OA16905A - Anticoagulant reversal agents. - Google Patents
Anticoagulant reversal agents. Download PDFInfo
- Publication number
- OA16905A OA16905A OA1201400228 OA16905A OA 16905 A OA16905 A OA 16905A OA 1201400228 OA1201400228 OA 1201400228 OA 16905 A OA16905 A OA 16905A
- Authority
- OA
- OAPI
- Prior art keywords
- compound
- dap
- subject
- anticoagulant
- pharmaceutically acceptable
- Prior art date
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Abstract
Novel anticoagulant reversal compounds are disclosed, as well as methods of making the compounds, pharmaceutical compositions including the compounds, methods of using the compounds to reverse the anticoagulant effects of coagulation inhibitors, and diagnostic assays comprising the compounds.
Description
FIELD OF THE INVENTION [0001] The présent invention discloscs compounds that completely or partially reverse anticoagulant effects of coagulation inhibitors, such as unfractionated heparin (’*UFH**), low molecular weight heparin (“LMWH”), fondaparinux, and other antithrombin binding anticoagulants, as well as direct Xa and lia inhibitors.
BACKGROUND OF THE INVENTION [0002] The coagulation cascade is a normal physiological process which aims at preventing significant blood loss or hemonhage following vascular injury. There are times, however, when a blood clôt (thrombus) will form when it is not needed. For instance, some high risk conditions such as acute medical illness, prolonged immobilization, surgery, or cancer can increase the risk of developing a blood clôt which can potentially lead to significant conséquences such as atherosclerotic cardiovascular disease and/or abnormal cardiac rhythms. [0003] The coagulation cascade consists of a sériés of steps in which a protease cleaves and subsequently activâtes the next protease in the sequence. Each protease can activate several molécules of the next protease in the séries, amplifying this biological cascade. The final resuit of these reactions is to
-2convert fibrinogen, a soluble protein, to insoluble threads of fibrin. Together with platelets, the fibrin threads form a stable blood clôt.
[0004] Antithrombin (AT), a serine protease Inhibitor, Is the major plasma inhibitor of coagulation proteases. AT blocks the coagulation cascade by, e.g., inhibiting thrombin (factor lia) and activated factor X (factor Xa). Heparin (unfractïonated heparin) and low molecular weight hcparins (LMWHs; fractionated heparin) inhibit the coagulation process through binding to AT via a pentasaccharide sequence. This binding leads to a conformational change of AT, which accelerates its inhibition of factors lia, Xa, and other proteases involved in blood clotting. Once dissociated, heparin and LMWH are free to bind to another antithrombin molécule and subsequently inhibit more thrombin and factor Xa. [0005] Unfractïonated heparin is a mixture of glycosaminoglycans (GAGs) discovered in the liver of dogs to hâve anti-coagulant properties in 1916 by McLean and Howeli at Johns Hopkins University. In addition lo anti-coagulation, unfractïonated heparin has been found to hâve other properties including anti-inflammation and angiogenesis. LMWHs are heparins consisting of short chains of polysaccharide, generally having molecular weight of less thon 8000 Da. LMWH and heparin are both used to prevent blood from clotting inside the body, but are used in different situations in the clinic.
[0006] Heparin is available as a liquid solution administered parenterally.
LMWH, such as enoxaporin, is a low molecular weight fraction of heparin. It is also available as a liquid injectable solution. The cunently available brands of LMWH approved by FDA in the United States are LOVENOX® (generic name, enoxaporin) and FRAGMIN © (generic name, dalteparin).
[0007] Low molecular weight or fractionated heparin has greater specificity for blood factor Xa and factor lia activity than unfractïonated heparin. Additionally, LMWH has a more reproducible effect on activated partial thromboplastin time (aPTT), a measure of coagulation time. LWMH has a lower incidence of Heparin Induced Thrombocytopenîa (ΗΓΓ). Because LMWH has more predictable efficacy and a lower incidence of adverse effects such as ΗΓΓ, patients can inject LMWH themselves at home, although it is also often used ïn the hospital. For these reasons, LMWHs hâve become the market-leading anticoagulant.
-3[0008] Protamîne, a posîtively charged molécule, can be used to reverse anti-coagulation resulting from administration of highly negatively charged unfractïonated heparin or low molecular weight heparin (LMWH). Protamîne is a natural product that has been associated with supply problems, which highllghts 5 a need for additional, ideaiiy synthetic, reversai agent options. The anticoagulant activity of LMWH can be partially, but not fully, rcversed by intravenous administration of protamîne. The reason for the reduced anticoagulation reversai activity of protamîne in the case of LMWH is believed to be due to a lesser binding affinity for the LMWH fraction in the blood than unfractionated heparin. Protamîne must be administered slowly, due to hypotensive effects and concems regarding anaphylaxis.
[0009] Recently, additional anticoagulant agents hâve begun to gain regulatory approval. Examples of such anticoagulants include dabigatran or PRADAXA®, argatroban or ARGATROBAN®, rivaroxaban or XARELTO®, apixaban or
ELIQUIS®, edoxaban or LIXIANA®, and fondaparinux or ARIXTRA®. These anticoagulants inhibit either factor lia or factor Xa from propagating coagulation. [0010] Anticoagulants such as dabigatran, fondaparinux, rivaroxaban and apixaban hâve no approved reversai agent. The current state of the art for dabigatran or PRADAXA® reversai is to employ activated charcoal to attempt to remove dabigatran from the blood and to use blood transfusions. Other than Eercnberg et al. Circulation. 2011 Oct 4;i 24(14): 1573-9. Epub 2011 Sep 6., which reports that in a s mal! clinical trial, prothrombin complex concentratc was able to reverse dabigatran, but not rivaroxaban, there is no data or clinically available antidote for reversing any of these coagulation Factor lia or Xa inhibitors. Therefore, when patients are anti-coagulatcd with these agents, adverse effects associated with overdosing, particularly significant or fatal bleeds, are much more dangerous than the side effects associated with administration of unfractionated heparin. The lack of reversa! agent therefore limits the use of these drugs.
[0011] For these reasons, there is a longstanding, strong, unmet clinical need for new anti-coagulation reversai agents.
SUMMARY OF THE INVENTION [0012] Inhibitors of heparin, hcparin fragments, fondaparinux and other factor Xa or factor Ua inhibitors has been developed. The general structure of the anticoagulant reversai agents of interest is: R-Z-R’, where R and R* are positively charged agents at physiologie pH and can be the same or different molécules and Z is a hydrophobie cyclic or fused ring compound. More specifically, the inhibitor is represented by a compound of formula I or a pharmaceutically acceptable sait thereof:
Y---M---X---L----A---L*---X’---W---Y (I) wherein:
A is a substituted or unsubstituted aromatic or non-aromatic, carbocyclic or heterocyclic ring or a linear moiety;
L and L’are the same or different and are linkers;
X and X* are the same or different and are absent or are a functional group thaï attaches the linker L to M and the linker L'to M\ respectively;
M and M* are the same or different and are absent or is a linker that attaches X to Y and X’ to Y’, respectively; and
Y and Y* are the same or different and are a moiety containing one or more 20 cationic atoms or groups or one or more groups that become cationic under physîological conditions.
[0013] The compounds can be symmetrical or asymmetrical; that is, one or more of L L’, X, X’, Μ, M’, Y, or Y’ can bc the same or different. The compounds can be chiral (i.e., contain one or more chiral centers) or ochiral.
[0014] In some embodiments, A is a heterocyclic moiety. In other embodiments,
A is a heterocyclic moiety and L and L' are a substituted or unsubstituted alkylene chain. In still other embodiments, A is a heterocyclic moiety, L and L' are a substituted or unsubstituted alkylene chain, and X and X’ are -NH-C(=O)-. In still otherembodiments, A is a heterocyclic moiety, Land L* are a substituted 30 or unsubstituted alkylene chain, X and X’ are -NH-C(=O)-, and M and M’ are a substituted alkylene chain. In still otherembodiments, A is aheterocyclic moiety, L and L’ are a substituted or unsubstituted alkylene chain, X is -NH16905
C(=O)-. M and M’ are a substituted alkylene chain, and Y and Y* are a guanidine moiety. In particular embodiments, A Is a 1,4 or 2,5 disubstituted plperazine ring.
[0015] In another embodiment of the invention the inhibitor is a compound represented by the formula II or a pharmaceutically acceptable sait thereof:
(Π) wherein each of L, L', Μ, M', Y and Y' are as described herein.
[0016] In another embodiment of the invention the inhibitor is a compound represented by the formula III or a pharmaceutically acceptable sait thereof:
ίο (ΠΙ) wherein L, L', Μ, M', Y and Y' are as described herein.
[0017] In yet another embodiment of the invention the inhibitor is a compound represented by the formula (IV) or pharmaceutically acceptable sait thereof:
wherein Y and Y* are as described herein and n is 3 to 5, m is 3 to 6 and G is selected from -NHi and OH. Most preferably, G is amino.
[0018] Yet another embodiment of the invention the inhibitor :s a compound represented by any of formula Π, III or IV and Y and Y* are independently selected from the group consisting of
NH2 and-NHi [0019] Most preferably G is -NH2 and Y and Y' arc
[0020] In the preferred embodiment, the compound is di-arginine piperazine (DAP), depicted in formula V, or a related compound, depicted in formula VI, or pharmaceutically acceptable salts of either compound:
(V)
2-Amino-5-guanidino-pentanoîc acid (3-{4-[3-(2-amino-5-guanîdinopentanoy 1 amino)-propyl]-pi perazïn-1 -y IJ -p ropyl )-amï de: or
2-Amîno-5-guanidino-pentanoic acid (5-[(2-amino-5-guanidinopentanoylamino)-methyl)-piperazin-2-ylmethyl|-amide.
[0021] In a spécifie embodiment, the compound of formula V is a stereoisomer as depicted in formula VII:
[0022] In another spécifie embodiment, the compound of formula VI is a
[0023] The compounds of the invention can be administered in a pharmaceutical composition as an aqueous solution as a boius and/or intravenous infusion, subcutaneous injection, or orally. In the preferred embodiment, the compounds are administered by injection (intravenous, intramuscuiar or subcutaneous) in a 15 carrier such as distilled stérile water, saline, buffered saline, or another pharmaceutically acceptable excipient for injection. In some embodiments, the inhibitor may be administered orally, to a mucosa! surface (nasal, pulmonary, vaginal, rectal or buccal) or by depot.
[0024] The compounds of the invention may be administered in pharmaceutical 20 composition to the patient in need of reversai of heparin, LMWH or other thrombin inhibitor-mediated anticoagulation in an effective amount to restore
-8normal coagulation and hemostasis. The pharmaceutical compositions including the compound of the inventions are suitable for hospital use or in non-emergency home reversai. It is administered to the patient in need of reversai of hcparin, LMWH or other thrombin inhibitor mediated anticoagulation in an effective amount to restore coagulation. The compounds and pharmaceutical compositions described herein can also be used to reduce the activity of heparin-binding growth factors and/or for reversing compietely or in part a combination of one or more Factor Ha and/or Factor Xa anticoagulant agents.
