WO2006067173A2 - Antithrombotic dual inhibitors comprising a biotin residue - Google Patents
Antithrombotic dual inhibitors comprising a biotin residue Download PDFInfo
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- WO2006067173A2 WO2006067173A2 PCT/EP2005/057011 EP2005057011W WO2006067173A2 WO 2006067173 A2 WO2006067173 A2 WO 2006067173A2 EP 2005057011 W EP2005057011 W EP 2005057011W WO 2006067173 A2 WO2006067173 A2 WO 2006067173A2
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- A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
- A61K47/665—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Definitions
- the present invention relates to new antithrombotic dual inhibitors comprising a biotin residue or a biotin derivative, a process for their preparation, pharmaceutical compositions containing the compounds as active ingredients, as well as the use of said compounds for the manufacture of medicaments.
- Org 42675 appeared to be highly efficacious in the prevention of thrombotic reocclusion following thrombolysis of occlusive arterial thrombi.
- the compound displays a 10-fold prolonged half-life in comparison to the corresponding non-conjugated direct thrombin inhibtor derived from NAPAP.
- heparin and fondaparinux showed improved efficacy.
- an antidote As a precautionary measure, within the field of anticoagulant and antithrombotic therapy, there is a need for an antidote to be able to effectively neutralize or minimize the activity of the anticoagulant or antithrombotic drug used. This is because it is well known that a haemorrhage can be triggered in a patient under treatment for any accidental cause. Further, it may be necessary to intervene surgically in a patient under antithrombotic or anticoagulant treatment. In addition, during some surgical procedures, anticoagulants may be used at a high dose so as to prevent blood coagulation and it is necessary to neutralize them at the end of the operation.
- antithrombotic / anticoagulant agents available which can be neutralized in order to stop the antithrombotic / anticoagulant activity at any time.
- the antithrombotic activity of certain polysaccharides may be reduced using avidin, if those polysaccharides contain at least a covalent bond with biotin or a biotin derivative.
- the present invention relates to novel neutralizable dual inhibitors derived from the dual inhibitors described in WO 99/65934 and WO 01/42262. It has been found that a certain biotin
- label being the group , also referred to in this document as "BT"
- the present invention relates to compounds of the formula (I) oligosaccharide-spacer-A (I), wherein the oligosaccharide is a negatively charged oligosaccharide residue comprising two to twenty five monosaccharide units, the charge being compensated by positively charged counterions, and wherein the oligosaccharide residue is derived from an oligosaccharide which has (AT-III mediated) anti-Xa activity per se; the spacer is an essentially pharmacologically inactive flexible linking residue having a chain length of 10 to 70 atoms;
- A is the residue -CH[NH-SO 2 -R 1 ] [CO-NR 2 -CH(4-benzamidine)-CO-NR 3 R 4 ], wherein R 1 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (iso)quinolinyl, tetrahydro(iso)quinolinyl, 3,4-di
- the compounds of the invention are dual inhibitors, having a tuneable mixed profile of both non- mediated, direct anti-thrombin (factor Ha) activity and anti-thrombin III (AT-III) mediated anti- Xa activity.
- the mixed profile of the compounds of the invention may be tuned by varying the nature of the oligosaccharide residue and the potency of the direct thrombin inhibitor (NAPAP analogues). A range of profiles is thereby available.
- Compounds of the invention have a long plasma half-life and, as a result, they possess prolonged anti-thrombin activity compared to NAPAP or its derivatives reported in literature previously.
- compounds of the invention may escape the neutralizing action of platelet factor 4 (PF4).
- PF4 platelet factor 4
- the compounds of the present invention are useful for treating and preventing thrombin- mediated and thrombin-associated diseases.
- the compounds of the invention may also be used as anticoagulants in extracorporeal blood circuits, as necessary in dialysis and surgery.
- the compounds of the invention may also be used as in vitro anticoagulants.
