salts particularly illustrative are alkali metals, especially Na and Li, and alkaline earth metals, especially magnesium and calcium. Also illustrative are aminosugars.
  • the term “salt” herein does not imply any particular structure at the molecular level but refers merely to a product formed by contacting together an acid and a base. Specific salts are of the acid boronate though in practice the acid salts may contain a very small proportion of the doubly deprotonated boronate.
  • acid boronate refers to trigonal -B(OH)2 groups in which one of the B-OH groups is deprotonated as well as to corresponding tetrahedral groups in equilibrium therewith. Acid boronates have a stoichiometry consistent with single deprotonation.
  • Suitable organic bases include those with a pKb of 7 or more, e.g. 7.5 or more, for example in the region of 8 or more.
  • Bases which are less lipophilic e.g. have at least one polar functional group (e.g. 1, 2 or 3 such groups) for example hydroxy] are favoured; thus aminosugars are one favoured class of base, for example N-methyl-D-glucamine.
  • Other organic bases to be mentioned are arginine and lysine.
  • Certain of the disclosed reversal agents contain a moiety -C(H)A- of (S)-configuration and are useful for neutralising the activity of boronic acids in which the boronate group is attached to a carbon atom forming a chiral centre of (R)-configuration.
  • neutralising agents are contemplated for use with boronic acid species corresponding to formulae (III) or (IX) in which fragment -C(H)R 9 - constitutes a chiral centre of (R)-configurati ⁇ nf particularly to be noted as neutralising agents in this context are compounds having a pharmacophore of formula (III) or (IV).
  • target compounds of formula (X) of (R,S,R) configuration are in particular susceptible to neutralising agents having a pharmacophore of formula (IV), (V) or (VI), notably linear aliphatic fatty acids which contain such a pharmacophore.
  • the products of the disclosure may be used as reversal agents (also known as antidotes) for organoboronate drugs, e.g. one described herein under the heading "Target Compounds”. They may therefore be administered when an organoboronate drug has produced unwanted side effects, e.g. bleeding after administration of an anticoagulant.
  • the products of the disclosure may also be used in any circumstances where an organoboronate compound has been ingested or absorbed and is causing toxicity.
  • the disclosure includes a method of preparing to supply a first pharmaceutical composition for the treatment of unwanted coagulation (e.g. thrombosis) by prophylaxis or therapy and, if required, a second pharmaceutical composition to inhibit the action of the first composition, comprising stocking a pharmaceutical composition comprising a target compound as hereinbefore described and stocking a pharmaceutical formulation or medicament comprising a product of the present disclosure.
  • unwanted coagulation e.g. thrombosis
  • a method of providing a medicament pair comprising a first medicament for the treatment of unwanted coagulation (e.g. thrombosis) by prophylaxis or therapy and a second medicament to inhibit the action of the first medicament in the event of undue bleeding, wherein the first medicament comprises a target compound as hereinbefore described and the second medicament comprises a pharmaceutical composition or medicament according to the present disclosure.
  • unwanted coagulation e.g. thrombosis
  • a method for treating unwanted coagulation e.g. thrombosis
  • prophylaxis or therapy or inhibiting thrombosis in the treatment of disease by prophylaxis or therapy, using an anticoagulant which results in inappropriate bleeding and then inhibiting the action of said anticoagulant
  • a therapeutically effective amount of an anticoagulant composition comprising a target compound as hereinbefore described is administered to a patient in need thereof, or to an extracorporeal blood circuit of a patient, to treat coagulation or inhibit coagulation in the treatment of disease (including in treatment by surgery), and, after the inappropriate bleeding, a therapeutically effective amount of a product the disclosure is administered to a patient to inhibit the anticoagulant.
  • the described active products and pharmaceutical formulations may administered orally. More typically, they may be administered intravenously.
  • a medicament pair comprising a first medicament for treating unwanted coagulation (e.g. thrombosis) by prophylaxis or therapy and a second medicament for, if required, stopping or reducing the anticoagulant treatment, of a target compound as herein before described, for the manufacture of the first medicament and a product of the present disclosure for the manufacture of the second medicament.
