WO2015107139A1 - Composés destinés à être utilisés en tant qu'agents anti-fibrinolytiques - Google Patents

Composés destinés à être utilisés en tant qu'agents anti-fibrinolytiques Download PDF

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Publication number
WO2015107139A1
WO2015107139A1 PCT/EP2015/050746 EP2015050746W WO2015107139A1 WO 2015107139 A1 WO2015107139 A1 WO 2015107139A1 EP 2015050746 W EP2015050746 W EP 2015050746W WO 2015107139 A1 WO2015107139 A1 WO 2015107139A1
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compound
use according
hemorrhage
formula
pharmaceutically
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PCT/EP2015/050746
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English (en)
Inventor
Josune Orbe Lopategui
Julen Oyarzabal Santamarina
José Antonio PÁRAMO FERNÁNDEZ
José Antonio RODRÍGUEZ GARCÍA
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Proyecto De Biomedicina Cima, S.L.
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Publication of WO2015107139A1 publication Critical patent/WO2015107139A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the present invention relates to a second medical indication of known therapeutic agents. Particularly, this invention relates to known compounds for use as antifibrinolytic agents, in particular, to prevent and control bleeding.
  • the hemostatic system is responsible for maintaining circulatory fluidity and for preventing hemorrhage in response to vascular injury.
  • Physiological hemostasis is controlled by mechanisms of coagulation and the formation of fibrin and by those favouring the degradation of fibrin (fibrinolysis).
  • Hyperfibrinolysis refers to a congenital or acquired condition due to
  • fibrinolytic system pathological activation of natural defense mechanisms, the fibrinolytic system. It is characterized by the generation of large amounts of plasmin, which degrades fibrin leading to massive clot lysis and clinical bleeding.
  • Post-partum hemorrhage is another leading cause of death in the developing world, accounting for 25% of maternal deaths, and rose in the the developed world from 1 .5% in 1999 to 4.1 % in 2009.
  • the risk of hemorrhage can also be important in cardiovascular patients on anti-coagulant therapy.
  • Pharmacological approaches are an important part of multimodal therapy aiming to reducing bleeding and transfusion in order to reverse specific defects associated with such states; among them, the role of fibrinolysis inhibitors is growing.
  • a major goal in surgery as well as in the treatment of major tissue damage is to avoid or minimise bleeding in order to ensure the formation of stable and solid hemostatic plugs that are not easily dissolved by fibrinolytic enzymes. Furthermore, it is of importance to ensure quick and effective formation of such plugs or clots.
  • Antifibrinolytic agents are widely used in major surgery to prevent fibrinolysis and reduce blood loss.
  • Currently two synthetic lysine analogs, epsilon- aminocaproic acid (EACA) and tranexamic acid (TXA) are the only antifibrinolytics commercially available to control bleeding. These agents competitively inhibit activation of plasminogen to plasmin, an enzyme that degrades fibrin clots, fibrinogen and other plasma proteins.
  • Inventors have identified a series of known therapeutic agents which show good antifibrinolytic properties.
  • these compounds which have in common that are capable of inhibiting matrix metalloprotease (MMP) activity, show a significant delay in the lysis time in a thromboelastometry assay.
  • MMP matrix metalloprotease
  • characteristics of the compounds of the invention allow a rapid cessation of hemorrhage; favor an effective formation of plugs or clots; have a sustained action (persistence of the clot and prevention of hemorrhage) and aid in minimizing the adverse effects related to other antifibrinolytic/antihemorrhag treatments having risk of thrombotic complications.
  • the present invention relates to a compound selected from the group consisting of:
  • MMP matrix metalloprotease
  • this aspect can also be formulated as the use of a compound which is selected from the group consisting of formula (I) to formula (XXII) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer either of any of the compounds of formula (I) to formula (XXII) or of any of their pharmaceutically or veterinary acceptable salts, for the manufacture of a medicament for use as antifibrinolytic agent.