[0025] Thus, the compounds of the invention can be used in a method of compietely or partïaüy reversing an anticoagulant effect of a coagulation inhibitor. The compounds of the invention can also be used as a part of a diagnostic kit, e.g., a diagnostic kit for determining concentration of an anticoagulant in the biood.
[0026] Exampies demonstrate that DAP directly bound rivaroxaban, apixaban, 15 unfractionated heparin, fondaparinux, and LMWH, reversing anticoagulant activity. DAP reversed oral rivaroxaban and subcutaneous LMWH anticoagulation in vivo as measured by aPTT and subcutaneous fondaparinux as measured by Xa activity ïn rats. DAP reversai, confirmed by statistically significant réduction in blood loss in tail rat transection assay, was shown for 20 apixaban, dabigatran, edoxaban, and rivaroxaban. DAP compietely reversed apixaban and rivaroxaban at a dose mass ratio of about 10: l DAP:anticoagulant in human blood ex vivo as measured using an antl-Xa kit DAP exhibited a dosedependent reversai of apixaban and rivaroxaban in human blood ex vivo. Rivaroxaban reversai in freshly drawn human whoie blood was confirmed by 25 aPTT mcasurements ex vivo. DAP dîd not bind argatroban concentrations upto 1:1000 in vitro. DAP reversed oral dabigatran in vivo in rats as measured by aPTT. Argatroban doscd rats remained anticoagulated after a 200x IV dose of DAP, showîng that DAP is safe and that the reversai interaction ïs spécifie for the heparins and new oral anticoagulants. In summary, the exampies demonstrate 30 complexation of DAP to heparin and LMWH and that DAP serves as an excellent reversai agent for heparin, heparin-like compounds and other thrombin înhibitors including dabigatran, approved low molecular weight heparins, as well as
rivaroxaban (XARELTO®), fondaparinux (ARIXTRA®), edoxaban (LIXIANA®), and apixaban (ELIQUIS®), as tested in in vitro assays with human blood, anti-Xa and aPTT tests and/or in vivo in a rat tail transection assay.
BRIEF DESCRIPTION OF THE DRAWINGS [0027] Figure 1 is a graph of heat flow versus température as measured by differen tial scanning calorimetry (DCS) in which DAP is heated from -20°C to 200°C fT or “first heat), cooled to -20°C, and heated back to 200°C (“2 or second heat).
[0028] Figure 2 is a graph of DAP alone, UFH alone, and DAP-UFH combination, as a fonction of volume percent compared to size (d.nm) as measured by Dynamlc Light Scattering (DLS).
[0029] Figure 3 is a graph of DAP alone, rivaroxaban alone and DAPrivaroxaban in ratios of 1:1 and 10:1, DAP:rivaroxaban, as a fonction of volume (percent) compared to size (d.nm) as measured by DLS.
[0030] Figure 4 is a graph of DAP alone, apixaban alone and DAP- apixaban binding in ratios of 1:1,10:1 and !00:1, as a fonction of volume (percent) compared to size (d.nm) as measured by DLS.
[0031] Figure 5 is a graph of DAP alone, fondaparinux alone and DAPfondaparinux binding in ratios of 1:1,10:1 and 100:1, as a fonction of volume 20 (percent) compared to size (d.nm) as measured by DLS.
[0032] Figure 6 is a graph of DAP alone, LMWH alone and DAP-LMWH binding in ratios of 1:1, l:i0and 100:1, as a fonction of volume (percent) compared to size (d.nm) as measured by DLS.
[0033] Figure 7 is a graph of DAP alone, argatroban alone and DAP-argatroban 25 binding in ratios of l : 1, 10:1, 100:1, and 1000:1, as a fonction of volume (percent) compared to size (d.nm) as measured by DLS.
[0034] Figure 8 is a graph ofactivated partial thrombopiastin time (aPTT, seconds) measured over time (hours) during five hours after subcutaneous administration of 10 mgof bemiparin (LMWH) to a rat. Four hours into treatment, the rat received an intravenous dose of 200 mg/kg ( lOOmg) DAP.
-ίο[0035] Figure 9 is a graph of activated partial thromboplastin time (aPTT, seconds) mcasured over time (hours) after oral administration of PRADAX A® (dabigatran) to a rat followed by intravenous administration of 200 and 100 mg/kg (lOOmg and 50 mg) DAP.
[0036] Figure 10 is a graph of activated partial thromboplastin time (aPTT) measured over time (hours) afïer subeutaneous administration of unfractionated heparin (UFH) to a rat followed by intravenous administration of 200 mg/kg (100 mg) and 400 mg/kg (200 mg) DAP.
[0037] Figure 11 is a graph of aPTT (seconds) measured over time (hours) after oral administration of 5mg/kg of rivoroxaban to a rat followed by intravenous administration of 5 mg/kg (2 mg) DAP.
[0038] Figure 12 is a graph of active fondaparinux concentration (pg/mL) measured over time (minutes after reversai) after a subeutaneous administration of 5 mg/kg fondaparinux to a rat, followed by intravenous administration of
200 mg/kg DAP (i.e., “reversai”).
[0039] Figure 13 is a graph of aPTT (seconds) measured over time (minutes after reversai) after oral administration of 15.5 mg/kg PRADAXA® (dabigatran) to a rat, followed by intravenous administration of 100 mg/kg DAP (i.e„ “reversai”).
[0040] Figure 14 is u graph of the aPTT time (seconds) for 0,2,10,25,50, and
100 mg intravenously administered DAP.
[0041] Figure 15 is a graph of blood collected (i.e., cumulative blood loss) over 30 minutes in a rat tail transection blceding assay in rats receiving 2 mg rivoroxaban and 0 mg DAP, 2 mg rivoroxaban and 2.5 mg DAP, 2 mg rivoroxaban and 12.5 mg DAP, or sham reversai and anticoagulant doses (“sham”). With groups of three age-matched rats, 12.5 mg of DAP reduced blood loss to sham dose levels yielding u statistically significant différence (* p<0.05) from rats receiving rivoroxaban only.
[0042] Figure 16 is a graph of blood collected (i.e., cumulative blood loss) over
30 minutes in a rat tail transection blceding assay in rats receiving 1.25 mg apixaban and 0 mg DAP, 1.25 mg apixaban and 5 mg DAP, 1.25 mg apixaban and 12.5 mg DAP, or sham reversai and anticoagulant doses (“sham”). With
-11groups of three age-matched rats, 5 mg and 12.5 mg of DAP reduced blood loss to sham dose levels yielding a statistically significant différence (*** p<0.01 ) from rats receiving apixaban only.
[0043] Figure 17 is a graph of blood collected (i.e., cumulative blood loss) over
30 minutes in a rat tail transection bleeding assay in rats receiving 1.25 mg edoxaban and 0 mg DAP, 1.25 mg edoxaban and 12.5 mg DAP, or sham reversai and anticoagulant doses (“sham”). With groups of three age-matched rats, 12.5 mg of DAP reduced blood loss to sham dose levels yielding a statistically significant différence (* p<0.05) from rats receiving edoxaban only.
[0044] Figure 18 is a graph of blood collected (i.e., cumulative blood loss) over minutes in a rat tail transection bleeding assay ln rats receiving 15 mg dabigatran etexilate and 0 mg DAP, 15 mg dabigatran etexilate and 5 mg DAP, 15 mg dabigatran etexilate and 12,5 mg DAP, or sham reversai and anticoagulant doses (“sham). With groups of three age-matched rats, 12.5 mg of DAP reduced blood loss to sham dose levels yielding a statistically significant différence (♦*♦ p<0.0l) from rats receiving dabigatran etexilate only.
[0045] Figure 19 is a graph of aPTT (seconds) measured in freshly drawn human blood treated ex vivo with 50 micrograms/ml DAP, 0.25 micrograms/ml rivaroxaban, 50 micrograms/ml DAP and 0.25 micrograms/ml rivaroxaban, or 20 saline.
[0046] Figure 20 is a graph showing effective anticoagulant concentration measured by anti-factor Xa activity assay in human plasma treated ex vivo with of 218 pg/L rivaroxaban alone or in combination with 1,250 mg/L DAP, and 459 pg/L rivaroxaban alone or in combination with 6,250 pg/L DAP.
[0047] Figure 21 is a graph showing effective anticoagulant concentration measured by anti-factor Xa activity assay in human plasma treated ex vivo with 156 pg/L apïxaban alone or in combination with 1,156 pg/L DAP, and 313 pg/L apixaban alone or in combination with 3,125 pg/L DAP.
[0048] Figure 22 is a graph showing effective anticoagulant concentration measured by anti-factor Xa activity assay In human plasma treated ex vivo with 218 pg/L rivaroxaban, alone or in combination with increasing amounts (1.25, 125,125, and 1,250 pg/L) of DAP.
DETAILED DESCRIPTION OFTHE INVENTION
Γ. Anticoagulant Reversai Agents [0049] Novel anticoagulant reversai agents are disclosed. The compounds of the invention include compounds described herein, as well as the pharmaceutically acceptable salts thereof.
[0050] Inhibitors of heparin, heparin fragments, fondaparinux and factor Xa or factor lia inhibitors (e.g., oral factor Xa or factor lia inhibitors) hâve been developed. The general structure of the anti-coagulant reversai agents of interest is: R*Z*R’, where R and R* are positively charged agents at physiologie pH and 10 can be the same or different molécules and Z is a hydrophobie cyclic or fused ring compound.
[0051] More specifically, the inhibitor is a compound of the formula (I) or pharmaceutically acceptable sait thereof:
Y----M----X----L----A----L'----X'---M*---Y* (I) wherein:
A is a substituted or unsubstituted aromatic or non-aromatic, carbocyclic or heterocyclic ring or a linear moiety;
L and L’ are the same or different and are linkers;
X and X* arc the same or different and are absent or are a functional group 20 that attaches the linker L to M and the linker L* to M’t respectively;
M and M* are the same or différent and are absent or is a linker that attaches X to Y and X’ to Y’, respectively; and
Y and Y* are the same or different and are a moiety containing one or more cationîc atoms or groups or one or more groups that become cationic under physiologicat conditions.
[0052] The compounds can be symmetrical or asymmetrical; that is, one or more of L, L’, X, X’, Μ, M’, Y, or Y* can be the same or different. The compounds can be chiral (i.e., contain one or more chiral centers) or achiral.
[0053] In some embodiments. A is a heterocyclic moiety. In other embodiments, 30 A is a heterocyclic moiety and L and L' are a substituted or unsubstituted alkylene chain. ln still other embodiments, A is a heterocyclic moiety, L and L’
-13are a substituted or unsubstituted alkylene chain, and X and X’ are -NH-C(=O)-. In still other embodiments, A is a heterocyclic moiety, L and L* are a substituted or unsubstituted alkylene chain, X and X' are -NH-C(=O)-, and M and M* are u substituted alkylene chain. As used herein, alkylene chain is a divalent alkelene moiety that is Ci to Cio, preferably Cj to Ci in length, and which may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxyl, hydroxyl alkyl, amino, amino alkyl, alkoxy, alkyt alkoxy. As used herein, the term alkyl is Ci to Cio, preferably Ci-Co straight chain or branched hydrocarbon. In still other embodiments, A is a heterocyclic moiety, L and L* are a substituted 10 or unsubstituted alkylene chain, X is -NH-C(=O)-, M and M' are a substituted alkylene chain, and Y and Y* are a guanidine moiety.
