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WO2017119417A1 - Antagoniste de clec-2, inhibiteur d'agrégation plaquettaire, agent antithrombotique, agent antimétastatique, agent anti-arthritique, composé ayant un squelette de porphyrine, et son procédé de production - Google Patents

Antagoniste de clec-2, inhibiteur d'agrégation plaquettaire, agent antithrombotique, agent antimétastatique, agent anti-arthritique, composé ayant un squelette de porphyrine, et son procédé de production Download PDF

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Publication number
WO2017119417A1
WO2017119417A1 PCT/JP2017/000059 JP2017000059W WO2017119417A1 WO 2017119417 A1 WO2017119417 A1 WO 2017119417A1 JP 2017000059 W JP2017000059 W JP 2017000059W WO 2017119417 A1 WO2017119417 A1 WO 2017119417A1
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general formula
clec
compound
group
protoporphyrin
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Japanese (ja)
Inventor
克枝 井上
長田　誠
聡一 小嶋
臣雄 斎藤
知幸 佐々木
俊光 白井
英之 新森
ちひろ 望月
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University of Yamanashi NUC
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University of Yamanashi NUC
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention has a CLEC-2 antagonist, a platelet aggregation inhibitor, an antithrombotic agent, an anti-metastatic agent, an anti-arthritic agent, and a porphyrin skeleton that can specifically inhibit the function of the platelet activating receptor CLEC-2
  • the present invention relates to a compound and a production method thereof.
  • Platelets play a central role in arterial thrombosis such as myocardial infarction and cerebral infarction.
  • Antiplatelet drugs have a market size of about 2 trillion yen worldwide, but the side effects of bleeding are a problem. According to a large cohort study, the use of antiplatelet drugs for primary prevention is currently not recommended because the risk of bleeding outweighs the benefits. Therefore, an antiplatelet drug with few side effects of bleeding is desired.
  • the platelet activating receptor CLEC-2 was discovered by the present inventors, and was identified on platelets as a receptor for rhodocytin, a snake venom that activates platelets (for example, Non-patent Document 1). reference).
  • the present inventors have found that the in vivo ligand of CLEC-2 is a membrane protein podoplanin expressed in certain types of cancer cells (see, for example, Non-Patent Document 2).
  • Non-Patent Documents 3 to 5 As a mouse deficient in CLEC-2 function, thrombus formation is suppressed in CLEC-2 deficient bone marrow chimeric mice and mice deficient in CLEC-2 by injecting anti-podoplanin antibody.
  • the present inventors have shown that there is no significant extension (see, for example, Non-Patent Documents 3 to 5).
  • the present inventors have reported that anti-podoplanin antibodies suppress lung metastasis of cancer in a mouse lung metastasis model (see, for example, Non-Patent Document 6).
  • drugs targeting CLEC-2 can be antithrombotic, antiplatelet and antimetastatic drugs with few side effects of bleeding.
  • no drugs targeting CLEC-2 have been identified, and research and development of platelet aggregation inhibitors with few bleeding side effects, antimetastatic agents that suppress cancer metastasis, and candidate compounds thereof are desired. It is rare.
  • the present invention relates to a CLEC-2 antagonist capable of specifically suppressing the function of the platelet activating receptor CLEC-2, a platelet aggregation inhibitor, an antithrombotic agent, an antimetastatic agent, an antiarthritic agent, and a metal ion
  • a CLEC-2 antagonist capable of specifically suppressing the function of the platelet activating receptor CLEC-2, a platelet aggregation inhibitor, an antithrombotic agent, an antimetastatic agent, an antiarthritic agent, and a metal ion
  • An object of the present invention is to provide a compound in which a ligand having a porphyrin skeleton is coordinated, and a method for producing the same.
  • a CLEC-2 antagonist comprising a compound represented by any one of the following general formula (1) and the following general formula (2).
  • M represents any one of H 2 and Group 2 to 12 elements, R 1 represents either a vinyl group or a 1-hydroxyethyl group, and X represents Group 1) Represents an element.
  • R 2 represents a phenyl group, a sulfophenyl group, a carboxyphenyl group, and 1-methylpyridinium-4-yl.
  • [General Formula (1-A)] (In the general formula (1-A), M represents any one of Co, Zn, Ni and Pd, and X represents a Group 1 element.) ⁇ 11> A compound represented by the following general formula (1-B) is obtained by reacting hematoporphyrin and metal acetate in the presence of either methanol or acetic acid at 15 ° C. to 30 ° C. for 5 hours to 30 hours. It is a manufacturing method of the compound characterized by including a process. [General formula (1-B)] (In the general formula (1-B), M represents any one of Co, Zn and Cu.)
  • a CLEC-2 antagonist capable of solving the above-described problems and achieving the above-mentioned object and capable of specifically suppressing the function of the platelet-activating receptor CLEC-2, platelet aggregation inhibition Agents, antithrombotic agents, antimetastatic agents, antiarthritic agents, compounds in which a ligand having a porphyrin skeleton is coordinated to a metal ion, and a method for producing the same can be provided.
