WO2015016750A1 - Dérivés de carbamoylphényle pour arrêter, prévenir et traiter des écoulements sanguins et renforcer le système d'hémostase - Google Patents

Dérivés de carbamoylphényle pour arrêter, prévenir et traiter des écoulements sanguins et renforcer le système d'hémostase Download PDF

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WO2015016750A1
WO2015016750A1 PCT/RU2014/000574 RU2014000574W WO2015016750A1 WO 2015016750 A1 WO2015016750 A1 WO 2015016750A1 RU 2014000574 W RU2014000574 W RU 2014000574W WO 2015016750 A1 WO2015016750 A1 WO 2015016750A1
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bleeding
deficiency
hemophilia
blood
factor
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Russian (ru)
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Арсений Валерьевич АЙБУШ
Фазоил Иноятович АТАУЛЛАХАНОВ
Владимир Николаевич КОЛЯДКО
Дмитрий Викторович МАЛАХОВ
Михаил Александрович ПАНТЕЛЕЕВ
Дмитрий Николаевич ТАРАСОВ
Дмитрий Геннадьевич ТОВБИН
Original Assignee
Aibush Arseny Valerievich
Ataullakhanov Fazoil Inoyatovich
Kolyadko Vladimir Nikolaevich
Malakhov Dmitry Viktorovich
Panteleev Mikhail Alexandrovich
Tarasov Dmitry Nikolaevich
Tovbin Dmitry Gennadievich
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Application filed by Aibush Arseny Valerievich, Ataullakhanov Fazoil Inoyatovich, Kolyadko Vladimir Nikolaevich, Malakhov Dmitry Viktorovich, Panteleev Mikhail Alexandrovich, Tarasov Dmitry Nikolaevich, Tovbin Dmitry Gennadievich filed Critical Aibush Arseny Valerievich
Publication of WO2015016750A1 publication Critical patent/WO2015016750A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to new carbamoylphenyl derivatives designed to stop, prevent and prevent bleeding or enhance the hemostatic system.
  • This invention also relates to a new class of substances, their pharmaceutically acceptable salts, their pharmaceutically acceptable compositions that can be used to stop, prevent and prevent bleeding in humans and other mammals that may be due to the hypocoagulation state of the blood coagulation system, blood coagulation disorders, hematological disorders, hemorrhagic disorders, hemophilia, factor VII deficiency, drug treatment, trauma, disease, disorders, connection GOVERNMENTAL with bleeding, surgery, hypothermia, menstruation, and pregnancy and other diseases in humans and mammals associated with blood clotting.
  • This invention also relates to the use of the claimed compounds in pharmaceutical compositions and methods for treating diseases associated with coagulation disorders in humans and other mammals.
  • Blood coagulation is the physiological process of the formation of a hemostatic clot to prevent significant loss of blood and to maintain the integrity of the bloodstream in case of injury, tissue damage or injury.
  • tissue factor TF
  • Inactive plasma precursors of coagulation factor proteins are dissolved in the blood plasma, which are activated during coagulation by proteolysis at special sites.
  • Coagulation factor VII (FVII) and its active form FVIIa form a complex with TF, which activates coagulation factors IX (FIX) and X (FX).
  • Activated factor FIXa also activates FX, while FXa proteolytically cleaves prothrombin, from which thrombin is formed - the main enzyme of the coagulation system.
  • Trace amounts of thrombin formed at the initiation stage are able to activate coagulation factors V (FV) and VIII (FVIII), which are cofactors of FXa and FDCa, respectively, as well as coagulation factor XI (FXI), which is active form is able to activate FIX.
  • complexes FXa and FVa, FIXa and FVIIIa are assembled on negatively charged phospholipid vesicles or cell membranes; the resulting complexes have thousands to tens of thousands more catalytic activity than single FXa and FrXa.
  • thrombin there is a rapid increase in the concentration of thrombin, up to a concentration of 1 ⁇ m.
  • fibrinogen a soluble plasma protein, fibrin is formed, which polymerizes into a gel-like fibrin clot.
  • a fibrin clot in the lumen of a vessel or wound occurs from the surface on which coagulation initiation by a tissue factor occurred.