[0054] In some embodiments, A is a non-aromatic, heterocyclic ring, such as piperazine or diketopipernzine. In other embodiments, A is a linear moiety, such as a linear diamine or other linear moiety containing reactive functional groups 15 that can form a bond to X and X\ when présent, or Y and Y*. In some embodiments, the linkers L and L' are attached to the heteroatoms in the ring A, such as the two nitrogen atoms in piperazine. In other embodiments, the linker L and L* are attached to atoms other than the heteroatoms in the ring, such as carbon. In particular embodiments, A ts a 1,4 or 2,5 disubstituted piperazine ring. 20 In some embodiments, L and L’and/or M and M* are a substituted or unsubstituted alkylene chains, such as-(CHi)n-, where n is an integer from MO, preferably from 1-6, e.g., 1-3. In particular embodiments, n is 3. In some embodiments, L and/or M are absent.
[0055] X and X* are a functional group that attaches the linkers L and L’to Y and Y’. Exemplary functional groups include, but are not limited to, esters, amldes, carbonates, and ketones. In particular embodiments, X and X' are a functional group that is résistant to simple hydrolysis, such as an amide group. [0056] Y and Y' are a moiety that contains one or more atoms or groups that are cationic or will be cationic under physiological conditions. Examples include amine and guanidine moieties as well as phosphorous containing moietîes, such as alkyltriphenylphosphonium, tetraphenylphosphonium, te traphenyl arsonium, tribenzy! ammonium, and phosphonium moieties. Additional cationic moieties
-14include cationïc oligomers nnd polymers, such as oligo- or polylysine, oligo- or polyargînine, N-alky!ated polyethylene imine, and the like. Other cationïc moieties include delocalized lipophilie cations containing one to three carbimino, sulfimino, orphosphinimino units as described in Kolomeitsev étal., Tet. Let.,
Vol. 44, No. 33,5795-5798 (2003).
[0057] In some embodiments, the compound is a piperazine dérivative, wherein the amino acid side chains contain one or more posltively charged atoms or atoms that will be positively charged under physiological conditions. Examples include diarginine piperazine. Other amino acids that are positively charged or will be positively charged under physiological conditions can be substituted for arginine. [0058] Aromatic”, as used herein, refers to 5-12-membered, preferably 5-, 6and 7-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bîhetereocycüc ring Systems, optionally substituted. Broadly defined, “Ar, as used herein, includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zéro to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles or “heteroaromatics. The aromatic ring can be substituted at one 20 or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy I, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldéhyde, ester, heterocyclyl, aromatic or heleroaromatic moieties, --CF3, —CN, or the like. The 25 term “Ar also includes polycyclic ring Systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e„ “fused rings) wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyis. cycloalkynyls, aryls and/or heterocycles. Examples of heterocyclic ring include, but are not Iimited to, bcnzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazoiyl, bcnztriazolyl, benztetrazolyl, benzisoxazolyl, benzîsothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyi, chromenyl,
-15cinnolinyl, decahydroquinolïnyl, 2H,6H-l3,2-dithlazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, îmidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3 H-in dolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, Isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4oxadiazolyl, 1,2,5-oxadîazolyl, 1,3,4-oxadiazoIyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrroIyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,6H-l,2,5-thiadiazinyl, 1,23-thiadiazolyl, 1,2,4thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thîenooxazolyl, thienoimidazolyl, thîophenyl andxanthenyl. [0059] “Heterocycle” or heterocyclic’*, as used herein, rcfers to a cyclic radical attached via a ring carbon or nitrogen of a monocyclic or bicyclic ring containing 20 3-10 ring atoms, and preferably from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur. and N(R) wherein R is absent or is H, O. (C|.4)alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Examples of heterocyclic ring include, but are not 25 limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, bcnzimidazolinyl, carbazolyl, 4a/7-carbazolyl, carbolinyl, chromanyl, chrome nyl, cinnolinyl, decahydroquinolïnyl, 2//,6//-1,5,2dithîazinyl, dihydrofuro[2,3-6]tetrahydrofuran, furanyl, furazanyl, îmidazolidinyl, 30 imidazolinyl, imidazolyl, l//-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H4ndolyl, isatinoyl, isobenzofuranyl, Isochromanyl, isoindazolyl, isoindolinyl, isoindolyl. isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl,
16IQ morpholinyl, naphthyridinyl, octahydroisoquînolinyl, oxadiazolyl, 1,2,3oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl. 1,3,4-oxadiazolyl, oxazolîdinyl, oxazolyl, oxîndolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phcnothîazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazînyl, pyridooxazole, pyridoimîdazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyirolinyl, 2H-pyrrolyl, pyrrolyl, qulnazolinyl, quinolinyl, 4ffquinolizinyl, quinoxalinyl, quinuclidinyl, teirahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6//-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl.
[0060] In another embodiment of the invention the inhibitor is a compound represented by the formula II or a pharmaceutically acceptable sait thereof:
(Π) wherein each of L, L\ Μ, M’, Y and Y' are as previously described.
[0061] In another embodiment of the invention the Inhibitor is a compound represented by the formula ΙΠ or a pharmaceutically acceptable sait thereof:
(HD wherein L, L'( Μ, M', Y and Y1 are as previously described.
[0062] In yet another embodiment of the invention the inhibitor is a compound represented by the formula (IV) or pharmaceutically acceptable sait thereof:
wherein Y and Y' are as previously described and n is 3 to 5. m is 3 to 6 and G is selected from -NHi and OH. Most preferably, G is amino.
[0063] Yet another embodiment ofthe invention the inhibitor is a compound represented by any of formula Π, IH or IV and Y and Y* are independently selected from the group consisting of
NHz and-NHj.
[0064] Most preferably G is -NHj and Y and Y' are
[0065] Thus, in one embodiment, the compound ofthe invention is di-arginîne piperazîne (“DAP”), such as the compound of formula V, or a related compound 15 of formula VI, or pharmaceutically acceptable salts of either compound:
2-Amino-5-guanidino-pentanoic acid (3-|4-[3-(2-amino-5-guanidinopcntanoylaminoï-propyll-piperazin-i-yll-propyO-amide; or
2-Amino-5-guanidino-pentanoic acid (5-[(2-aminO’5-guanidino5 pentanoylamino)-methyl]-piperazin-2-ylmcthyl }-amide.
[0066] In a spécifie embodiment, the compound of formula V is a stereoisomer as depicted in formula VII:
[0067] In another spécifie embodiment, the compound of formula VI is a stereoisomer as depicted in formula V1IL·
[0068] The phrase pharmaceutically acceptable sait of a compound as used herein means a sait that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Pharmaceutically
-19acceptable salts include salts of acidic or basic groups présent in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodlde, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotlnate, acetate, loctate, salîcylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumaratc, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoatc (i.e., l,r-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnésium, potassium, sodium, zinc, and diethanolamine salts.
[0069J The compound of the invention inhibits activity ofcoagulation inhibitors. One proposed mechanism of action of the compound of the invention is through binding negatively charged molécules (e.g., fondaparinux, unfractionated heparin, LMWH, described herein). Other coagulation inhibitors (e.g., factor lia and factor Xa inhibitors such as dabigatran, apixaban, edoxaban, and rivaroxaban, described herein) also possess négative charges; thus, the compound of the invention may inhibit these coagulation inhibitors through neutralization of their negatively charged moieties.
[0070] Another proposed mechanism of action of the compound of the invention is through weak physica! interactions such as hydrogen bonding and hydrophobie interactions with the coagulation inhibitors. Oral Factor Πα and Xa inhibitors possess hydrophobie portions, which may cause hydrophobie association with the compound of the invention, e.g., DAP.
[0071] Thus, in some embodiments, the compounds of the invention contain at least one cyclic hydrophobie moiety, e.g., one or a combination of aliphatic or aromatic rings ïnctuding fused rings. In other embodiments, the compounds of the invention contain at least one cyclic hydrophobie moiety and a least two positively charged or partially charged moieties at physiological pH. [0072] In some embodiments of the invention, one or both arginines ofthe compounds of Formulas V and VI (or the compounds of Formulas VII and VTII) are substituted by one or more positively charged amino acids, their dérivatives, or similarly charged compounds, e.g., lysine, histidine, omithine. The arginines
-20in the compounds of Formulas V and VI or positively charged amino acids substituted for such arginines can be naturally occurring amino acids (i.e., Lamino acids), their enantiomers (i.e., D-amino acids), or racemic or other mixtures thereof. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
[0073] Stereochemical définitions and conventions used herein generally foliow S. P. Parker, Ed., McGraw-Hill Dictionarvof Chemical Terms (19841 McGrawHill Book Company, New York; and Eliel, E and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic 10 compounds exist in optically active forms, i.e., they hâve the ability to rotate the plane of plane-poiarized light. In describing an optically active compound, the préfixés D and L or R and S are used to dénoté the absolute configuration of the moiecuie about its chiral centerfs). The préfixés D and L or (+) and (-) are employed to designate the sîgn of rotation of plane-polarized light by the compound, with (-) or L meaning that the compound is levorotatory. A compound prefixed with (+) or D is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A spécifie stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture, A 50:50 20 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and*’racemate refer to an equîmolar mixture of two enantiomeric species, devoid of optical activity. [0074] In other embodiments of the invention, the compound of the invention 25 contains at least one cyclic hydrophobie moiety, e.g., one or a combination of aliphatic and aromatic rings including fused rings. Compounds of interest contain at least one cyclic hydrophobie moiety and at least two positively charged or partially charged moieties at physiologïcal pH.
[0075] Spécial considération should be given to the design of peptide-based therapeutic agents, since such agents may cause unwanted and often severe immunological reactions once administered to a subject. The compound of the invention is designed to be of sufficiently low molecular weight to minimize
-21immunogenicîty issues. In one embodiment, in order to avoid activation of the immune response, the compound is designed such that its molecular weight is less than about 5000 daltons, such as iess than or about 1000 daltons, e.g., about 500 daltons. In one embodiment, the molecular weight of the compound is about 5 512 daltons.
[0076] It is préférable that the compounds of the invention do not bind, or otherwise interfère with the function of the ERG, a potassium ion channel that contributes to the electrical conductivity of the heart. Inhibition of this potassium channel may lead to potentially fatal long QT syndrome, and some otherwise successful drug candidates hâve exhibited human ERG binding.
[0077] In addition, it is préférable that the compound of the invention does nol inhibit or serve as substrates for membrane-bound cytochrome p450 (CYP) enzymes. CYPs are major enzymes involved in drug metabolism, and modulation of CYP activity may interfère with clearance and metabolism of other 15 drugs administered to a subject, causing unwanted drug interactions.
