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WO2025118719A1 - Agent de réversion de l'héparine à petites molécules avec squelette triazine, sa méthode de préparation et son utilisation - Google Patents

Agent de réversion de l'héparine à petites molécules avec squelette triazine, sa méthode de préparation et son utilisation Download PDF

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WO2025118719A1
WO2025118719A1 PCT/CN2024/116034 CN2024116034W WO2025118719A1 WO 2025118719 A1 WO2025118719 A1 WO 2025118719A1 CN 2024116034 W CN2024116034 W CN 2024116034W WO 2025118719 A1 WO2025118719 A1 WO 2025118719A1
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preparation
triazine
ethyl
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韩进松
王路
张文慧
缪顺童
黄慧
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine and relates to a triazine skeleton small molecule heparin reversal agent and a preparation method and use thereof, and in particular to a triazine skeleton small molecule compound capable of reversing the anticoagulant activity of heparin and a preparation method and use thereof, as well as a pharmaceutical composition comprising the triazine skeleton small molecule compound.
  • Heparin is widely used clinically as an intravenous anticoagulant to prevent excessive coagulation during cardiac surgery, extracorporeal circulation or dialysis.
  • Heparin anticoagulation mainly forms antithrombin-heparin-coagulation factor complexes, which inactivate thrombin through an antithrombin-dependent mechanism.
  • the heparin level in the blood must be quantified in time to neutralize the anticoagulant effect of heparin and begin to restore coagulation.
  • Protamine is the only heparin reversal agent approved in China. It is a mixture of highly positively charged polycationic strong basic peptides with a relative molecular mass of 5 to 10 kDa. Protamine binds to heparin through anions and cations to form a stable neutrally charged salt complex, which competes to separate heparin from antithrombin to restore the original flow characteristics of blood. The reticuloendothelial system then immediately clears the heparin-protamine complex. Heparin is a mixture of linear helical polysaccharides with chains of different lengths.
  • Uric acid and glucosamine are mainly connected by 1 ⁇ 4 bonds, in which sulfur-containing groups and carboxyl groups extend along the flexible polysaccharide backbone at specified intervals and directions, and provide the highest negative charge density of any known biomacromolecule. Therefore, the key features to be considered in heparin neutralization are anion-cation interactions and conformational flexibility.
  • Protamine can quickly reverse the effects of heparin, but its use may cause adverse reactions, including allergic reactions, respiratory problems, and severe cardiovascular reactions such as hypotension and bradycardia, which can cause coronary thrombosis and myocardial infarction in severe cases. It is reported that protamine can only partially reverse the anticoagulant effect of low molecular weight heparin. In addition, the metabolite of protamine, propylamine, is highly toxic. Environmental pollution, seasonal shortages and other factors further limit the acquisition and application of protamine.
  • Delparantag is a class of small molecule salicylic acid derivatives that have good neutralizing effects in vivo and in vitro, but its development was terminated due to cases of hypotension in Phase II clinical trials.
  • Ciraparantag binds to heparin through hydrogen bonds and charge interactions, and uses whole blood clotting time to measure the reversal effect. The measuring equipment has not yet been approved by the FDA and is currently in Phase II clinical trials.
  • the purpose of the present invention is to provide a novel triazine compound or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof having heparin anticoagulant reversal activity, better pharmacodynamic properties, and low blood and cell toxicity.
