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WO2020060964A1 - Dérivés de 1, 2, 4-oxadiazole et leurs utilisations - Google Patents

Dérivés de 1, 2, 4-oxadiazole et leurs utilisations Download PDF

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Publication number
WO2020060964A1
WO2020060964A1 PCT/US2019/051391 US2019051391W WO2020060964A1 WO 2020060964 A1 WO2020060964 A1 WO 2020060964A1 US 2019051391 W US2019051391 W US 2019051391W WO 2020060964 A1 WO2020060964 A1 WO 2020060964A1
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Prior art keywords
triazol
oxadiazole
alkyl
ethyl
oxadiazol
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Francisco-Javier PEDRENO
Luis CAVEDA
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Alxerion Biotech Corp
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Alxerion Biotech Corp
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention is in the field of medicine and pharmacology. More particularly, the invention relates to hemostasis and compounds useful for the treatment of cancer and disorders resulting from a disruption of hemostasis.
  • l,2,4-oxadiazoles are flat, aromatic linkers able to bend a drug’s structure, and to exert an electron-withdrawing effect. They have been used as bioisosteric replacements of esters and amides, and have been used as a pharmacophore.
  • Compounds containing 1,2,4- oxadizole cores have a broad biological activity spectrum.
  • certain 1,2,4- oxadiazole derivative are known to have biological activities useful in treating certain diseases and disorders, including antibacterial, antifungal, analgesic, anti-inflammatory, antiviral, anticancer, antihypertensive, anticonvulsant, and anti-diabetic properties.
  • proteases are produced to degrade proteins into peptides or amino acids to be used either as an energy source or as building blocks for resynthesize proteins. Proteases also modify cellular environments and facilitate cell migration in connection with wound repair and cancer, ovulation and implantation of the fertilized egg, embryonic morphogenesis, and involution of mammary glands after lactation.
  • proteases are regulators in processes such as inflammation, infection and blood clotting.
  • proteolytic enzymes act on their natural substrates, proteins and peptides by hydrolyzing one or more peptide bond(s). This process is usually highly specific in the sense that only peptide bonds adjacent to certain amino acids are cleaved. Consequently, most proteolytic enzymes are highly specific for their substrates.
  • Mammalian serine proteases are one type of protease that may be divided into two families: the trypsins; and the subtilisins.
  • the trypsin family contains, among others, trypsin and chymotrypsin, elastase, mast cell tryptase, and many of the factors regulating blood coagulation and fibrinolysis, including thrombin, Factor Xa, plasmin, tissue plasminogen activator (tA), urokinase plasminogen activator (uPA), and others.
  • Fibrinolysis is the degradation of the blood plasma protein, fibrin.
  • Plasminogen is an inactive protein found in blood and is a precursor to plasmin. Plasmin is an enzyme that degrades blood plasma proteins such as fibrin, fibrinogen, Factors V, VIII, IX, XI, and XII, inter alia. Serine proteases are known to activate plasminogen to plasmin.
  • serine proteases are involved in the breakdown of the extracellular matrix, allowing for cancer invasion and metastasis. It is accomplished by the concerted action of several proteases, including the serine protease plasmin and several matrix
  • plasmin involves the pro-enzyme plasminogen, the urokinase type plasminogen activator, uPA, and its pro-enzyme, pro-uP A, the uPA inhibitor, PAI-l, the cell surface uPA receptor uPAR, and the plasmin inhibitor a2- anti plasmin.
  • the plasminogen system promotes tumor metastasis by several different mechanisms.
  • One of these mechanisms is the uPA and uPAR (uPA receptor) system, which initiates the activation of MMPs as well as the conversion of plasminogen to plasmin followed by ECM degradation and reduced cellular interaction.
  • the uPA system is a conversion system from plasminogen into plasmin, which plays a key role in cancer invasion and metastasis dissemination by allowing malignant cells to invade the tumor site locally and spread to distant sites.
  • This system includes the serine protease, uPA, membrane-linked receptor uPAR, and two serpin inhibitors, PAI-l and PAI-2.
  • plasmin plays a role during multiple steps of cancer invasion and metastasis, by inducing the degradation of a number of ECM proteins and activating certain growth factors leading to aggressive cancers.
  • Plasminogen receptors also play a role in the proliferation and migration of tumor cells in many cancer types and may serve as prognostic and diagnostic markers. They are involved in mediating colocalization of plasminogen and its activators such as uPA and tPA on cell surfaces and markedly decrease the Km for plasminogen activation. Plasminogen receptors are expressed on the cell surface of most tumors and their expression frequently correlates with cancer diagnosis, survival and prognosis. Notably, they can trigger multiple specific immune responses in cancer patients, highlighting their role as tumor-associated antigens. Cell surface receptors loaded with plasmin, which is protected from inhibitors, play a key role in cancer progression.