- the biotin label (or analogue thereof) in the compound of the present invention is rapidly recognized by and binds to a specific antidote, being avidin (The Merck Index, Twelfth edition, 1996, M.N. 920, pages 151-152) or streptavidin, two tetrameric proteins with respective masses equal to approximately 66 000 and 60 000 Da which have a very high affinity for biotin.
- avidin The Merck Index, Twelfth edition, 1996, M.N. 920, pages 151-152
- streptavidin two tetrameric proteins with respective masses equal to approximately 66 000 and 60 000 Da which have a very high affinity for biotin.
- the action of the dual inhibitor can be rapidly neutralized by using avidin or streptavadin, for example by injection of a pharmaceutical solution containing the same.
- Analogues of avidin and streptavidin having high biotin affinity may be used similarly.
- the resulting inactive antidote -inhibitor complex is cleared from
- Biotin analogues which may be used as a label according to this invention, may be selected from, but are not limited to, the biotin analogues shown in the Pierce catalogue, 1999-2000, pages 62 to 81, for example 6-biotinamidohexanoate, 6-(6-biotinamidohexanamido)hexanoate, and 2-biotinamidoethanethiol, etc.
- the biotin residue BT as previously defined, is a characteristic part of the molecule.
- analogues are for example biotin analogues that are alkyated at the biotinamide bond (wherein alkyl is (l-4C)alkyl, preferably methyl) and which are stable to biotinidase cleavage (Bioconjugate Chem., Vol. 11, 2000, 569- 583; Bioconjugate Chem., Vol. 11, 2000, 584-598) or other biotin analogues comprising for example a hydroxymethylene, carboxylate, or acetate alpha to the biotinamide bond, such as described in Bioconjugate Chem., Vol. 12, No. 4, 2001 , 616-623.
- oligosaccharide residue of two to twenty five monosaccharide units is usable in the compounds of the present invention.
- Suitable compounds of the invention are compounds wherein the oligosaccharide is a sulfated oligosaccharide residue.
- the oligosaccharide residue is derived from an oligosaccharide which has (AT-III mediated) anti-Xa activity per se, such as the oligosaccharides disclosed in EP 0,454,220, EP 0,529,715, WO 97/47659, WO 98/03554, WO 99/36443 and WO 99/36428.
- oligosaccharide residues having two to sixteen, in particular two to six, monosaccharide units. Most preferably the oligosaccharide is a sulfated pentasaccharide residue. Preferred pentasaccharide residues have the formula (II)
- R 5 is independently a biotin residue or analogue thereof, OSO 3 - or (l -8C)alkoxy.
- the total number of sulfate groups is 4, 5, 6 or 7.
- Preferred compounds according to the invention are compounds wherein the pentasaccharide residue has the structure: wherein R 5 is OCH 3 or OSO 3 -.
- R 1 is phenyl or naphthyl, optionally substituted with one or more substituents selected from methyl or methoxy. More preferred, R 1 is 4-methoxy-2,3,6-trimethylphenyl.
- NR 3 R 4 represents the piperidinyl group.
- R 2 is H.
- the spacer is an essentially pharmacologically inactive flexible linking residue, preferably having 10-50 atoms counted along the "backbone" of the spacer, the oxygen of the oligosaccharide residue not included. Further preferred is a length of 13-25 atoms, preferably 16-22, and most preferred 19 atoms.
- the chemical nature of the spacer is of minor importance for the antithrombotic activity of the compounds of the invention.
- the spacer may comprise (somewhat) rigid elements, such as ring structures and unsaturated bonds. Highly flexible spacers are more suitable than others. Suitable spacers may easily be designed by a person skilled in the art. For synthetic reasons longer spacers are considered less suitable, however, longer spacers may still successivefully be applied in the compounds of the present invention.
- Preferred spacers comprise at least one -(CH 2 CH 2 O)- element.
- Preferred compounds according to the invention comprise one covalent bond with a biotin residue or analogue thereof.