  • FIG. 1 is a diagram for explaining the flow and results of primary screening in Example 1.
  • FIG. 2 is a diagram for explaining the results of secondary screening in Example 1.
  • FIG. 3 is a graph showing the evaluation results of protoporphyrin IX (H 2 -PP) in Example 1 using a flow cytometer.
  • FIG. 4 is a graph showing the measurement results of the protoporphyrin zinc complex (Zn-PP) of Example 2 by UV-vis spectrum and fluorescence spectrum.
  • FIG. 5 is a diagram showing the results of 1 H-NMR measurement of the protoporphyrin zinc complex (Zn—PP) of Example 2.
  • FIG. 6 is a view showing the evaluation results of a protoporphyrin zinc complex (Zn—PP) in Example 2 using a flow cytometer.
  • FIG. 1 is a diagram for explaining the flow and results of primary screening in Example 1.
  • FIG. 2 is a diagram for explaining the results of secondary screening in Example 1.
  • FIG. 3 is a graph showing the evaluation results of
  • FIG. 7 is a graph showing the measurement results of the protoporphyrin nickel complex (Ni—PP) of Example 3 by UV-vis spectrum and fluorescence spectrum.
  • FIG. 8 is a view showing the evaluation results of the protoporphyrin nickel complex (Ni—PP) in Example 3 using a flow cytometer.
  • FIG. 9 is a graph showing the measurement results of the protoporphyrin cobalt complex (Co-PP) of Example 4 by UV-vis spectrum and fluorescence spectrum.
  • FIG. 10 is a view showing the evaluation results of the protoporphyrin cobalt complex (Co-PP) in Example 4 using a flow cytometer.
  • FIG. 11 is a graph showing the measurement results of the protoporphyrin palladium complex (Pd-PP) of Example 5 by UV-vis spectrum and fluorescence spectrum.
  • FIG. 12 is a view showing the evaluation results of a protoporphyrin palladium complex (Pd-PP) in Example 5 using a flow cytometer.
  • FIG. 13 is a diagram showing the evaluation results of hematoporphyrin (H 2 -HP) in Example 6 using a flow cytometer.
  • FIG. 14 shows the measurement results of UV-vis spectrum and fluorescence spectrum of the hematoporphyrin zinc complex (Zn—HP) of Example 7.
  • FIG. 15 shows the results of 1 H-NMR measurement of the hematoporphyrin zinc complex (Zn—HP) of Example 7.
  • FIG. 16 is a view showing the evaluation results of a hematoporphyrin zinc complex (Zn—HP) in Example 7 using a flow cytometer.
  • FIG. 17 shows the measurement results of the hematoporphyrin copper complex (Cu—HP) of Example 8 using the UV-vis spectrum and fluorescence spectrum.
  • FIG. 18 is a diagram showing the evaluation results of a hematoporphyrin copper complex (Cu—HP) in Example 8 using a flow cytometer.
  • FIG. 19 shows the measurement results of the hematoporphyrin cobalt complex (Co—HP) of Example 9 using UV-vis spectrum and fluorescence spectrum.
  • FIG. 20 is a diagram showing the evaluation results of a hematoporphyrin cobalt complex (Co—HP) in Example 9 using a flow cytometer.
  • FIG. 21 is a diagram showing the results of evaluation by flow cytometer of 5,10,15,20-tetrakis (p-sulfophenyl) -21H, 23H-porphyrin (TPPS) in Example 10.
  • FIG. 22 is a diagram showing the results of evaluation by flow cytometer of p-toluenesulfonate (TMPyP4OTs) of ⁇ , ⁇ , ⁇ , ⁇ -tetrakis (1-methylpyridinium-4-yl) porphyrin in Example 11.
  • TMPyP4OTs p-toluenesulfonate
  • FIG. 23 is a diagram showing the evaluation results of the platelet aggregation inhibitory effect on human platelet aggregation.
  • FIG. 24 is a diagram showing the evaluation results of the platelet aggregation inhibitory effect on mouse platelet aggregation.
  • FIG. 25 is a photograph showing the state of the lung on the 14th day after the start of compound administration (DMSO or Co-HP) in a mouse lung metastasis model.
  • FIG. 26 is a graph showing the weight of the lung on the 14th day from the start of compound administration (DMSO or Co-HP) in a mouse lung metastasis model.
  • FIG. 27 is a diagram showing the effect of prolonging the vascular occlusion time using a mouse in vivo iron chloride thrombus formation model.
  • FIG. 28 is a diagram showing the effect on bleeding time in mice in vivo.
  • FIG. 29 is a graph showing the degree of inflammation of rheumatoid arthritis in a K / BxN mouse serum transfer arthritis model using wild-type mice and CLEC-2 deficient bone marrow chimeric mice as recipient mice.
  • FIG. 30 shows the effect of Co-HP administration on rheumatoid arthritis in a K / BxN mouse serum transfer arthritis model using wild-type mice as recipient mice.