  • SERPIN serine protease inhibitory
  • the disclosure provides a compound of Formula I:
  • X and Y are independently CH or N; X and Y are both not N, and X and Y both not CH; R is hydrogen, C 1-4 alkyl, arylamine, or piperadin-4-yl; R 1 is hydrogen, -OH, C 1-4 alkyl, C 1-4 alkoxy, ketone, or -C(0)R 2 ;
  • R 2 is Ci- 4 alkyl, C 1-4 alkoxy, NFE. N(H)C I-4 alkyl, N(C H alkyl) 2 , hydrogen, or -OH; and - is an optional double bond, and wherein the compound is not 3-(l-(piperidin-4-yl)-lH-l,2,3- triazol-4-yl)-l,2,4-oxadiazol-5(4H)-one; 3-(l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l,2,4- oxadiazol-5(4H)-one; or 3 -(l-ethyl-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazol-5(4H)-one.
  • the compound is selected from the group consisting of 3- (l-(piperidin-4-yl)-lH-l,2,3-triazol-3-yl)-l,2,4-oxadiazole; 3-(l -(piperidin-4-yl)-lH- 1,2,4- triazol-3-yl)-l,2,4-oxadiazole; 3-(l-ethyl-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazole; 3-(l-ethyl- lH-l,2,4-triazol-3-yl)-l,2,4-oxadiazole; 3-(l-propyl-lH-l,2,3-triazol-4-y
  • the compound is 3-(l-(piperidin-4-yl)-lH-l,2,4- triazol-3-yl)-l,2,4-oxadiazol-5(4H)-one.
  • a pharmaceutical formulation comprising a therapeutically effective amount of at least one l,2,4-oxadiazole derivative and a
  • the pharmaceutical formulation further comprises a therapeutically effective amount of at least one agent which treats a bleeding disorder.
  • the pharmaceutical formulation further comprises at least one therapeutic agent for treating a cancer.
  • the disclosure provides a method of treating a patient afflicted with a bleeding disorder, comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising at least one compound of Formula I:
  • X and Y are independently CH or N; X and Y are both not N, and X and Y both not CH; R is hydrogen, C 1-4 alkyl, arylamine, or piperadin-4-yl; R 1 is hydrogen, -OH, C 1-4 alkyl, C 1-4 alkoxy, ketone, or - C(0)R 2 ;R 2 is Ci-4 alkyl, Ci-4 alkoxy, NH 2 , N(H)CI-4 alkyl, N(CI-4 alkyl)2, hydrogen, or -OH; and - is an optional double-bond, and a pharmaceutically acceptable carrier.
  • the method further comprises administering a therapeutically effective amount of a second therapeutic agent which treats a bleeding disorder.
  • the bleeding disorders that are treated the pharmaceutical formulations and methods according to the disclosure include, but are not limited to, spontaneous bleeding, cardiac surgery (i.e., cardiopulmonary bypass), liver transplant, following therapeutic thrombolysis, congenital anti-plasmin deficiency, acquired anti-plasmin deficiency, hemophilia A and B, quantitative and qualitative platelet dysfunction, genitourinary bleeding, upper and lower urinary tract, dysfunctional uterine bleeding (essential menorrhagia and menorrhagia associated with intrauterine device), gastrointestinal bleeding (upper by varices, gastritis, ulcers, and lower by inflammatory bowel disease), mucous membrane bleedings for recurrent epistaxis or for excessive bleeding following tonsillectomy, traumatic hyphemia, trauma, general surgery, orthopedic surgery or cancer.
  • the methods are also useful to treat bleeding due to lack of coagulation factors, V, VII, VIII, or IX, or lack of von Willebrand’s factor.
  • the methods according to the invention can be used to treat bleeding as the result of administration of an anticoagulant treatment.
  • the disclosure provides a method of treating a patient afflicted with a cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising a compound of Formula I:
  • X and Y are independently CH or N; X and Y are both not N, and X and Y both not CH; R is hydrogen, Ci- 4 alkyl, arylamine, or piperadin-4-yl; R 1 is hydrogen, -OH, Ci- 4 alkyl, Ci- 4 alkoxy, ketone, or -C(0)R 2 ;
  • R 2 is Ci-4 alkyl, Ci-4 alkoxy, NFF.
  • the method further comprises administering a second therapeutically effective amount of a second therapeutic agent which treats a cancer.
  • X and Y are independently CH or N; X and Y are both not N, and X and Y both not CH; R is hydrogen, Ci-4 alkyl, arylamine, or piperadin-4-yl; R 1 is hydrogen, -OH, Ci- 4 alkyl, Ci- 4 alkoxy, ketone, or -C(0)R 2 ;
  • R 2 is Ci- 4 alkyl, Ci- 4 alkoxy, NFF. N(H)C I-4 alkyl, N(C H alkyl) 2 , hydrogen, or -OH; and - is an optional double bond.
  • the disclosure also provides the use of any of the 1, 2, 4-oxadiazole compounds described above for the manufacture of a medicament for treating bleeding episodes.
  • the medicament is for reducing clotting time, in other embodiments, the medicament is for prolonging the clot lysis time. In yet other embodiments, the medicament is for increasing clot strength.
  • the medicament is formulated for topical, oral, or for intravenous or intramuscular injection administration.
  • the disclosure provides the use of any of the 1, 2, 4-oxadiazole compounds described above for the manufacture of a medicament for treating a cancer.
  • the medicament is for inhibiting the growth, reducing the size, or inhibiting the metastasis of, a cancer.
  • the medicament is formulated for topical, oral, or intravenous or intramuscular injection administration.