  • the spatial growth rate of a fibrin clot is determined by the diffusion of active coagulation factors in the direction of clot growth, such as thrombin, FXa, FVa, FIXa, FVIIIa, FXIa, FXIIa. (Panteleev et al. Biophys J. 2006: 90 (5) pp. 1489 - 1500).
  • Diffusion of active coagulation factors is limited to plasma protease inhibitors, such as antithrombin-III, ⁇ 1 -antitrypsin, ⁇ x2-macroglobulin, C 1 -inhibitor, A2-antiplasmin, ⁇ 1 -inhibitor of proteinases, ⁇ -antichymotrypsin, which irreversibly inactivate these factors .
  • plasma protease inhibitors such as antithrombin-III, ⁇ 1 -antitrypsin, ⁇ x2-macroglobulin, C 1 -inhibitor, A2-antiplasmin, ⁇ 1 -inhibitor of proteinases, ⁇ -antichymotrypsin, which irreversibly inactivate these factors .
  • Bleeding is a general clinical problem. They can be the result of a violation of the blood coagulation system, as well as a disease, trauma, surgical intervention or medical treatment. With bleeding, excessive blood loss and even death of the subject can occur, therefore, it is imperative to stop them. Mechanical stopping of bleeding may not be possible due to the location or a large number of damaged vessels. Therefore, a subject with bleeding may need treatment with agents that support hemostasis. Such agents may include whole donated blood, freshly frozen plasma, cryoprecipitate derived from plasma or an activated prothrombin complex concentrate, purified and recombinant coagulation factors (Elliott J. Et al. Anesth Analg. May 2010 110: 5 pp 1419-1427).
  • Hemophilia A is a pathology characterized by an increased tendency to bleeding; it is the most common hereditary coagulation disorder, with a frequency of one in 5,000 men. Hemophilia A is caused by deficiency or structural defects of FVIII. Hemophilia B, which is 5 times less common than hemophilia A, is caused by deficiency or structural defects of FIX. FIXa is least susceptible to inactivation by plasma protease inhibitors, and its diffusion determines the growth rate of a clot in the blood plasma of a healthy subject. In the absence of FIXa activity in such pathologies, the clot growth rate is determined by the diffusion of other factors, such as FXa and thrombin.
  • FVIII has a short elimination half-life (about 11 hours) from human bloodstream. (Tiede A. et al. J Thromb Haemost. 2013; 11: 670-678). Therefore, the administration of the drug to subjects is prescribed several times a week throughout life. The need for frequent intravenous administration creates huge barriers to patient compliance with the treatment regimen and regimen, and also greatly increases the cost of treatment.
  • the short lifetime of coagulation factors in human blood plasma can be slightly increased by various modifications of FVIII, for example, by covalent attachment of long-chain polyethylene glycol (PEG) molecules to a protein. (Patapp. WO 2006/053299, Site-Directed Modification Of FVIII)
  • a serious medical problem is inhibitory hemophilia, which is characterized by the formation of autoantibodies to replacement factors. About 25-30% of subjects with hemophilia A develop autoantibodies that inhibit FVIII activity. (Saenko EX. Et al. Haemophilia (2002), 8, 1-11). The development of antibodies that block the activity of the administered drug prevents the use of FVIII in replacement therapy. Treatment of subjects with inhibitory hemophilia is more expensive due to the use of high-dose recombinant FVIII and immuno-resistant therapy. The production of anti-FIX antibodies in a subject is less common, but has more serious consequences, because such antibodies are less susceptible to therapy in which immune tolerance is induced (Di Michele D.M. Br J Haematol. 2012, 159: 2, p 123-134).
  • FVIIa in high concentrations is able to activate such amounts of FX that are sufficient for the rapid production of thrombin and the formation of fibrin without the positive feedback of thrombin activation factors FVIII and FXI.
  • FVIIa allows one to achieve the formation of a hemostatic clot, bypassing the amplification stage.
  • FVIIa has a short half-life in human plasma, about 2 hours, and this is a serious drawback for the therapeutic use of FVIIa, because multiple intravenous injections or continuous infusion of the drug are necessary to achieve hemostasis. This greatly increases the cost of treatment and creates inconvenience to the subject.