  • FIG. 31 is a photograph visualizing platelet adhesion of human lymphatic epithelial cells (LEC).
  • FIG. 32 is a graph showing a quantified platelet adhesion area of human lymphatic epithelial cells (LEC).
  • the CLEC-2 antagonist of the present invention comprises a compound having a porphyrin skeleton represented by any of the following general formula (1) and the following general formula (2).
  • the CLEC-2 antagonist is a drug having an action of suppressing the function of CLEC-2 which is a platelet activation receptor.
  • the CLEC-2 antagonist preferably has an action of suppressing the binding between CLEC-2 and podoplanin, which is a ligand in vivo of CLEC-2.
  • CLEC-2 has an official name: C-type lectin-like receptor-2 and was identified as a receptor for rhodocytin, a snake venom that activates platelets (Blood. 2006; 107 (2): 542-549. ). In humans, it is known to be specifically expressed only in platelets. On the other hand, podoplanin, an in vivo ligand for CLEC-2, is a membrane glycoprotein rich in sialic acid, and is expressed in squamous cell carcinoma, malignant mesothelioma, etc. It was known.
  • the CLEC-2 antagonist of the present invention functions as an antagonist that suppresses the function of CLEC-2 by specifically binding to CLEC-2 or competing with podoplanin.
  • M is any one of H 2 and Group 2 to 12 elements, and H 2 , Group 8 elements, Group 9 elements, Group 10 elements, Group 11 elements, Group 12 elements are preferred, and H 2 , Fe, Co, Ni, Pd, Cu, and Zn are more preferred.
  • the Group 2 elements and the like are based on a new notation of the International Pure Applied Chemical Association (IUPAC), and the Group 2 to 12 elements are Group IIA to Group VIIIA and IB of the former IUPAC notation. Corresponding to the Group and Group IIB respectively.
  • X is a Group 1 element, preferably H, Li, Na, or K, and more preferably H or Na.
  • the compound represented by the general formula (1) is preferably any one of a compound represented by the following general formula (1-A) and a compound represented by the following general formula (1-B).
  • Examples of the compound represented by the general formula (1-A) include a protoporphyrin IX represented by the following structural formula A1, a protoporphyrin zinc complex represented by the following structural formula A2, and a structural formula represented by the following structural formula A3.
  • Examples thereof include a protoporphyrin nickel complex, a protoporphyrin cobalt complex represented by the following structural formula A4, and a protoporphyrin palladium complex represented by the following structural formula A5.
  • a protoporphyrin IX represented by the following structural formula A1, a protoporphyrin zinc complex represented by the following structural formula A2, and a protoporphyrin cobalt complex represented by the following structural formula A4 are preferable, and represented by the following structural formula A1.
  • Protoporphyrin IX is more preferred.
  • the compound represented by the general formula (1-B) is specifically represented by hematoporphyrin represented by the following structural formula B1, hematoporphyrin zinc complex represented by the following structural formula B2, and represented by the following structural formula B3.
  • hematoporphyrin represented by the following structural formula B1 hematoporphyrin copper complex represented by the following structural formula B3, and hematoporphyrin cobalt complex represented by the following structural formula B4 are preferable, and CLEC-2, podoplanin, A hematoporphyrin cobalt complex represented by the following structural formula B4 is more preferable in that the activity of suppressing the binding of is particularly high.
  • M is any of H 2 and Group 2 to 12 elements, and H 2 , Group 8 elements, Group 9 elements, Group 10 elements, Group 11 elements, Group 12 elements are preferred, and H 2 , Fe, Co, Ni, Pd, Cu, and Zn are more preferred.
  • Examples of the compound represented by the general formula (2) include 5,10,15,20-tetrakis (p-sulfophenyl) -21H, 23H-porphyrin (“TPPS”) represented by the following structural formula C1.
  • TPPS 5,10,15,20-tetrakis (p-sulfophenyl) -21H, 23H-porphyrin
  • C1 5,10,15,20-tetrakis (p-sulfophenyl) -21H, 23H-porphyrin
  • TPPS 5-10,15,20-tetrakis (p-sulfophenyl) -21H, 23H-porphyrin
  • C2 5,10,15,20-tetrakis (p-sulfophenyl) -21H, 23H-porphyrin
  • TMPyP4OTs Toluenesulfonate
  • TPP tetraphenylporphyrin
  • TPPC 5,10,15,20-tetrakis (p-carboxyphenyl) -21H, 23H -Porphyrin
  • TPPS represented by the following structural formula C1 is preferable.
  • the platelet aggregation inhibitor of the present invention comprises the CLEC-2 antagonist of the present invention.
  • the platelet aggregation inhibitor is a drug having an action of suppressing platelet aggregation.
  • the antithrombotic agent of the present invention comprises the CLEC-2 antagonist of the present invention.
  • the antithrombotic drug is a drug having an action of suppressing the formation of a thrombus and preventing vascular occlusion.