- biotin (or analogue thereof) label may be present in all parts of the compound formula I. Therefore, embodiments of this invention are compounds wherein (a) the oligosaccharide residue of the compound of formula I comprises a covalent bond with a biotin residue or analogue thereof, (b) the spacer of the compound of formula I comprises a covalent bond with a biotin residue or analogue thereof and (c) the residue A of the compound of formula I comprises a covalent bond with a biotin residue or analogue thereof (which means that a hydrogen atom or substituent in the definition of A has been replaced by the biotin residue).
- biotinylated dual inhibitors of the present invention are:
- (l-4C)alkyl and (l-8C)alkyl mean a branched or unbranched alkyl group having 1-4 and 1-8 carbon atoms, respectively, for example methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, tert -butyl, hexyl and octyl. Methyl and ethyl are preferred alkyl groups.
- (l-8C)alkoxy means an alkoxy group having 1-8 carbon atoms, the alkyl moiety having the meaning as previously defined. Methoxy is a preferred alkoxy group.
- (3-8C)cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo-octyl. Cyclopentyl and cyclohexyl are preferred cycloalkyl groups.
- the spacer length is the number of atoms of the spacer, counted along the shortest chain between the oligosaccharide residue and the peptide part of the molecule, not counting the oxygen atom of the oligosaccharide residue which is connected to the spacer.
- prodrug means a compound of the invention in which for instance the amino group of the amidino -moiety is protected, e.g. by hydroxy or a (1 -6C)alkoxycarbonyl group.
- Solvates according to the invention include hydrates.
- biotin residue comprising a reactive group of for instance the activated ester, maleimide, iodoacetyl or primary amine type
- the biotin residue will preferably be reacted with an amine functional group, or a thiol functional group, or a carboxylic acid functional group, or an aldehyde functional group, the reaction taking place according to the conditions described in the literature (cf. Savage et al., Avidin-Biotin Chemistry: A Handbook; Pierce Chemical Company, 1992).
- the biotin residue can for instance be bonded directly to the (negatively charged) oligosaccharide residue or via an optionally N-(l-4C)alkylated amino functional group of a oligosaccharide-spacer residue or via an optionally N-(l-4C)alkylated amino acid residue to an optionally N-(l-4C)alkylated amine functional group of the oligosaccharide residue of the compound of formula I.
- biotin residue can for instance be bonded directly to residue A or via an optionally N-(l-4C)alkylated amino functional group of a linking residue or via an optionally N-(l-4C)alkylated amino acid residue to an optionally N-(l-4C)alkylated amine functional group of residue A of the compound of formula I.
- biotin residue can for instance be introduced stepwise by first bonding directly to residue A or via an optionally N-(l-4C)alkylated amino functional group of a part of the spacer of formula I or via an optionally N-(l-4C)alkylated amino acid residue to an optionally N-(l-4C)alkylated amine functional group of residue A of the compound of formula I and second bonding directly to an oligosaccharide or via an optionally N-(l-4C)alkylated amino functional group of part of the spacer of formula I or via an optionally N-(l-4C)alkylated amino acid residue to an optionally N-(l-4C)alkylated amine functional group of the (negatively charged) oligosaccharide of the compound of formula I, or vice versa.
- N-alkylated amino acid residues or ⁇ -N-substituted (beta-)amino acid analogues such as described in [Bioconjugate Chem., Vol. 12, No. 4, 2001, 616-623] may be introduced by a peptide coupling using methods known in the art.
- the azido group is a suitable latent amine functional group which can be used in precursors of the compound of the formula I for the subsequent introduction of the biotin residue.
- a preferred process for the preparation of the compound of formula I comprises a step wherein the benzamidine moiety in the residue A is in the form of a precursor, preferably being the 1,2,4- oxadiazolin-5-one group, and is subsequently converted into the benzamidine by deprotection, in particular by hydrogenation (Bolton, R.E. et al, Tetrahedron Letters, VoI 36, No 25, 1995, pp 4471-4474).
