WO2015107139A1

WO2015107139A1 - Compounds for use as antifibrinolytic agents

Info

Publication number: WO2015107139A1
Application number: PCT/EP2015/050746
Authority: WO
Inventors: Josune Orbe Lopategui; Julen Oyarzabal Santamarina; José Antonio PÁRAMO FERNÁNDEZ; José Antonio RODRÍGUEZ GARCÍA
Original assignee: Proyecto De Biomedicina Cima, S.L.
Priority date: 2014-01-17
Filing date: 2015-01-16
Publication date: 2015-07-23

Abstract

It relates to matrix metalloprotease (MMP) inhibitors for their pharmaceutically or veterinary acceptable salts for use as antifibrinolytic agents, in particular, to prevent and control bleeding.

Description

Compounds for use as antifibrinolytic agents

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.

BACKGROUND ART

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

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.

Hyperfibrinolytic states predispose to important hemorrhagic complications, often requiring transfusions and the need for re-exploration having a detrimental effect on patient outcome. Hemorhage is responsible for almost 50% of deaths occurring within 24 hours of traumatic injury and for up to 80% of intraoperative trauma mortality. In western countries about one third of in- hospital deaths due to trauma is caused by abnormal blood loss which is an important contributory factor for other causes of death, particularly multi- organ failure, requiring massive blood transfusion. Failure to start appropriate early management in bleeding trauma patients is a leading cause of preventable death from trauma. Post-partum hemorrhage (PPH) 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.

It is well known that subjects who bleed excessively in association with surgery or major trauma and need blood transfusions develop more complications than those who do not experience any bleeding. However, moderate bleeding requiring the administration of human blood products may lead to complications associated with the risk of transferring human viruses. Extensive bleeding requiring massive blood transfusions may lead to the development of multiple organ failure including lung or kidney function.

Therefore, 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.

However, there are some concerns with these currently available

antifibrinolytic agents due to the potential risk of thrombotic complications.

There is still a need for improved treatment of subjects experiencing bleeding episodes, including those due to surgery, trauma, or other forms of tissue damage, as well as in clinical scenarios characterized by excessive fibrinolysis.

SUMMARY OF THE INVENTION

Inventors have identified a series of known therapeutic agents which show good antifibrinolytic properties. In particular, 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. In addition, they also show an important reduction of the bleeding time in vivo animal model as it will be shown in detail in the examples. These

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.

Accordingly, the present invention relates to a compound selected from the group consisting of:

VII) (VIM) (IX)

(XIII) (XIV) (XV)

(XVI) (XVII) (XVIII)

XIX) (XX)

(XXI) 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 use as an antifibrinolytic agent.

As mentioned above, the compounds of formula (I) to formula (XXII) have in common that they are capable of inhibiting matrix metalloprotease (MMP) activity. Further, there are also some structural similarities between some of them.

As far as the inventors know, a link between the ability of a small molecule of inhibiting matrix metalloprotease (MMP) activity and an antifibrinolytic effect has not been established in the prior art.

Thus, 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. DETAILED DESCRIPTION OF THE INVENTION

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

In all embodiments of the invention referring to some of the compounds of formula (I) to formula (XXII), the pharmaceutically or veterinary acceptable salts thereof and the stereoisomers either of any of the compounds of formula (I) to formula (XXII) or of any of their pharmaceutically or veterinary

acceptable salts are always contemplated even if they are not specifically mentioned.

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. The term "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. Generally, 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.

Methods of solvation are generally known within the art. In general, the 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. Moreover, 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

intermediate or on products of general formula (I) to formula (XXII). Optically pure isomers can also be individually obtained using enantiospecific synthesis.

In the table below, the common names, synonyms, chemical structures, chemical names and CAS Registry numbers for some of the compounds of the invention are summarized.

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. For example, the compound of formula (XII) may be synthethized as described in

EP719770. 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

synthetized by routine methods well-known in the art. In a particular embodiment, optionally in combination with any of the embodiments above or below, 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.

In a more particular embodiment, 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).

As mentioned above, 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.

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. In humans at least 26 MMPs are known, which are classified on the basis of their specificity into collagenases (such as MMP1 , MMP8, MMP13, and MMP18), gelatinases (such as MMP2 and MMP9), stromelysins (such as MMP3, MMP10, and MMP-1 1 ), and matrilysins (such as MMP7 and MMP26). The term "capable of inhibiting matrix metalloprotease (MMP) activity" as used herein 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. The ability of the compounds of formula (I) to formula (XXII) of inhibiting matrix metalloprotease (MMP) activity is disclosed for example in the bibliographic references summarized in the table below.

In another embodiment, optionally in combination with any of the

embodiments above or below, 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).

In another embodiment, optionally in combination with any of the

embodiments above or below, 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).

In another embodiment, optionally in combination with any of the

embodiments above or below, 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. In a particular embodiment, optionally in combination with any of the embodiments above or below, 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. In some cases, 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

disseminated intravascular coagulation (DIC), or in situations of failure to clear plasminogen activators.

