WO2020060963A1 - Dérivés de 1, 3, 4-oxadiazole et leurs utilisations - Google Patents
Dérivés de 1, 3, 4-oxadiazole et leurs utilisations Download PDFInfo
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- WO2020060963A1 WO2020060963A1 PCT/US2019/051390 US2019051390W WO2020060963A1 WO 2020060963 A1 WO2020060963 A1 WO 2020060963A1 US 2019051390 W US2019051390 W US 2019051390W WO 2020060963 A1 WO2020060963 A1 WO 2020060963A1
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- 0 **(CC1)CCC1I Chemical compound **(CC1)CCC1I 0.000 description 2
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- 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
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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
- A61K31/41—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
- A61K31/4245—Oxadiazoles
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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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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, cancer, and compounds useful for the treatment of disorders resulting from a disruption of hemostasis and for treating cancer.
- 1,3, 4-oxadiazoles have been used as bioisosteric replacements of esters and amides, and have been used as a pharmacophore. These compounds have a broad biological activity spectrum.
- certain l,3,4-oxadiazole derivative are known to have biological activities useful in treating certain diseases and disorders, including antibacterial, antifungal, analgesic, anti-inflammatory, antiviral, anticancer, antihypertensive,
- 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 (tPA), 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 serine protease inhibitors
- 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.
- the compound is hydrochloride 5-(l-(piperidin-4-yl)-lH-
- the compound is selected from a group consisting of: 2-(l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l,3,4- oxadiazole; 2-(l-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-l,3,4-oxadiazole; 2-(l-ethyl-lH-l,2,4- triazol-3-yl)-l,3,4-oxadiazole; 2-(l-ethyl-lH-l,2,4-triazol-3-yl)-l,3,4-oxadiazole; 2-(l-propyl- lH-l,2,3-triazol-4-yl)-l,3,4-oxadiazole; 2-(l-propyl- lH-l,2,3-triazol-4-yl)-l,3,4-oxadiazole; 2-(l-propyl-
- the disclosure provides a pharmaceutical formulation comprising a 1,3,4- oxadiazole derivative and a pharmaceutically acceptable carrier.
- the pharmaceutical formulation further comprises a therapeutic agent for treating a bleeding disorder in a patient.
- the pharmaceutical formulation further comprises a therapeutic agent for treating a cancer in a patient.
- 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 a l,3,4-oxadioazole derivative to the patient.
- the pharmaceutical formulation further comprises at least one therapeutically effective amount of an agent which treats a bleeding disorder.
- the method further comprises administering to the patient a therapeutically effective amount of at least one 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.
- 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 bleeding episodes treated with the l,3,4-oxadiazole derivative according to the disclosure include, but are not limited to , spontaneous bleeding, cardiac surgery, including 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, lack of coagulation factors, V, VII, VIII, or IX, or lack of von Willebrand’s factor, and anticoagulant treatment.
- the disclosure provides a method of treating a patient afflicted with a cancer, comprising administering a therapeutically effective amount of a
- the pharmaceutical formulation comprising a l,3,4-oxadiazole derivative to the patient.
- the pharmaceutical formulation further comprises at least one therapeutically effective amount of an agent which treats a cancer.
- the method further comprises administering to the patient a therapeutically effective amount of at least one agent which treats a cancer.
- the cancer treated with the pharmaceutical formulations and methods of the invention include, but are not limited to, alkylating agents (including, but not limited to, cisplatin, chlorambucil, and procarbazine) , antimetabolites (including, but not limit 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 (including, but not limited to, bleomycin).
- alkylating agents including, but not limited to, cisplatin, chlorambucil, and procarbazine
- antimetabolites including, but not limit to, methotrexate, cytarabine, and gemcitabine
- anti-microtubule agents including, but not limited to, vinblastine and paclitaxel
- topoisomerase inhibitors including, but not
- the disclosure also provides the use of any of the l,3,4-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. In yet other embodiments, the medicament is formulated for topical, oral, or intravenous or intramuscular injection administration.
- the disclosure provides the use of any of the l,3,4-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.
- the disclosure also provides a method of inhibiting the serine protease activity of an enzyme selected from the group consisting of tissue plasminogen activator, urokinase plasminogen activator, and plasmin, comprising contacting the enzyme with a compound of formula 1.