  • the platelet aggregation inhibitor and the antithrombotic agent act via function suppression of CLEC-2 which is a platelet activating receptor, and podoplanin which is an in vivo ligand of CLEC-2 and CLEC-2 It is more preferable to have an action of suppressing the binding with.
  • the antimetastatic agent of the present invention comprises the CLEC-2 antagonist of the present invention.
  • the antimetastatic drug is a drug having an action of suppressing cancer cell metastasis.
  • the anti-metastatic agent preferably acts through suppression of the function of CLEC-2, which is a platelet activation receptor, and suppresses the binding of CLEC-2, which is a ligand in vivo of CLEC-2, to CLEC-2 More preferably, it has an action.
  • the anti-arthritic agent of the present invention comprises the CLEC-2 antagonist of the present invention.
  • the anti-arthritic drug is a drug having an action of suppressing joint inflammation, and examples thereof include an anti-rheumatic drug.
  • the anti-arthritic agent preferably acts through suppression of the function of CLEC-2, which is a platelet activating receptor, and suppresses the binding of CLEC-2 in vivo to podoplanin, which is a ligand of CLEC-2. More preferably, it has an action.
  • the preparation includes at least one of the CLEC-2 antagonist of the present invention, a platelet aggregation inhibitor, an antithrombotic drug, an antimetastatic drug, and an antiarthritic drug, and further pharmacologically acceptable as necessary. Contains other ingredients such as a carrier.
  • the CLEC-2 antagonist, the platelet aggregation inhibitor, the antithrombotic agent, the antimetastatic agent, and the antiarthritic agent are represented by any one of the general formula (1) and the general formula (2). Or a pharmacologically acceptable salt, solvate or prodrug of the compound.
  • the preparation is prepared by formulating into any dosage form such as liquid, powder, granule, tablet, etc. according to a conventional method using a pharmacologically acceptable carrier such as dextrin and cyclodextrin, and an auxiliary agent.
  • a pharmacologically acceptable carrier such as dextrin and cyclodextrin
  • an auxiliary agent in addition to being used in other compositions (for example, eye drops, oral pharmaceuticals, etc.), it can also be used as an ointment, a solution for external use, a patch, and the like.
  • an excipient filler, binder, a disintegrating agent, a lubricant agent, a stabilizer, a corrigent, a corrigent etc. can be used, for example.
  • excipient examples include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like. It is done.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol.
  • examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, and the like.
  • examples of the flavoring agent or flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
  • the method for administering the preparation is not particularly limited, and administration conditions such as an administration route, administration timing, dosage, and administration schedule suitable for each drug can be appropriately selected according to the purpose.
  • administration conditions such as an administration route, administration timing, dosage, and administration schedule suitable for each drug can be appropriately selected according to the purpose.
  • administration route There is no restriction
  • the dosage of the preparation is not particularly limited and may be appropriately selected depending on factors such as the disease state of the subject requiring treatment, body weight, etc., but preferably 1 mg to 1,000 mg per day. ⁇ 200 mg is more preferred.
  • the compound of the present invention is a compound having a porphyrin skeleton represented by any one of the following general formula (1-A) and the following general formula (1-B).
  • the compound having a protoporphyrin skeleton represented by the general formula (1-A) can be preferably produced by the method for producing a compound represented by the general formula (1-A) of the present invention.
  • the compound having a hematoporphyrin skeleton represented by the general formula (1-B) can be preferably produced by the method for producing a compound represented by the general formula (1-B) of the present invention.
  • a method for producing a compound of the present invention is a method for producing a compound represented by the above general formula (1-A), comprising a salt of protoporphyrin and a metal acetate, either dimethyl sulfoxide or acetic acid, and water. Including a step of obtaining a compound represented by the following general formula (1-A) by reacting at 70 ° C. to 95 ° C. for 1 to 30 hours in the presence, and further including other steps such as a purification step, if necessary. .
  • the salt of protoporphyrin is not particularly limited as long as it is a salt of a compound in which M of the compound represented by the general formula (1-A) is H 2 , and can be appropriately selected depending on the purpose.
  • examples thereof include protoporphyrin IX represented by the following structural formula A1.
  • the metal in the metal acetate is any one of Co, Zn, Ni and Pd represented by M in the general formula (1-A).
  • the compound represented by the general formula (1-A) is a protoporphyrin zinc complex represented by the following structural formula A2
  • the salt of protoporphyrin and zinc acetate are reacted in the presence of dimethyl sulfoxide and water.
  • the reaction temperature is preferably 70 ° C. to 90 ° C. (eg, 80 ° C.), and the reaction time is preferably 1 hour to 10 hours (eg, 2 hours).
  • the compound represented by the general formula (1-A) is a protoporphyrin nickel complex represented by the following structural formula A3
  • the salt of protoporphyrin and nickel acetate are reacted in the presence of dimethyl sulfoxide and water.
  • the reaction temperature is preferably 70 ° C. to 90 ° C. (eg, 80 ° C.), and the reaction time is preferably 5 hours to 20 hours (eg, 8 hours).