- the compounds of the present invention are further prepared by derivatizing NAPAP (or a NAPAP-analogue) at the glycine position with cysteine or lysine or aspartate using methods generally known in the art, which compound subsequently (a) is coupled to a oligosaccharide- spacer residue or (b) is coupled to a spacer, which then is derivatized with a thiol functional group or a carboxylic acid functional group and subsequently is coupled to an oligosaccharide residue.
- Any suitable oligosaccharide may be used for this purpose, for example oligosaccharides known in literature (e.g.
- the peptide coupling a procedural step in the above described method to prepare the compounds of the invention, can be carried out by methods commonly known in the art for the coupling - or condensation - of peptide fragments such as by the azide method, mixed anhydride method, activated ester method, the carbodiimide method, or, preferably, under the influence of ammonium/uronium salts like TBTU, especially with the addition of catalytic and racemisation suppressing compounds like N-hydroxysuccinimide, N-hydroxybenzotriazole and 7-aza-N- hydroxybenzotriazole. Overviews are given in The Peptides, Analysis, Synthesis, Biology, VoI 3,
- N-protecting group means a group commonly used in peptide chemistry for the protection of an ⁇ -amino group, like the tert-butyloxycarbonyl (Boc) group, the benzyloxycarbonyl (Z) group, the 9-fluorenylmethyloxycarbonyl (Fmoc) group or the phthaloyl (Phth) group, or may be introduced by demasking of an azide moiety.
- the compounds of the invention which can occur in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
- the pharmaceutically acceptable salts may also be obtained by treating the free base of formula (I) with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
- an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
- the compounds of this invention or intermediates thereof possess chiral carbon atoms, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers.
- Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. For diastereomers straight phase or reversed phase columns may be used.
- the compounds of the invention may be administered enterally or parenterally.
- the exact dose and regimen of these compounds and compositions thereof will neccessarily be dependent upon the needs of the individual subject to whom the medicament is being administered, the degree of affliction or need and the judgment of the medical practitioner.
- parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption.
- the daily dosages are for humans preferably 0.001-100 mg per kg body weight, more preferably 0.01-10 mg per kg body weight.
- the medicament manufactured with the compounds of this invention may also be used as adjuvant in acute anticoagulant therapy. In such a case, the medicament is administered with other compounds useful in treating such disease states.
- Mixed with pharmaceutically suitable auxiliaries e.g.
- the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
- solid dosage units such as pills, tablets, or be processed into capsules or suppositories.
- the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray.
- dosage units e.g. tablets
- conventional additives such as fillers, colorants, polymeric binders and the like
- any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
- Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
- Figure 1 Mean plasma levels determined by measurement of the anti-Xa or anti-IIa activity after s.c. administration of 100 nmol/kg of the biotinylated compound III of this invention ("biotin"). Besides the plasma levels are given of Org 42675 ("original") after determination of the anti-Xa activity.
- Boc tert-butyloxycarbonyl
- NMM N-methyl morpholine
- TBTU 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate
- TFA trifluoroacetic acid
- N ⁇ -deprotetced lysine derivative (0.14 mmol) was dissolved in DMF (3 mL) and was added to a solution of D-(+)-biotin (34 mg, 1 equiv.), TBTU (45 mg, 1 equiv.) and DiPEA (61 uL, 2.5 equiv.) in DMF (4 mL) that had been stirred under a nitrogen atmosphere for 1 h. The resulting mixture was stirred for 16 h. The solvent was removed under reduced pressure. EtOAc (30 mL) was added and stirred. The solid product 3 was collected by filtration and was washed with MeOH and EtOAc and dried in vacuo. Yield 86 mg (57%). Rf 0.15 (DCM/MeOH, 9/1, v/v). ESI-MS: 1083.6 [M+H] + .