[0078] Also preferably, the compounds of the invention do not exhibit significant plasma protein binding in vitro (e.g., albumin binding). Because the compounds of the invention are iargely unbound to plasma proteins, lhey exhibit short activity half-lives minimizing the risk of accumulation-based overdose.
II. Synthesis of Anticoagulant Reversai Agents [0079] The compounds and their pharmaceutically acceptable salts described herein are prepared using a variety of methods starting from commercially available compounds. known compounds, or compounds prepared by known methods. Exemplary synthetic routes to one of the compounds described herein 25 (Compound of Formula V, di-arginine piperazine, “DAP”) are included in the schemes below. The schemes below are also applicable to the DAP stereoisomer compound of Formula VII by selecting the appropriate stereoisomeric starting compounds. Other compounds of the invention may be synthesized following a similar synthetic scheme. It is understood by those skilled in the art that the order 30 of steps shown herein may be changed to accommodate functionality in the target molécule. It is also understood by those skilled in the art that various protection and deprotection steps may bc required for synthesis. The need for protection
-22and deprotection, and the sélection of appropriate protecting groups are found, for example, in Greene and Wuts, Protecting Groups in Organic Synthesis, Second Edition, John Wiley & Sons (1991), which is incorporated herein by reference in its entirety.
[0080] In some embodiments of the présent invention, the protecting group is tertiary butyloxycarbonyl group (Boc). In other embodiments of the présent invention, the protecting group is 2,2,4,6,7-Pentamethyldihydrobenzofuran-5sulfonyl group (Pbf). In another embodiment, amino acid protecting group may be, but is not limited to, 2,23,7,8-pentamethyl-chroman-6-sulphonyl (PMC).
[0081] Protecting groups may be removcd by a variety of routes. Removalof protecting group comprises, e.g., treating protected compound with trifluoroacetic acid (TFA), aqueous HCl, or heating in acetic acid. Because removal of protecting groups, e.g., removal of protecting groups under acidic conditions, can resuit in production of cationic species that can alkylate the functional groups on the peptide chain, scavengers may be added during the deprotection step to react with any of the free reactive species. Examples of scavengers include, but are not limited to, water, anisol dérivatives and thiol dérivatives. Thus, in one embodiment, removal of protecting groups comprises treating protected compound with TFA and a scavcnger (e.g., TFA and water).
[0082] Various solvents, e.g., organic solvents, may be used in the steps ofthe synthesis. Appropriate solvents include, but are not limited to, dimethyl sulfoxide, di methyl formamide (DMF), tetrahydrofuran, methanol, éthanol, methylene chloride, toluene, and acetone. In some embodiments, the solvent is DMF.
[0083] Suitable acid binding agents may be used in the steps of the synthesis.
These include, but are not limited to. organic bases, such as, for example, pyridîne, triethylamine, trieihanolamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and diisopropylethylamine (DŒA); and inorganic bases, such as, for example, sodium hydride, potassium carbonate, and sodium carbonates. In some embodiments, the acid binding agent is DŒA.
[0084] Synthesis may include peptide coupling reagents. Peptide coupling reagents may include, but are not limited to, l-ethyl-3-(3-dimethylaminopropyl)
-23carboditmlde (EDC), N-Hydroxybenzotriazolc (HOBt), carbonyldiimidazole (CDD, dicyclohexylcarbodiimide (DCC), active Ν-hydroxysuccinamide (OSu) ester, O-Benzotriazole-NJî.N’^I’-tetramethyl-uronium-hexafluoro-phosphate (HBTU), and combinations thereof. In one embodiment, the peptide coupling reagent is HBTU. In another embodiment, the peptide coupling reagent is EDC/HOBt. In yet another embodiment, the peptide coupling reagent is an active OSu ester.
[0085] Additionally, the synthesis may include a step in which a crude product is purified, e.g., by column chromatography. The desired products ofeach step or séries of steps may be separated and/or purified to the desired degree of homogeneity by the techniques common in the art. Typically such séparations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (S MB) and preparatîve thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
[0086] In one scheme, the compound of Formula V (DAP)
is synthesized by reacting excess équivalents (e.g., at least about two équivalents) of compound 1
with one équivalent of conipound 2
wherein PI is a protecting group and P2 is a protecting group or is a hydrogen. [0087] In one embodiment, the peptide coupling reagent is HBTU, EDC/HOBt, or an active OSu ester. In one embodiment, the protecting group PI is Boc. In another embodiment, the protecting group P2 is Pbf. In a different embodiment, the protecting group PI is Boc and P2 is a hydrogen.
[0088] Subsequently, 3 may be purified. This purification may involve various column chromatography methods known in the art.
-25[0089] Protecting groups of 3 may be removed by a variety of methods known in the art in order to obtain the compound of Formula V. Deprotection can be achieved by, e.g., removal of protecting groups using trifluoroacetic acid (TFA) and water, TFA and water or another scavenger, including, but not limited to aqueous HCl, or heating in acetic acid.
[0090] The compound may be further purified using a column chromatography method, such as ion exchange chromatography with sait buffers or préparative HPLC with trifluoroacetic acid or acetic acid as a buffer.
[0091] In a more spécifie scheme, the coupling involved reactlng compound 1, wherein PI was Boc and P2 was a hydrogen (depicted as Boc-Arg-OH-HCl below), with compound 2 as depicted below:
The résultant crude product was more than 95% pure by thin layer chromatography (TLC).
[0092] Subsequently, the deprotection step was carried out as depicted below:
Boc-Arg^ | u | TFA/HjO k^Ara-Boc (M/J) H |
u A | i CT | |
H-Arg > | ] | |
1 | H J TFA |
-26[0093] The deprotected product was purified by préparative HPLC using 1% acetic acid buffer. Product purity of >98% was observed. Residual TFA was removed by low quantity of DOWEX resin. The molecular weight of DAP (the compound of Formula V) is 512.4, and the compound synthesized according to the above scheme exhibited the following primary peak by mass spectroscopy: [M+H]+=513.4.
III. Pharmaceutical Compositions [0094] Pharmaceutical compositions comprising the compounds described herein are provided. Such a composition may contain, in addition to the compound of 10 the invention, a pharmaceutically acceptable carrier or excipient The term '‘pharmaceutically acceptable” means a nontoxîc material that is compatible with the physical and chemical characteristics of the active ingrédient and does not interfère with the effectiveness of the biological activity of the active. The compositions may contain various diluents, fï 11ers, salts, buffers, stabilizers, 15 solubllizers, and other materials well known in the art. The characteristics of the carrier will dépend on the route of administration, and are generaily well known in the art [0095] The pharmaceutical composition of the invention may be adapted for enterai administration - administration of the composition, wherein the composition is absorbed through the digestive tract, e.g., oral ingestion, rectal administration. In other embodiments, the pharmaceutical composition of the invention may be adapted for parentéral administration - administration of the composition, wherein the composition is introduced via a route other than digestive tract, e.g., intravenous, subeutaneous, cutaneous, nasal, pulmonary, 25 vaginal, buccal route.
[0096] Suitable pharmaceutical compositions, e.g., compositions for oral administration, may be prepared as described in references such as Pharmaceutical dosage form tablets, eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), Remington-The science and practice of pharmacy, 20th 30 ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and Pharmaceutical dosage forms and drug delivery Systems”, 6lh Edition, Ansel ctal., (Media, PA: Williams and Wilkins, 1995), incorporated herein by référencé, which provide
-27Information on carriers, materials (e.g., coating materials), equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.
[0097] Examples of suitable coating materials include, but are not iimited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic restas that are commercially available under the trade name Eu dr agit® (Roth Pharma, i 0 Westeratadt, Germany), Zêta, shellac, and polysaccharides. Additionally, the coating material may contain conventional carriers such as plasticîzers, pigments, colorants, gltdants, stabilization agents, pore formera and surfactants.
[0098] Optional pharmaceutically acceptable excipients présent in the drageon taining tablets, beads, granules or particles include, but are not limited to, 15 diluents, bindera, fabricants, disintegrants, colorants, stabilizers, and surfactants.
[0100] Diluents, also termed fillers, are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents Include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, 20 sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnésium aluminum silicate and powder sugar.
[0101] Bindera are used to impart cohesive quali lies to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains Intact after the formation of 25 the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcelfalose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl méthacrylate copolymers,
-28aminoalkyl méthacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvînylpyrrol idone.
[0102] Lubricants are used to facilitate tablet manufacture. Examples of suitable fabricants include, but are not limited to, magnésium stéarate, calcium stéarate, stearic acid, glycerol behenate, polyethylene glycol, talc, and minerai oil.
[0103] Désintégrants are used to facilitate dosage form dislntegratlon or breakup after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethy (cellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or 10 cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF
Chemical Corp).
[0104] Stabilizers are used to inhibit or retard drug décomposition reactions which include, by way of example, oxidative reactions.
[0105] Surfactants may be anionic, cationic, amphoteric or nonionic surface active 15 agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl su [fanâtes and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants Include, but are not limited to, quatemary ammonium compounds such as benzalkonium chloride, benzéthonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stéarate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, 30 stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
Examples of amphoteric surfactants include sodium N-dodccyl-.beta.-alanine,
-29sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
[0106] Pharmaceutical compositions of the invention may be designed to provide delayed, sustained, pulsatile or other modified release.
[0107] If desired, the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifyîng agents, dyes, pH buffering agents, and preservatîves.
[0108] Bioadhesive formulations may also be utüized to enhance uptake or modify release. Such formulations are known in the art See, for example, US Patent Application No. 20060045865 by Jacob, incorporated herein by référencé.
[0109] Pharmaceutical compositions adapted for delivery via nasal or pulmonary administration may also be useful. Aérosols for the delivery of therapeutic agents to the respiratory tract hâve been described, for example, Adjei, A. and Garren, J. Pharm. Res., Z- 565-569 (1990); and Zanen, P. and Lamm, J.-WJ. Int. J. Pharm., 114: 111-115 (1995). The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchioli which then lead to the ultîmate respiratory zone, the alveoli, or deep lung. Gonda, I. Aérosols for delivery of therapeutic and diagnostic agents to the respiratory tract, in Critical Reviens in Therapeutic Drug Carrier Systems, 6:273-313(1990). The deep lung, or alveoli, is the primary [0110] Drugs administered by inhalation may corne as liquid aérosol formulations. [0111] For injectable compositions (e.g., intravenous compositions), the carrier is di st il led stérile water, saline, buffered saline, or another pharmaceutically acceptable excipient for injection. Additives may include preservatîves and acids or base to adjust pH, to alter solubility or uptake.
[0112] In one embodiment, wherein the pharmaceutical composition comprises the DAP compound of formula V (or its stereoisomer of formula VIT) and the composition is adapted for parentéral administration in an injection, the compound is dissolved in water with appropriate tonicity and molality modifiers (such as
-30phosphate buffered saline). DAP is water-soluble at greater than 100 mg/ml. In the one embodiment, DAP is adapted as a stérile solution for IV administration. In one aspect, the molality of the pharmaceutical composition in which DAP is adapted for IV administration is adjusted to 290 mOsm/L with sodium chloride, and the pH is adjusted to 7.4 with sodium hydroxide. Preferably the pharmaceutical composition is administered as an intravenous bolus by slow push.