  • There are several ways to increase the half-life of a factor including the production of FVII as a fusion protein with albumin or as a protein modified with PEG, but these methods do not completely solve this problem. (EP1816201 A1 "Modified coagulation factor Vila with extended half-life").
  • rhFVIIa preparations Another disadvantage of using rhFVIIa preparations is the low activity of the drug during therapeutic use, which is caused by the absence of certain modifications of the protein molecules that are necessary for the manifestation of the functional activity of the protein in human blood.
  • Proteins of the coagulation system are synthesized in liver cells and undergo many co- and post-translational modifications, for example, asparagine-linked ( ⁇ -linked) glycosylation; O-linked glycosylation and ⁇ -carboxylation of Glu residues.
  • the location of the modified amino acid residues in the protein molecule which is obtained by expression in heterologous host cells, can vary greatly compared to a functionally active natural protein molecule.
  • rhFVIIa glycoform variants differ in oligosaccharide configuration, and therefore in vivo activity, immunogenicity, and in vivo clearance (WO2004111242A1, Factor VII or Vila gla domain variants; US6903069 B2, Factor VII glycoforms).
  • FVIIa Attempts are known to use FVIIa as a universal hemostatic agent for stopping bleeding in various pathologies, for example, with hemorrhages in organs, internal bleeding, and injuries.
  • NovoSeven® is low in activity, and relatively high doses of the drug are required to prevent uncontrolled bleeding in subjects with injuries.
  • NovoSeven® cases of arterial and venous thrombosis and cases of inhibitory antibodies in subjects with FVII deficiency.
  • NovoSeven® Another drawback of NovoSeven® is the impossibility of its use in pathological conditions in which the release of tissue factor is increased (conditions such as atherosclerosis, septicemia, crushed wounds, DIC), due to the high risk of thrombotic complications. Such conditions are characterized by both a risk of thrombotic complications and increased bleeding. (Lin Y. et al. Transfusion medicine, 2012, v. 22: 6, pp 383-394; Logan AC et al, Hematology Am Soc Hematol Educ Program. 2010; 2010: 153-9.).
  • hemostatic agents As a local hemostatic, a collagen gel is used, on which a platelet aggregate is formed; a solution containing metal ions that form an insoluble complex with plasma albumin; polymer sponges of chitosan; solutions, aerosols, films or gels containing activated coagulation factors.
  • heparin and its derivatives low molecular weight heparin, fragmentin, fondaparinux, idraparinux, enoxaparin
  • Heparin and its derivatives mediate the binding of antithrombin-III to thrombin and FXa, thereby increasing the rate of irreversible inactivation of active coagulation factors.
  • heparin in approximately 10% of cases contributes to the development of heparin-induced thrombocytopenia - a condition in which the subject's hemostatic system is suppressed, and at high concentrations of the drug can cause uncontrolled bleeding.
  • the known antidote of heparin is protamine, which competes with it for binding to antithrombin-III.
  • protamine is complicated by the narrow therapeutic window for this drug - with an overdose, the drug has an anticoagulant effect.
  • warfarin is used, which blocks the vitamin K-dependent ⁇ -carboxylation of coagulation factors in liver cells.
  • warfarin causes a decrease in the concentration of coagulation factors in the blood and contributes to the occurrence of coagulopathy as well as spontaneous hemorrhage in the brain of the subject (Cervera A. et al. J Neurol. 2012, v.259 (2) pp 212-224).
  • antifibrinolytic agents In cases of excessive bleeding after anticoagulant therapy, the use of antifibrinolytic agents is known. For example, tranexamic acid inhibits the formation from plasminogen of the main protein of plasmin fibrinolysis, which proteolytically cleaves a fibrin clot.
  • antifibrinolytic agents can contribute to the recurrence of thrombosis, in particular, they contribute to the development of generalized thrombosis in DIC (disseminated internally vascular coagulation), a clinical condition characterized by massive hemorrhage. (Gando S. et al. Ann Surg. July 2011 254 (1): 10-19).