  • FIG. 1 is a schematic representation of the structure of 3-[l-(l-ethanoyl-4- piperidy 1)- 1H- 1 ,2,3 -triazol-4-yl] -4H- 1 ,2,4-oxadiazol-5-one;
  • FIG. 1A are schematic representations of 1,2,4- oxadiazole derivatives of the disclosure where Rl is always -H and R2 could be different derivatives;
  • FIG. 1B are schematic representations of 1,2,4- oxadiazole derivatives of the disclosure where Rl is always -OH and R2 could be different derivatives;
  • FIG. 1C are schematic representations of 1,2,4- oxadiazole derivatives of the disclosure where Rl is always -CH 3 and R2 could be difference derivatives;
  • FIG. 1D are schematic representations of 1,2,4- oxadiazole derivatives of the disclosure where Rl is always -CFb - CFb and R2 could be different derivatives;
  • FIG. 1E are schematic representations of 1,2,4- oxadiazole derivatives of the disclosure where Rl is always -Carbonyl and R2 could be different derivatives;
  • FIG. 2A is a graphic representation showing the fibrinolytic activity of
  • A is 3-(l-(piperidin-4- yl)-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazol
  • B is 3-(ethylamine-lH-l,2,3-triazol-4-yl)-l,2,4- oxadiazol
  • C is 3-(l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazol-5(4H)-one
  • D is 3-(ethylamine-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazol-5(4H)-one
  • marine blue represents the control (tissue factor, t-PA and calcium), and dark blue represents the blank (calcium and plasma);
  • FIG. 2B is a graphic representation showing the fibrinolytic activity of
  • E is 3 -(propyl amine- lH-l,2,4-triazol-3-yl)-l,2,4-oxadiazol-5(4H)-one
  • F is 3-(l-(piperidin-4-yl)-lH-l,2,4-triazol- 3-yl)-l,2,4-oxadiazol-5(4H)-hydroxyl
  • G is 3-(propylamine-lH-l,2,3-triazol-4-yl)-l,2,4- oxadiazol-5(4H)-hydroxyl
  • H is 3-(l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazol- 5(4H) methyl
  • marine blue represents the control (tissue factor, t-PA and calcium), and dark blue represents the blank (calcium and plasma)
  • FIG. 2C is a graphic representation showing the fibrinolytic activity of
  • I 3-(ethylamine- lH-l,2,4-triazol-3-yl)-l,2,4-oxadiazol-5(4H)-methyl
  • J is 3-(l-(piperidin-4-yl)-lH-l,2,4- triazol-3-yl)-l,2,4-oxadiazol-5(4H)-ethyl
  • K is 3-(ethylamine-lH-l,2,3-triazol-4-yl)-l,2,4- oxadiazol-5(4H)-ethyl
  • L is 3-(l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazol- 5(4H)-carbonyl
  • M is 3-(propylamine-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazol-5(4H)-methyl
  • FIG. 3B is a graphic representation of the results of chromogenic assays showing the inhibitory effect of 1, 2, 4- oxadiazole derivatives on the disclosure on t-pa activity, plasmin (S-2782) as identified above in FIGS. 2A-2C; and
  • FIG. 3C is a graphic representation of the results of chromogenic assays showing the inhibitory effect of 1, 2, 4- oxadiazole derivatives of the disclosure on uPA activity (S- 2444) as identified above in FIGS. 2A-2C.
  • l,2,4-oxadiazoles have broad biological activity. However, to date, specific and direct serine protease inhibitor activity has not been reported for these compounds.
  • the present disclosure provides certain l,2,4-oxadiazoles derivatives, and their salts and prodrugs, which are serine protease inhibitors (SERPINs) and which specifically and directly inhibit plasminogen activation and proteolytic activity of plasmin and plasminogen activation via direct inhibition of the serine proteases tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), and plasmin.
  • SERPINs serine protease inhibitors
  • 1,2,4- oxadiazole derivatives are useful in the treatment and/or prevention of hemorrhages in a mammalian subject and in the treatment of cancer and metastasis of cancer cells expressing high levels of plasmin and plasminogen activators activity.
  • the 1, 2, 4-oxadiazole derivatives according to the disclosure comprise a compound of formula I:
  • X and Y are independently CH or N, wherein X and Y are both not N, and X and Y both not CH;
  • R is hydrogen, C M alkyl, arylamine, or piperadin-4-yl
  • R 1 is hydrogen, -OH, C alkyl, CM alkoxy, ketone, or -C(0)R 2 ;
  • R 2 is CM alkyl, CM alkoxy, Nfl ⁇ .
  • - is an optional double bond; and salts and prodrugs thereof.
  • Exemplary 1, 2, 4- oxadiazole derivatives according to the disclosure are substituted at position C5 and/or at position C3 (see FIGS. 2A-2B).
  • 1, 2, 4- oxadiazole can be substituted with -H, -Cl, methanol, phenol, ethyl, methyl, phenyl, fluorophenyl, bromophenyl, thienyl, isopropyl, pyridil, amine, aminomethyl, carboxiamidamide, methanamine, carbothiamide, triazol, carboxylic acid, or benzoid acid.