  • unwanted coagulation e.g. thrombosis
  • second medicament for, if required, stopping or reducing the anticoagulant treatment, of a target compound as herein before described
  • a medicament pair comprising a first medicament for treating unwanted coagulation (e.g. thrombosis) by prophylaxis or therapy and a second medicament for, if required, stopping or reducing undue or inappropriate bleeding caused by the first medicament, of a target compound as herein before described for the manufacture of the first medicament and a product according to the present disclosure for the manufacture of the second medicament.
  • a method of preparing for the administration to a patient or an extracorporeal blood circuit of a first pharmaceutical composition for the treatment of unwanted coagulation e.g.
  • thrombosis by prophylaxis or therapy and, if required, a second pharmaceutical composition for reacting with the active agent of the first composition to inactivate molecules thereof, comprising supplying a pharmaceutical composition comprising a target compound, as hereinbefore described, and supplying a pharmaceutical composition or a medicament according to the present disclosure.
  • either or both of the first and second pharmaceutical compositions are administered orally and/or intravenously.
  • Preferred target compounds are thrombin inhibitors. They are therefore useful for inhibiting thrombin. There are therefore provided compounds which have potential for controlling haemostasis and especially for inhibiting coagulation, for example in the treatment or prevention of secondary events after myocardial infarction.
  • the medical use of the compounds may be prophylactic (including to treat thrombosis as well as to prevent occurrence of thrombosis) as well as therapeutic (including to prevent re-occurrence of thrombosis or secondary thrombotic events).
  • the anticoagulant target compounds may be employed when an anti-thrombogenic agent is needed. Further, it has been found that anti-thrombotic target compounds, including those of boronic acids of Formula (DC), are beneficial in that the class is useful for treating arterial thrombosis by therapy or prophylaxis. The target compounds are thus indicated in the treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues of animals including man.
  • anti-thrombotic target compounds including those of boronic acids of Formula (DC)
  • DC boronic acids of Formula
  • thrombosis includes inter alia atrophic thrombosis, arterial thrombosis, cardiac thrombosis, coronary thrombosis, creeping thrombosis, infective thrombosis, mesenteric thrombosis, placental thrombosis, propagating thrombosis, traumatic thrombosis and venous thrombosis.
  • boronic acid inhibitors of coagulation serine proteases include the therapeutic and/or prophylactic treatment of venous thrombosis and pulmonary embolism.
  • Preferred indications envisaged for the described thrombin inhibitory boronic acids include:
  • venous thromboembolic events e.g. deep vein thrombosis and/or pulmonary embolism
  • examples include patients undergoing orthopaedic surgery such as total hip replacement, total knee replacement, major hip or knee surgery; patients undergoing general surgery at high risk for thrombosis, such as abdominal or pelvic surgery for cancer; and in patients bedridden for more than 3 days and with acute cardiac failure, acute respiratory failure, infection.
  • thrombolytics see below for examples
  • antiplatelet agents see below for examples
  • the disclosed compounds may be administered to a host, for example, when an organoboronate drug is resulting in undesired effects which it is wished to stop or reduce.
  • the compounds may be administered alone or in combination with pharmaceutically acceptable diluents, excipients or carriers.
  • pharmaceutically acceptable includes acceptability for both human and veterinary purposes, of which acceptability for human pharmaceutical use is preferred.
  • the compounds of the disclosure may be combined and/or co-administered with another medicament.
  • they may be combined and/or co-administered with a procoagulant when the target boronic acid drug is an anticoagulant.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration (referred to herein as a "therapeutically effective amount").
  • the selected dosage level will depend upon the activity of the particular compound, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • a parenteral formulation including a compound as described herein.
  • the formulation may consist of the compound alone or it may contain additional components, in particular the compound may be in combination with a pharmaceutically acceptable diluent, excipient or carrier, for example a tonicity agent for the purpose of making the formulation substantially isotonic with the body of the subject to receive the formulation, e.g. with human plasma.