IV. Methods of Use [0113] The présent invention provides a method of completely or partially revcrsïng an anticoagulant effect of a coagulation inhibitor comprising administering to a subject in need thereof a therapeuücally effective amount of a compound of the invention (e.g., a compound of formula I, Π, ΙΠ, IV, V, VI, VII, or Vin) or pharmaceutically acceptable sait thereof. The présent invention also provides a method of promoting coagulation in a subject in need thereof, wherein the subject is receiving a coagulation inhibitor, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable sait thereof. In addition, the présent invention provides a method of neutralizing or inhibiting a coagulation inhibitor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable sait thereof.
[0114] In the présent invention, coagulation inhibitor (also referred to herein as anticoagulant) is a molécule that inhïbits coagulation process. Exemplary coagulation inhibitors include, but are not limited to, antithrombin activators (e.g., unfractionated heparia and LMWH), factor lia inhibitors, and factor Xa inhibitors. [0115] Heparin; Heparin is a naturally occurring mucopolysaccharide that nets in the body as an antithrombin co-factor to prevent intravascular clotting. The substance is produced by basophils and mast cells, which are found in large numbers in the connective tissue surrounding capillaries, particularly in the iungs and liver. In the form of sodium sait, heparin is used therapeuücally as an anticoagulant.
[0116] Low Molecular Weight Heparin: Low Molecular Weight Heparin (LMWH) is made from heparin using various methods of depolymerization, including oxidative depolymerization with hydrogen peroxide, used in the manufacture of
-31ardeparin (NORMIFLO®); deaminative cleavage with isoamyl nitrite, used In the manufacture of certoparin (SANDOPARIN®); alkaline beta-eliminative cleavage of the benzyl ester of heparin, used in the manufacture ofenoxaparin (LOVENOX® and CLEXANE®); oxidative depolymerizatîon with CuI+ and hydrogen peroxîde, used in the manufacture of pamaparin (FLUXUM®); betaeliminative cleavage by the heparinase enzyme, used in the manufacture of tinzaparin (INNOHEP® and LOGIPARIN®); deaminative cleavage with nitrous acid, used in the manufacture of dalteparin (FRAGMIN®), revlparin (CLIVARIN®) and nadroparin (FRAXIPARIN®), which results in the formation of an unnatural anhydromannose residue at the reducing terminal of the oligosaccharides produced. This can subsequently be converted to anhydromannîtol using a suitable reducing agent. Both chemlcal and enzymatic bcta-elimïnation resuit in the formation of an unnatural unsaturated uronate residue (UA) at the non-reducing terminal.
[0117] Summary of anticoagulant activities ofseveral LMWHs Is presented in
Table 1.
Table 1: Molecular weight (MW) data and anticoagulant activities of currcntly available LMWH products.
| LMWH | Average molecular weight | Ratio anti-Xa/anti-Ila activity 1 |
BEMIPARIN | 3600 | 9.7 |
CERTOPARIN | 5400 | 2.4 |
DALTEPARIN | 6000 | 2.5 |
ENOXAPARIN | 4500 | 3.9 |
NADROPARIN | 4300 | 3.3 |
PARNAPARIN | 5000 | 2.3 |
REVIPARIN | 4400 | 4.2 |
TINZAPARIN | 6500 | 1.6 | |
Adaptedfrom Gray E. et al., Thromb Haetnost, 99:807-818 (2008).
-32[0118] Clinically. LMWH (average molecular weight ofabout 4.5 kDa) differs from heparin (i.e., unfrnctioned heparin; average molecular weight of about 15 kDa) in a varicty of ways: (a) LMWH rcquires less frequent subcutaneous dosing for postoperative prophylaxie of venous thromboembolism; (2) LMWH requires once or twice daily subcutaneous injection in patients treated for venous thromboembolism and unstable angina instead of intravenous infusion required with heparin; (3) LMWH requires no monitoring of the aPTT coagulation parameter, (4) LMWH poses a lower risk of bleeding; (5) long term use of LMWH poses a lower risk of osteoporosis; and (6) LMWH poses a lower risk of heparin· 10 induced thrombocytopenia (a potential side effect of heparin administration).
However, the anticoagulant effects of heparin are typically réversible with protamine sulfate, while protamine's effect on LMWH is limited. In addition, LMWH has less effect on thrombin (Factor lia) activity compared to heparin, while both LMWH and heparin hâve a similar effect on Factor Xa activity.
[0119] Thrombin and Other Factor Ha orXa Inhibitors: Examples of thrombin (Factor Ha) and factor Xa inhibitors inciude anticoagulants such as dabigatran (PRADAXA®), rivaroxaban (XARELTO®), apixaban (ELIQUIS®), edoxaban (LIXIANA®), fondaparinux (ARIXTRA®), and argatroban (ARGATROBAN®). [0120] The chemical name for oral anticoagulant PRADAXA®, dabigatran etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N-I[2-[[[4HKhexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-l-methyl-lHbenzimidazoL5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. Dabigatran and its acyl glucuronides are compétitive, direct thrombin inhibitors. Because thrombin (Factor Ha, serine protease) enables the conversion of fïbrinogen 25 into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus.
[0121] Rivaroxaban, a factor Xa inhibitor, is the active ingrédient in XARELTO®, and has the chemical name 5-Chloro-N-({(5S)-2-oxo-3-]4-(3-oxo-4morpholinyl)pheny!J-1,3-oxazolidin-5-yl ) methyl)-2-thiophenecarboxamide.
Rivaroxaban is a pure (S)-enantiomer. XARELTO® is an orally bioavailablc factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin ΠΙ) for activity.
[0122] Apixaban or ELIQUIS® is l-(4-methoxyphenyl)-7-oxo-6-[4(2-oxopiperi din- 1-y IJphenyl] -4.5· dihyd ropyrazolo[5,4-c]pyri d ine3-carboxamide. It Is an o rail y administered direct factor Xa inhibitor approved in Europe and presently undergoing phase ΙΠ trials In the U.S. for the prévention of 5 venous thromboembolism.
[0123] Edoxaban or LIXIANA® is N,-(5-chloropyridin-2-yl)-N-[(lS^R,4S)-4(dimethylcarbamoyl)-2-[(5-niethyl-617-dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2carbonyl)amino]cyclohexyl]oxamide. Edoxaban is a direct factor Xa inhibitor, and it has been approved in Japan for use in preventing venous thromboembolism.
[0124] ARKTRA® is fondaparinux sodium. It is a synthetic and spécifie inhibitor of activated Factor X (Xa). Fondaparinux sodium is methyl O-2-deoxy-60-sulfo-2-(sulfoamino)-a-D-glucopyranosyl-(l-*4)-0-P-D-glucopyra-nuronosyl( 1 —»4)-0-2-dcoxy-3,6-d i-O-sulfo-2-(sul foami no)-a-D-g I ucopyranosy l-( 1 -+4)-0-20-sulfo-a-L-idopyranuronosy!-(l-+4)-2-deoxy-6-0-sulfo-2-(sulfoamino)-a-D15 glucopyranosîde, decasodium sait The molecular formula of fondaparinux sodium is CjjHiiNiNajoOjgSg and its molecular weight is 1728. The structural formula is provided below:
coati oso/o
OS O/li
DSO,»
NHSO/il
OH
HHS0R1
OSO/Ü
NHSOjMl [0125] The antithrombotic activity of fondaparinux sodium is the resuit of antîthrombin ΙΠ (ATIID-mediated sélective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ΑΤΠΤ. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. Fondaparinux sodium does not inactivate thrombin (activated Factor
II) and has no known effect on platclct function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic activity or bleeding time. The pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations quantifïed via anti-factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. (The international
-34standards of heparin or LMWH are not appropriate for this use.) As a resuit, the activity of fondaparinux sodium is expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity ofthe drug increases with increasing drug concentration, reaching maximum values in approximately three hours.
Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). In patients undergoing treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steadystate plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L. In patients with symptomatlc deep vein thrombosis and pulmonary embolism undergoing treatment with fondaparinux sodium injection 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), and |0 mg (body weight >100 kg) once daily. the body-weight-adjustcd doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L. [0126] ARGATROBAN® is a synthetic direct thrombin (Factor Ha) inhibitor, derived from L-orgininc. The chemical name for ARGATROBAN® is l-[520 [(aminoiminomethyl) amino]-l-oxo-2-[[( 1,2,3,4-tetrahydro-3-methyl-8quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate. The molecular formula of ARGATROBAN® is CnHjeNûOjS’HjO. Its molecular weight is 526.66. ARGATROBAN® is a direct thrombin inhibitor that reversibly binds to the thrombin active site. ARGATROBAN® does not require the co-factor antithrombin III for antithrombotic activity. ARGATROBAN® is administered by injection, and ït exerts its anticoagulant effects by inhibiting thrombin-catalyzed or thrombin-induced reactions, including fibrin formation; activation of coagulation factors V, VIII, andXIII; activation of protein C; and platelet aggregation.
[0127] An anticoagulant effect is any effect of a coagulation inhibitor (e.g., heparin, LMWH, Factor Xa inhibitor, Factor Ha inhibitor) that results from its blockage of the propagation of the coagulation cascades. Nonlîmiting examples of
-35anticoagulation effects include upregulation of antithrombin activity, decreased Factor Xa activity, decreased Factor lia activity, increased blood loss, and any other conditions wherein the activity or concentrations of clotting factors are altered in such a way as to Inhibit blood clôt formation.
[0128] Activity of a coagulation inhibitor (i.e., its anticoagulant effects) may be measured by a variety of methods, including but not limited to a chromogenic antifactor Xa activity assay, activated partial thromboplastin time assay, prothrombin time, bleeding assay (e.g., rat taü bleeding assay), thromboelastography, thrombin génération assay, dilute Russel’s viper venom time, ecarin clotting time, kaolin clotting time, International Normalized Ratio (INR), fibrinogen testing (Clauss), thrombin time (TCT), mîxïng time, and euglobulin lysis time. These methods aid in determining various anticoagulation parameters. and are known to those skilled in the art. Thus, in some embodiments, anticoagulation can be monitored by one or a combination of the above listed assays.
[0129] The anti-factor Xa assay directly measures antl-factor Xa activity. The methodology behind an anti-factor Xa assay is that patient plasma is added to a known amount of excess factor Xa and excess antithrombin. If a factor Xa inhibitor is présent in the patient plasma, it will reduce the enzymatic activity of factor Xa. The amount of residual factor Xa is inverseiy proportional to the 20 amount of anti-Xa agent in the plasma. The amount of residual factor Xa is detected by adding a chromogenic substrate that mimics the natural substrate of factor Xa, making residual factor Xa cleave it, releasing a colored compound that can be detected by a spectrophotometer. Antithrombin deficiencies in the patient do not affect the assay, because excess amounts of antithrombin are provided in the 25 reaction. Results are given in anticoagulant concentration in units/mL of antifactor Xa, such that high values indicate high levels of anticoagulation and low values indicate low levels of anticoagulation.