  • the triazine skeleton small molecule heparin reversal agent is selected from the triazine compound or its pharmaceutically acceptable salt, stereoisomer, solvate as shown in Formula I:
  • X 1 , X 2 , and X 3 are the same as or different from each other and are independently selected from N or phenyl;
  • L 1 , L 2 , and L 3 are the same or different from each other, unsubstituted or independently selected from H, alkyl;
  • R 1 , R 2 , and R 3 are independently optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heterocyclic aryl, optionally substituted halogenated aryl, or optionally substituted heterochain alkyl; the nitrogen atom is optionally quaternized and may be optionally oxidized;
  • the alkyl group is a C 1 -C 10 straight chain or branched chain alkyl group
  • the alkylamino group refers to an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group, wherein the nitrogen atom of the amino group is optionally quaternized;
  • the cycloalkyl group is a C 3 -C 6 cycloalkyl group, and optionally, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
  • the heterocycloalkyl group is a 3-6 membered monocyclic or polycyclic non-aromatic ring structure, including but not limited to piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, hexahydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, etc.; the 3-6 membered heterocycloalkyl group may be connected to the rest of the molecule via a heteroatom or carbon atom or an alkyl group, including but not limited to 1-(2-piperazin-1-ylacetyl)pyrrolidine;
  • the aryl group includes but is not limited to phenyl
  • the heterocyclic aromatic group is a saturated or unsaturated 5-6-membered monocyclic or polycyclic aromatic ring structure containing 1-3 heteroatoms selected from N, O, and S on the ring, including but not limited to thienyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, etc.; the 5-6-membered heterocyclic aromatic group can be connected to the rest of the molecule through a heteroatom or a carbon atom or an alkyl group, including but not limited to 4-(4-morpholinyl)aniline, 4-amino-1-benzylpiperidine, 1-(4-fluorobenzyl)piperazine, N-benzylpiperazine, etc.;
  • the heterochain hydrocarbon structure of the heterochain hydrocarbon group is a C 1 -C 20 saturated or unsaturated straight chain or branched heterochain structure containing 1 to 3 heteroatoms selected from N, O, and S;
  • the heteroatom may occupy the connecting position between molecules, and the heteroatom is selected from nitrogen, oxygen or sulfur;
  • substitution refers to substitution by one or more of the following substituents, and the substituents are selected from: halogen, C 1 -C 5 alkyl, hydroxyl, cycloalkyl, heterocycloalkyl, alkoxy, carbonyl, heterocyclic aromatic, aryl and the like.
  • the halogen is selected from fluorine, chlorine, bromine or iodine.
  • the R 1 -X 1 -L 1 group is selected from:
  • the R 2 -X 2 -L 2 group is selected from:
  • the R 3 -X 3 -R 3 group is selected from:
  • R 1 -X 1 -L 1 group is selected from:
  • the R 2 -X 2 -L 2 group is selected from:
  • the R 3 -X 3 -R 3 group is selected from:
  • the R 1 -X 1 -L 1 group is selected from The R 2 -X 2 -L 2 group is selected from The R 3 -X 3 -R 3 group is selected from The R 1 -X 1 -L 1 group is selected from The R 2 -X 2 -L 2 group is selected from The R 3 -X 3 -R 3 group is selected from The R 1 -X 1 -L 1 group is selected from The R 2 -X 2 -L 2 group is selected from The R 3 -X 3 -R 3 group is selected from The R 1 -X 1 -L 1 group is selected from The R 2 -X 2 -L 2 group is selected from The R 3 -X 3 -R 3 group is selected from The R 1 -X 1 -L 1 group is selected from The R 2 -X 2 -L 2 group is selected from The R 3 -X 3 -R 3 group is selected from The R 1 -X 1 -L 1 group is selected from The R 2 -X 2 -L 2 group is selected
  • the triazine compound of the present invention is selected from the following compounds:
  • the triazine skeleton small molecule heparin reversal agent is selected from the triazine compound or its pharmaceutically acceptable salt, stereoisomer, solvate thereof, which has passed the anti-Xa enzyme activity test, and has been subjected to the acute toxicity test in mice and the heparin reversal test in mice:
  • the solvate of the triazine compound is a hydrate of the triazine compound.
  • Another object of the present invention is to provide a method for preparing the triazine compound, the synthesis route of which is as follows:
  • R 1 -X 1 -L 1 group when the R 1 -X 1 -L 1 group is selected from When A n is When the R 1 -X 1 -L 1 group is selected from the group consisting of When the above groups are other than those mentioned above, An is selected from R 1 -X 1 HL 1 , that is, X 1 is selected from N, R 1 -X 1 -L 1 is as described above, and An is specifically selected from
  • B m is selected from R 2 -X 2 HL 2 , R 2 -X 2 -L 2 is as described above, and B m is specifically selected from
  • C z is selected from R 3 -X 3 HR 3 , R 3 -X 3 -L 3 as described above, C z is specifically selected from
  • Step (1) using tetrahydrofuran (THF) as a reaction solvent and N,N-diisopropylethylamine (DIPEA) as an acid-binding agent, cyanuric chloride and An are reacted at a temperature of -20°C to obtain intermediate III; wherein the molar ratio of cyanuric chloride to An is 1:1 to 1:2; and the molar ratio of cyanuric chloride to N,N-diisopropylethylamine is 1:1 to 1:2.5;
  • THF tetrahydrofuran
  • DIPEA N,N-diisopropylethylamine
  • Step (2) using tetrahydrofuran as a reaction solvent and N,N-diisopropylethylamine as an acid-binding agent, the intermediate III and Bm are reacted at a temperature of 25° C. to obtain the intermediate II; the molar ratio of the intermediate III to Bm is 1:1 to 1:2; the molar ratio of the intermediate III to N,N-diisopropylethylamine is 1:1 to 1:2.5;
  • Step (3) using tetrahydrofuran as a reaction solvent and N,N-diisopropylethylamine as an acid-binding agent, the intermediate II and Cz react under reflux conditions to obtain a triazine compound with a structure as shown in formula I; the molar ratio of the intermediate II and Cz is 1:1 to 1:2.5; the molar ratio of the intermediate II and N,N-diisopropylethylamine is 1:1 to 1:4.