  • the compound represented by the general formula (1-A) is a protoporphyrin cobalt complex represented by the following structural formula A4, a salt of protoporphyrin and cobalt (II) acetate are added in the presence of acetic acid and water.
  • the reaction temperature is preferably 80 ° C. to 95 ° C. (eg, 90 ° C.), and the reaction time is preferably 12 hours to 30 hours (eg, 24 hours).
  • the compound represented by the general formula (1-A) is a protoporphyrin palladium lead complex represented by the following structural formula A5
  • a salt of protoporphyrin and palladium (II) acetate are present in the presence of acetic acid and water.
  • the reaction temperature is preferably 80 ° C. to 95 ° C. (eg, 90 ° C.), and the reaction time is preferably 12 hours to 30 hours (eg, 24 hours).
  • the method for producing a compound of the present invention is a method for producing a compound represented by the general formula (1-B), wherein hematoporphyrin and metal acetate are added at 15 ° C. to 15 ° C. in the presence of either methanol or acetic acid. It includes a step of obtaining a compound represented by the following general formula (1-B) by reacting at 30 ° C. for 5 to 30 hours, and further includes other steps such as a purification step as necessary.
  • the hematoporphyrin is a compound represented by the following structural formula B1.
  • the metal in the metal acetate is any one of Co, Zn and Cu represented by M in the general formula (1-B).
  • the compound represented by the general formula (1-B) is a hematoporphyrin zinc complex represented by the following structural formula B2, it is preferable to react hematoporphyrin and zinc acetate in the presence of methanol.
  • the temperature is preferably 15 ° C. to 30 ° C. (eg, 25 ° C.), and the reaction time is preferably 5 hours to 20 hours (eg, 8 hours).
  • the compound represented by the general formula (1-B) is a hematoporphyrin copper complex represented by the following structural formula B3
  • hematoporphyrin and copper (II) acetate can be reacted in the presence of acetic acid.
  • the reaction temperature is preferably 15 ° C. to 30 ° C. (eg, 25 ° C.), and the reaction time is preferably 12 hours to 30 hours (eg, 24 hours).
  • the compound represented by the general formula (1-B) is a hematoporphyrin cobalt complex represented by the following structural formula B4
  • the hematoporphyrin and cobalt (II) acetate can be reacted in the presence of acetic acid.
  • the reaction temperature is preferably 15 ° C. to 30 ° C. (eg, 25 ° C.), and the reaction time is preferably 12 hours to 30 hours (eg, 24 hours).
  • Example 1 Protoporphyrin IX
  • ⁇ Search for compounds that suppress the binding of CLEC-2 to podoplanin (primary screening)>
  • each compound solution (10 ⁇ g / mL) of the low molecular compound library was dropped, and after removing the solution, washed with 400 ⁇ L of the washing solution three times. did.
  • 100 ⁇ L of a detection protein solution PBS containing 1 ⁇ g / 100 mL of human podoplanin-hFc2-Biotin, pH 7.4 was added dropwise and reacted at room temperature (25 ° C.) for 1 hour. After removing the detection protein solution, it was washed with 400 ⁇ L of the washing solution three times.
  • a detection reagent (streptAvidin-HRP, Vector Laboratories, CA) was added dropwise and reacted for 1 hour. After removing the detection reagent, it was washed 3 times with 400 ⁇ L of washing solution. Next, 100 ⁇ L of TBM solution (T0440, manufactured by SIGMA-ALDRICH) was dropped and reacted in a dark room for 3 to 5 minutes. Then, 50 ⁇ L of a reaction stop solution (0.5 M HCl) was added, and a microplate reader (apparatus Name: Absorbance at 450 nm was measured with a multi-label counter, ARV0mx-U1, 1420-050J, manufactured by Perkin Elmer).
  • Binding inhibition rate (%) 100 ⁇ (absorbance of each compound ⁇ absorbance of negative control) / (absorbance of positive control ⁇ absorbance of negative control)
  • FIG. 1 is a diagram for explaining the flow and results of the primary screening in Example 1.
  • a signal having a wavelength of 450 nm derived from the binding of CLEC-2 and podoplanin is observed.
  • Compound A that binds to CLEC-2 is administered, the binding between CLEC-2 and podoplanin is suppressed, and the signal observed in the positive control is reduced.
  • Compound B that does not bind to CLEC-2 or does not suppress binding to podoplanin
  • the signal observed in the positive control does not change because binding between CLEC-2 and podoplanin is not suppressed. .
  • CLEC-2 expressing cultured cells human CLEC-2 expressing 293TRex cells were prepared according to the method described in the literature “J Virol. 2003; 77 (7): 4070-4080”. This cell is a cell that expresses CLEC-2 by the addition of doxycycline by the Tet on system, and CLEC-2 is added by adding doxycycline at a final concentration of 1 ⁇ g / mL 24 hours before measurement with a flow cytometer. Expression was induced.
  • human podoplanin-human Fc2 was prepared according to the method described in the document “JBC, 2007; 282 (36): 25993-2601”.
