WO2013091285A1 - Composé de l'urée, son procédé de préparation et son utilisation - Google Patents

Composé de l'urée, son procédé de préparation et son utilisation Download PDF

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WO2013091285A1
WO2013091285A1 PCT/CN2012/001719 CN2012001719W WO2013091285A1 WO 2013091285 A1 WO2013091285 A1 WO 2013091285A1 CN 2012001719 W CN2012001719 W CN 2012001719W WO 2013091285 A1 WO2013091285 A1 WO 2013091285A1
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group
methyl
urea
alkyl group
urea compound
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PCT/CN2012/001719
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Chinese (zh)
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南发俊
左建平
李佳
张梅
布鲁姆·安娜
唐炜
杨筱莹
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中国科学院上海药物研究所
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Publication of WO2013091285A1 publication Critical patent/WO2013091285A1/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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a urea compound, a preparation method thereof, a pharmaceutical composition comprising the same, and a use thereof, and the compound has complement inhibitory activity and can be applied to treat inflammatory reaction, hyperthyroidism and organ transplantation. Rejection and other aspects.
  • the complement system is a group of immunologically-activated, enzymatically active proteins present on the surface of human and vertebrate serum, tissue fluid and cell membranes, including more than 20 serum proteins (as intrinsic components of complement) and complement regulatory proteins. And mediating complement activity fragments or regulatory protein biological effector receptors of the immune system.
  • complement components in serum are present as inactive enzyme precursors.
  • the components of complement are activated in turn only under the action of certain activators or on specific solid surface. Whenever the former component is activated, it has the activity of cleavage of the next component, thereby forming a series of amplified chain reactions, ultimately leading to a cytolytic effect.
  • a variety of hydrolyzed fragments produced during the activation of complement have different biological effects and are widely involved in the immune regulation and inflammatory response of the body.
  • complement inhibitors may be used to treat inflammatory reactions, hyperimmunity, and organ transplant rejection.
  • the hemolytic inhibition test (classical approach) is based on the principle that sheep red blood cells (SRBC) bind to the corresponding antibody (hemolysin) to activate complement in the serum to be tested, resulting in hemolysis of SRBC, the degree of hemolysis and the content and function of complement in serum. related.
  • the complement inhibitory activity of the compound can be reflected by the degree of hemolysis (absorbance value).
  • the more mature complement inhibitors currently studied are complement regulatory proteins, such as SCR1 and antibodies, which are less toxic, but more expensive and can only be administered intravenously.
  • SCR1 and antibodies which are less toxic, but more expensive and can only be administered intravenously.
  • small molecule complement inhibitors have been reported in different stages. There are two main types: peptides and their analogues and various types of small molecule compounds.
  • FUT-175 Nafomostat
  • BCX-1470 are in clinical research.
  • small molecule complement inhibitors Compared with traditional protein molecules, small molecule complement inhibitors have many advantages in terms of drug delivery, cost and pharmacokinetics, and have good application prospects. Therefore, it is necessary to develop novel small molecule complement inhibitors.
  • the inventors designed and synthesized a urea compound.
  • the in vitro hemolysis inhibition test found that the compound has complement inhibitory activity, and the IC 5Q of the representative compound is about 20 nM.
  • the mechanism of the further study suggests that the target of the compound is complement. Terminal Pathway C9 o of the Activation Pathway Accordingly, it is an object of the present invention to provide a novel urea compound having complement inhibitory activity;
  • Another object of the present invention is to provide a process for producing such a urea compound having complement inhibitory activity
  • Still another object of the present invention is to provide a pharmaceutical composition having complement inhibitory activity, which comprises the urea compound of the present invention as an active ingredient.
  • a further object of the present invention is to provide a pharmaceutical composition of the present invention and a pharmaceutical composition thereof for use in the preparation of a medicament for the treatment of inflammatory response, hyperthyroidism and organ transplant rejection.