- the carboxylic acid derivative (33 ⁇ mol) (i.e. compound 3 or 11 ) was dried by repeated concentration in dry DMF (2 x 2 mL), dissolved in DMF (1 mL) and stirred in the presence of TBTU (11 mg, 33 ⁇ mol) and DiPEA (5.7 ⁇ L, 33 ⁇ mol), under an atmosphere of N 2 . After Ih, pentasaccharide 4 (31 ⁇ mol) was added. The reaction mixture was stirred for 16 h at RT and analyzed by ion exchange (Mono-Q) chromatography. The reaction mixture was concentrated ( ⁇ 50°C, 15 mmHg).
- the (crude) product (10 mg/mL in H 2 O/t-BuOH, 1/1, v/v) was deprotected by hydrogenation (H 2 ) over 10% Pd/C (an equal amount in weight was added with respect to the crude product). After 16h the solution was degassed, filtered over a 0.45 ⁇ M HPLC filter and concentrated under reduced pressure ( ⁇ 50°C, 15 mmHg). The conjugate was purified by ion exhange chromatography (Q-sepharose, buffer: H 2 O ⁇ 2M NaCl), followed by desalting with a Sephadex G25 -column (H 2 O) and lyophilization.
- the crude oil was purified by silica column chromatography (DCM/MeOH/AcOH, 99/0/1 ⁇ 89/10/1, v/v/v), to give compound 7.
- Remaining AcOH was removed by dissolving the crude oily product in DCM/Et 2 O (1/2, v/v) and washing with H 2 O (3 times) and brine followed by drying over MgSO 4 . After filtration the solvent was removed under atmospheric pressure (50°C) to give compound 7 as a yellowish oil (0.37 g, 67%).
- Rf 0.32 DCM/MeOH, 89/10/1, v/v).
- D-(+)-Biotine 75 mg, 0.31 mmol was suspended in DCM (7 mL). DIPEA (0.11 mL, 0.62 mmol, 2 eq) and TBTU (0.10 g, 0.31 mmol) were subsequently added under an atmosphere of N 2 and the solution was allowed to stir for Ih. A solution of the above described N-L-lysine deprotected intermediate in DCM (3 mL) was added to the reaction mixture. The mixture was allowed to stir for 16 h. H 2 O was added and extracted with DCM (3x). The organic layer was dried (MgSO 4 ), filtered and concentrated under reduced pressure (850 mbar, 50 °C).
- the anti-factor Xa and Ha activity of the tested compounds in human plasma were measured amidolytically using S2222 or S2238 (Chromogenix, Chromogenics Ltd, Molndal, Sweden) as substrates, respectively.
- the protcols were based on the method described by Teien and Lie. (Teien AN, Lie M. Evaluation of an amidolytic heparin assay method increased sensitivity by adding purified antithrombin III. Thromb. Res. 1977, 10: 399-410). Both activities are expressed in IC-50 (Mol/L).
- Org 42675 and of compound III of this invention were studied in male Wistar rats of 300 - 400 gr.
- the rats were anaesthetized by inhalation of a mixture of ⁇ 2/N2 ⁇ /isoflurane, after which the right jugular vein was cannulated.
- rats were treated s.c. with doses of 100 nmol/kg.
- blood was sampled at several time intervals. Then the blood was centrifuged after which the plasma was siphoned off and stored at -20°C until use.
- the concentration of the tested compound was measured amidolytically using S-2222 or S-2238 as substrates (Chromogenix, Chromogenics Ltd, Molndal, Sweden) to determine the anti-Xa or anti-IIa activity, respectively. Both procedures were based on the methods of Teien and Lie (Teien AN, Lie M. Evaluation of an amidolytic heparin assay method increased sensitivity by adding purified antithrombin III. Thromb. Res. 1977, 10: 399-410). The concentrations in the obtained plasma samples were determined against a calibration curve which was made of the stock solution of the tested compound itself. The concentration in the samples was expressed in nmol/mL and the kinetic parameters were calculated with the noncompartment model of WinNonlin . (see Figure 1)
- Rats were treated with compound III of this invention, or Org 42675 at a dose of 100 nmol/kg s.c.