  • a negative control a sample to which 1 ⁇ L of DMSO was added instead of the solution of each compound was used.
  • a sample to which human Fc2 was added instead of human podoplanin-human Fc2 was used.
  • a positive control a sample to which rhodocytin having a final concentration of 50 nM was added instead of the solution of each compound was used.
  • FIG. 2 shows a diagram for explaining the results of the secondary screening in Example 1.
  • a peak shift derived from the binding of CLEC-2 and podoplanin is observed by substituting human podoplanin-human Fc2 as a negative control.
  • a compound that binds to CLEC-2 is administered (see the right panel of FIG. 2), when the binding between CLEC-2 and podoplanin is completely suppressed, the peak derived from the binding between CLEC-2 and podoplanin No shift is observed and a peak that completely overlaps the peak from the negative control is observed.
  • Binding inhibition rate (%) 100-100 ⁇ (TN) / (PN)
  • P, N, and T are as follows.
  • N MFI derived from negative binding control (human Fc2, DMSO)
  • T MFI derived from administration of compound
  • FIG. 3 shows the evaluation results of protoporphyrin IX (H 2 -PP) in Example 1 using a flow cytometer. The binding inhibition rate of protoporphyrin IX was 86.2%.
  • protoporphyrin metal complex and hematoporphyrin are used as analogs of protoporphyrin IX.
  • a metal complex was prepared.
  • CLEC-2 and CLEC-2 were obtained in the same manner as in the secondary screening of Example 1, except that the compounds to be evaluated were similar to the protoporphyrin IX of Examples 2 to 11. Evaluation and optimization of compounds that inhibit the binding to podoplanin were performed.
  • Example 2 Protoporphyrin zinc complex
  • Zinc acetate (390 mg, 1.78 mmol) was added to a solution obtained by adding 20 mL of dimethyl sulfoxide (DMSO) and 5 mL of distilled water to protoporphyrin disodium salt (manufactured by Tokyo Chemical Industry Co., Ltd., 100 mg, 0.165 mmol). And stirred for 2 hours. Then, it cooled to room temperature (25 degreeC), ethanol was added and crystallized, and the obtained precipitation was wash
  • DMSO dimethyl sulfoxide
  • protoporphyrin disodium salt manufactured by Tokyo Chemical Industry Co., Ltd., 100 mg, 0.165 mmol
  • FIG. 4 shows the measurement results of the UV-vis spectrum and fluorescence spectrum of Example 2.
  • the measurement result by 1 H-NMR of Example 2 is shown in FIG.
  • UV-vis spectrum measurement was performed using UV-1800 (manufactured by Shimadzu Corporation), and fluorescence spectrum measurement was performed using FP-6300 (manufactured by JASCO Corporation).
  • the UV-vis spectrum is indicated by a solid line.
  • the fluorescence spectrum is shown by a broken line.
  • AVANCE 400 manufactured by Bruker
  • Example 4 Protoporphyrin cobalt complex
  • protoporphyrin disodium salt Tokyo Chemical Industry Co., Ltd., 100 mg, 0.165 mmol
  • cobalt acetate (II) tetrahydrate 410 mg, 1.65 mmol
  • the reaction mixture was added to 150 mL of distilled water and cooled to about 4 ° C. to obtain a deep purple precipitate (102 mg) at a yield of 93%.
  • FIG. 9 shows the measurement results of the UV-vis spectrum and fluorescence spectrum of Example 4.
  • Example 6 Hematoporphyrin
  • Example 6 Hematoporphyrin ⁇ Evaluation of binding inhibition between CLEC-2 and podoplanin>
  • CLEC was performed in the same manner as the secondary screening of Example 1, except that hematoporphyrin (manufactured by Wako Pure Chemical Industries, Ltd.) having a final concentration of 5 ⁇ g / mL was used as the evaluation target compound.
  • hematoporphyrin manufactured by Wako Pure Chemical Industries, Ltd.
  • -2 was evaluated for compounds that inhibit the binding of podoplanin.
  • the evaluation results of hematoporphyrin using a flow cytometer are shown in FIG.
  • the binding inhibition rate of hematoporphyrin was 90.2%.
  • the obtained compound was identified by 1 H-NMR, UV-vis spectrum, and fluorescence spectrum, and it was found that a hematoporphyrin zinc complex was obtained.
  • the reaction formula is shown in the following reaction formula (5).
  • FIG. 14 shows the measurement results of the UV-vis spectrum and the fluorescence spectrum of Example 7. Further,
  • FIG. 15 shows the measurement result of Synthesis Example 1 by 1 H-NMR.
  • FIG. 16 shows the results of evaluation of the hematoporphyrin zinc complex using a flow cytometer. The binding inhibition rate of the hematoporphyrin zinc complex was 81.3%.
  • FIG. 17 shows the measurement results of the UV-vis spectrum and fluorescence spectrum of Example 8.