  • Representative compounds within the scope of the present disclosure include: 3-(l- (piperidin-4-yl)-lH-l,2,3-triazol-3-yl)-l,2,4-oxadiazole; 3-(l-(piperidin-4-yl)-lH-l,2,4- triazol-3-yl)-l,2,4-oxadiazole; 3-(l-ethyl-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazole; 3-(l-ethyl- lH-l,2,4-triazol-3-yl)-l,2,4-oxadiazole; 3-(l-propyl-lH-l,2,3-triazol-4-yl)-l,2,4-oxadiazole;
  • the salts of the compounds of formula (I) are be pharmaceutically acceptable salts such as other salts may, however, be useful in the preparation of the compounds according to the disclosure or of their pharmaceutically acceptable salts or prodrugs. Suitable
  • pharmaceutically salts of the compounds include acid addition salts which can be formed by mixing a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • Prodrugs of these 1 ,2, 4 oxadiazole derivatives are compounds that when cleared, are active as SERPINS, and are useful when activated to treat bleeding disorders and cancer.
  • Such prodrugs include inactive intermediates in the synthetic scheme of the active derivatives, and which can be enzymatically or chemically modified in or on the body, when administered, to derive the active derivative.
  • Some representative and non-limiting prodrugs include the l,2,4-oxadiazole derivatives as described herein further functionalized with acid and base labile functional groups that cleave in vivo. Some acid and base labile functional groups include, but are not limited to, carbonates, carbamates, ureas, and esters.
  • prodrugs include, but are not limited to: /er/-butyl 4-(4-(etho ⁇ ycarbonyl)- 1 H- 1 2.3-triazol- 1 - yl)piperidine-l-carboxylate; /e/ /-butyl (Z)-4-(4-0V-hydro ⁇ ycarbamimidoyl)- 1 H- 1 2.3-triazol- l-yl)piperidine-l-carboxylate; and /e/ /-butyl 4-(4-carbamoyl- 1 H- 1 2.3-triazol- 1 -yl)piperidine- l-carboxylate.
  • the 1, 2, 4 oxadiazole derivatives according to the disclosure are useful in part in controlling hemostasis, which maintains blood in a fluid state under physiologic conditions.
  • the oxadiazole derivative stem abnormal bleeding by affecting the two mechanism of hemostasis.
  • the first mechanism of hemostasis comprises two phases.
  • the first phase is characterized by the occurrence of vasoconstriction at the vascular lesion site and platelet aggregation.
  • the fibrin clot is formed due to the action of the different coagulation cascade proteolytic enzymes.
  • This phase and it consists of several steps ending with fibrin polymer formation from fibrinogen hydrolysis due to the action of thrombin.
  • Fibrin polymers are further stabilized by covalent isopeptide bonds formed by factor XIII activated (Factor XHIa) by thrombin.
  • Factor XHIa The mechanical strength of the fibrin gel is useful to impede blood loss when exposed to sheer forces in the circulation. There is a shift in the equilibrium between the formation of soluble fibrin polymers and the assembly of insoluble fibrin fibers. Factor XHIa lowers the fibrin concentration needed for an insoluble clot to form.
  • the second mechanism of hemostasis is accomplished by localized activation of the plasminogen-plasmin enzyme, whereby it can heal a vascular lesion.
  • Fibrinolysis counteracts the consequences of the coagulation process.
  • the dissolution or solubilization of the fibrin clot at the correct time is needed for the orderly process of wound healing.
  • Fibrinolysis is also required for angiogenesis as recanalization after clot formation.
  • excessive local or systemic fibrinolytic activity can result in bleeding, as the weakened plug is dissolved.
  • an inadequate fibrinolytic response may retard lysis of a thrombus and contribute to its extension.
  • Plasmin is a fibrinolytic serine protease that degrades fibrin, and is generated by activation of the zymogen, plasminogen (PLG).
  • PLG is converted to plasmin by two serine protease enzyme plasminogen activators (PA): tissue-type plasminogen activator (tPA); and urokinase-type plasminogen activator (uPA).
  • PA plasminogen activators
  • tPA tissue-type plasminogen activator
  • uPA urokinase-type plasminogen activator
  • Secretion of t-PA by endothelial cells may be stimulated by fibrin, by thrombin bound to the thrombus, or by the effects of vessel occlusion, thereby increasing the local concentration of PA.
  • tPA exerts high affinity for fibrin and increased PA activity, whereas, u-PA does not express any interaction with fibrin.
  • tPA converts glu-PLG to the two-chain glu-plasmin.
  • endothelial cells are capable of releasing t-PA thereby stimulating the activation of glu-PLG 500-fold, an effect that keeps PLG activation localized to the site of a clot.
  • glu-plasmin begins to digest the clot by catalyzing cleavages after selected arginine and lysine residues in the a, b and g-chains in regions connecting the D- and E- domains of the fibrin protomers.
  • vasoconstriction the vessel walls closing temporarily
  • an abnormal obstruction such as a plaque
  • coagulation or surgical means such as ligation
  • Abnormal bleeding occurs under certain disease conditions when normal clot formation fails to occur (e.g. hemophilia). Abnormal bleeding may also occur as the result of certain medications prescribed to treat another disorder. In addition, abnormal bleeding also occurs due to physical injuries sustained by otherwise healthy individuals. For example, surgery, dental procedures, accidents, and over-doses of anti-coagulant drugs can result in ruptured vessels and/or organs can result in abnormal bleeding.