  • the active components of existing drugs are protein in nature. As a result, the half-life in the plasma of the subject is very short, of the order of an hour or several hours, which requires repeated administration of the drug.
  • the use of protein drugs is carried out by intravenous injection, which prevents the repeated and frequent use of drugs.
  • inhibitory antibodies When coagulation factors FVIII and FIX are used in the treatment of hemophilia A and B, inhibitory antibodies (“inhibitory hemophilia”) appear in some subjects, which block the therapeutic effect of the drug and render the treatment ineffective. Among subjects suffering from hemophilia, about 30% have inhibitory antibodies, and their proportion is constantly growing.
  • Fig. 1 Fig. 2 and fig. 3 for substances from the number given in the examples (Note 1, Note 2, Note 3), as well as for the well-known drug against hemophilia A “OE-DVI” (Bayer, USA) (Kopylov et al. Problems of hematology; 2003/2: 5-11) shows the dependence of the steady-state growth rate of the Vst clot on the concentration of the active substance in human plasma with a deficiency of factor VIII (hemophilia A) (Fig. 1), with a deficiency of GC factor (hemophilia B) (Fig. 2) and in the blood plasma of a healthy person to which unfractionated heparin is added under in vitro conditions. The concentration was calculated in ⁇ g / ml. Fig. 1. Dependence of the stationary cluster growth rate Vst on concentration. active substance in human blood plasma with a deficiency of factor USH (hemophilia A).
  • Z] Z 2 , Z3, Z 4 , Z5, Z 6 , Z 7 and Zg are each independently selected from H, —CI, —F, —Br, —OH, —Me, —Ome;
  • Ri, R 2 , R 3 and R 4 are each independently selected from H, —CI, —F, —Br, —OH, —Me, —Ome;
  • R5 is selected from H or CgC b alkyl, which may also contain hydroxyl, carboxyl or ester groups;
  • Xb X 2 and Xz are each independently selected from H or -Ce alkyl, which may also contain hydroxyl, carboxyl or ester groups
  • Particularly preferred compounds are compounds selected from
  • a further aspect of the invention is a pharmaceutical composition for stopping, preventing and preventing bleeding or enhancing a hemostasis system in a subject by administering to the subject a therapeutically effective amount of a compound.
  • Bleeding in a subject can be a consequence of the hypocoagulation state of the blood coagulation system, disorders, blood coagulability, hematological disorders, hemorrhagic disorders, hemophilia, factor VII deficiency, drug treatment, trauma, disease, bleeding disorders, surgical intervention, hypothermia, menstruation and pregnancy .
  • the pharmaceutical composition in addition to the active ingredient, which is a compound of general formula (I), contains a pharmaceutically acceptable carrier, solvent or diluent.
  • the claimed compounds can also be used for the manufacture of a pharmaceutical composition for its use as a medicine in cases where stopping, prophylaxis of bleeding or normalization of the hemostasis system in a subject is required, and such a composition contains a therapeutically or prophylactically effective amount of said compound and, optionally, pharmaceutically an acceptable carrier, diluent or excipient.
  • the claimed compounds can be used on their own or in the composition to block the action of indirect anticoagulants after administration to the subject, by introducing a therapeutically effective amount of the compound to the subject.
  • the compounds of the invention can be used in cases in which hemophilia is hemophilia A or hemophilia B, when hemophilia is congenital or acquired, including when the subject is being developed
  • the compounds of the invention can be used in cases in which bleeding in a subject is caused by a deficiency of hemostasis that has developed as a result of treatment with drugs, such as anti-platelet drugs or anticoagulants.
  • drugs such as anti-platelet drugs or anticoagulants.
  • the anticoagulant is selected from the group consisting of heparin, fragmentin, low molecular weight heparin, a coumarin derivative such as warfarin and dicumarol, FXa inhibitors such as fondaparinux, idraparinux and enoxaparin.
  • the anticoagulant may be selected from the group consisting of FXa inhibitors, including direct FXa inhibitors such as DX-9065a, rivaroxaban, apixaban, razaksaban (DPC906), YM-60828, YM-150, betriksaban, PD-348292, otamiksaban, DU- 176b, LY517717, GSK913893, thrombin inhibitors, including hirudin, bivalirudin, argatroban, ximelagatran and direct thrombin inhibitors such as dabigatran.