  • Another object of the present invention is to provide a pharmaceutical composition, wherein the pharmaceutical composition comprises the triazine compound or its pharmaceutically acceptable salt, stereoisomer, solvate as an effective ingredient or a main effective ingredient and is prepared into a preparation with a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide the triazine compound or its pharmaceutically acceptable salt, stereoisomer, Use of a solvate in preparing an anticoagulant reversal agent.
  • Another object of the present invention is to provide the use of the triazine compound or its pharmaceutically acceptable salt, stereoisomer, solvate in the preparation of a drug for treating the excessive anticoagulant side effects caused by the use of heparin to treat diseases, and in the preparation of a drug for treating surgical operations that require reversal of the anticoagulant activity of heparin.
  • the diseases treated with heparin are thromboembolic diseases; the embolic diseases are myocardial infarction, thrombophlebitis, and pulmonary embolism; the surgical operations are hemodialysis, extracorporeal circulation, catheterization, and microvascular surgery.
  • the triazine skeleton small molecule heparin reversal agent of the present invention has a simple preparation method, low cost, low toxicity, strong ability to bind to heparin, and can be used to prepare drugs for treating and/or preventing adverse reactions and diseases caused by excessive heparin anticoagulation in subjects through in vitro and in vivo tests.
  • the compounds of the present invention can be prepared according to conventional methods in the art, and using suitable reagents, raw materials and purification methods known to those skilled in the art.
  • the preparation method of the compounds of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.
  • Step 2 Synthesis of 6-chloro-N 2 -phenyl-N 4 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine
  • Step 3 Synthesis of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -phenyl-N 6 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine
  • 6-chloro-N 2 -phenyl-N 4 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine 280 mg, 0.895 mmol
  • 2-(4-methylpiperazin-1-yl)ethane-1-amine (257 mg, 1.791 mmol)
  • DIPEA 405 mg, 3.133 mmol
  • 3 mL tetrahydrofuran reflux at 80°C for 2 hours.
  • Cyanuric chloride (10.00 g, 54.2 mmol), phenylmagnesium bromide (54.2 mL, 1 M THF solution of phenylmagnesium bromide, 54.2 mmol), DIPEA (10.98 mL, 65.1 mmol) and 200 mL tetrahydrofuran were added to an eggplant-shaped bottle at -20°C in sequence, and reacted at 0°C for 1 hour. TLC monitored the reaction to be complete.
  • Step 2 Step 3: Replace pyridin-3-ylmethylamine in step 2 of Example 1 with L-histidine methyl ester, and the rest is the same as Example 1 to obtain Compound 1.
  • LC-MS (ESI): m/z 466.27 [M+H] + .
  • Example 25 Preparation of N 2 -cyclopropyl-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 -pyridin-3-ylmethyl-1,3,5-triazine-2,4-diamine (24)
  • Example 27 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclopropyl-N 6 -(2-(4-methylpiperazin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (26)
  • Example 28 Preparation of N 2 -(2-(1H-imidazol-2-yl)ethyl)-N 4 -cyclopropyl-6-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazine-2,4-diamine (27)
  • Example 36 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclohexyl-N 6 -(2-(dimethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine (35)
  • Example 37 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclohexyl-N 6 -(2-(dimethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine (36)
  • Example 38 Preparation of N 2 -cyclohexyl-N 4 -(pyridin-2-ylmethyl)-N 6 -(2-pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (37)
  • Example 40 Preparation of N 2 -cyclohexyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -pyridin-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (39)
  • Example 50 Preparation of methyl 2-(4-(cyclohexylmethyl)amino)-6-(2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (49)
  • Example 51 Preparation of methyl 2-(4-(cyclohexylmethyl)amino)-6-(2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (50)
  • Example 52 Preparation of methyl 2-(4-(cyclohexylmethyl)amino)-6-(2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (51)
  • Example 54 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclohexylmethyl-N 6 -(2-(dimethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine (53)
  • Example 56 Preparation of N 2 -cyclohexylmethyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -pyridin-4-yl-1,3,5-triazine-2,4,6-triamine (55)