- t 2h
- a blood sample was taken and 10 mg/kg of Avidin (from egg white, Sigma) was administered i.v. to the rats treated with compound III of this invention or Org 42675.
- Blood was sampled at 0.17, 0.5, 1, 2, 3, and 7 hours subsequently.
- the blood was treated as described in the pharmacokinetic experiment and the concentration of the samples was determined by measuring the (residual) anti-Xa or anti-IIa activity, (see Figure 2)
- the antithrombotic activity as determined by measuring the (residual) anti-Xa and anti-IIa activity can be neutralized by administration of 10 mg/kg i.v. of avidin.
- the neutralization of compound III of this invention by avidin is reflected by the is reflected by the rapid reduction of its plasma concentration and the strongly reduced AUCinf. of compound III of this invention after administration of Avidin in comparison to compound Org 42675.
- the pharmacokinetic behavior of the non-biotinylated equivalent compound Org 42675 is not affected by the addition of avidin. The latter confirms that the neutralization is associated with the presence of the biotin label and that it does not affect the pharmacokinetic behavior of the dual inhibitor.
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Priority Applications (21)
Application Number | Priority Date | Filing Date | Title |
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JP2007547509A JP5130051B2 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors containing biotin residues |
AU2005318134A AU2005318134B2 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
PL05821769T PL1830887T3 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
DE602005026859T DE602005026859D1 (en) | 2004-12-23 | 2005-12-21 | ANTITHROMBOTIC DUAL-HEMMER WITH A BIOTINREST |
SI200531279T SI1830887T1 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
BRPI0518560-2A BRPI0518560A2 (en) | 2004-12-23 | 2005-12-21 | antithrombotic compound, pharmaceutical composition, process for compound preparation and compound use |
DK05821769.6T DK1830887T3 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic double inhibitors comprising a biotin residue |
EP05821769A EP1830887B1 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
KR1020077017005A KR101284922B1 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
US11/722,444 US8168595B2 (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
AT05821769T ATE500846T1 (en) | 2004-12-23 | 2005-12-21 | ANTITHRBOTIC DUAL INHIBITORS WITH A BIOTIN REST |
MX2007007837A MX2007007837A (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue. |
NZ555739A NZ555739A (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
CA2592436A CA2592436C (en) | 2004-12-23 | 2005-12-21 | Antithrombotic dual inhibitors comprising a biotin residue |
IL183713A IL183713A (en) | 2004-12-23 | 2007-06-06 | Antithrombotic dual inhibitors comprising a biotin residue |
NO20072878A NO20072878L (en) | 2004-12-23 | 2007-06-06 | Antithrombotic dual inhibitors comprising a biotin residue |
HK08100324.9A HK1106712A1 (en) | 2004-12-23 | 2008-01-10 | Antithrombotic dual inhibitors comprising a biotin residue |
HR20110330T HRP20110330T1 (en) | 2004-12-23 | 2011-05-06 | Antithrombotic dual inhibitors comprising a biotin residue |
IL217047A IL217047A0 (en) | 2004-12-23 | 2011-12-18 | Avidin or streptavidin for use to neutralise the anti-thrombotic activity of anti-thrombotic compounds |
US13/439,012 US20120238512A1 (en) | 2004-12-23 | 2012-04-04 | Antithrombotic dual inhibitors comprising a biotin residue |
US13/438,905 US8445450B2 (en) | 2004-12-23 | 2012-04-04 | Antithrombotic dual inhibitors comprising a biotin residue |