[0130] The activated partial thromboplastin time (aPTT) assay is an assay that measures how long it takes for the blood to clôt. Blood samples are coüected for 30 direct measurement or in tubes with oxaiate and citrate to arrest coagulation by calcium until the assay canbe performed. In the assay, a phospholipid, an activator (silica, celîte, kaolin, ellagic acid, etc.), and calcium are mixed into the
-36plasma to induce coagulation. The assay measures the time until a thrombus (clôt) forms.
[0131] Rat tail bleeding assay or rat tail transection assay is an assay that measures blood loss, e.g., blood loss after drug administration. In one embodiment, where the effect of the compound of the invention (e.g., DAP) is being tested, at the
Tmax of the anticoagulant, DAP is administered intravenously. After 20 minutes, rat tails are transected approximately 1 mm from the tip, placed in room température saline, and blood is collected for 30 minutes and weighed. [0132] Assays used to measure activity ofcoagulation inhibitors maybe used in the laboratory or în the clinic to measure reversa! of an anticoagulant effect of a coagulation inhibitor, e.g., reversa! of an anticoagulant effect of a coagulation inhibitor due to administration of a pharmaceutical composition comprising n compound of the invention. Thus, in one embodiment, the assays are utilized to measure complété or partial reversa! of an anticoagulant effect of a coagulation inhibitor (such as heparin, LMWH, Factor lia inhibitor, and Factor Xa inhibitor). [0133] A complété reversai of an anticoagulant effect of a coagulation inhibitor occurs upon neutralization of the anticoagulant activity. In one embodiment, a complété reversa! of an anticoagulant effect of a coagulation Inhibitor, as measured by the anti-Xa activity assay, occurs when anticoagulant concentration is brought 20 below the minimum effective concentration (MEC) foranticoagulation. MEC, as used herein, is a lowest amount of the drug (e.g., coagulation inhibitor) required for therapeutic effect. In another embodiment, a complété reversa! of an anticoagulant effect of a coagulation inhibitor, as measured by the aPTT assay, occurs when the aPTT returns within about 10% of baseline. A baseline, as used herein, refers to aPTT în the absence of coagulation inhibitors.
[0134] In many cases, anticoagulation wiiI still be desired, but to a lesser degree. Thus, a partial reversa! of an anticoagulant effect of a coagulation inhibitor will be indicated. Partial reversai of an anticoagulant effect of a coagulation inhibitor, as measured by the anti-Xa activity assay, occurs when the anticoagulant concentration is brought below the anticoagulant concentration in the absence of an anticoagulation reversai agent (e.g., a compound of the invention), but remains above the MEC foranticoagulation. Thus, in someembodiments, partial reversa!
-37of an anticoagulation effect of coagulation inhibitors occurs when the concentration of anticoagulant is lower than about four times the MEC, preferably about twice the MEC, more preferably less than about twice the MEC (e.g., at about the MEC). Partial reversai of an anticoagulant effect of coagulation inhibitor, as measured by aPTT assay, occurs when aPPT Is reduced below the measurement in the absence of an anticoagulation reversai agent (e.g., a compound of the invention) but above the baseline. Thus, in other embodiments, partial reversai of an anticoagulation effect of coagulation Inhibitors occurs when the aPTT measurement is reduced below about four times the baseline, preferably about twice the baseline, more preferably less than about twice the baseline.
Generaily, the extent and duration of anticoagulation reversai is determined by the physician or veterinarian.
[0135] As used herein, “subject in need thereof' is a subject in need of either acute or planned reversai of anticoagulation, e.g., a subject suffering from anticoagulant overdose, a subject suffering from hcmorrhage (e.g., trauma-induced hemorrhagc or spontaneous hcmorrhage in the GI tract or elsewhere), a subject requiring planned surgical intervention, a subject undeigoing an invasive or non-invasive procedure requiring a biopsy, a subject undcrgoing a procedure wherein a procédural enror may risk hemorrhage if the subject remains anticoagulated, a subject requiring spinal or épidural anesthésia. “Subject in need thereof* may be a patient in whom the presence of a direct factor inhibitor (Factor Xa, Factor lia and/or antithrombin) is producing or is likely to produce bleeding effects. Thus, “subject in need thereof” may be a subject receiving anticoagulation therapy (e.g.< subject receiving heparin, LMWH, Factor lia inhibitor, or Factor Xa inhibitor) for,
e.g., stroke prévention, cardiac surgical and diagnostic procedures, cardiac arrhythmias. deep vein thrombosis (DVT) prévention, pulmonary embolism, general prévention of the formation of pathologie blood clots.
[0136] “Subject in need thereof, as used herein, is on animal. “Subject in need thereof' includes, without limitation, a human. mouse. rat, guinea pig, dog, eut, horse, cow, pig, monkey, chïmpanzce, baboon, or rhésus monkey. In one embodiment, “subject in need thereof* is a mammal. In another embodiment, “subject in need thereof’ is a human.
-38[0137] As used herein, “therapeutically effective amount refers to an amount of an anticoagulation reversai agent (e.g., a compound of the invention described herein), which is effective, upon single or multiple dose administration (e.g., bolus and/or maintenance doses) to a subject, in neutralizing or inhibiting (completely or 5 partially reversing) an anticoagulant effect of a coagulation inhibitor or in promoting coagulation.
[0138] In one aspect, a therapeutically effective amount is a dose of on anticoagulation reversai agent that is between 0.01 and 10,000 times the anticoagulant dose by weight. In another aspect, the nnticoagulation reversai agent 10 is administered at a dose mass ratio of between about 1:1 and 1000:1 of the anticoagulation reversai agent to anticoagulant, e.g., 100:1 of the anticoagulation reversai agent to anticoagulant, such as 10:1 of anticoagulation reversai agent to anticoagulant. In one embodiment of the présent method, a iherapeutically effective amount of the anticoagulation reversai agent may be administered by 15 subcutaneous, intramuscular, or intravenous route of administration. For example, it may be administered intravenously as a stérile solution. In another embodiment, a therapeutically effective amount of the anticoagulation reversai agent is administered by oral, nasal, or pulmonary route, or to a mucosal région (mouth, rectum, or vagina).
[0139] The therapeutically effective amount of the anticoagulation reversai agent (i.c„ the compound of the invention) will typically range from about 0.001 mg/kg to about 1 g/kg of body weight per day; in another embodiment, from about 0.01 mg/kg to about 600 mg/kg body weight per day; in another embodiment, from about 0.01 mg/kg to about 250 mg/kg body weight per day, in another embodiment, from about 0.01 mg/kg to about 400 mg/kg body weight per day; in another embodiment, from about 0.01 mg/kg to about 200 mg/kg of body weight per day; in another embodiment, from about 0.01 mg/kg to about 100 mg/kg of body weight per day; in one embodiment. from about 0.01 mg/kg to about 25 mg/kg body weight per day; in another embodiment, from about 0.1 mg/kg to 30 about 10 mg/kg body weight per day, in another embodiment, from about
0.001 mg/kg to about 100 mg/kg of body weight per day, in another embodiment, from about 0.001 mg/kg to about 10 mg/kg of body weight per day; and in another
-39embodiment, from about 0.001 mg/kg to about 1 mg/kg of body weight per day. Standard coagulation assays (as those described herein) and other in vitro assays can be used to détermine the therapeuticaliy effective amount [0140] In some aspects ofthe invention, the compound of the invention may be co-administered with at least one additional therapeutic agent In one embodiment, the nt least one additional therapeutic agent may be vitamin K, which is typically used to correct clotting deficiencies induced by warfarin compounds. [0141] The présent invention also provides a diagnostic assay for determîning the anticoagulant concentration in the blood. As shown in Example 13 below, DAP demonstrates a dose-responsive trend in reversing rivaroxaban ex vivo in human plasma using a 5 lOk-cleared anti-factor Xa chromogenic assay. Thus, the compound of the invention, e.g., DAP, can be used in a diagnostic assay to détermine the concentration of an anticoagulant, e.g., a Factor Xa inhibitor, in the blood. In such an assay, the compound of the invention, e.g., DAP, can be used either in conjunction with the currently available kit reagents or as a direct binding substrate replacing synthetic factors présent in currently available kits. In one embodiment, the diagnostic assay may comprise the compound of the invention (e.g., DAP) as a binding substrate, wherein the compound of the invention binds an anticoagulant in a blood sample, and the residual activity of the clotting factor (e.g.. Factor Xa) is quantifïed to détermine the concentration of the anticoagulant in the sample. In another embodiment, the diagnostic assay may comprise the compound of the invention (e.g., DAP) conjugated to magnetic microparticles, wherein the compound of the invention can bind an anticoagulant in a blood sample in order to either remove the anticoagulant from the sample or to concentrate ït. The DAP-based chromogenic or point of care assay of the invention can aid in the détermination of anticoagulant levels in subjects, which Is currently a significant clinical unmet need since current diagnostics cannot détermine blood concentrations of direct inhibitors with high accuracy.
[0142] Additionally, the présent invention provides an assay, e.g., a chromogenic assay, to détermine the concentration of the compound of the invention, e.g., DAP, required to reverse the anticoagulant présent in the blood. In one embodiment, the assay uses DAP as a direct binding agent for various anticoagulants.
-40[0143] The invention also provides an assay, e.g., a chromogenic assay, to détermine the amount of the compound of the invention, e.g., DAP, in the blood. Such assay may utilize predetermined concentrations of an anticoagulant.
[0144] The présent invention also provides a diagnostic kit that incorporâtes a diagnostic assay described herein above. Thus, in one embodiment, the kit is used for determining the anticoagulant concentration in the blood. The kit may contain other components, packaging, instructions, reagents, and/or other material to aîd in the détermination of anticoagulant (e.g., Factor Xa inhibitor) or DAP concentration and to aid in the use of the kit. Additionally, the kit may be used to détermine if there is a combination of warfarin and another anticoagulant as warfarin will be unaffected by the compound of the invention, while other anticoagulants will be reversed.
[0145] As demonstrated in the following examples, a compound of the invention (e.g., DAP) is capable of binding heparîn, inactivating it in vivo. Thus, in addition 15 to its effects on coagulation, a compound of the invention may also be used to deprive tissues of the biochemical activities of heparin. For example, other heparin-binding molécules hâve demonstrated the abllity to reduce fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothélial growth factor (VEGF), and other heparin binding growth factors. VEGF and FGF deprivatîon has been sbown useful tn anti-cancer therapy, making compounds of the invention possible candidates for the treatment of cancer. Therefore, in one aspect, the présent invention provides u method for treating, preventing, or ameliorating a cancer in a subject, comprising administering to a subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable sait thereof.