- FIG. 1A displays schematic representations of l,3,4-oxadiazole derivatives including 1,2,3- and 1 ,2,4-triazole derivatives, where Rl is always -H, and R2 can be different derivatives;
- FIG. 1B displays schematic representations of 1,3,4- oxadiazole derivatives including 1, 2, 3- and 1, 2, 4- triazole derivatives where Rl is always -OH, and R2 can be different derivatives;
- FIG. 1C displays schematic representations of l,3,4-oxadiazole derivatives where Rl is -CH 3, and R2 can be different derivatives;
- FIG. 1D displays schematic representations of l,3,4-oxadiazole derivatives including 1,2,3- and 1 ,2,4-triazole derivatives, where Rl is -CH 2 CH 3 and R2 can be different derivatives;
- FIG. 2 is a graphic representation of the results of fibrinolytic assays.
- the present invention relates to certain l,3,4-oxadiazoles derivatives, and their salts and prodrugs thereof, which are SERPINs, and which specifically and directly inhibit plasminogen activation and proteolytic activity of plasmin and plasminogen activation via direct inhibition of tPA and uPA)activities.
- these 1,3,4- oxadiazole derivatives are useful in the treatment and/or prevention of hemorrhages in a mammalian subject and in the treatment of cancer and metastasis in cancer cells expressing high levels of plasmin and plasminogen activators activity.
- 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, Ci-4 alkyl, arylamine, or piperadin-4-yl
- RHs hydrogen, -OH, Ci-4 alkyl, CM alkoxy, ketone, or C(0)R 2 ;
- R 2 is hydrogen, C14 alkyl, C1-4 alkoxy, NH 2 , N(H)Ci4 alkyl, N(Ci4 alkyl) 2 , or -OH; and - is an optional double bond, wherein the compound is not 5-(l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l,3,4-oxadiazol- 2(3H)-one or 5 -( 1 -(piperidin-4-yl)- 1 H- 1 ,2,3-triazol-4-yl)- 1 ,3 ,4-oxadiazol-2-ol
- X is N and Y is CH, or X is CH and Y is N.
- R 1 is a ketone.
- Specific compounds within the scope of the present disclosure include: 2-(l- (piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l,3,4-oxadiazole; 2-(l-(piperidin-4-yl)-lH-l,2,4- triazol-3-yl)-l,3,4-oxadiazole; 2-(l-ethyl-lH-l,2,4-triazol-3-yl)-l,3,4-oxadiazole; 2-(l-ethyl- lH-l,2,4-triazol-3-yl)-l,3,4-oxadiazole; 2-(l-propyl-lH-l,2,3-triazol-4-yl)-l,3,4- oxadiazole;2-(l-propyl-lH-l,2,4-triazol-3-yl)-l,3,4-oxadiazole; 5-(l-(piperidin-4-y
- the l,3,4-oxadiazole derivatives according to the disclosure are useful in part in controlling hemostasis, which maintains blood in a fluid state under physiologic conditions. These oxadiazole derivatives stem abnormal bleeding by affecting the two mechanisms 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 Xllla 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 tPA 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, uPA does not express any interaction with fibrin.
- tPA converts glu-PLG to the two-chain glu-plasmin.
- endothelial cells are capable of releasing tPA, and 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.
- 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.
- the l,3,4-oxadiazole derivatives according to the disclosure affect hemostasis by directly inhibiting plasminogen activation and the proteolytic activity of plasmin, tPA, and uPA.
- the 1,3,4- oxadiazole derivatives are useful in the treatment of spontaneous bleeding, cardiac surgery (e.g., 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 (e.g., essential menorrhagia and menorrhagia associated with intrauterine device), gastrointestinal bleeding (e.g., 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 important for 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.
- the regulation of extracellular proteolysis in cancer involves a complex interplay between cancer cells and non-malignant stromal cells in the expression of the molecular components involved.
- this cellular interplay mimics that observed in the tissue of origin during non-neoplastic tissue remodeling processes.
- 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.
- 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.
- the uPA system is a conversion system from plasminogen into plasmin, which plays important physiological roles. It also 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 SERPINs, PAI-l and PAI-2.
- the 1,3,4 oxadiazole derivatives according to the disclosure can treat cancer and inhibit the metastasis of cancer cells.
- the l,3,4-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.
- compositions useful in methods of treating bleeding disorders and cancer according to the disclosure comprise a therapeutically effective amount of a 1,3,4- oxadiazole derivative in a pharmaceutically acceptable carrier.
- 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,3,4-oxadiazole derivative in addition to other known therapeutic agents for stemming bleeding.
- Such therapeutic include, but are not limited to, thrombin, Tissue factor, and/or Factor VIIA.
- 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.