  • R 2 are each independently H, a substituted or unsubstituted C1 to C8 alkyl group, the substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 cycloalkyl group, or a N or 0 atom C3 ⁇ C7 heterocyclic group, C2 ⁇ C8 alkenyl group, C2 ⁇ C8 alkynyl group; preferably and one of them is methyl group, the other is H, substituted or unsubstituted C1 ⁇ C8 An alkyl group, the substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 cycloalkyl group, or a heterocyclic group having a C or C atom of C or C, a C2 to C8 alkenyl group, An alkynyl group of C2 to C8; preferably a C4 to C6 alkyl group
  • R 3 and R 4 are each independently H, C1 to C4 alkyl, C1 to C4 alkyl optionally substituted by at least one hydroxy or amino group; preferably C1 to C3 substituted by H, methyl or hydroxy
  • the alkyl group is H, C1 ⁇ C4 alkyl; more preferably 14 is 11, methyl, hydroxy substituted C2 ⁇ C3 alkyl, R 3 is H;
  • R 5 is a methyl group
  • R 6 to R 7 are each independently selected from one of the following groups: H, halogen, hydroxy, amino, a carboxyl group, an alkoxycarbonyl group of C1 to C4, an alkoxy group of C1 to C4, a cyano group, a trifluoromethyl group or a fluorenyl group; preferably R 6 is a halogen or a hydroxyl group, and R 7 is H; more preferably R 6 is F, a hydroxyl group , R 7 is H;
  • n 0, 1, 2, preferably n is 0;
  • X is CH or N, and preferably X is CH;
  • Y is 0 or S, and preferably Y is 0.
  • the present invention further provides a urea compound having the structure shown in Formula II.
  • one of R and R 2 is a methyl group, and the other is H, a substituted or unsubstituted C1 to C8 alkyl group, the substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 naphthenic group. a heterocyclic group having a C or C atom of N or 0 atoms, an alkenyl group of C2 to C8, an alkynyl group of C2 to C8;
  • R 3 and R 4 are each independently H, a C1 to C4 alkyl group, optionally a C1 to C4 alkyl group substituted with at least one hydroxyl group or an amino group;
  • R 5 is an alkyl group of C1 to C4;
  • R 4 and R 5 together with the carbon atom and the nitrogen atom to which they are bonded form a 5-7 membered ring;
  • R 6 to R 7 are each independently selected from one of the following groups: H, halogen, hydroxy, amino, a carboxyl group, an alkoxycarbonyl group of C1 to C4, an alkoxy group of C1 to C4, a cyano group, a trifluoromethyl group;
  • X is CH or N
  • Y is 0 or 8.
  • the alkyl group includes a linear or branched alkyl group
  • the alkenyl group includes a linear or branched alkenyl group
  • the alkynyl group includes a straight chain or Branched alkynyl
  • said halogen includes? , Cl, Br and I.
  • the urea compound having complement inhibitory activity of the present invention is most preferably selected from the following compounds.
  • aromatic oxypyrimidinecarboxamide or the aryloxypyridine carboxamide compound represented by the formula in the present invention can be produced by various steps and synthetic routes, and representative steps and synthesis methods are as follows, but are not limited to the following methods. :
  • Step A1 The iso-vanillin 1 is protected with a benzyl group to give the intermediate 2, which is carried out by a conventional method in the art;
  • Step A3 Intermediate 3 is subjected to a modified Curtius rearrangement to obtain isocyanic acid.
  • Step A5 Intermediate 5 is deprotected by benzyl to give intermediate 6;
  • Step A7 The intermediate 7 is reacted with R 3 I under NaH under basic conditions to obtain the urea compound of the present invention as shown in Formula 8;
  • ⁇ 1 7 is the same as defined in the formula I.
  • reaction conditions such as reaction temperature, time, atmosphere and the like can be determined by those skilled in the art based on the relevant reactions.
  • Ho step B2 the intermediate 10 oxidation of 2 PO 4/30% H 2 O 2 or PCC or Na 2 Cr 2 0 7 acts as an oxidizing agent NaClO 2 / NaH to give intermediate acid 11;
  • Step B3 Intermediate 11 is subjected to a modified Curtius rearrangement to obtain isocyanate 12;
  • Step B5 Intermediate 13 is deprotected by benzyl to give intermediate 14;
  • Step B6 The intermediate 14 and the different substituted bromine R 2 -Br (both obtained by commercially available route:) are reacted to obtain a urea compound represented by the intermediate 15;
  • Step B7 The intermediate 15 is reacted with R 3 I under NaH under basic conditions to obtain the urea compound of the present invention as shown in Formula 16; in Scheme B, ⁇ 17 and Formula I
  • the definition is the same.