[0146] As demonstrated in the examples, one compound of the invention, DAP, bound XARELTO®, ELIQUIS®, ARIXTRA® and LMWH in vitro as measured by dynamlc light scattering (DLS). DAP reversed subcutaneously administered ARIXTRA® and LMWH in vivo. DAP reversed XARELTO®, ELIQUIS®,
PRADAXA®, LKIANA®, unfractionated heparin and bemiparin in vivo. DAP intravenously administered at lOOmg/kg, 250mg/kg and 400mg/kg doses in rats showed no adverse effect. DAP was orally bioavailable in rats. DAP exhibited no
-41human ERG binding, dîd not inhibit or serve as a substrate of CYP enzymes, and did not appreciably bind any plasma proteins (data not shown). In addition, it appears that DAP has a short élimination half-life, because anti-coagulation induced by PRADAXA® retumed in 20-30 minutes following an intravenous 5 bolus dose of DAP in rats. Moreover, DAP was stable to sterilization (survived heating to 200° C) and to storage as a lyophilized powder at 4°C for more than one year. Summary of anticoagulant reversai by DAP is presented in Table 2.
Table 2: Anticoagulant reversai
Trade Name | Generlc Name | Company | Blood Factor Inhlblted | Route of Administration | Bind a DAP | Reversai Agents |
Lovenox® Hîbot® | Enoxaparfn Bamiparin | Sanofi, Sandoz/ Momenta. Rovi | -80-90% Xa. -10-20% lia | s.c. Injection | X | Protamine •&DAP |
Arixtra® | Fondapartnux | QSK | Xa | s.c. Injection | X | DAP |
Ellquls® | Apixaban | Pflzer, QMS | Xa | Oral | X | DAP |
Xarelto® | Rlvaroxaban | Bayer, Janssen, J&J | Xa | Oral | X | DAP |
Argatroban® | Argatroban | GSK | lia | s.c. Injection | - | None |
Pradaxa® | Dabigatran etexllate | Boehringer Ingelhelm | lia | Oral | X | DAP |
*Protamine partially reverses low molecular weig | it heparins. |
Table 3: In vitro in vivo corrélation
Drug Generlc Name | DLS Binding Molar Ratio [DAP/drugl | Reversai Molar Ratio [DAP/drugl | ln vivo Measure | Blood Fectorfs) Inhlblted | Route of Administration |
Rlvaroxaban | 9 | 3· | Bleeding assay | Xa | Oral |
Apixaban | 10 | B* | Bleecfing assay | Xa | Oral |
Fondaparinux | 3 | 130 | Xaklt | Xa | s.c. Injection |
Bemlparin | 7 | 140 | aPTT | -80-90% Xa, -10-20% lia | e.c. Injection |
Argatroban | N/A | N/A | aPTT | Ha | s.c. Injection |
Assumes oral bioavailabilities of 60% for rivaroxaban, 50% for apixaban, and 5% for dabigatran; Assumes 100% bioavailability for injectable anticoagulants.
-42[0147] Summary of in vitro-in vivo corrélation of treatment with DAP is presented in Table 3. DLS binding molar ratio is calculated by dividing the lowest mass ratio of DAP to anticoagulant that shows significant binding, defined as an association in phosphate buffered saline above 50nm in apparent diameter, by the molecular weight ratio of DAP and the anticoagulant. The molecular weights used in the calculations were 5l2Da (DAP), 436Da (rivaroxaban), 46ODa (apixaban), 1.7kDa (fondaparinux), 3.6kDa (bemiparin), 628Da (dabigatran), and 509Da (ARGATROBAN®). Reversai molar ratio was calculated similarly using the minimal in vivo reversai dose of DAP necessary to achieve reversai as measured by the rat tail transection bleeding assay, chromogenîc anli-Xa kit, or by activated partial thromboplastin time (aPTT). For the bleeding assay, the anticoagulant was considered reversed if the blood loss over a period of 30 minutes after tail transection, with the eut tail immersed in room température saline, was within 25% of the control (no anticoagulant administered). As measured by the Xa kit, reversai was achieved when the effective anticoagulant concentration was brought below the minimum effective concentration (MEC) for onticoagulation. As measured by aPTT, reversai was considered achieved when on anticoagulated rat aPTT retumed to within 10% of baseline. In the case of fondaparinux, although 200mg/kg DAP was the lowest dose administered in vivo, the in vitro data îndicate that significantly lower reversa] doses are possible.
[0148] The entire contents of ail référencés, patent applications, and patents cited throughout this application arc hereby incorporated by référencé herein.
EXAMPLES [0149] The invention will be further illustrated in the following nonlimîting
Examples. These Examples are set forth to aid in the understanding of the invention but are not intended to, and should not be construed to, limit its scope in any way. The Examples do not include detailed descriptions of conventional methods that are well known to those of ordinary skill in the art.
-43Example 1: In vitro Stability Testing of Dlarglnlne plperazlne (“DAF’)
Materials and Methods [0150] An acetate sait ofDAP was prepared as described herein. As described in these examples, DAP solid or powder refers to the acetate sait, while DAP in solution refers to lhe free base as the sali ionizes in aqueous solution. As described in these examples, the DAP compound used was the compound of Formula VII. [0151] The DAP powder was tested for thermal stability in two ways. DAP was stored at 4°C for 7 months prior to use. Additionally, the DAP solid was tested by differenti al scanning calorimetry (DSC) by heating from -20°C to 200°C, back to 10 20°C and again to 200°C.
Results [0152] DAP powder was stable at 4°C for more than 12 months. The results of DSC are shown in Figure 1. The second beat (“2) showed similar thermal behavtor to the first beat (“1”), indicating that DAP survived repeated heating to 15 200°C. This finding indicates that DAP is able to survive heating to températures above those necessary for sterilization.
Example 2: Binding of DAP to Heparin and LMWII
Materials and Methods [0153] Dynamic light scattering (DLS) was used to assess association of I mg/ml unfractionated heparin and i mg/ml bemiparin (LMWH; HIBOR®), either alone or in combination with 100 mg/mi DAP in water (mass ratios of i 00: i of DAP to heparin or LMWH).
Results [0154] DAP physically associated in water with both unfractionated heparin (Figure 2) and LMWH (not shown) to form physical associations that increase lhe apparentdiameter. When solutionsofDAP weremixedwithsolutionsofLMWH or unfractionated heparin, they formed particles due to their physical interactions, which supports the theory that DAP could reverse heparin and LMWH anticoagulation by physically associatlng with these molécules.
-44Example 3: DAP Binding to Anticoagulants as Measured by DLS.
Materials and Methods [0155] Rivaroxaban (XARELTO®) alone, DAP alone, and DAPirivaroxaban combinations at mass ratios of 1: i and 10: i were added into an aqueous solution 5 and analyzed by dynamic light scattering (DLS) to assess association of the DAP and rivaroxaban. A similar experiment was conducted on apixaban (ELIQUIS®) alone, DAP alone, and DAP:apixaban combinations at mass ratios of 1:1,10:1 and 100:t. Fondaparinux (ARIXTRA®) alone, DAP alone, and fondaparinux:DAP combinations at mass ratios of 1:1,10: ! and 100:1 were similarly tested. LMWH ! 0 (bemiparin; HIBOR®), alone, DAP alone, and LMWH'.DAP combinations at mass ratios of 1:1, 10:1, and 100: t were also tested. The concentration of LMWH tested was 0.1 mg/ml. Therefore, at 1:1,0.1 mg/ml DAP was tested, at 10:1,1 mg/ml was tested, and at 100:1, 10 mg/ml DAP was tested.
[0156] Additionally, dabigatran alone, DAP alone, and dabigatran:DAP combination at mass ratios of 1:1,10:1,100:1,1,000:1, and 10,000:1 DAP were tested. Finally, ARGATROBAN® alone, DAP alone, or combinations of argatroban:DAP at mass ratios of 1:1,10:1,100:1, and 1,000:1 were tested.
Results [0157] The results are shown in Figure 3 for rivaroxaban; Figure 4 for apixaban; 20 Figure 5 for fondaparinux (ARIXTRA®), Figure 6 for LMWH; and Figure 7 for argatroban. Each figure shows individual peaks representïng DAP and the anticoagulant alone in aqueous solution. When the anticoagulant was mixed with DAP at sufficiently high mass ratios, a change in size was observed. In this assay, even a slight increase in size indïcates physical interaction between the two;
however, only significant shifls in the apparent diameter are used in assessing the in vitro in vivo corrélation. Apparent diameter is a measure of the degree of interaction.
-45Example 4: DAP Reversai of LMWH Anticoagulation In Vivo
Materials and Methods [0158] A male albino rat, weighing 470 g, was administered 10 mg of bemiparin (an overdose of LMWH) by subcutaneous injection. oPTT time was measured over the course of five hours. Four hours after LMWH administration, the rat received an intravenous dose of 200 mg/kg of DAP (lOOmg DAP).
Results [0159] Upon administration of LMWH, the aPTT rose from 53 to 246 seconds over the course of four hours. Intravenous administration of200 mg/kg of DAP ( 100 mg DAP) brought aPTT time below baseline within 60 minutes (Figure 8).
Example 5: DAP Reversai of Dabigatran (PRADAXA®) Antlcoaguiatlon In Vivo; an Overdose Study
Materials and Methods [0160] A male albino rat, weighing 430 g, was administered 40 mg/kg of
PRADAXA® (20mg PRADAXA®; overdose of PRADAXA®) by oral gavage. [0161] Approximately 2 hours into PRADAXA® treatment, 200 mg/kg DAP (100 mg DAP) was administered os an intravenous bolus Injection. Approximately 2 hours later, the rat was administered a dose of 100 mg/kg of DAP (50mg DAP). In another hour, the rat was administered another dose of 100 mg/kg of DAP (50 mg DAP). aPTT was measured throughout the course of the entire treatment.
Results [0162] The results are shown in Figures 9 and 13. 2 hours following administration of PRADAXA®, aPTT rose from 43 to 81 seconds, showing significanl anti-coagulation. 100 mg of DAP was administered ns an intravenous bolus irtfection. which brought aPTT down below baseline within 25 minutes.
hours later, aPIT had risen back to 79 seconds and the rat was administered a dose of 50 mg of DAP. Within 30 minutes, aPTT was brought down below baseline. Both limes, within 60 minutes following DAP administration, the aPTT levels had retumed above baseline. After the second dose of DAP, the aPTT rose
-46to 53 seconds. A third dose of DAP, 100 mg/kg of DAP (50 mg DAP), was administered intravenously and the aPTT was dropped to baseline within 20 minutes. Figure 13 demonstrates a similar experiment where, after 15.5 mg/kg administration of PRADAXA®, the aPTT retumed to normal within about 30 minutes of initiation of 100 mg/kg DAP treatment.
Example 6: DAP Reversai οΓ Unfractionated Heparin (“UHF*) Anticoagulation In Vivo.
Materials and Methods [0163] A male albino rat, weighing 515 g, was administered 10 mg /kg of unfractionated heparin (5 mg UFH) by subcutaneous injection.
[0164] 200 mg/kg of DAP (!00 mg DAP) was administered as two intravenous bolus injections after UFH administration. Subsequently, the rat was administered a dose of400mg/kg of DAP (200mg of DAP). a P11 was measured throughout the course of the entire treatment.