- the pharmaceutical formulations according to the disclosure may alternatively comprise a therapeutically effective amount of other known therapeutic agents for treating cancer, 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 pacbtaxel), 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 not limited to, vinblastine and pacbtaxel
- a "therapeutically effective amount” as used herein refers to that amount which provides a therapeutic and/or prophylactic therapeutic effect for treating a cancer, including inhibiting its growth, reducing its size, and/or inhibiting its metastasis.
- pharmaceutically acceptable carrier refers to any substance that may, medically, be acceptably administered to a patient, together with a l.3.4-oxadiazole derivative and which does not undesirably affect the pharmacological activity thereof.
- pharmaceutically acceptable carrier may thus be, for example, a pharmaceutically acceptable member(s) selected from the group comprising or consisting of diluents, preservatives, solubilizers, emulsifiers, adjuvant, tonicity -modifying agents, buffers as well as any other physiologically acceptable vehicle.
- Formulations according to the disclosure are prepared with a 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 butyl 4-(4-(etho ⁇ y carbonyl)- 1 H- 1 2.3-triazol- 1 -yl)piperidine- 1 - carboxylate, tert- butyl 4-(4-(5-o ⁇ o-4.5-dihydro- 1 3.4-oxadiazol-2-yl)- 1 H- 1 2.3-triazol- 1 - yl)piperidine-l-carboxylate, and / -butyl 4-(4-(etho ⁇ ycarbonyl)- 1 H- 1 2.3-triazol- 1 - yl)piperidine- 1 -carboxylate
- the pharmaceutical formulations may take different 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 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
- 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.
- Formulations suitable for oral administration may be presented in discrete units or dosage forms, such as capsules, cachets, lozenges, tablets, sublingual tablets, pills, powders, granules, chewing gum, suspensions, solutions, and the like.
- Each dosage form contains a predetermined amount of 1,3,4- oxadiazole derivative.
- the pharmaceutically acceptable carrier may be an aqueous liquid, such as buffered with a pharmaceutically acceptable pH buffer, or in non-aqueous liquid such as DMSO, or be prepared as an oil-in-water or water-in-oil emulsion.
- 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.
- preformulation compositions as“homogeneous”, it is meant that the active ingredient 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 preformulation 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.
- Favored unit dosage forms contain froml to 100 mg, e.g., 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 therapeutically effective dosage of the l,3,4-oxadiazole derivatives according to the disclosure and/or of another therapeutic agent which treats a bleeding disorder or which treats 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
- dosage amounts and frequency of administration may vary or change as a function of time and severity of the disorder.
- a suitable dosage level is about O.OOlmg/kg per day to about 250 mg/kg per day.
- the compounds may be administered on bolus and or a regimen of 1 to 4 times per day.
- the activity of the l,3,4-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.
- Fibrinolytic activity in human plasma was determined by a one-step
- Fibrin clot formation in anticoagulant citrate dextrose ( ACD) plasma samples obtained from healthy volunteers is triggered by tissue factor (TF) and can be quantified by spectrometry as a significant increase in basal plasma absorbance at 340 nm.
- tissue factor TF
- FIG. 3 in the absence of tPA, plasma absorbance remains permanently elevated.
- tPA in the presence of tPA, plasma absorbance returns quickly to basal values, indicating that plasmin is able to lysis completely the formed fibrin clot.
- Spectrophotometric assays can be used to determine the inhibitory effect of 1,3,4 oxadiazole on serine proteases (see. e.g. Jespersen et ah, edr. (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.
- EXAMPLE 4 The ability of 1,3,4- oxadiazole derivatives cording to the disclosure to inhibit cancer cell migration and proliferation in vitro can be measured by a wound healing assay (EXAMPLE 4) (Rodriguez et al, in Cell Migration: Developmental Methods and Protocols Web et al., Guan ed., Humana Press 294:. 23-29).