  • the respective reactions in the above experimental steps are conventional experimental means by those skilled in the art, wherein the reaction conditions such as reaction temperature, time, atmosphere and the like can be determined by those skilled in the art according to relevant reactions.
  • Step CI Intermediate 17 (prepared by reference method: Molecular Simulation, Vol. 33, No. 14, December 2007, 1109-1117) is reacted with bromo: 3 ⁇ 4 to give intermediate 18;
  • Step C2 hydrolysis of intermediate 18 to give acid 19;
  • Step C3 The acid 19 is prepared as the isocyanate 20 in the same manner as in Scheme A;
  • Step C4 Isocyanate 20 (The preparation of the amine is given in the examples, and the remaining amines are commercially available.) After the condensation reaction, the intermediate 21 is obtained, and the condensation reaction is carried out by a conventional method in the art; Step C5: reacting intermediate 21 with R 3 I under NaH under basic conditions to obtain a urea compound of the present invention as shown in Formula 22;
  • ⁇ 1 7 is the same as defined in Formula I.
  • reaction conditions such as reaction temperature, time, atmosphere and the like can be determined by those skilled in the art based on the relevant reactions.
  • the novel complement C9 inhibitor provided by the invention inhibits total complement hemolytic activity in vitro and finds that the compound has complement inhibitory activity and can be used for treating complement-associated inflammation, hyperthyroidism, transplant rejection, etc., including treating patients.
  • Another object of the present invention is to provide a method for preventing or treating inflammatory response, hyperthyroidism and organ transplant rejection comprising administering to a patient a therapeutically effective amount of one selected from the group consisting of urea compounds of the formula (I) Or several compounds.
  • the present invention provides a pharmaceutical composition for treating complement-associated inflammation, hyperthyroidism, transplant rejection, and the like, comprising a therapeutically effective amount of one or more of the above compounds of the present invention as an active ingredient, and further comprising Pharmaceutically acceptable adjuvants such as dispersing agents, excipients, disintegrating agents, antioxidants, sweeteners, coating agents and the like.
  • the composition can be prepared according to a conventional preparation method in the pharmaceutical field, and can be prepared into various conventional dosage forms such as tablets, coated tablets, capsules, powders and the like.
  • Another object of the present invention is to provide a use of a urea compound of the formula 1 for the preparation of a medicament for preventing or treating inflammatory response, hyperthyroidism and organ transplant rejection.
  • Figure 1 shows the OD value at 450 nm of Compound 11 of the classical route C4 component.
  • Figure 2 is the OD value at 450 nm of Compound 11 of the classical route C3 component.
  • Figure 3 is the OD value at 450 nm of Compound 11 of the classical route C9 component.
  • Figure 4 is the OD value at 450 nm of Compound 11 of the classical pathway C5b-9 component.
  • Figure 5 is the OD value at 450 nm of Compound 11 of the mannose pathway C4 component.
  • Figure 6 is the OD value at 450 nm of Compound 11 of the mannose pathway C3 component.
  • Figure 7 is the OD value at 450 nm of Compound 11 of the mannose pathway C9 component.
  • Figure 8 is the OD value at 450 nm of Compound 11 of the mannose pathway C5b-9 component.
  • Figure 9 is the OD value at 450 nm of Compound 11 of the alternative pathway C3 component.
  • Figure 10 is the OD value at 450 nm of Compound 11 of the bypass route C9 component.
  • Figure 11 is the OD value at 450 nm of Compound 11 of the alternative pathway C5b-9 component.
  • NMR was measured with a Mercury-Vx 300M instrument manufactured by Varian, NMR calibration: 5 H 7.26 ppm (CDC1 3 ); mass spectrometer with Agilent 1200 Quadrupole LC/MS LC/MS; reagent mainly from Shanghai Provided by chemical reagent companies;
  • TLC thin layer chromatography silica gel plate is produced by Shandong Yantai Huiyou Silicone Development Co., Ltd., model HSGF 254; normal phase column chromatography silica gel used for compound purification is produced by Shandong Qingdao Marine Chemical Plant Branch, model zcx-l l, 200-300 Head.