  • Example 62 Preparation of N 2 -(3-dimethylamino)propyl-N 4 -phenyl-N 6 -(pyridin-4-yl)-1,3,5-triazine-2,4,6-triamine (62)
  • Example 64 Preparation of 6-(4-fluorobenzyl)piperazin-1-yl)-N 2 -phenyl-N 4 -pyridin-2-ylmethyl-1,3,5-triazine-2,4-diamine (64)
  • Example 70 Preparation of N 2 -benzyl-N 4 -(2-morpholinoethyl)-N 6 -pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (70)
  • Example 72 Preparation of N 2 -benzyl-N 4 -(2-(pyrrolidin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (72)
  • Example 80 Preparation of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-4-yl-N 6 -thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (80)
  • Example 82 Preparation of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-N 4 -thiophen-2-ylmethyl-1,3,5-triazine-2,4-diamine (82)
  • Example 83 Preparation of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-N 4 -thiophen-2-ylmethyl-1,3,5-triazine-2,4-diamine (83)
  • Example 84 Preparation of 6-(4-benzylpiperazin-1-yl)-N 2 -pyridin-2-ylmethyl-N 4 -thiophen-2-ylmethyl-1,3,5-triazine-2,4-diamine (84)
  • Example 88 Preparation of (S)-methyl 2-((4-((2-(1H-indol-3-yl)ethyl)amino)-6-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (88)
  • Example 90 Preparation of methyl 2-(4-(2-(1H-indole-3-ethyl)ethylamino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (90)
  • Example 96 Preparation of N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (96)
  • Example 101 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(1H-indol-3-yl)ethyl)-N 6 -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (101)
  • Example 102 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(1H-indol-3-yl)ethyl)-N 6 -(3-(4-methylpiperazin-1-yl)propyl)-1,3,5-triazine-2,4,6-triamine (102)
  • Example 103 Preparation of N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (103)
  • Example 104 Preparation of N-(2-(1H-indol-3-yl)ethyl)-4-(4-methylpiperazin-1-yl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2-amine (104)
  • Example 105 Preparation of 2-(4-(2-(1H-indol-3-ethyl)ethylamino)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (105)
  • Example 106 Preparation of 2-(4-(4-(2-(1H-indole-3-ethyl)ethylamino)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2-yl)piperazin-1-yl)ethyl-1-ol (106)
  • Example 111 Preparation of N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -pyridin-4-ylmethyl-1,3,5-triazine-2,4,6-triamine (111)
  • Example 120 Preparation of N 2 -(3,4-dimethoxyphenyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (120)
  • Example 121 Preparation of N 2 -(2-(1H-imidazol-2-yl)ethyl)-N 4 -(3,4-dimethoxyphenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2,4-diamine (121)
  • Example 122 Preparation of N 2 -(3,4-dimethoxyphenyl)-6-(4-(dimethylamino)piperidin-1-yl)-N 4 -pyridin-4-yl-1,3,5-triazine-2,4-diamine (122)
  • Example 125 Preparation of N 2 -(3,4-dimethoxyphenyl)-N 4 -pyridin-4-ylmethyl-N 6 -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (125)
  • Example 126 Preparation of N 2 -(3,4-dimethoxyphenyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(pyridin-4-ylmethyl)-1,3,5-triazine-2,4,6-triamine (126)
  • Example 127 Preparation of N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -(3,4-dimethoxyphenethyl)-6-(4-(dimethylamino)piperidin-1-yl)-1,3,5-triazine-2,4-diamine (127)
  • Example 128 Preparation of N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (128)
  • Example 129 Preparation of N 2 -(3,4-dimethoxyphenethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (129)
  • Example 130 Preparation of N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(4-ylpyridine)-1,3,5-triazine-2,4,6-triamine (130)
  • Example 131 Preparation of N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (131)
  • Example 133 Preparation of N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(dimethylamino)ethyl)-N 6 -pyridin-4-ylmethyl-1,3,5-triazine-2,4,6-triamine (133)
  • Example 135 Preparation of N 2 -(2-(1H-benzoimidazol-2-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 -tetrahydropyran-4-yl)-1,3,5-triazine-2,4-diamine (135)
  • Example 137 Preparation of 6-(4-fluorobenzyl)piperazin-1-yl)-N 2 -(pyridin-3-ylmethyl)-N 4 -tetrahydropyran-4-yl-1,3,5-triazine-2,4-diamine (137)
  • Example 138 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-6-(4-benzylpiperazin-1-yl)-N 4 -tetrahydropyran-4-yl-1,3,5-triazine-2,4-diamine (138)
  • Example 139 Preparation of N 2 -(1-benzylpiperidin-4-yl)-N 4 -pyridin-4-yl-N 6 -tetrahydropyran-4-yl)-1,3,5-triazine-2,4,6-triamine (139)