  • a pharmaceutically acceptable diluent, excipient or carrier for example a tonicity agent for the purpose of making the formulation substantially isotonic with the body of the subject to receive the formulation, e.g. with human plasma.
  • the formulation may be in ready-to-use form or in a form requiring reconstitution prior to administration. More particularly, the parenteral formulation may be an intravenous formulation.
  • a particular embodiment resides in intravenous formulations, whether in liquid ready-to-use form or in solid form for reconstitution, or otherwise, comprising an acid having a pharmacophore of formula III, IV, V, or VI or a salt or prodrug thereof.
  • the compounds in the case of parenteral administration, for example i.v. administration, might for instance be administered to a 70kg adult patient, usually as a bolus, in an amount of at least about 200mg, e.g. about 500mg or more and often in an amount of about Ig or more, calculated as 9-HODE. It Is envisaged that the dosage is unlikely to exceed about 3g and more probably will not exceed about 2g, e.g. will be no more than about 1.5g; in some cases, the maximum dosage may be about 1.25g, again calculated as 9-HODE. In accordance with normal medical practice, the dosage may be varied for patients of different weights, although it is anticipated that small variations from 70kg will be disregarded.
  • Parenteral preparations can be administered by one or more routes, such as intravenous, subcutaneous, intradermal and infusion; a particular example is intravenous.
  • routes such as intravenous, subcutaneous, intradermal and infusion; a particular example is intravenous.
  • a formulation disclosed herein may be administered using a syringe, injector, plunger for solid formulations, pump, or any other device recognized in the art for parenteral administration.
  • Liquid dosage forms for parenteral administration may include solutions, suspensions, liposome formulations, or emulsions in oily or aqueous vehicles.
  • the liquid dosage forms may contain other compounds.
  • Tonicity agents for the purpose of making the formulations substantially isotonic with the subject's body, e.g. with human plasma
  • Tonicity agents such as, for instance, sodium chloride, sodium sulfate, dextrose, mannitol and/or glycerol may be optionally added to the parenteral formulation.
  • a pharmaceutically acceptable buffer may be added to control pH.
  • Thickening or viscosity agents for instance well known cellulose derivatives (e.g. methylcellulose, carboxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose), gelatin and/or acacia, may optionally be added to the parenteral formulation.
  • Solid dosage forms for parenteral administration may encompass solid and semi-solid forms and may include pellets, powders, granules, patches, and gels.
  • the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier.
  • the disclosed compounds may be presented as solids in finely divided solid form, for example they may be milled or micronised.
  • the formulations may also include antioxidants and/or preservatives.
  • antioxidants may be mentioned thiol derivatives (e.g. thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione), tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, sulfurous acid salts (e.g.
  • Suitable preservatives may for instance be phenol, chlorobutanol, benzylalcohol, methyl paraben, propyl paraben, benzalkonium chloride and cetylpyridinium chloride.
  • the parenteral formulations may be prepared as large volume parenterals (LVPs), e.g. larger than 100 ml, more particularly about 250 ml, of a liquid formulation of the active compound.
  • E ⁇ xamples of LVPs are infusion bags.
  • the parenteral formulations may alternatively be prepared as small volume parenterals (SVPs), e.g. about 100 ml or less of a liquid formulation of the active compound.
  • SVPs small volume parenterals
  • Examples of SVPs are vials with solution, vials for reconstitution, pref ⁇ lled syringes for injection and dual chamber syringe devices.
  • the formulations of the disclosure include those in which the active compound is 9(S)-HODE, 8(S)-HETTRE or 8(S)-HEPE.
  • the compounds mentioned in this paragraph, or their salts or prodrugs may be administered as solutions or suspensions in water, typically containing one or more additives, for example isotonicity agent(s) and/or antioxidants).
  • a way to store the compounds is in solid form, for example as dry powder, and to make them up into solutions for administration prior to administration. Alternatively, the compounds may be stored as liquid formulations ready for use.
  • One class of formulations disclosed herein is intravenous formulations.