  • abnormal bleeding may occur due to physically injured ruptured vessels or organs, and has treated by surgical ligation to repair the vessel or organ.
  • surgical ligation of bleeding fails, or is not possible, a number of hemostatic aids have been used.
  • abnormal bleeding can be treated with coagulant drugs such as thrombin, Tissue Factor, Factor VII, and Factor Vila.
  • coagulant drugs such as thrombin, Tissue Factor, Factor VII, and Factor Vila.
  • Thrombin production is the final coagulation step required to cleave fibrinogen into fibrin which provides a hemostatic lattice for platelet aggregation and thrombus formation at the site of injury.
  • Thrombin is often used in conjunction with other hemostatic aids, including absorbable agents (e.g., gelfoam, collagen, and cellulose), and with fibrinogen in fibrin glue.
  • Factor VII initiates the process of coagulation in conjunction with Tissue Factor. Once bound to Tissue Factor, Factor VII is activated to Factor Vila by different proteases, including thrombin. Factor Vila has been used to treat uncontrolled bleeding in hemophilia patients, but there have been safety concerns. Other treatments include protamine sulfate, vitamin K, and plant substances such as leaf of nettle, and water pepper. Antagonists of anti coagulant drugs, such as protamine sulfate, vitamin K, and inhibitors of fibrinolysis such as aminocaproic acid, contrycal, and aprotinin, have also been used to stem abnormal bleeding.
  • l,2,4-oxadiazole derivatives affect hemostasis by directly inhibiting plasminogen activation and the proteolytic activity of plasmin, t-pa, and u- PA. As such these derivatives are useful in the treatment of bleeding disorders and abnormal bleeding.
  • the terms“bleeding disorder” and“abnormal bleeding” encompasses disorders and diseases affecting hemostasis and blood coagulation, spontaneous bleeding, cardiac surgery (i.e., cardiopulmonary bypass), liver transplant, following therapeutic thrombolysis, congenital anti-plasmin deficiency, acquired anti-plasmin deficiency, hemophilia A and B, quantitative and qualitative platelet dysfunction, genitourinary bleeding, upper and lower urinary tract, dysfunctional uterine bleeding (essential menorrhagia and menorrhagia associated with intrauterine device), gastrointestinal bleeding (upper by varices, gastritis, ulcers, and lower by inflammatory bowel disease), CCM, cerebral aneurysm, stroke, vasospasm after subarachnoid hemorrhage, spinal cord injury, mucous membrane bleedings for recurrent epistaxis or for excessive bleeding following tonsillectomy, traumatic hyphemia, trauma, general surgery, and orthopedic surgery.
  • bleeding disorder also encompasses physical trauma causing unwanted or uncontrolled bleeding in a subject such as, but not limited to, an accident causing an injury, surgery, dental procedure such as extractions, synovectomy, joint replacement, and in postoperative settings, drugs such as thrombolytic agents, -.
  • the methods are also useful to treat bleeding due to lack of coagulation factors, V, VII, VIII, or IX, or lack of von Willebrand’s factor.
  • the methods according to the invention can be used to treat bleeding as the result of administration of an anti-coagulant treatment.
  • the methods according to the disclosure are useful in the treatment of spontaneous bleeding, cardiac surgery (i.e., cardiopulmonary bypass), liver transplant, following therapeutic thrombolysis, congenital anti-plasmin deficiency, acquired anti-plasmin deficiency, hemophilia A and B, quantitative and qualitative platelet dysfunction,
  • essential menorrhagia and menorrhagia associated with intrauterine device gastrointestinal bleeding (upper by varices, gastritis, ulcers, and lower by inflammatory bowel disease), CCM, cerebral aneurysm, stroke, vasospasm after subarachnoid hemorrhage, spinal cord injury, mucous membrane bleedings for recurrent epistaxis or for excessive bleeding following tonsillectomy, traumatic hyphemia, trauma, general surgery, orthopedic surgery or cancer.
  • the methods are also useful to treat bleeding due to lack of coagulation factors, V, VII, VIII, or IX, or lack of von Willebrand’s factor.
  • the methods according to the invention can be used to treat bleeding as the result of administration of an anti-coagulant treatment.
  • Breakdown of the extracellular matrix is involved in cancer invasion and metastasis. It is accomplished by the concerted action of several proteases, including the serine protease, plasmin, and several matrix metalloproteases. The activity of each of these proteases is regulated by an array of activators, inhibitors and cellular receptors.
  • the generation of plasmin involves the pro-enzyme, plasminogen, the urokinase type plasminogen activator, uPA, and its pro-enzyme, pro-uP A, the uPA inhibitor PAI-l, the cell surface uPA receptor uPAR, and the plasmin inhibitor a2-anti plasmin.
  • This system promotes tumor metastasis by several different mechanisms.
  • One of these mechanisms is the uPA and uPAR (urokinase plasminogen activator receptor) system, which initiates the activation of MMPs as well as the conversion of plasminogen to plasmin followed by ECM degradation and reduced cellular interaction.