  • Example 140 Preparation of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -tetrahydropyran-4-yl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (140)
  • Example 141 Preparation of N 2 -pyridin-2-ylmethyl-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 -tetrahydropyran-4-yl)-1,3,5-triazine-2,4,6-triamine (141)
  • Example 142 Preparation of N 2 -(4-methylpyridine)-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 -tetrahydropyran-4-yl)-1,3,5-triazine-2,4,6-triamine (142)
  • Example 144 Preparation of N 2 -(2-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-2-yl-N 6 -tetrahydropyran-4-yl-1,3,5-triazine-2,4,6-triamine (144)
  • Example 145 Preparation of N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (145)
  • Example 150 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (150)
  • Example 151 Preparation of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-4-yl-N 6 -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (151)
  • Example 152 Preparation of 4-(4-benzylpiperazin-1-yl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-N-(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2-amine (152)
  • Example 154 Preparation of N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (154)
  • Example 156 Preparation of N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(dimethylamino)ethyl)-N 6 -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (156)
  • Example 158 Preparation of N 2 -(2-dimethylamino)ethyl-N 4 -(tetrahydro-2H-pyran-4-yl)methyl)-6-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (158)
  • Example 160 Preparation of N 2 -(2-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-2-yl-N 6 -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (160)
  • Example 162 Preparation of N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-6-morpholinyl-1,3,5-triazine-2,4-diamine (162)
  • Example 164 Preparation of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-morpholinyl-N 4 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (164)
  • Example 166 Preparation of N 2 -(2-(dimethylamino)ethyl)-6-morpholinyl-N 4 -(pyridin-4-yl)-1,3,5-triazine-2,4-diamine (166)
  • Example 170 Preparation of N 2 -(2-(dimethylamino)ethyl)-6-morpholinyl-N 4 -(pyridin-4-ylmethyl)-1,3,5-triazine-2,4-diamine (170)
  • Example 175 Preparation of N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -pyridin-3-ylmethyl-N 6 -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (175)
  • Example 176 Preparation of N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (176)
  • Example 177 Preparation of N 2 -(2-(1H-imidazol-2-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 ,N 4 -bis(2-methoxyethyl)-1,3,5-triazine-2,4-diamine (177)
  • Example 178 Preparation of N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 -pyridin-4-yl-1,3,5-triazine-2,4,6-triamine (178)
  • Example 179 Preparation of 6-(4-(dimethylamino)piperidin-1-yl)-N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(4-pyridinyl)-1,3,5-triazine-2,4-diamine (179)
  • Example 181 Preparation of N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -pyridin-2-ylmethyl-N 6 -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (181)
  • Example 182 Preparation of N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -(4-methylmethylpyridine)-1,3,5-triazine-2,4,6-triamine (182)
  • Example 184 Preparation of N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 -pyridin-2-yl-1,3,5-triazine-2,4,6-triamine (184)
  • Example 190 Preparation of 6-(4-methylpiperazin-1-yl)-N 2 -(4-morpholinylphenyl)-N 4 -pyridin-4-yl-1,3,5-triazine-2,4-diamine (190)
  • Example 192 Preparation of N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -(4-morpholinylphenyl)-N 6 -pyridin-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (192)
  • Example 196 Preparation of 6-(4-fluorobenzyl)piperazin-1-yl)-N 2 -(4-morpholinylphenyl)-N 4 -pyridin-2-yl-1,3,5-triazine-2,4-diamine (196)
  • DLS dynamic light scattering
  • the particle size of the compound is 1-10nm, and the particle size of heparin sodium is 1-10nm.
  • m compound : m heparin 1:1 mixing. If a polymer is formed, the particle size increases to about 100nm.
  • LMWH Low molecular weight heparin selected was enoxaparin sodium injection (hereinafter referred to as enoxaparin solution), from sanofi-aventis (40 mg: 4000AXa IU, product number CS543A); tris(hydroxymethylaminomethane) (Tris), from GBCBIO (product number G3470); compound 1-compound 196.
  • enoxaparin solution enoxaparin sodium injection
  • Tris tris(hydroxymethylaminomethane)
  • the experimental results are shown in Table 2.
  • the triazine compounds of the present invention have binding activity with heparin sodium in vitro.