  • the active compound or compounds can be present at varying concentrations, with a carrier acceptable for parenteral preparations making up the remainder.
  • the carrier is water, particularly pyrogen free water, or is aqueous based.
  • the carrier for such parenteral preparations is an aqueous solution comprising a tonicity agent, for example a sodium chloride solution.
  • aqueous based is meant that formulation comprises a solvent which consists of water or of water and water-miscible organic solvent or solvents; as well as containing a compound of disclosure in dissolved form, the solvent may have dissolved therein one or more other substances, for example an antioxidant and/or an isotonicity agent.
  • organic cosolvents may be mentioned those water-miscible solvents commonly used in the art, for example propyleneglycol, polyethyleneglycol 300, polyethyleneglycol 400 and ethanol.
  • organic co-solvents are only used in cases where the active agent is not sufficiently soluble in water for a therapeutically effective amount to be provided in a single dosage form.
  • the disclosure includes formulations of alkali metal salts of the disclosed acids having a solvent which consists of water.
  • the solubility of the active compound in the present formulations may be such that the turbidity of the formulation is lower than 50 NTU, e.g. lower than 20 NTU such as lower than 10 NTU.
  • parenteral formulations are administered at or near physiological pH. It is believed that administration in a formulation at a high pH (i.e., greater than 8) or at a low pH (i.e., less than 5) is undesirable. In particular, it is contemplated that the formulations would be administered at a pH of between 6,0 and 7.0 such as a pH of 6.5.
  • the parenteral formulation may be purged of air when being packaged.
  • the parenteral formulation may be packaged in a sterile container, e.g. vial, as a solution, suspension, gel, emulsion, solid or a powder.
  • a sterile container e.g. vial
  • Such formulations may be stored either in ready-to-use form or in a form requiring reconstitution prior to administration.
  • Parenteral formulations according to the disclosure may be packaged in containers.
  • Containers may be chosen which are made of material which is non-reactive or substantially non-reactive with the parenteral formulation.
  • Glass containers or plastics containers e.g. plastics infusion bags, may be used.
  • a concern of container systems is the protection they afford a solution against UV degradation. If desired, amber glass employing iron oxide or an opaque cover fitted over the container may afford the appropriate UV protection.
  • Plastics containers such as plastics infusion bags are advantageous in that they are relatively light weight and non-breakable and thus more easily stored. This is particularly the case for Large Volume parenterals.
  • the intravenous preparations may be prepared by combining the active compound or compounds with the carrier. After the formulation is mixed, it may be sterilized, for example using known methods. Once the formulation has been sterilized, it is ready to be administered or packaged, particularly in dark packaging (e.g. bottles or plastics packaging), for storage. It is envisaged, however, that the disclosed compounds might not be stored in solution but as dry solids, particularly a finely divided form such as, for example, a lyophilisate, in order to prolong shelf life; this would of course apply to other parenteral formulations, not only intravenous ones.
  • the intravenous preparations may take the form of large volume parenterals or of small volume parenterals, as described above.
  • kits for producing a single-dose administration unit.
  • the products may each contain both a first container having the active compound (optionally combined with additives, for example antioxidant, preservative and, in some instances, tonicity agent) and a second container having the carrier/diluent (for example water, optionally containing one or more additives, for example tonicity agent).
  • additives for example antioxidant, preservative and, in some instances, tonicity agent
  • second container having the carrier/diluent (for example water, optionally containing one or more additives, for example tonicity agent).
  • additives for example antioxidant, preservative and, in some instances, tonicity agent
  • the carrier/diluent for example water, optionally containing one or more additives, for example tonicity agent
  • Such dual chamber syringes or binary syringes will have in one chamber a dry preparation including or consisting of the active compound and in another chamber a suitable carrier or diluent such as described herein.
  • the two chambers are joined in such a way that the solid and the liquid mix to form the final solution.
  • the active compound and the carrier are typically combined, for example in a mixer. After the formulation is mixed, it is preferably sterilized, such as with U.V. radiation. Once the formulation has been sterilized, it is ready to be injected or packaged for storage. It is envisaged, however, that the disclosed compounds will not be stored in liquid formulation but as dry solids, in order to prolong shelf life.