  • uPA and uPAR urokinase plasminogen activator receptor
  • Plasminogen receptors also play a role in the proliferation and migration of tumor cells in many cancer types and may serve as prognostic and diagnostic markers. They are involved in mediating colocalization of plasminogen and its activators such as uPA and tPA on cell surfaces and decrease the Km for plasminogen activation. Plasminogen receptors are expressed on the cell surface of most tumors and their expression frequently correlates with cancer diagnosis, survival and prognosis. They can trigger multiple specific immune responses in cancer patients, highlighting their role as tumor-associated antigens. Cell surface receptors loaded with plasmin, which are protected from inhibitors, play a key role in cancer progression.
  • the uPA system which converts plasminogen into plasmin, plays a key role in cancer invasion and metastasis dissemination by allowing malignant cells to invade the tumor site locally and spread to distant sites.
  • This system includes the serine protease, uPA, membrane-linked receptor uPAR, and two serpin inhibitors, PAI-l and PAI-2.
  • the l,2,4-oxadiazole derivatives according to the disclosure can be used to treat cancer and inhibit the metastasis of cancer cells.
  • the l,2,4-oxadiazole derivatives according to the disclosure are useful in treating cancers, such as, but are not limited to, carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, and blastomas.
  • the pharmaceutical formulations useful in the therapeutic methods according to the disclosure include a therapeutically effective amount of at least one 1, 2. 4- oxadiazole derivative, and/or a salt and/or a prodrug thereof.
  • a "therapeutically effective amount” as used herein refers to that amount which provides a therapeutic and/or prophylactic therapeutic effect for treating a bleeding disorder or trauma resulting in unwanted, uncontrolled bleeding.
  • the pharmaceutical formulations according to the disclosure may also comprise more than one l,2,4-oxadiazole derivative, and/or other known therapeutic agents for stemming bleeding.
  • Such therapeutic include, but are not limited to, thrombin, Tissue factor, and/or Factor VII A.
  • Different combinations of a therapeutically effective amount of at least one derivative according to the disclosure and a therapeutically effective amount of one or more therapeutic anti-bleeding agents can be applied together, e.g. topically.
  • A“therapeutically effective amount” of a 1, 2, 4-oxadiazole derivative, or salt or prodrug thereof alternatively refers to that amount which treats, kills, and/or controls the growth and/or metastasis of a tumor or cancer cell affecting.
  • the pharmaceutical formulations contain 1, 2, 4- oxadiazole derivatives according to the disclosure may comprise a therapeutically effective amount of at least one known anti-cancer genet or cancer therapeutic including, but not limited to, alkylating agents (including, but not limited to, cisplatin, chlorambucil, and procarbazine), antimetabolites (including, but not limited to, methotrexate, cytarabine, and gemcitabine), anti-microtubule agents (including, but not limited to, vinblastine and paclitaxel), topoisomerase inhibitors (including, but not limited to, etoposide and doxorubicin) and cytotoxic agents such as, but not limited to, bleomycin.
  • alkylating agents including, but not limited to, cisplatin, chlorambucil, and procarbazine
  • antimetabolites including, but not limited to, methotrexate, cytarabine, and gemcitabine
  • anti-microtubule agents including, but
  • the pharmaceutical formulations including 1, 2, 4-oxadiazole derivatives of the disclosure can be administered alone or in combination with other known therapeutic agents.
  • the pharmaceutical formulations according to the disclosure further comprise a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” is to be understood herein as referring to any substance that may, medically, be acceptably administered to a patient, together with a compound of this invention, and which does not undesirably affect the pharmacological activity thereof; a “pharmaceutically acceptable carrier” may thus be, for example, a pharmaceutically acceptable member(s) comprising of diluents, preservatives, solubilizers, emulsifiers, adjuvant, tonicity modifying agents, buffers as well as any other physiologically acceptable vehicle. These formulations are prepared with the pharmaceutically acceptable carrier in accordance with known techniques, for example, those described in Remington, The Science And Practice of Pharmacy (9th Ed. 1995).
  • the salts of the compounds of formula (I) are pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds or of their pharmaceutically acceptable salts according to the disclosure. Suitable
  • pharmaceutically salts of the compounds of this invention include acid addition salts with may, for example, be formed by mixing a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g,. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • the pharmaceutical formulations may also or instead comprise prodrugs of the derivatives according to the disclosure include inactive intermediates in the synthetic scheme of the active derivatives, and which can be enzymatically or chemically modified in or on the body, when administered, to derive the active derivative.
  • Some representative and non- limiting prodrugs include the l,2,4-oxadiazole derivatives as described herein further functionalized with acid and base labile functional groups that cleave in vivo.
  • Some acid and base labile functional groups include, but are not limited to, carbonates, carbamates, ureas, and esters.
  • the pharmaceutical formulation may be prepared for injectable use, topical use, oral use, intramuscular or intravenous injection, inhalation use, transdermal use,
  • transmembrane use and the like.
  • compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral parenteral, intranasal, sublingual topical or rectal administration, or for administration by inhalation or insufflation.