  • the cationic dye Azure A colorimetric method was used to quantitatively evaluate the ability of small molecule heparin reversal agents to bind to enoxaparin.
  • Azure A (absorption peak 590nm/630nm) is a cationic dye, and heparin sodium is a strongly negatively charged polysaccharide structure. Heparin sodium and Azure A are reversibly combined through electrostatic neutralization to form a complex (absorption peak 520nm). Small molecule reversal agents compete with heparin sodium for Azure A, restoring the absorption peak of Azure A to varying degrees while reducing the absorption peak of the complex.
  • protamine sulfate from TCI (product number P0675); Ciraparantag, from Peptide Plus Biotechnology; low molecular weight heparin selected from enoxaparin sodium injection, from sanofi-aventis (40 mg: 4000AXa IU, product number CS543A); Azure A, from Shanghai MacLean Biochemical Technology Co., Ltd. (product number C14252971); triazine compounds synthesized by the present invention.
  • Table 3 shows the reversal percentage of triazine compounds on heparin sodium competition binding.
  • Azine compounds can reverse the binding of Azure A to heparin to varying degrees in vitro and have the ability to reverse the activity of heparin.
  • cytotoxicity When cells are stimulated, potential changes may occur based on the resting potential.
  • the metabolic transport of cationic compounds in the body needs to take into account changes in the surface potential of human cells and cytotoxicity.
  • the anti-angiogenic activity of heparin may have different effects on the structure and mechanical properties of fibrin, and cationic compounds targeting heparin may have the same effect.
  • the experimental steps for testing cytotoxicity are as follows:
  • Experimental instruments clean bench (THermo); electronic balance (METTLER TOLEDO AL104); centrifuge (Dalong Xingchuang Experimental Instrument DM0412); cell counter (THermo Countess3 automatic cell counter); CO2 incubator (THermo); microplate reader (SpectraMax iD3).
  • HUVECs were inoculated in DMEM+10% FBS complete medium and cultured at 37°C, 5% CO 2 , and 95% humidity for adherent growth.
  • HUVEC in logarithmic growth were digested with trypsin and centrifuged to obtain cell pellets, which were resuspended in fresh culture medium and counted by trypan blue staining.
  • the cells were diluted to an appropriate concentration, and 50 ⁇ L of the cell suspension was seeded in a 96-well plate, 4000 cells/well.
  • the 96-well plate was placed in a carbon dioxide incubator and cultured overnight. The mother solution of the compound to be tested was prepared.
  • All compounds (triazine compounds, Ciraparantag, protamine sulfate) were prepared with ultrapure water to a mother solution with a concentration of 5 mg/mL, 5% DMSO was used for solubilization, stored at -80°C, and packaged for use. According to the required working concentration, the compound mother solution was diluted with culture medium to an appropriate concentration, so that the final test concentration was 50 ⁇ g/mL, 50 ⁇ L of the compound solution to be tested was added to a 96-well plate, and each well to be tested was added with 50 ⁇ L of the compound solution to be tested.
  • the compound was set up in triplicate wells; the 96-well plate was placed in a carbon dioxide incubator and continued to be cultured for 1 day to allow the cells to adhere to the wall and grow. 20 ⁇ L of 5 mg/mL MTT reagent was added to each well, and after incubation for 4 hours, 150 ⁇ L of DMSO was added to each well and mixed and shaken for 5 minutes; the absorbance value was read at 580 nm using an ELISA reader, and the cell growth inhibition efficiency was calculated.
  • OD drug to be tested absorbance of triazine compounds or Ciraparantag or protamine sulfate at 580nm;
  • OD culture medium control the absorbance of the blank control group with only culture medium added at 580nm;
  • OD cell control The absorbance at 580 nm of the control group with culture medium and cells added.
  • cationic compounds After intravenous injection, the drug directly contacts the blood tissue, and cationic compounds have the potential to directly induce erythrocyte rupture (i.e., hemolysis).
  • erythrocyte rupture i.e., hemolysis
  • the ability of cationic compounds to induce erythrocyte hemolysis is one of the most important and most frequently studied biocompatibility tests.
  • the compound is prepared into a solution with a concentration of 2.5 mg/mL using PBS buffer.
  • the compound solution or reference substance (the absorbance of the sample with 100% hemolysis in ultrapure water is the positive control, and the absorbance in PBS is the negative control) and the fresh blood sample are added to the centrifuge tube at a volume ratio of 9:1, and mixed by inversion.
  • Three parallel experiments are set for each compound to be tested.