Results [0165] As demonstrated in Figure 10, the aPTT time rose significantly from 28 to 102 seconds over the course of one hour after administration of heparin. 100 mg of DAP was administered intravenously and it brought aPTT time to48 seconds in 20 minutes. Within 1 hour, aPTT rose to 120 seconds, then another lOOmgof DAP was administered intravenously. In 15 minutes, the aFTT was lowered to 47 seconds. Within ! hour, aPTT rose to 96 seconds, then a dose of 200mg of DAP was administered intravenously. 10 minutes after, aPTT dropped to 33 seconds.
Example 7: DAP Reversai of Rivaroxaban (XARELTO®) Anticoagulation
In Vivo
Materials and Methods [0166] 5 mg /kg rivaroxaban (XARELTO®) was orally administered to rats. After four hours, 5 mg/kg of DAP (2 mg DAP) was administered intravenously. aPTT were measured at zéro, 15,30,45,60 and 240 minutes, prior to
-47administration of DAP. aPTT was again measured at about 5,10,25,35,45,60, 120, and 240 minutes after DAP administration.
Results [0167J The results are shown in Figure 11. DAP cffectively reversed the rivaroxaban (XARELTO®) anticoagulation in vivo in rats.
Example 8: DAP Reversai of Fondaparinux (ARIXTRA®) Anticoagulation In Vivo.
Materials and Methods [0168] 5 mg/kg fondaparinux was administered subcutaneously to rats.
200 mg/kg DAP was administered intravenously after 2 hours. Activity was measured by chromogenic 510k cleared Factor Xa Assay (Biophen) at 10,20,30 and 60 minutes after DAP admlnsitration.
Results [0169] Figure 12 demonstrates DAP-mediated reversai of fondaparinux anticoagulation within 10 minutes of administration.
Exemple 9: Intravenous DAP does not influence aPTT
Materials and Methods [0170] 0,2, 10.25,50 or i 00 mg DAP were administered intravenously to male, weight matched CD rats and aPTT was measured.
Results [0171] The results shown ln Figure 16 demonstrate that DAP administered intravenously did not influence aPTT in a dose dépendent fashion in the absence of anticoagulants. Error bars represent standard crror from seven aPTT measuremcnts averaged over 90 minutes.
-48Example 10: DAP Reversai of Anticoagulation in a Rat Tail Transection Model.
Materials and Methods [0172] Three rats each were administered 2 mg of rivaroxaban. One rat received a sham reversai containing no DAP, the second received 2.5 mg of DAP, and the third received 12.5 mg DAP. A fourth fat received sham anticoagulant and reversai doses (“sham). 20 minutes after the reversai dose, tails were transected 1 mm from the tlp, placed in room température saline, and blood ioss was collected for 30 minutes and then weighed.
[0173] Same procedures were used with 1.25 mg apixaban (ELIQUIS®) alone or in combination with 5 or 12.5 mg DAP; with 15.5 mg dabigatran etexilate (PRADAXA®) alone or in combination with 5 or 123 mg DAP; and with 5 mg edoxaban (LIXIANA®) alone or in combination with 12.5 mg DAP.
Results [0174] The results are shown in Figure 15 for rivaroxaban, in Figure 16 for apixaban, in Figure 17 for edoxaban, and in Figure 18 for dabigatran etexilate. The rat tail transection bleeding assay is analogous to the clinical situation in which acute anticoagulant reversai is needed. Results show that DAP effectively reversed anticoagulant activity leading to statistically significant réduction in blood 20 loss compared to rats receiving anticoagulant only.
Example 11: DAP Reversai of Rivaroxaban (XARELTO®) Anticoagulation in Freshly Drawn Human Blood Ex Wvo.
Materials and Methods [0175] Human blood was drawn from a volunteer. Rivaroxaban at 0.25 pg/ml was 25 added alone or in combination with 50 pg/ml DAP. Controls contained 50 pg/ml DAP or saline. aPTT was measured within 2 minutes of blood collection.
-49Results [0176] Figure 19 demonstrates that administration of DAP ied to a reversai of rivaroxaban-induced anticoagulation in freshly drawn human blood, as measured by aPTT. Errer bars represent standard errer from three Independent experiments.
Example 12: DAP Reversai of Rivaroxaban and Apixaban Anticoagulation In Human Plasma Ex Vivo
Materials and Methods [0177] 218 pg/L or 459 pg/L of rivaroxaban was added to human plasma, with or without 1,250 pg/L or 6,250 pg/L of DAP, respectively. Similarly, 156pg/Lor
313 pg/L of apixaban was added to human plasma with or without 1,156 pg/L or
3,125 pg/L of DAP, respectively. DAP effect on anticoagulation was measured by 510k cleared Biophcn anti-Factor Xa chromogenic assay. Rivaroxaban concentrations were determined by comparison with plasma calibration standards, while apixaban concentrations were inferred from stock solution dilutions as calibration standards are not yet available.
Results [0178] For both concentrations of rivaroxaban and apixaban, DAP retumed the effective anticoagulant concentration to below the minimum effective concentration. Figure 20 shows the results for rivaroxaban and Figure 21 shows 20 the results for apixaban.
Example 13: DAP Dose-Dependent Reversai of Rivaroxaban Anticoagulation In Human Plasma Ex Vivo
Materials and Methods [0179] 218 pg/L rivaroxaban was added to human plasma either alone or in combination with 1.25,12.5,125, or 1,250 pg/L ofDAP. Factor Xa activity was measured by 510k cleared Biophen anti-Xa chromogenic assay kit. Rivaroxaban concentrations were determined by comparison with plasma calibration standards.
-50Results [0180] Figure 22 demonstrates that DAP was effective in dose-dependent reversai of rivaroxaban anticoagulation in human plasma, as demonstrated by its effect on rivaroxaban concentration (measured by Factor Xa activity assay).
Claims (17)
- WHATIS CLAIMED IS:1. A compound of formula IY----M----X----L----A----L'----X*---M’---Y (I) or a pharmaceutically acceptable sait thereof, wherein:5 A is a substituted or unsubstituted aromatic or non-aromatic, carbocyclic or heterocyclic ring or a linear moiety;L and L’ are the same or different and are linkers;X and X’ are the same or different and are absent or are a functional group that attaches the linker L to M and linker L’to M’, respectively;10 M and M’ are the same or different and are absent or is a linker that attaches X to Y and X’ to Y', respectively; andY and Y* are the same or different and are a moiety containing one or more cationic atoms or groups or one or more groups that become cationic under physiological conditions.15
- 2. The compound of claim 1, wherein A is a non-aromatic, heterocyclic ring or a linear moiety, and wherein the ring or the linear moiety contain reactive functional groups that can form a bond to X and/or X’, when présent, or Y and/or Y’.
- 3. The compound of claim 2, wherein A is a piperazine or diketopiperazine.20
- 4. The compound of any one of daims 1-3, wherein X and X’, when présent, is a functional group that attaches linker L to Y and linker L* to Y’, respectively, and wherein the functional group is selected from the group consisting of esters, amides, and ketones.
- 5. The compound of any one of daims 1-4, wherein L and/or L’is a25 substituted or unsubstituted alkylene chain that is Ci to Cg.
- 6. The compound of claim 1, wherein the compound is represented by formulaII:(Π) or a pharmaceutically acceptable sait thereof.5
- 7. The compound of claim 6, wherein the compound is represented by formulaIII:or a pharmaceutically acceptable sait thereof.
- 8. The compound of claim 7, wherein the compound is represented by formula10 IV:o o or a pharmaceutically acceptable sait thereof, wherein n is 3 to 5, m is 3 to 6 and G is selected from -NH2 and OH.
- 9. The compound of claim 8, wherein G is amino.
- 10. The compound of any one of claims 1-9, wherein Y and Y’ are independently selected from nh2 and -NH2.or a pharmaceutically acceptable sait thereof.
- 14. A compound of formula VII5 or a pharmaceutically acceptable sait thereof.
- 15. A compound of formula VIII (VIII) or a pharmaceutically acceptable sait thereof.
- 16. A pharmaceutical composition comprising the compound of any one of claims 1-15 and a pharmaceutically acceptable carrier.
- 17. The pharmaceutical composition of claim 16, wherein the composition is 15 adapted for enterai administration.
- 18. The pharmaceutical composition of claim 17, wherein the composition is adapted for oral administration.
- 19. The pharmaceutical composition of claim 16, wherein the composition is adapted for parentéral administration.-5520. The pharmaceutical composition of claim 19, wherein the composition is adapted for intravenous or subcutaneous administration.21. Use of a compound of any one of daims 1-15 or pharmaceutically acceptable sait thereof in the manufacture of a pharmaceutical composition for use5 in a method of completely or partially reversing an anticoagulant effect of a coagulation inhibitor said composition being for administration of a therapeuticaliy effective amount of said compound to a subject in need thereof.22. The use of claim 21, wherein the coagulation inhibitor is selected from the group consisting of an unfractionated heparin, low molecular weight heparin10 (LMWH), Factor Ha inhibitor, and Factor Xa inhibitor.23. The use of claim 22, wherein the coagulation inhibitor is a factor Xa inhibitor.24. The use of claim 23, wherein the factor Xa inhibitor is selected from the group consisting of rivaroxaban, apixaban, edoxaban, and fondaparinux.15 25. The use of claim 21, wherein the subject is a mammal.26. The use of claim 25, wherein the subject is a human.27. The use of claim 21, wherein the complété or partial reversai of an anticoagulant effect of a coagulation inhibitor is measured by anti-factor Xa activity assay.
- 20 28. The use of claim 21, wherein the subject in need thereof is a subject in whom acute or planned reversai of anticoagulation is indicated.29. The use of claim 28, wherein the subject in whom acute or planned reversai of anticoagulation is indicated is a subject suffering from anticoagulant overdose, a subject suffering from hemorrhage, a subject requiring planned surgical-56intervention, a subject undergoing an invasive or non-invasive procedure requiring a biopsy, a subject undergoing a procedure wherein a procédural error may resuit in hemorrhage if the subject remains anticoagulated, or a subject requiring spinal or épidural anesthésia.5 30. The use of claim 28, wherein the subject in need thereof is a subject receiving anticoagulation for stroke prévention, cardiac surgical and diagnostic procedures, cardiac arrhythmias, deep vein thrombosis (DVT) prévention, pulmonary embolism, or generaily for the prévention of pathologie blood clots.31. The use of claim 22, wherein the coagulation inhibitor is a LMWH, and10 wherein the LMWH is selected from the group consisting of bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, pamaparin, reviparin, and tinzaparin.32. The use of claim 21, wherein said composition is for administration of said compound or the pharmaceutically acceptable sait thereof at a dose mass ratio of between about 0.01:1 to about 1000:1 of the compound or the pharmaceutically15 acceptable sait thereof to anticoagulant.33. The use of claim 32, wherein said composition is for administration of said compound or the pharmaceutically acceptable sait thereof at a dose mass ratio of about 10:1 of the compound or the pharmaceutically acceptable sait thereof to anticoagulant.20 34. The use of claim 21, wherein the method comprises administration of at least one addition al therapeutic agent.35. The use of claim 34, wherein the at least one additional therapeutic agent is vitamin K.36. A diagnostic kit comprising the compound of any one of daims 1-15.37. The kit of claim 36, wherein the kit is used for determining an anticoagulant concentration in blood.
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