  • Example 9 Hematoporphyrin cobalt complex
  • hematoporphyrin Waako Pure Chemical Industries, Ltd., 100 mg, 0.167 mmol
  • cobalt (II) acetate tetrahydrate 410 mg, 1.65 mmol
  • room temperature 25 ° C.
  • FIG. 20 shows the results of evaluation of the hematoporphyrin cobalt complex using a flow cytometer. The binding inhibition rate of the hematoporphyrin cobalt complex was 101.1%.
  • Example 10 5,10,15,20-tetrakis (p-sulfophenyl) -21H, 23H-porphyrin) ⁇ Evaluation of binding inhibition between CLEC-2 and podoplanin>
  • protoporphyrin IX having a final concentration of 5 ⁇ g / mL
  • the compound to be evaluated was replaced with 5,10,15,20-tetrakis (p-sulfo) represented by the following structural formula C1.
  • Phenyl) -21H, 23H-porphyrin (manufactured by Tokyo Chemical Industry Co., Ltd., sometimes referred to as “TPPS”) was used in the same manner as in the secondary screening of Example 1, except that CLEC-2 and podoplanin Evaluation of compounds that inhibit binding was performed.
  • FIG. 21 shows the results of evaluation using a TPPS flow cytometer. The binding inhibition rate of TPPS was 89.8%.
  • Example 11 p-toluenesulfonate of ⁇ , ⁇ , ⁇ , ⁇ -tetrakis (1-methylpyridinium-4-yl) porphyrin
  • ⁇ Evaluation of binding inhibition between CLEC-2 and podoplanin In the secondary screening of Example 1, instead of protoporphyrin IX having a final concentration of 5 ⁇ g / mL, the ⁇ , ⁇ , ⁇ , ⁇ -tetrakis (1-methyl) represented by the following structural formula C2 was used as the evaluation target compound.
  • TMPyP4OTs p-toluenesulfonate (manufactured by Tokyo Chemical Industry Co., Ltd., sometimes referred to as “TMPyP4OTs”) of pyridinium-4-yl) porphyrin (sometimes referred to as “TMPyP”) was used.
  • TMPyP4OTs p-toluenesulfonate (manufactured by Tokyo Chemical Industry Co., Ltd., sometimes referred to as “TMPyP4OTs”) of pyridinium-4-yl) porphyrin (sometimes referred to as “TMPyP”) was used.
  • TMPyP4OTs p-toluenesulfonate (manufactured by Tokyo Chemical Industry Co., Ltd., sometimes referred to as “TMPyP4OTs”) of pyridinium-4-yl) porphyrin (sometimes referred to as “TMPyP”) was used.
  • TMPyP4OTs
  • the compound was administered on the 2nd day, the 4th day, the 6th day, the 8th day, the 10th day, and the 12th day every 2 days, and the lungs were removed from the mice on the 14th day and the lung weight was measured. did.
  • FIG. 26 shows a graph showing the weight of the lungs on the 14th day from the start of compound administration (DMSO or Co-HP) in the mouse lung metastasis model.
  • the mouse was placed in a box to introduce anesthesia. Anesthesia was maintained under this anesthesia condition until the end of the experiment.
  • the compound was administered by administering 200 ⁇ L of 1% by mass DMSO or 100 ⁇ g / mL Co-HP from the orbit (20 ⁇ g per animal, 10 ⁇ g / mL as 2 mL of circulating blood volume).
  • the limbs were fixed with vinyl tape to expose the left femoral artery, and then the left femoral artery was detached from other tissues using a tapered tweezers, and infiltration of tissue fluid was prevented with a parafilm interposed therebetween.
  • a laser blood flow meter (device name: ALF21RD, manufactured by Advance Co., Ltd.), use the blood flow of 60 mL / min / 100 g or more as a guide to search for the position with the highest blood flow and fix the sensor, and blood flow for 2 to 3 minutes was measured to measure each stable parameter before injury (stimulation of thrombus formation by iron chloride administration).
  • Thrombus formation was induced by placing a filter paper immersed in an aqueous solution of 10% by mass iron chloride on the exposed left femoral artery.
  • measurement with a laser blood flow meter was continued until a blood flow of 5 mL / min / 100 g or less continued for 1 min or longer.
  • the vascular occlusion time was the time required from the administration of iron chloride to the occlusion start time when blood flow of 5 mL / min / 100 g or less continued for 1 min or more.
  • FIG. 27 shows the effect of prolonging the vascular occlusion time using the mouse in vivo iron chloride thrombus formation model.
  • the compound was administered by administering 200 ⁇ L of 1% by mass DMSO or 100 ⁇ g / mL Co-HP from the orbit (20 ⁇ g per animal, 10 ⁇ g / mL as 2 mL of circulating blood volume).
  • the mouse tail was cut from the tip with a 2 mm razor, the stump was immersed in 37 ° C. physiological saline, and the bleeding time was recorded.
  • the reference for hemostasis was that no rebleeding occurred for 30 seconds or more, and the bleeding time was the time required from the tail cut to the start time of hemostasis.
  • FIG. 28 shows the effect on bleeding time in mice in vivo.