  • the mixed sample is incubated in a 37°C constant temperature incubator for 1 hour, then centrifuged at 3500rpm for 15 minutes, the supernatant in the centrifuge tube is aspirated, and the absorbance is measured at the 575nm absorption band using an ELISA reader to calculate the hemolysis rate.
  • Hemolysis rate (%) (OD of drug to be tested - OD of PBS control ) / (OD of ultrapure water control - OD of PBS control ) ⁇ 100%
  • OD test drug the absorbance value of the test sample at 575nm.
  • OD PBS control absorbance value of negative control well at 575 nm.
  • OD ultrapure water control The absorbance value of the positive control well at 575nm.
  • Table 5 shows the hemolytic toxicity experimental data of triazine compounds.
  • the results show that the triazine compounds of the present invention have no hemolytic toxicity (hemolysis rate ⁇ 5%) at an extremely high concentration of 2.5 mg/mL and have good safety, while the positive control protamine shows significant blood toxicity at high concentrations.
  • the hemolytic toxicity of protamine is one of its important toxicity characteristics.
  • the experimental data are consistent with literature reports and clinical data.
  • the triazine compounds of the present invention have no hemolytic toxicity and meet the requirements of intravenous injection materials.
  • Example 201 Compound Coagulation Factor Activity Test (Anti-Xa Factor Test)
  • Enoxaparin mainly produces anticoagulant effect by forming antithrombin-heparin-coagulation factor Xa ternary complex through antithrombin-dependent mechanism.
  • Anti-Xa test is an enzyme activity test used in clinical and scientific research to test the ability of compounds to reverse heparin.
  • Reconstitute the kit According to the instructions of the BiopHen Heparin Anti-Xa (kit), dilute the sample to be tested and reconstitute the kit. Take out the lyophilized antithrombin, coagulation factor Xa, and coagulation factor Xa specific chromogenic substrate factor in the kit, add Tris-NaCl pH7.4 to reconstitute. In ultrapure water, incubate the compound with enoxaparin at a mass ratio of 2:1 at 37°C for 10 minutes, dilute to an appropriate concentration and prepare the sample. Ultrapure water is used as the heparin-free control sample, and enoxaparin solution of appropriate concentration is diluted with ultrapure water as the heparin control substance.
  • Neutralization rate (%) (OD test drug - OD heparin control ) / (OD no heparin control - OD heparin control ) ⁇ 100%
  • OD test drug the absorbance value of the test sample at 405nm.
  • OD Heparin Control The absorbance value of the heparin control well at 405 nm.
  • OD no heparin control absorbance value of the heparin control well at 405nm.
  • the anti-Xa activity of the 22 triazine compounds of the present invention is better than that of protamine sulfate, among which compounds 194, 131, 195, 61 and 145 have an anti-Xa neutralization activity of more than 70%, showing a strong heparin reversal activity.
  • mice weighing 18-20 g were randomly divided into blank control group (NS): normal saline was injected into the tail vein, and normal saline was injected into the tail vein 5 minutes later, and the mice were immediately anesthetized by intraperitoneal injection of 2.5% avertin; enoxaparin group (LMWH): 3 mg/kg enoxaparin (prepared in normal saline) was injected into the tail vein, and normal saline was injected into the tail vein 5 minutes later, and the mice were immediately anesthetized by intraperitoneal injection of 2.5% avertin; experimental group: 3 mg/kg enoxaparin (prepared in normal saline) was injected into the tail vein, and 4.5 mg/kg reversal agent (compounds 61, 131, 145, 154, 194, 195, Ciraparantag, all prepared in normal saline) was injected into the tail vein 5 minutes later, and the mice were immediately anesthetized by intraperitone
  • the tail of the mouse was cut transversely at a diameter of 2.5 mm and immediately immersed in a centrifuge tube containing 15 mL of 37°C saline to collect the blood flowing out of the wound.
  • the blood loss observation window was 20 minutes.
  • the tail of the mouse was cauterized to stop bleeding.
  • mice The results of the in vivo heparin reversal experiment of the triazine compounds of the present invention in mice are shown in Table 7.
  • the tested triazine compounds and Ciraparantag both significantly reversed the bleeding time and blood loss caused by heparin to the baseline.
  • mice weighing 18-20g were randomly divided into groups, and each group was injected with the corresponding compound (prepared with saline) or saline through the tail vein.
  • the activity status of the mice after injection was observed regularly, and the tail vein injection was dissected 24 hours later to observe and record the conditions of various organs (lungs, kidneys).
  • the results of the acute toxicity test in vivo of some compounds are shown in Table 8.
  • Tail vein injection of the triazine compound of the present invention had no effect on the normal activities of mice 24 hours later.