- Step 1 Tert-butyl 4-((methylsulfonyl)oxy) piperidine- l-carboxylate
- Step 2 Tert-butyl 4-azidopiperi dine- l-carboxylate
- Step 3 T ert-buty 1 4-(4-(ethoxy carbonyl)- ⁇ H- ⁇ ,2,3 -triazol- 1 -yl)piperidine- 1 -carboxylate
- Step 4 Tert-butyl 4-(4-(hydrazinecarbonyl)- 1 H- 1 ,2,3-triazol- 1 -yl)piperidine-l -carboxylate
- Step 5 Tert-butyl 4-(4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-li/-l,2,3-triazol-l-yl)- piperidine- 1 -carboxylate
- Step 6 Hydrochloride 5-( 1 -(piperidin-4-yl)- 1 //- 1 2.3-triazol-4-yl)- 1 3.4-oxadiazol-2(3//)-one
- Step 1 Tert-butyl 4-(3-(methoxycarbonyl)-li/-l, 2, 4-triazol-l-yl)piperidine-l -carboxylate
- Step 2 Tert-butyl 4-(3-(hydra/inecarbonyl)- 1 H- 1 2.4-tria/ol- 1 -yl)piperidine- 1 -carboxylate
- Step 3 T ert-butyl 4-(3 -(5 -oxo-4,5 -dihy dro- 1 ,3,4-oxadiazol-2-yl)- 1 H- 1 ,2,4-triazol- 1 - yl)piperidine- 1 -carboxylate
- Step 4 Hydrochloride of 5-( 1 -(piperidin-4-yl)- 1 H- 1 2.4-triazol-3-yl)- 1 3.4-oxadiazol-2(3//)- 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 dEhO to a final concentration of 100 mg/ml.
- Fibrin clot formation in human plasma was induced as follows: An aliquot of 150 ml of plasma was incubated in a 96-well plate at 37°C during 30 min in the presence of 50 ml of reconstituted Thromborel S reagent (Fisher Scientific, USA), and 20 ml of 1 mM Tris-HCl buffer and clot formation was quantified spectrophotometrically at 340 nm.
- Each vial of human recombinant t-PA (Sigma- Aldrich, US) was reconstituted with dEhO 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) at 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 mi of PBS to a final concentration of 50 pg / l.
- Each vial of recombinant human thrombin (Sigma- Aldrich, USA) containing 100 NIH units/mg of protein was reconstituted with CIH2O to a final concentration of 100 NIH units/mg of protein per ml.
- Each vial of trypsin from human pancreas (Sigrna- Aldrich, USA) containing 1,000 BAEE units was reconstituted with CIH2O 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 dfhO to a final concentration of 10 BTEE units/ml.
- Each vial of chromogenic substrates (Diapharma, USA) and working solutions were prepared and reconstituted following the instructions of the manufacturer.
- Chromogenic assays were performed as follows: An aliquot of 900 m ⁇ 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 m ⁇ of each reconstituted proteolytic enzyme and 10 m ⁇ of 1 mM Tris-HCl buffer, mix and read each 2 min the absorbance at 405 nm.
- 1,3,4- oxadiazole derivatives of present disclosure displayed specific inhibitory effect on Plasmin, tPA and uPA activities and Plasminogen activation mediated by tPA at below' 100 mM concentration. How- ever, no effects at 1000 mM of concentration on Thrombin, Factor X activated, Kaliikrein, Trypsin and Chymotrypsin, were detected.
- HT-1080 human cells about lOVwell
- Both fibrin clot formation and clot lysis assays in human plasma were performed simultaneously as follows: 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), 10 m ⁇ of reconstituted human recombinant t-PA and 10 m ⁇ of 1 mM Tris-HCl buffer and clot formation followed by clot lysis were quantified spectrophotometrically at 340 nm.
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Abstract
L'invention concerne des dérivés de 1, 3, 4-oxadiazole utiles dans le traitement du saignement et dans le traitement du cancer.
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Citations (2)
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US5668159A (en) * | 1996-05-08 | 1997-09-16 | The Dupont Merck Pharmaceutical Company | 1,3,4-thiadiazoles and 1,3,4-oxadiazoles as IIb/IIIa antagonists |
US6326388B1 (en) * | 1999-12-21 | 2001-12-04 | Celgene Corporation | Substituted 1,3,4-oxadiazoles and a method of reducing TNF-alpha level |
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US5668159A (en) * | 1996-05-08 | 1997-09-16 | The Dupont Merck Pharmaceutical Company | 1,3,4-thiadiazoles and 1,3,4-oxadiazoles as IIb/IIIa antagonists |
US6326388B1 (en) * | 1999-12-21 | 2001-12-04 | Celgene Corporation | Substituted 1,3,4-oxadiazoles and a method of reducing TNF-alpha level |
Non-Patent Citations (2)
Title |
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GOPALSAMY, A. ET AL.: "Design and synthesis of oxadiazolidinediones as PA1-1 inhibitors", ABSTRACTS OF PAPERS, 227TH AMERICAN CHEMICAL SOCIETY NATIONAL MEETING, 28 March 2004 (2004-03-28), Anaheim, CA , United States * |
SANGSHETTI, J. N. ET AL.: "Microwave assisted one pot synthesis o some novel 2, 5- disubstituted 1, 3, 4-oxadiazoles as antifungal agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, no. 1, 2011, pages 444 - 448, XP027566679 * |
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