Thus, in a more particular embodiment, optionally in combination with any of the embodiments above or below, 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.

In another more particular embodiment, optionally in combination with any of the embodiments above or below, 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.

In another more particular embodiment, optionally in combination with any of the embodiments above or below, 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). In another more particular embodiment, optionally in combination with any of the embodiments above or below, the hyperfibrinolysis is caused by surgery or tumours of tissues or organs rich in fibrinolysis activators. In another more particular embodiment, optionally in combination with any of the embodiments above or below, the hyperfibrinolysis is caused by failure to clear plasminogen activators, more particularly, caused by severe liver disease or acute promyelocytic leukaemia associated with DIC.

In another more particular embodiment, optionally in combination with any of the embodiments above or below, the hyperfibrinolysis is caused by trauma, by thrombolytics administered to patients suffering acute heart attack, ischemic stroke or acute peripheral artery disease.

In another more particular embodiment, optionally in combination with any of the embodiments above or below, the hyperfibrinolysis is caused by thrombolytics administered to patients suffering vascular graft occlusion.

In a more particular embodiment, optionally in combination with any of the embodiments above or below, 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.

In one embodiment, the hemorrhage caused by surgery comprises

hemorrhage prior, during and/or post surgery and includes transplants and biopsies. More particularly, 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. In one embodiment of the invention, optionally in combination with any of the embodiments above or below, 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.

The expression "effective amount" as used herein, 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.

The expression "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 election of 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. In one embodiment of the invention, optionally in combination with any of the embodiments above or below, the pharmaceutical or veterinary composition is administered orally, topically or parenterally. For example, 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. These

pharmaceutical or veterinary 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. Thus, it also forms part of the invention a topical composition comprising a carrier material, which can be a solid support. Illustrative, non-limiting examples of 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

combinations of the invention and the material carrier.

The pharmaceutical or veterinary 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. The appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared.

Throughout the description and claims the word "comprise" and variations of thereof, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise" encompasses the case of "consisting of. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. EXAMPLES Antifibrinolytic effect on whole blood clot formation and lysis

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

subsequent lysis over time. The rheological conditions of this method mimic the sluggish flow of blood in veins.

Detection method:

Blood samples were obtained between 8-9 a.m. from healthy volunteers and mice in tubes containing citrate solution (0.129 M sodium citrate, Vacutainer BD) and ROTEM tests were performed following the technical details of the ROTEM® analyser (Pentapharm GmbH, Munich, Germany). A modification of in-tem test as described below was used for the examination of antifibrinolytic effects of tested compounds and its interaction with platelets in citrated blood. Kits: START-TEM assay as a recalcification reagent (ref#503-01 ) and IN-TEM assay for activation of intrinsic coagulation pathway (ref#503-02).

Procedure:

In a pre-warmed cuvette and holder 1 μΙ_ of tPA (150,000 U/mL, Actylise), 20 μΙ_ of start-tern reagent (CaCI₂), 20 μί of in-tem reagent (activators of coagulation system), 3 μΙ_ of DMSO (control) or tested compounds (CMs) in DMSO and 300 μΙ_ of citrated blood pre-warmed were pipetted. The cup holder containing the sample mixture was placed immediately on the appropriate channel. The measurement was recorded for 60 min to allow clot formation and lysis.

Table 1 shows the results in human blood as effective concentration to delay lysis time by 50% (EC₅₀LT); where, EC₅₀LT≥ 25 μΜ (+),10 μΜ < EC₅₀LT < 25 μΜ (++), 1 μΜ < ECSO_LT < 10 μΜ (+++), EC_50LT < 1 μΜ (++++) at all the assayed concentrations (1000-0.2 μΜ).

Example EC50LT

llomastat ++++

Isotretionine +++

Marimastat +++

Doxycycline ++++

Tanomastat +++

CTS-1027 ++++

Table 1

Table 2 shows the results in mice blood as effective concentration to delay lysis time by 50% (EC₅₀LT); where, EC₅₀LT≥10μΜ (+),1 μΜ < EC₅₀LT < 10μΜ (++),1 nM < EC50LT < 1 μΜ (+++) and EC_50LT < 1 nM (++++) for all the assayed concentrations (1000-0.2 μΜ).

Table 2

As observed in the tables above (Tables 1 and 2), compounds of the invention show significant delay in the lysis time, in many cases higher than TXA.

Antifibrinolvtic effect in vivo (tail bleeding assay)

Bleeding time was evaluated in 2 months old wild-type C57BI6 (n=10) mice by removing the tail tip. Mice (20-25 g) were anaesthetized with 2.5% isoflurane and maintained at 37 °C on heating pads. The hemostatic efficacy was evaluated in a hyperfibrinolytic bleeding model.