  • compositions comprising an alkali metal salt, particularly sodium salt, of a disclosed hydroxy fatty acid in dry fine particle form, suitable for reconstitution into an aqueous read-to-use parenteral formulation.
  • the alkali metal salt is suitably an acid salt.
  • the alkali metal salt may be in a small volume parenteral unit dosage form.
  • the alkali metal salt may be presented in a form, e.g. dry powder form, suitable for reconstituting as a large volume parenteral.
  • One example is a sodium salt of 9(S)-HODE, 8(S)-HETTRE or 8(S)-HEPE in dry powder form for reconstitution as a liquid intravenous formulation (solution) containing a tonicity agent, particularly sodium chloride.
  • the dry powder form of a salt used in a parenteral formulation may be a lyophilisate.
  • the reconstituted solution may be administered by injection or infusion.
  • liquid formulations e.g. solutions, comprising a liquid vehicle (typically water) and species which will result in in vivo hydroxy fatty acid upon administration of the formulation.
  • the species may comprise a hydroxy fatty acid, the deprotonated acid or a protected form of the fatty acid (whether or not in ionised form).
  • the compounds of the invention may be used in combination with the target compounds.
  • the compounds of the invention may be used in this way when they are formulated to have a predetermined release time.
  • the period of activity of the target compound may be predetermined in that, just prior to expiration of the predetermined period of activity, a compound of the present invention is released in the patient and the activity of the target compound is neutralised.
  • Peptide boronate inhibitor of thrombin (TRI 50c, 10OnM) was incubated with thrombin (33.3ng/ml) in assay buffer (10OmM sodium phosphate, 20OmM NaCI, 0.5% PEG 6000 and 0.02% sodium azide, pH 7.5) for 5 minutes at 37 0 C. Test compounds were then added and incubated for various amounts of time prior to the addition of S2238 chromogenic substrate (5uM). The reaction was followed at 405nM and 37 0 C using a Thermomax kinetic plate reader (Molecular Devices Corporation). Results of the assay are expressed as percentage activities of thrombin relative to that seen in the absence of inhibitor or antidote.
  • Figure 1 shows the assay results for the TRI 50c-neutralising activity of the materials:
  • Figure 3 summarises the neutralising ability of three particular 9(S)linoleates against TRI 50c over 30 minutes and shows that while the neutralising abilities of 9(S)-CLOH and 9(S)-CLOOH are very good, a particularly good effect is shown by 9(S)-HODE.
  • thrombin 33.3ng/ml in assay buffer
  • 20 ⁇ l TRI 50c 30OnM final
  • lO ⁇ l assay buffer 10OmM Na orthophosphate (80% Na 2 HPO 4 and 20% NaH 2 PO 4 ), 20OmM NaCI, 0.5% PEG 6000, 0.02% Na azide, pH 7.5
  • lOO ⁇ l of hydroxy fatty acid was added and further incubated for 30 minutes at 37°C.
  • boronate inhibitors [Groziak MP. Boron therapeutics on the horizon. Am J Ther 2001; 8:321-8] have been described as proteasome inhibitors [Shah SA, Potter MW, McDade TP, et al. 26S Proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell
  • This Example relates to a method for detecting the amount of deboronation of a product, TRI50, in the presence of 9-HODE.
  • the thrombin buffer was made up of 10OmM NaOphosphate [80% Na 2 HPO 4 (11.36g/l anhydrous)
  • TGN 255 (20mg) was dissolved in DMSO (1.9ml). To this was added thrombin buffer (0.8 ml), followed by 9(S)-HODE (supplied by Cayman Chemical) in thrombin buffer (0.3ml, 337uM). The solution was incubated at 37 0 C for 30 mins.
  • the uv chromatogram for TGN 255/ 9(S)-HODE clearly shows the presence of Impurity I.