  • This aspect may also be formulated as a method for the treatment and/or prevention of hyperfibrinolysis comprising administering an effective amount of compound which is selected from the group consisting of formula (I) to formula (XXII) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer either of any of the compounds of formula (I) to formula (XXII) or of any of their pharmaceutically or veterinary acceptable salts, and one or more pharmaceutically or veterinary acceptable excipients or carriers, in a mammal in need thereof, including a human.
  • salts there is no limitation on the type of salt that can be used, provided that these are pharmaceutically or veterinary acceptable when they are used for therapeutic purposes.
  • pharmaceutically or veterinary acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • the preparation of pharmaceutically or veterinary acceptable salts of the compounds of formula (I) to formula (XXII) can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate pharmaceutically or veterinary acceptable base or acid in water or in an organic solvent or in a mixture of them.
  • the compounds of formula (I) to formula (XXII) and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention.
  • Some compounds of formula (I) to formula (XXII) may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention.
  • solvated forms with pharmaceutically or veterinary acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for the purposes of the invention.
  • Some compounds of the invention can have chiral centres that can give rise to various stereoisomers.
  • the present invention relates to each of these stereoisomers and also mixtures thereof.
  • some of the compounds of the present invention can show cis/trans isomers.
  • the present invention relates to each of the geometric isomers and mixtures thereof.
  • Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic
  • Optically pure isomers can also be individually obtained using enantiospecific synthesis.
  • the compounds of formula (l)-(XI), (XIV), (XVI), (XVIII)-(XX), and (XXII) are commercially available.
  • the compounds of formula (XII)-(XIII), (XV), (XVII), and (XXI) can be synthetized by methods well-known in the art.
  • the compound of formula (XII) may be synthethized as described in
  • the compound of formula (XV) may be synthethized as described in WO9817643.
  • the compound of formula (XVII) may be synthethized as described in WO9600214.
  • the compounds (XIII) and (XXI) may be
  • the invention relates to a compound for use as an antifibrinolytic agent, which is selected from the group consisting of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), and formula (VII) as previously defined.
  • the compound for use as an antifibrinolytic agent is selected from the group consisting of formula (I), formula (II), formula (III), and formula (IV); more particulary, formula (I) and formula (II); and even more particularly formula (I).
  • the compounds of formula (I) to formula (XXII) for use as antifibrinolytic agents have in common that they are capable of inhibiting matrix metalloprotease (MMP) activity.
  • MMP matrix metalloprotease
  • MMPs Matrix metalloproteinases
  • ECM extracellular matrix
  • collagenases such as MMP1 , MMP8, MMP13, and MMP18
  • gelatinases such as MMP2 and MMP9
  • stromelysins such as MMP3, MMP10, and MMP-1 1
  • matrilysins such as MMP7 and MMP26.
  • MMP activity refers to their capacity to inhibit partially or totally, directly or indirectly, MMP by inhibiting the catalytic activity of MMPs, by reducing MMPs at pre- and post-translational levels, or by decreasing the degradation of endogenous tissue inhibitors of metalloproteinases (TIMPs) indirectly.
  • the inhibition of MMP activity can be total if the MMP activity measure is equal to or below than 10% compared to basal values. If the MMP activity measure is higher than 10% and lower than 100%, more particularly higher than 10% and equal or lower than 90%, the MMP activity is considered partially inhibited.
  • the ability of the compounds of formula (I) to formula (XXII) of inhibiting matrix metalloprotease (MMP) activity is, in particular, referred to one or more MMPs selected from the group consisting of MMP1 , MMP2, MMP3, MMP8, MMP9, MMP10, MMP13 and MMP14, more particularly selected from the group consisting of MMP2, MMP3, MMP9, and MMP13.