Hyperfibrinolytic bleeding model, consisted in injection of 0.5 mg/kg tPA into the ocular plexus to prolong bleeding time due to excessive fibrinolysis. First, the femoral vein was exposed and cannulated with a saline-filled

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 μΙ_ (10% bolus, 90% perfusion during 40 minutes) of tested agents. Then, 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. Five minutes later, 5 mm of tail tip were removed using a scalpel blade and the tail tip bathed in 1 mL of sterile saline at 37 °C. The time of bleeding was defined as the interval between initial transections and the visual cessation of bleeding, that was measured up to 30 minutes. A value of 30 min was assigned to those animals bleeding longer than the observation period. Table 3 shows the results reporting bleeding time (BT); where BT > 20 minutes (+),10 minutes < BT < 20 minutes (++), 5 minutes < BT < 10 minutes (+++) and BT < 5 minutes (⁺⁺⁺⁺). Bleeding time was determined in wild type mice (C57/BI6), where n > 10 per assayed compound; therefore, BT is reported as a mean value - in the case of saline, BT is reported as mean±ESM.

*p<0.05;**p<0.01 vs saline;†p<0.05 vs TXA

Table 3

As shown table 3, tested compounds of the invention show a significant reduction of the bleeding time when compared to the control or TXA.

REFERENCES CITED IN THE APPLICATION

- EP719770.

- WO9817643.

- WO9600214.

- Fingleton, B., "Matrix Metalloproteinases as Valid Clinical Targets", Current Pharmaceutical Design 2007, vol. 13, pp. 333-346.

- Liu, J. et al., "Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells", Journal of Vascular Surgery, 2003, vol 38, pp. 1376-1383.

- Pasternak, B et al, "Doxycycline impairs tendon repair in rats", Acta Orthop. Belg. 2006, vol. 72, pp. 756-760.

- EP780386.

- Papakonstantinou, E. et al., "Matrix Metalloproteinases of Epithelial Origin in Facial Sebum of Patients with Acne and their Regulation by Isotretinoin", Journal of Investigative Dermatology 2005, vol. 125, pp. 673-684.

- Dahl, Ronald et al., "Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: A randomized controlled trial", Pulmonary Pharmacology & Therapeutics 2012, vol . 25, pp. 169-177.

- WO2000044739.

- WO9817643.

- WO9600214.

- Koistinaho, M. et al., "Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice" ,

Journal of Cerebral Blood Flow & Metabolism 2005, vol. 25, pp. 460-467.

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hypertension and diabetic Nephropathy", Am. J. Physiol. Renal Physiol. 201 1 , vol. 300, F983 - F998.

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Claims

1 . A compound capable of inhibiting matrix metalloprotease (MMP) activity which is selected from the group consisting of:

(VII) (VIII) (IX)

(XIII) (XIV) (XV)

(XVI) (XVII) (XVIII)

XIX) (XX)

(XXI) or a pharmaceutically or veterinary acceptable salt thereof, or any

2. The compound for use according to claim 1 , wherein the compound is selected from the group consisting of:

(I) (II) (HI)

(VII)

3. The compound for use according to claim 2, wherein the compound is selected from the group consisting of:

(I) (II)

(IV)

4. The compound for use according to claim 3, wherein the compound is selected from the group consisting of:

(I) (II)

5. The compound for use according to any of the claims 1 -4, in the treatment and/or prevention of hemorrhage associated to hyperfibnnolysis in a mammal.

6. The compound for use according to claim 5, wherein the hyperfibrinolsis is associated to congenital abnormalities.

7. The compound for use according to claim 5, wherein the mammal is a mammal receiving receiving fibrinolytic or anticoagulant treatment.

8. The compound for use according to claim 5, wherein the mammal is a mammal with disseminated intravascular coagulation.

9. The compound for use according to claim 5, wherein the hyperfibnnolysis is caused by surgery or tumours of tissues or organs rich in fibrinolysis activators.

10. The compound for use according to claim 5, wherein the hyperfibnnolysis is caused by failure to clear plasminogen activators.

1 1 . The compound for use according to claim 5, wherein the hyperfibnnolysis is caused by trauma, or by thrombolytics administered to patients suffering acute heart attack, ischemic stroke or acute peripheral artery disease.

12. The compound for use according to claim 5, wherein the hyperfibnnolysis is caused by thrombolytics administered to patients suffering vascular graft occlusion.

13. The compound for use according to claim 5, wherein the hemorrhage associated to hyperfibrinolysis is selected from the group consisting of: major hemorrhage, intracraneal hemorrhage, menstrual hemorrhage (menorrhage), post-partum hemorrhage, gastrointestinal hemorrhage, subarachnoid haemorrhage, urinary hemorrhage, tooth hemorrhage, and hemorrhage caused by surgery.

14. The compound for use according to any of the claims 1 -13, as an active pharmaceutical or veterinary ingredient of a pharmaceutical or veterinary composition comprising an effective amount of the compound as defined in any of the claims 1 -4, 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.

15. The compound for use according to claim 14, wherein the pharmaceutical or veterinary composition is administered orally, topically or parenterally.