  • direct FXa inhibitors such as DX-9065a, rivaroxaban, apixaban, razaksaban (DPC906), YM-60828, YM-150, betriksaban, PD-348292, otamiksaban, DU- 176b, LY517717, GSK913893
  • the anticoagulant may also be selected from the group consisting of tissue factor pathway inhibitor (TFPI), antithrombin-III, lupus anticoagulant, anticoagulant peptide nematodes, factor FVIIa with a blocked active center (FVIIai), FIXa inhibitors, factor Va and Villa inhibitors, including activated factors Va and Villa, including activated protein C (aPC) and soluble thrombomodulin, and inhibitory antibodies that bind to coagulation factor.
  • tissue factor pathway inhibitor TFPI
  • antithrombin-III lupus anticoagulant
  • anticoagulant peptide nematodes include a blocked active center (FVIIai), FIXa inhibitors, factor Va and Villa inhibitors, including activated factors Va and Villa, including activated protein C (aPC) and soluble thrombomodulin, and inhibitory antibodies that bind to coagulation factor.
  • TFPI tissue factor pathway inhibitor
  • FVIIai lupus anticoagulant
  • FVIIai with
  • the compounds of the invention can be used in cases in which bleeding is associated with impaired liver function, leading to impaired blood coagulation; with impaired renal function; deficiency of hemostasis that developed during infections or during illness, such as vitamin K deficiency or severe liver disease; with hemostatic deficiencies that developed as a result of snake bites. And also in cases where bleeding is associated with a deficiency or violation of coagulation factors other than FVIII and FIX; deficient in FV; deficient in FVII; deficient in FX; deficient in FXIII; deficiency of a2-antiplasmin; with deficiency or impairment of fibrinogen, including afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia.
  • the claimed compounds can be used in cases in which bleeding is the result of a massive transfusion of blood, plasma, blood substituting or plasma substituting agents (dilational coagulopathy).
  • Bleeding can occur from varicose veins or manifest as acute hemarthrosis, chronic hemophilic arthropathy, hematomas, hematuria, bleeding in the central nervous system, gastrointestinal bleeding, cerebral hemorrhage, acute, recurrent or chronic tracheal, bronchial or alveolar hemorrhage or hemoptysis subject.
  • Bleeding can be caused by thrombolytic or fibrinolytic therapy.
  • thrombolytic or fibrinolytic therapy was carried out using a plasminogen activator.
  • the cause of bleeding may be a subject's condition associated with von Willebrand disease (VWD), hemolytic uremic syndrome (HUS). And also when the cause of bleeding may be the condition of the subject associated with congenital or acquired platelet diseases and disorders, such as thrombocytopenia, heparin-induced thrombocytopenia, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP, Trombone, Tromben, Tromben, Tromben, Tromben, Tromben, Tromben, Tromben, Tromben, Tromben, Tromben, Tromben, Tromben, Germansky-Pudlak syndrome, HELLP syndrome, Chediak-Higashi syndrome, Genoch-Shenlein purpura.
  • VWD von Willebrand disease
  • HUS hemolytic uremic syndrome
  • TTP thrombotic thrombocytopenic purpura
  • the compounds of the invention can be used in cases in which a disease or condition of a subject is treatable by administration of a pro-coagulant.
  • SUBSTITUTE SHEET by any suitable method, for example, by attaching the corresponding amine (II) to a derivative of the corresponding carboxylic acid (III)
  • Suitable coupling agents such as 1, carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminoopril) - ⁇ ethylcarbodiimide hydrochloride (EDCI), or other similar reagents.
  • CDI 1, carbonyldiimidazole
  • DCC dicyclohexylcarbodiimide
  • EDCI N- (3-dimethylaminoopril) - ⁇ ethylcarbodiimide hydrochloride
  • EDCI N-dimethylaminoopril
  • the formation of an amide bond can also be ensured by the interaction of acid chlorides (IV) with amines (II).
  • the acid chlorides (IV) can be obtained from the corresponding carboxylic acids (III) by treatment with a suitable reagent, such as SOCl 2 or POC1 3 .