  • the identity of the peak is confirmed by the corresponding mass. Due to the large excess of TGN 255 in the assay sample the Impurity I uv peak is significantly weaker in comparison. However, it is apparent that degradation has occurred, resulting in generation of Impurity I.
  • Cholesteryl linoleate hydroperoxide (44 ⁇ M) was incubated with TRI-50b in the range 0 to 4.9mM.
  • nucleophilic group is a hydroxy, hydroperoxy or amino group. 6.
  • acid contains a plurality of the nucleophilic groups.
  • R is -COOH, -P(O)(OH) 2 , -HPOOH, or -SO 3 H;
  • A is a nucleophilic group; the sum of a and b is an integer from 4 to 9 inclusive and a or b may be 0; the sum of c and d is an integer from 1 to 6 inclusive and c or d may be 0 e and f are independently 0 or 1; r is an integer from 1 to 6; and p, q, s and t are independently 0 or 1, the value of each instance of s and t being independent of the value of each other instance (if any) and there being at least one -C(H)A- moiety; and at least one -CH 2 - group within the compound may be replaced by an ether linkage -O- or an amine linkage -N-. 13.
  • paragraph 25 in which p+q is 1.
  • R is -COOH, -P(O)(OH) 2 , -HPOOH, or -SO 3 H;
  • A is a nucleophilic group; the sum of a and b is an integer from 4 to 9 inclusive and a or b may be 0; the sum of c and d is an integer from 1 to 6 inclusive and c or d may be 0 z is 1 or 2; and p and q are independently 0 or 1 and p+q is at least 1.
  • A is a nucleophilic group
  • L is a linker containing from 5, 6, 7, 8, 9 or 10 in-chain atoms.
  • R 3 is a linear aliphatic moiety
  • R 1 is H or 1C-10C alkyl or 2C-10C alkenyl, optionally substituted by one or more substituents, e.g. 1, 2, 3 or 4 substituents selected from A groups, halogen (e.g. F or Cl), 1C to 4C alkyl, 1C to 4C alkoxy, 1C to 4C haloalkyl and carboxy.
  • substituents e.g. 1, 2, 3 or 4 substituents selected from A groups, halogen (e.g. F or Cl), 1C to 4C alkyl, 1C to 4C alkoxy, 1C to 4C haloalkyl and carboxy.
  • organoboronate drug is a peptide boronate.
  • An intravenous formulation comprising a compound as defined in any one of paragraphs 41 to 80.
  • Y 1 comprises a hydrophobic moiety which, together with the aminoboronic acid residue -
  • NHCH(R 9 )-B(OH)2 has affinity for the substrate binding site of thrombin
  • R ⁇ is a straight chain alkyl group interrupted by one or more ether linkages and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 or R ⁇ is -(CH2) m -W where m is 2, 3, 4 or 5 and W is -OH or halogen.
  • An intravenous formulation of any of paragraphs 87 to 93 which includes a pharmaceutically acceptable diluent, excipient or carrier.
  • the acid is selected from 9(S)-hydroxy-10E, 12Z-octadecadienoic acid, 8(S)-hydroxy-9E, HZ, 14Z-eicosatrienoic acid or 8(S)-hydroxy-5Z, 9E, HZ, 14Z, 17Z-eicosapentaenoic acid, substantially free of other isomers thereof.
  • X is H (to form NH2) or an amino-protecting group
  • aa 1 is Phe, Dpa or a wholly or partially hydrogenated analogue thereof
  • aa ⁇ is an imino acid having from 4 to 6 ring members
  • R 9 is a straight chain alkyl group interrupted by one or more ether linkages and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 or R 9 is -(CH2)m" w where m is 2, 3, 4 or 5 and W is -OH or halogen.
  • a method of neutralising a boropeptidyl serine protease inhibitor comprising contacting said boropeptidyl serine protease inhibitor with a compound as defined in any of paragraphs 1 to 80.
  • a method of paragraph 109 which is an ex vivo method.
  • a method for at least reducing the activity of an organoboronate drug in a subject comprising administering to the subject an effective amount of a compound as defined in any of paragraphs 1 to 80.