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US13/438,905 Division US8445450B2 (en) | 2004-12-23 | 2012-04-04 | Antithrombotic dual inhibitors comprising a biotin residue |
US13/439,012 Division US20120238512A1 (en) | 2004-12-23 | 2012-04-04 | Antithrombotic dual inhibitors comprising a biotin residue |
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WO2006067173A3 WO2006067173A3 (en) | 2007-04-26 |
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US (3) | US8168595B2 (en) |
EP (1) | EP1830887B1 (en) |
JP (2) | JP5130051B2 (en) |
KR (1) | KR101284922B1 (en) |
CN (1) | CN101087622A (en) |
AR (1) | AR053657A1 (en) |
AT (1) | ATE500846T1 (en) |
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BR (1) | BRPI0518560A2 (en) |
CA (1) | CA2592436C (en) |
DE (1) | DE602005026859D1 (en) |
DK (1) | DK1830887T3 (en) |
ES (1) | ES2361921T3 (en) |
HK (1) | HK1106712A1 (en) |
HR (1) | HRP20110330T1 (en) |
IL (2) | IL183713A (en) |
MX (1) | MX2007007837A (en) |
MY (1) | MY146121A (en) |
NO (1) | NO20072878L (en) |
NZ (1) | NZ555739A (en) |
PE (1) | PE20060773A1 (en) |
PL (1) | PL1830887T3 (en) |
PT (1) | PT1830887E (en) |
RU (1) | RU2403259C2 (en) |
SI (1) | SI1830887T1 (en) |
TW (1) | TWI403334B (en) |
UA (1) | UA88793C2 (en) |
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Cited By (6)
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WO2011073408A2 (en) | 2009-12-18 | 2011-06-23 | Endotis Pharma | Pharmaceutical oral dosage form containing a synthetic oligosaccharide |
WO2012146774A1 (en) | 2011-04-28 | 2012-11-01 | Endotis Pharma | Oligosaccharide conjugates in the prevention of ischemia-reperfusion injury |
WO2012172104A1 (en) | 2011-06-17 | 2012-12-20 | Endotis Pharma | Synthetic pentasaccharides having short half-life and high activity |
WO2013007762A1 (en) | 2011-07-11 | 2013-01-17 | Endotis Pharma | Combination of an anticoagulant and avidin useful in surgical intervention and clinical procedure |
US10660973B2 (en) | 2015-04-28 | 2020-05-26 | Duke University | Thrombus imaging aptamers and methods of using same |
US10889816B2 (en) | 2016-09-16 | 2021-01-12 | Duke University | Von Willebrand Factor (VWF)—targeting agents and methods of using the same |
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TWI403334B (en) * | 2004-12-23 | 2013-08-01 | Merck Sharp & Dohme | Antithrombotic dual inhibitors comprising a biotin residue |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011073408A2 (en) | 2009-12-18 | 2011-06-23 | Endotis Pharma | Pharmaceutical oral dosage form containing a synthetic oligosaccharide |
WO2012146774A1 (en) | 2011-04-28 | 2012-11-01 | Endotis Pharma | Oligosaccharide conjugates in the prevention of ischemia-reperfusion injury |
WO2012172104A1 (en) | 2011-06-17 | 2012-12-20 | Endotis Pharma | Synthetic pentasaccharides having short half-life and high activity |
US9556215B2 (en) | 2011-06-17 | 2017-01-31 | Carbomimetics | Synthetic pentasaccharides having short half-life and high activity |
WO2013007762A1 (en) | 2011-07-11 | 2013-01-17 | Endotis Pharma | Combination of an anticoagulant and avidin useful in surgical intervention and clinical procedure |
US10660973B2 (en) | 2015-04-28 | 2020-05-26 | Duke University | Thrombus imaging aptamers and methods of using same |
US11565002B2 (en) | 2015-04-28 | 2023-01-31 | Duke University | Thrombus imaging aptamers and methods of using same |
US10889816B2 (en) | 2016-09-16 | 2021-01-12 | Duke University | Von Willebrand Factor (VWF)—targeting agents and methods of using the same |
US11965160B2 (en) | 2016-09-16 | 2024-04-23 | Duke University | Von Willebrand Factor (VWF)-targeting agents and methods of using the same |
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