  • the acid chloride (IV) of the corresponding carboxylic acid readily reacts with amines (II) to yield the target compound (I).
  • Amines (II) can be obtained by reduction of the corresponding nitro compounds (V) under suitable conditions.
  • reducing agents for example, SnCl 2 or hydrogenation in the presence of Raney nickel can be used.
  • Nitro compounds (V) can be synthesized from the corresponding amines (VI) and nitro substituted carboxylic acids (VII)
  • Carboxylic acids (VII) are converted to the corresponding acid chlorides (VIII) by treatment with a suitable reagent, such as SOCl 2 or POC1 3 . Chlorides (!!!) then react smoothly with amines (VI) to form nitro compounds
  • UV-absorbing fractions are collected, the purity of the product is controlled by thin-layer chromatography in a mixture of chloroform: ethanol 20: 1.
  • the product rf is 0.6.
  • the initial p-chloroaniline composition is Rf Yield 0.7 yaet 1chG- (4-chlorophenyl) -2-nitrobenzamide is 2.0 g Mass spectrum (MALDI-VP). M + H 277, M + Na 299.
  • the plasma was mixed with a stock solution of the test compound in water and incubated at 37 ° C. To prepare stock solutions of some compounds insoluble in water, preliminary dissolution in DMSO or isopropanol was used. The final plasma concentration did not exceed: isopropanol - 0.5%, DMSO - 0.2%. In these cases, plasma samples with the corresponding content of isopropanol or DMSO were used as control.
  • T-2 Thrombodynamics Recorder Studies using the “T-2 Thrombodynamics Recorder” were carried out in accordance with the guidelines for the “Diagnostic kit for plasma thrombodynamics studies” (LLC Gemakor, Moscow, Russia) (Balandina et al. Biophys J. 2011; ⁇ .101 ( 8): 1816-1824). The calculation of the results of the study was carried out automatically by the software (user manual “Diagnostic laboratory system software“ T-2 Thrombodynamics Recorder ”, LLC Gemakor, Moscow, Russia).
  • the effectiveness of the compounds as a means of normalizing the blood coagulation system was determined by a concentration of C 12 5%, at which the clot growth rate increases by 25% compared with the clot growth rate in human blood plasma
  • the claimed compounds are capable of normalizing the blood coagulation system at low concentrations in the case of hemophilia A, hemophilia B and other cases of impaired blood coagulation (when heparin is added to the human blood plasma).

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une nouvelle classe de composés pour arrêter, prévenir et traiter des écoulements sanguins et renforcer le système d'hémostase. L'invention concerne de nouveaux composés, leurs sels pharmaceutiquement acceptables et/ou leurs compositions, qui peuvent être utilisés pour arrêter, prévenir et traiter des écoulements sanguins chez l'homme ou d'autres mammifères résultant d'un état d'hypo-coagulation du système de coagulation du sang, d'une diminution de la capacité du sang à coaguler, de troubles hématologiques, d'hémophilie, de déficit du facteur VII, de traitement médicamenteux, de traumatisme, de maladies, de troubles liés à des saignements, d'une intervention chirurgicale, de menstruations, de grossesse, et de toute une série d'autres maladies chez l'homme et les mammifères liées à la capacité du sang à coaguler.
PCT/RU2014/000574 2013-08-01 2014-07-30 Dérivés de carbamoylphényle pour arrêter, prévenir et traiter des écoulements sanguins et renforcer le système d'hémostase WO2015016750A1 (fr)

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EA201300843 2013-08-01
EA201300843A EA201300843A1 (ru) 2013-08-01 2013-08-01 Карбамоилфенильные производные для остановки, предотвращения и профилактики кровотечений или усиления системы гемостаза

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WO2015016750A1 true WO2015016750A1 (fr) 2015-02-05

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CN109180573A (zh) * 2018-09-17 2019-01-11 珠海润都制药股份有限公司 一种贝曲西班中间体的制备方法

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Publication number Priority date Publication date Assignee Title
CN109180573A (zh) * 2018-09-17 2019-01-11 珠海润都制药股份有限公司 一种贝曲西班中间体的制备方法

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