  • the compositions may be presented in a form suitable for one-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • An erodible polymer containing the active ingredient may be envisaged.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, di calcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, di calcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • formulations may be homogeneous, i.e., the l,2,4-oxadiazole derivative, or salt or prodrug thereof, is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 mg to about 500 mg of the active ingredient of the present invention.
  • Some useful unit dosage forms contain froml to 100 mg, for example 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg, of the derivative.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • liquid forms in which the novel compositions if the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils as well as elixirs and similar pharmaceutical vehicles.
  • a suitable dosage level is about 0.001 mg/kg to 250 mg/kg per day.
  • the compounds may be administered on bolus and or a regimen of 1 to 4 times per day.
  • Injectable dosage forms may be sterilized in a pharmaceutically acceptable fashion, for example by steam sterilization of an aqueous solution sealed in a vial under an inert gas atmosphere at l20°C for about 15 minutes to 20 minutes, or by sterile filtration of a solution through a 0.2 mM or smaller pore-size filter, optionally followed by a lyophilization step, or by irradiation of a composition containing a compound of the present invention by means of emissions from a radionuclide source.
  • a therapeutically effective dosage of the 1, 2, 4- oxadiazole derivatives according to the disclosure or of another therapeutic which treats a bleeding disorder or cancer may vary from patient to patient, and may depend upon factors such as the age of the patient, the patient’s genetics, and the diagnosed condition of the patient, and the route of delivery of the dosage form to the patient.
  • a therapeutically effective dose and frequency of administration of a dosage form may be determined in accordance with routine pharmacological procedures known to those skilled in the art. For example, dosage amounts and frequency of
  • administration may vary or change as a function of time and severity of the disorder.
  • a dosage from about 0.1 mg/kg to 1000 mg/kg, or from about 1 mg/kg to about 100 mg/kg may be suitable.
  • the enzymatic and/or inhibitory activity of the l,2,4-oxadiazole derivatives according to the disclosure can be determined by assaying for their fibrinolytic potentials, their serine protease inhibitory activities, and their ability to inhibit cancer growth and migration of cancer cells. These activities can be determined by any assay known in the art, including the following assays.
  • Fibrinolytic activity in human plasma was determined by a one-step
  • Spectrophotometric assays can be used to determine the inhibitory effect of 1,2,4 oxadiazole on serine proteases (see. e.g. Jespersen et al, eds. (1992) ECAT Assay
  • spectrophotometric assays use chromogenic substrates (peptides) that react with different proteases under the formation of color.
  • the synthetically made substrates are designed to possess selectivity similar to that of the natural substrate for the enzyme. The ability of these chromogenic substrates to detect low enzyme concentrations makes them useful to investigate the specificity of SERPINs.
  • Measurements made using chromogenic substrates reflect specifically enzyme activity. Attached to the peptide portion of the chromogenic substrate is a chemical group which when released after the enzyme cleavage gives rise to color. The color change can be followed spectrophotometrically and is proportional to the proteolytic activity.
  • 1,2,4- oxadiazole derivatives cording to the disclosure to inhibit cancer cell migration and proliferation in vitro can be measured, e.g., by a wound healing assay (Rodriguez et al, in Cell Migration: Developmental Methods and Protocols. Web el al, Guan ed., Humana Press 294:. 23-29).
  • This assay is based on the observation that, upon the creation of an artificial gap on a confluent cancer cell monolayer, the cells on the edge of the created gap will start migrating and proliferating until new cell-cell contacts are established.
  • the l,2,4-oxadiazole derivatives according to the disclosure were able to significantly inhibit the proliferation and migration of fibrosarcoma cells in vitro.
  • Step 1 /e/V-butyl 4-((methylsulfonyl)oxy) piperidine- 1 -carboxylate
  • Step 2 fer/-butyl 4-azidopiperidine-l-carboxylate
  • Step 4 tert-butyl 4-(4-carbamoyl- 1 H- 1 2.3-triazol- 1 -yl)piperidine- 1 -carboxyl ate
  • Step 5 fer/-butyl 4-(4-cyano- 1 H- 1 2.3-tria/ol- 1 -yl (piperidine- 1 -carboxylate
  • Step 6 tert- butyl (Z)-4-(4-(7V-hydroxycarbamimidoyl)-li/-l,2,3-triazol-l- yl)piperidine- 1 -carboxylate
  • Step 7 fe/7-butyl 4-(4-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-li/-l,2,3-triazol-l- yl)piperidine- 1 -carboxylate
  • Step 8 3-(l-(piperidin-4-yl)-li/-l,2,3-triazol-4-yl)-l,2,4-oxadiazol-5(4i7)-one
  • Step 1 /e/V-butyl 4-(3-(methoxy carbonyl)- 1 H- 1 2.4-tria/ol- 1 - ⁇ 1 /piperidine- 1 -carboxylate
  • Step 2 fer/-butyl 4-(3 -carbamoyl- 1 H- 1 2.4-triazol- 1 -yl)piperidine- 1 -carboxylate
  • Step 3 /e/7- butyl 4-(3-cyano- 1 H- 1 2.4-triazol- 1 -yl)piperidine- 1 -carboxylate
  • Step 4 /e/V-butyl (Z)-4-(3 -(/V -hydroxy carbamimidoyl)- ⁇ H- 1,2, 4-triazol-l - yl)piperidine- 1 -carboxylate
  • Step 5 /er/-butyl 4-(3-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-li/-l,2,4-triazol-l- yl)piperidine- 1 -carboxylate
  • Step 6 3 -( 1 -(piperidin-4-yl)- 1 H- 1 ,2,4-triazol-3-y 1)- 1 ,2,4-oxadiazol-5 (4H)-one
  • Thromborel S (Siemens, USA) containing a lyophilized extract of rabbit-brain thromboplastin (tissue factor) was reconstituted with 10 ml of a 3.2 mM solution of CaCh .