  • MMPs selected from the group consisting of MMP1 , MMP2, MMP3, MMP8, MMP9, MMP10, MMP13 and MMP14, more particularly selected from the group consisting of MMP2, MMP3, MMP9, and MMP13.
  • the compound for use as antifibrinolytic agent is a diaryl ether hydroxamate selected from the group consisting of formula (III), formula (XIX), and formula (XXI).
  • the compound for use as antifibrinolytic agent is a tetracycline-based compound selected from the group consisting of formula (II), formula (XI), and formula (XVIII).
  • the compound is a thiol-based compound selected from the group consisting of formula (I), and formula (VIII).
  • the compounds of the present invention are useful as antifibrinolytic agents inhibiting the degradation of fibrin, and can be used in a broad range of therapeutic applications.
  • the invention relates to a compound for use as antifibrinolytic agent in the treatment and/or prevention of hemorrhage associated to hyperfibrinolysis in a mammal, including a human.
  • hyperfibrinolytic states can be associated to congenital abnormalities or acquired complications, e.g. those related to treatment with fibrinolytic or anticoagulant agents, others related to some surgery or tumours of tissues or organs rich in fibrinolysis activators, in mammals with
  • DIC disseminated intravascular coagulation
  • the hyperfibrinolysis is associated to congenital abnormalities, more particularly, in a mammal suffering from Hemophilia A, von Willebrand disease, deficiency of Plasminogen Activator Inhibitor 1 (PAI-1 ), or deficiency of Alpha2-Antiplasmin.
  • PAI-1 Plasminogen Activator Inhibitor 1
  • the invention relates to a compound for use antifibrinolytic agent in the treatment and/or prevention of hemorrhage associated to hyperfibrinolysis in a mammal receiving fibrinolytic or anticoagulant treatment.
  • the invention relates to a compound for use as antifibrinolytic agent in the treatment and/or prevention of hemorrhage associated to hyperfibrinolysis in a mammal with disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • the hyperfibrinolysis is caused by surgery or tumours of tissues or organs rich in fibrinolysis activators.
  • the hyperfibrinolysis is caused by failure to clear plasminogen activators, more particularly, caused by severe liver disease or acute promyelocytic leukaemia associated with DIC.
  • the hyperfibrinolysis is caused by trauma, by thrombolytics administered to patients suffering acute heart attack, ischemic stroke or acute peripheral artery disease.
  • the hyperfibrinolysis is caused by thrombolytics administered to patients suffering vascular graft occlusion.
  • the hemorrhage is selected from the group consisting of: major hemorrhage, intracraneal hemorrhage, menstrual hemorrhage (menorrhage), post-partum hemorrhage, gastrointestinal hemorrhage, subarachnoid haemorrhage, urinary hemorrhage (including prostatectomy), tooth hemorrhage, and hemorrhage caused by surgery.
  • the hemorrhage caused by surgery comprises
  • the surgery is selected from surgery on organs rich in plasminogen activators (prostate, lung, uterus); cardiac surgery, orthopaedic surgery, liver surgery, spinal and cranial surgery, and other surgical procedures such as ocular and dental surgery.
  • organs rich in plasminogen activators prostate, lung, uterus
  • cardiac surgery orthopaedic surgery
  • liver surgery spinal and cranial surgery
  • other surgical procedures such as ocular and dental surgery.
  • the compound of formula (I) to formula (XXII) for use as antifibrinolytic agent is an active pharmaceutical or veterinary ingredient of a pharmaceutical or veterinary composition, which comprises an effective amount of the compound sleeted from the group consisting of formula (I) to formula (XXII), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer either of any of the compounds of formula (I) to formula (XXII) or of any of their pharmaceutically or veterinary acceptable salts, together with one or more pharmaceutically or veterinary acceptable excipients or carriers.
  • an effective amount refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
  • the specific dose of the compound of the invention to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration. For example, a dose of from about 0.01 to about 300 mg/kg may be used.