  • a method for treating bleeding following administration of a boropeptide inhibitor of a coagulation serine protease to an individual comprising administering to the individual a therapeutically effective amount of a compound as described in any of paragraphs 41 to 80.
  • a method of preparing to supply a first pharmaceutical composition for the treatment of thrombosis by prophylaxis or therapy and, if required, a second pharmaceutical composition to inhibit the action of the first composition comprising: stocking a pharmaceutical composition comprising a pharmaceutically acceptable active compound which is capable of providing in the plasma a peptide boronic acid of formula
  • X is H (to form NH2) or an amino-protecting group
  • aa ⁇ is Phe, Dpa or a wholly or partially hydrogenated analogue thereof
  • aa ⁇ is an imino acid having from 4 to 6 ring members
  • R 1 is a group of the formula -(CH2) m -W, where m is 2, 3 or 4 and W is -OH, -OMe, -
  • a method of providing a medicament pair comprising a first medicament for the treatment of thrombosis by prophylaxis or therapy and a second medicament to inhibit the action of the first medicament in the event of undue bleeding comprising: providing a pharmaceutical composition comprising a compound as recited in paragraph 114, and providing a pharmaceutical composition comprising a compound as defined in any of paragraphs 41 to 80.
  • a method for treating thrombosis by prophylaxis or therapy using a medicament which results in inappropriate bleeding and then inhibiting the action of said medicament wherein: a therapeutically effective amount of a pharmaceutical composition comprising a compound as recited in paragraph 92 is administered to a patient in need thereof to treat thrombosis, and, after the inappropriate bleeding, a therapeutically effective amount of a compound as defined in any of paragraphs 41 to 80 is administered to the patient to inhibit the pharmaceutical composition.
  • a method for inhibiting thrombosis in the treatment of disease by prophylaxis or therapy using a medicament which results in inappropriate bleeding and then inhibiting the action of said medicament wherein a therapeutically effective amount of a pharmaceutical composition comprising a compound as recited in paragraph 108 is administered to a patient in need thereof to treat thrombosis, and, after the inappropriate bleeding, a therapeutically effective amount of a compound as defined in any of paragraphs 41 to 80 is administered to the patient to inhibit the pharmaceutical composition comprising a compound as recited in paragraph 114.
  • a method of providing a medicament pair comprising a first medicament for the treatment of thrombosis by prophylaxis or therapy and a second medicament to inhibit the action of the first medicament in the event of undue bleeding comprising: providing a pharmaceutical composition comprising a compound as recited in paragraph
  • a method of preparing for the administration to a patient of a first pharmaceutical composition for the treatment of thrombosis by prophylaxis or therapy and, if required, a second pharmaceutical composition for reacting with the active agent of the first composition to inactivate molecules thereof comprising supplying a pharmaceutical composition comprising a compound as recited in paragraph 114, and supplying a pharmaceutical formulation comprising a compound as defined in any of paragraphs 41 to 80.

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Abstract

La présente invention décrit l’emploi de composés précis pour la fabrication d’un médicament employé dans la neutralisation thérapeutique d’un médicament de type organoboronate. Les composés spécifiés sont typiquement des acides gras hydroxylés ou des acides gras hydroperoxydes, par exemple 9(S)-HODE, 8(S)-HETRE ou 8(S)-HEPE, leurs sels ou leurs prodrogues. Le médicament de type organoboronate peut être le TRI 50c ou un sel ou une prodrogue de cette substance. La présente invention décrit également des formules pour administration intraveineuse contenant lesdits composés.
PCT/GB2005/004565 2004-11-30 2005-11-30 Agents neutralisants pour médicaments de type acides boroniques WO2006059083A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives

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Publication number Priority date Publication date Assignee Title
EP2283839A1 (fr) * 2009-06-30 2011-02-16 Institut National des Sciences Appliquées de Lyon Molécule hydroxylée polyinsaturée dotée d'une géométrie d'EZE et son utilisation pour une thérapie
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
US11866422B2 (en) 2016-06-21 2024-01-09 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives

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