  • the bleeding time (mean ⁇ standard deviation: 212.0 ⁇ 86.4 seconds) in the Co-HP administration group was compared to the bleeding time (152.0 ⁇ 52.6 seconds) of the control administered with DMSO. No statistically significant difference was observed, and therefore, it was found useful as an antithrombotic agent with few side effects of bleeding.
  • the forefoot thickness, the front ankle thickness, the heel thickness, and the rear foot thickness were measured with a digital caliper once a day until the 10th day after treatment (Day 10).
  • the total of these measured values was used as an index of the degree of arthritis.
  • the results are shown as mean values ⁇ standard deviation, and a significant difference test was performed by Student's t-test.
  • FIG. 29 shows the degree of inflammation of rheumatoid arthritis in a K / BxN mouse serum transfer arthritis model using wild type mice (WT) and CLEC-2 deficient bone marrow chimeric mice (CLEC-2 KO) as recipient mice.
  • FIG. 30 shows the effect of Co-HP administration on rheumatoid arthritis in a K / BxN mouse serum transfer arthritis model using wild-type mice as recipient mice. From the results in FIG. 29, the degree of rheumatoid arthritis inflammation was significantly suppressed in CLEC-2 deficient bone marrow chimeric mice compared to wild type mice. Therefore, it was suggested that CLEC-2 is involved in rheumatoid arthritis. From the results of FIG.
  • the degree of rheumatoid arthritis inflammation was significantly suppressed by Co-HP administration.
  • the combination of podoplanin expressed on the intra-articular synoviocytes and platelet CLEC-2 may activate platelets and promote inflammation. From these results, it was suggested that CLEC-2 antagonists including Co-HP could be used as anti-arthritic agents such as anti-rheumatic drugs.
  • Human lymphatic epithelial cells are cultured in a monolayer on a parallel plate flow chamber (ibidi ⁇ -slide VI 0.1 , ibiTreat, ibidi) and endothelial cells containing 1% by weight bovine serum albumin (BSA)
  • BSA bovine serum albumin
  • EGM-2 a growth medium
  • the blood was pretreated with endothelial cell growth medium containing 5 ⁇ M 3-dihexyloxycarbocyanine iodide (DiOC 6 , Thermo Fisher Scientific) and compound (Co-HP) or control solvent (DMSO) for 10 minutes. went.
  • the obtained blood sample was perfused into the parallel plate flow chamber at a shear rate of 400 s ⁇ 1 for 10 minutes.
  • Platelet adhesion was visualized using a fluorescent video microscope, and still images were taken after 1, 3, 5, 7, and 10 minutes from the start of perfusion. The still image after 10 minutes passed, and the platelet adhesion area was quantified using image processing software Image J (URL: https://imagej.nih.gov/ij/).
  • FIGS. 31 and 32 A photograph visualizing platelet adhesion of human lymphatic epithelial cells (LEC) and a graph quantifying the platelet adhesion area are shown in FIGS. 31 and 32, respectively.
  • LEC lymphatic epithelial cells
  • Co-HP hematoporphyrin cobalt complex
  • Lymphedema may occur after lymph node dissection in malignant tumor surgery. There are 50,000 patients with upper limb lymphedema and 70,000 patients with lower limb lymphedema in Japan, and this number is increasing year by year. When lymphedema becomes chronic, it progresses to elephantization and fibrosis, and repeats infection, or QOL becomes extremely low. As one of the treatments for lymphedema, there is a treatment method in which lymphatic vein anastomosis is performed and the lymph fluid in the lymphatic vessels is perfused into the vein. This is an effective treatment, but the long-term patency rate is only 40%. One of the causes that the anastomosis is blocked is the formation of a thrombus at the anastomosis.

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Abstract

La présente invention concerne un antagoniste de CLEC-2 comprenant un composé représenté par la formule générale (1) ou la formule générale (2). (Dans la formule générale : M représente H2 ou un des éléments des groupes 2 à 12, R1 représente un groupe vinyle ou un groupe 1-hydroxyéthyle, et X représente un élément du groupe 1.) (Dans la formule générale (2), M représente H2 ou un des éléments des groupes 2 à 12, et R2 représente un groupe phényle, un groupe sulfophényle, un groupe carboxyphényle, ou un groupe 1-méthylpyridinium-4-yle.)
PCT/JP2017/000059 2016-01-04 2017-01-04 Antagoniste de clec-2, inhibiteur d'agrégation plaquettaire, agent antithrombotique, agent antimétastatique, agent anti-arthritique, composé ayant un squelette de porphyrine, et son procédé de production Ceased WO2017119417A1 (fr)

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CN109575036A (zh) * 2018-12-11 2019-04-05 怀化学院 金属血卟啉双醚二酯类化合物，催化剂及其制备方法以及环己烷催化氧化方法
CN109575036B (zh) * 2018-12-11 2020-09-22 怀化学院 金属血卟啉双醚二酯类化合物，催化剂及其制备方法以及环己烷催化氧化方法

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