  • pharmaceutically or veterinary acceptable excipients or carriers refers to pharmaceutically or veterinary acceptable materials, compositions or vehicles. Each component must be pharmaceutically or veterinary acceptable in the sense of being compatible with the other ingredients of the pharmaceutical or veterinary composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the pharmaceutical or veterinary formulation will depend upon the nature of the active compound and its route of administration. Any route of administration may be used.
  • the pharmaceutical or veterinary composition is administered orally, topically or parenterally.
  • the pharmaceutical or veterinary composition may be formulated for oral administration and may contain one or more physiologically
  • compatible carriers or excipients in solid or liquid form.
  • These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the pharmaceutical or veterinary composition may be formulated for parenteral administration in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical or veterinary excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such compositions.
  • compositions may be injected subcutaneously, intramuscularly, intraperitoneal ⁇ , or intravenously.
  • the pharmaceutical or veterinary composition may be formulated for topical administration.
  • Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.
  • the topical compositions of the invention may be administered by means of a carrier material, which can be a solid support.
  • a topical composition comprising a carrier material, which can be a solid support.
  • solid supports include intelligent textiles, dressings, coatings, sponges, band-aids, sanitary pads, compresses, plasters, etc.
  • the manufacture of such compositions can be obtained by conventional methods, for example, by mixing the
  • compositions may be in any form, including, among others, tablets, pellets, capsules, aqueous or oily solutions,
  • suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release can readily be determined by those skilled in the art according to the type of formulation being prepared.
  • Thromboelastometry is a viscoelastometric method for hemostasis testing in whole blood.
  • TEM® measures the interactions of coagulation factors, inhibitors and cellular components during the phases of clotting and
  • Table 1 shows the results in human blood as effective concentration to delay lysis time by 50% (EC 50 LT); where, EC 50 LT ⁇ 25 ⁇ (+),10 ⁇ ⁇ EC 50 LT ⁇ 25 ⁇ (++), 1 ⁇ ⁇ ECSO LT ⁇ 10 ⁇ (+++), EC 50LT ⁇ 1 ⁇ (++++) at all the assayed concentrations (1000-0.2 ⁇ ).
  • Example EC50LT
  • Table 2 shows the results in mice blood as effective concentration to delay lysis time by 50% (EC 50 LT); where, EC 50 LT ⁇ 10 ⁇ (+),1 ⁇ ⁇ EC 50 LT ⁇ 10 ⁇ (++),1 nM ⁇ EC50LT ⁇ 1 ⁇ (+++) and EC 50LT ⁇ 1 nM (++++) for all the assayed concentrations (1000-0.2 ⁇ ).
  • Hyperfibrinolytic bleeding model consisted in injection of 0.5 mg/kg tPA into the ocular plexus to prolong bleeding time due to excessive fibrinolysis.
  • tPA 0.5 mg/kg tPA
  • polyurethane catheter (Microcannula 72-9030, Harvard Apparatus) for agents administration.
  • the catheter was connected to a syringe pump (AL-1000, WPI) for the infusion of 200 ⁇ _ (10% bolus, 90% perfusion during 40 minutes) of tested agents.
  • tPA 0.5 mg/kg was injected into the ocular plexus and five minutes after tPA administration, saline or the different compounds was infused through the femoral catheter to ensure systemic distribution of all the agents.
  • Reference compounds, TXA and Aprotinin were administered at 300 and 10 mg/Kg respectively; however, all compounds of the invention were administered at 1 mg/Kg.
  • tested compounds of the invention show a significant reduction of the bleeding time when compared to the control or TXA.

Abstract

L'invention concerne des inhibiteurs de métalloprotéase matricielle (MMP) ou leurs sels acceptables d'un point de vue pharmaceutique ou vétérinaire destinés à être utilisés en tant qu'agents anti-fibrinolytiques, en particulier, pour prévenir et réguler un saignement.
PCT/EP2015/050746 2014-01-17 2015-01-16 Composés destinés à être utilisés en tant qu'agents anti-fibrinolytiques WO2015107139A1 (fr)

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EP14382013 2014-01-17

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US11622893B2 (en) 2020-04-09 2023-04-11 Bio 54, Llc Devices for bleeding reduction and methods of making and using the same
US11642324B1 (en) 2022-03-01 2023-05-09 Bio 54, Llc Topical tranexamic acid compositions and methods of use thereof

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