  • Each vial of human recombinant t-PA (Sigma-Aldrich, US) was reconstituted with chUO to a final concentration of 100 pg/ml.
  • Fibrin clot formation in human plasma was induced as follows: An aliquot of 150 pl of plasma was incubated in a 96- well plate at 37°C during 30 min. in the presence of 50 pl of reconstituted Thromborel S reagent (Fisher Scientific, USA), and 20 pl of 1 mM Tris-HCl buffer. Clot formation was quantified spectrophotometrically at 340 nm.
  • Each vial of human recombinant t-PA (Sigma- Aldrich, US) was reconstituted with dEbO to a final concentration of 100 pg/ml.
  • Each vial of human plasmin (Roche, Sigma- Aldrich, USA) in 0.5 ml of working solution (Roche, Sigma-Aldrich, USA) pH 8.6 (provided by the supplier) has the activity of 5 U
  • Each vial of recombinant human uPA (Sigma- Aldrich, USA) containing 50 pg was reconstituted with 1 ml of PBS to a final concentration of 50 pg/ml.
  • Each vial of recombinant human thrombin (Sigma-Aldrich, USA) containing 100 NTH units/mg of protein was reconstituted with cUrhO to a final concentration of 100 NIH units/mg of protein per ml.
  • Each vial of trypsin from human pancreas (Sigma-Aldrich, USA) containing 1,000 BAEE units was reconstituted with cUrhO to a final concentration of 1,000 BAEE units/ml.
  • Each vial of a-chymotrypsin from human pancreas (Sigma-Aldrich, USA) containing 10 BTEE units was reconstituted with cUrhO to a final concentration of 10 BTEE units/ml.
  • Chromogenic assays were performed as follows: An aliquot of 900 pi of working solution containing each reconstituted chromogenic substrate was incubated in a 96 well-plate at 37°C during 30 min in the presence of 90 pi of each reconstituted proteolytic enzyme and 10 pi of 1 mM Tris-HCl buffer, mix and read each 2 min the absorbance at 405 nm.
  • HT-1080 human cells about lOVwell
  • Gap formation in the monolayer is created manually with a scrapper and cell proliferation and migration is determined recording a time-lapse video for 20 hr with a time interval of 30 min.
  • the microscopic pictures are manually analyzed for obtaining information about the proliferation and migration characteri stics of the cultured cells and the image analysis detects the cell covered area.

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Abstract

L'invention concerne des dérivés de 1, 2, 4-oxadiazole utiles dans le traitement du saignement et dans le traitement du cancer.
PCT/US2019/051391 2018-09-18 2019-09-17 Dérivés de 1, 2, 4-oxadiazole et leurs utilisations Ceased WO2020060964A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000009542A1 (fr) * 1998-08-17 2000-02-24 Cortech, Inc. INHIBITEURS DE SERINE PROTEASE CONTENANT DES α-CETO HETEROCYCLES
WO2016113344A1 (fr) * 2015-01-15 2016-07-21 Actelion Pharmaceuticals Ltd Dérivés de l'hydroxyalkyl pipérazine utilisés comme modulateurs du récepteur cxcr3

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000009542A1 (fr) * 1998-08-17 2000-02-24 Cortech, Inc. INHIBITEURS DE SERINE PROTEASE CONTENANT DES α-CETO HETEROCYCLES
WO2016113344A1 (fr) * 2015-01-15 2016-07-21 Actelion Pharmaceuticals Ltd Dérivés de l'hydroxyalkyl pipérazine utilisés comme modulateurs du récepteur cxcr3

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CHEMICAL ABSTRACTS, 1 August 2017, Columbus, Ohio, US; abstract no. 2106473-30-5 *
CHEMICAL ABSTRACTS, 17 April 2017, Columbus, Ohio, US; abstract no. 2091202-12-7 *
CHEMICAL ABSTRACTS, 24 May 2015, Columbus, Ohio, US; abstract no. 1710844-96-4 *
CHEMICAL ABSTRACTS, 27 May 2015, Columbus, Ohio, US; abstract no. 1713461-85-8 *
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CHEMICAL ABSTRACTS, 9 June 2016, Columbus, Ohio, US; abstract no. 1928756-59-5 *
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ZHURILO, NIKOLAY I. ET AL.: "Isosteric ribavirin analogues: Synthesis and antiviral activities", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 28.1, 2018, pages 11 - 14, XP055693462, Retrieved from the Internet <URL:https://ars.els-cdn.com/content/image/1-s2.0-S0960894X17311162-mmcl.pdf> [retrieved on 20191023] *

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