  • mice After the tail vein injection of triazine compounds in mice, a few developed lung symptoms such as edema, discoloration, and dark plaques; after the tail vein injection of Ciraparantag in mice, a few developed lung symptoms; 24 hours after the tail vein injection of protamine in mice, most kidneys were obviously discolored and yellowed.
  • the triazine compound of the present invention has good safety.
  • the small molecule triazine compounds of the present invention were subjected to qualitative test of dynamic photobinding ability of sodium heparin in vitro, quantitative test of competitive binding of azure A to sodium heparin, in vitro cytotoxicity test and hemolytic toxicity test, anti-Xa factor test, acute toxicity test, and in vivo heparin reversal test in mice, showing potent and low-toxic heparin reversal activity.
  • Compounds 61, 131, 145, 154, 156, 194, and 195 were superior to or equivalent to the positive control protamine or ciraparantag in reversing heparin anticoagulant activity in vitro and in vivo and had good biocompatibility.

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Abstract

La présente invention se rapporte au domaine de la chimie médicale. L'invention divulgue un composé triazine tel que représenté par la formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère ou un solvate de celui-ci. La présente invention divulgue également l'utilisation du composé triazine ou du sel pharmaceutiquement acceptable, du stéréoisomère ou du solvate de celui-ci dans la préparation d'un agent de réversion d'anticoagulant. La présente invention concerne en outre l'utilisation du composé triazine ou du sel pharmaceutiquement acceptable, du stéréoisomère ou du solvate de celui-ci dans la préparation d'un médicament destiné au traitement des effets secondaires d'une anticoagulation excessive provoquée par l'utilisation d'héparine pour traiter des maladies, et dans la préparation d'un médicament pour inverser l'activité anticoagulante de l'héparine pendant des opérations chirurgicales. Le composé triazine de la présente invention présente les avantages d'une méthode de préparation simple, de faibles coûts, d'une faible toxicité et d'une forte capacité de liaison à l'héparine, et peut inverser l'effet anticoagulant de l'héparine.
PCT/CN2024/116034 2023-12-04 2024-08-30 Agent de réversion de l'héparine à petites molécules avec squelette triazine, sa méthode de préparation et son utilisation Pending WO2025118719A1 (fr)

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CN1625410A (zh) * 2002-02-05 2005-06-08 山之内制药株式会社 2,4,6－三氨基－1,3,5－三嗪衍生物
WO2007095812A1 (fr) * 2006-02-27 2007-08-30 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composés triazine [1,3,5] substitués, procédés de préparation et utilisations de ceux-ci
WO2012136873A2 (fr) * 2011-04-05 2012-10-11 Universidad Miguel Hernández De Elche Antagonistes de trpv1 et leurs utilisations
WO2014093228A1 (fr) * 2012-12-10 2014-06-19 Cellceutix Corporation Antagonisation d'héparine avec des composés de salicylamide et des antihistaminiques
CN104080772A (zh) * 2011-11-29 2014-10-01 佩罗斯菲尔股份有限公司 抗凝血逆转剂
WO2023072434A1 (fr) * 2021-10-25 2023-05-04 Consejo Superior De Investigaciones Científicas Dérivés de spermine en tant qu'antidotes de l'héparine
CN117624137A (zh) * 2023-12-04 2024-03-01 中国药科大学 三嗪骨架小分子肝素逆转剂及其制备方法与用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1625410A (zh) * 2002-02-05 2005-06-08 山之内制药株式会社 2,4,6－三氨基－1,3,5－三嗪衍生物
WO2007095812A1 (fr) * 2006-02-27 2007-08-30 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composés triazine [1,3,5] substitués, procédés de préparation et utilisations de ceux-ci
WO2012136873A2 (fr) * 2011-04-05 2012-10-11 Universidad Miguel Hernández De Elche Antagonistes de trpv1 et leurs utilisations
CN104080772A (zh) * 2011-11-29 2014-10-01 佩罗斯菲尔股份有限公司 抗凝血逆转剂
WO2014093228A1 (fr) * 2012-12-10 2014-06-19 Cellceutix Corporation Antagonisation d'héparine avec des composés de salicylamide et des antihistaminiques
WO2023072434A1 (fr) * 2021-10-25 2023-05-04 Consejo Superior De Investigaciones Científicas Dérivés de spermine en tant qu'antidotes de l'héparine
CN117624137A (zh) * 2023-12-04 2024-03-01 中国药科大学 三嗪骨架小分子肝素逆转剂及其制备方法与用途

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