  • PREPARATION EXAMPLE 1 Synthesis of intermediate (S)-l-(3-hydroxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea
  • the iso-vanillin (3.04 g, 20 nmol) was taken into a 100 ml round bottom flask, 15 ml of DMF was added, 4-methyl-1-bromopentane (3.465 g, 21 nmol), anhydrous K 2 C0 3 (l lg, 80 nmol), .
  • Compound 12 was prepared in the same manner as in the above Preparation Example 11 (3), using 3-(4-methylpentyloxy)-4-methoxy-benzoic acid (150 mg). Pentyloxy)-4-methoxy-phenylisocyanate, the isocyanate is dissolved in 10 ml of dichloromethane, and (S)-3-(l-phenyl-ethylamino)propan-1-ol is added, stirred at room temperature. After 10 minutes, the reaction was completed by TLC, and the reaction mixture was concentrated under reduced pressure.
  • 3-butoxy-4-methoxy-phenylisocyanate was prepared by the same procedure as in the above Preparation Example 3 (3) using 3-butoxy-4-methoxy-benzoic acid (50 mg).
  • the isocyanate was dissolved in 5 ml of dichloromethane, and (S)-N-methyl-1-phenylethylamine (50 mg) was added, and the mixture was stirred at room temperature for 10 minutes, and the reaction was completed by TLC.
  • N-(3) was obtained in the same manner as in Preparation Example 16 except that the corresponding moles of 2-phenylpyrrolidine was used instead of (S)-N-methyl-1-phenylethylamine in Preparation Example 16. - Butoxy-4-methoxyphenyl)-2-phenylpyrrolidine-1-amide.
  • Compound 22 was prepared from (S)-l-(3-butoxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea (100 mg), and 3 ml of anhydrous DMF was added. Cool to 0 ° C, add NaH (24 mg, 0.6 mmol), keep the temperature for 15 minutes, warm to room temperature for half an hour, add methyl iodide (85 mg, 0.6 mmol), stir at room temperature for half an hour, complete the disappearance of TLC detection, add 1M HC1 The reaction was quenched, EtOAc (EtOAc) (EtOAc (EtOAc). -l-(3-Butoxy-4-methoxy-phenyl)-1-methyl-3-(1-phenyl-ethyl)-urea, 15 mg, yield 14%.
  • 3-(4-methylpentyloxy) was prepared by the same procedure as in the above Preparation Example 11 (3) using 3-(4-methylpentyloxy)-4-methoxy-benzoic acid (50 mg).
  • Base -4-methoxy-phenyl isocyanate the isocyanate is dissolved in 10 ml of dichloromethane, 3-hydroxy-(S)-a-phenylethylamine is added, stirred at room temperature for 10 minutes, and the reaction is complete by TLC. The reaction solution.
  • Complement is a group of plasma proteins that exist in the form of inactive zymogen under natural conditions.
  • the binding of specific antibodies to red blood cells activates complement through the classical pathway, resulting in the formation of a membrane complex on the surface of red blood cells, with an inner diameter of l lnm, allowing water and electrolytes to pass but not allowing macromolecules to pass through.
  • the formation of a large number of attacking membrane complexes causes moisture to enter the cells due to the large difference in osmotic pressure, causing hemolysis of red blood cells.
  • Sheep red blood cells were purchased from Shanghai Jiayu Biotechnology Co., Ltd.; normal human serum, self-lifting; hemolysin (anti-sheep red blood cell antibody), sigma products
  • the sheep red blood cell suspension was taken, washed and diluted with barbiturate buffer DGVB++, hemolysin was added at 1:3000, and incubated at 37 ° C for 100 minutes to sensitize sheep red blood cells. Wash and dilute the sensitized sheep red blood cells with DGVB++ buffer, add normal human serum and test samples of different concentrations, incubate at 37 °C for 240 hours, centrifuge for 1 hour, centrifuge, take the supernatant, and measure the OD value at 405 nm. The 50% hemolysis state is a control, and the degree of hemolysis of the sample well is detected.
  • the plate was coated with lOug/mL IgM (classical route), lOOug/mL mannan (mannose pathway) or 20ug/mL zymosan (bypass pathway) one day before the experiment, overnight at 4 °C.
  • the cells were blocked with PBS containing 10% serum, and then normal human serum and test samples of different concentrations were added, and incubated at 37 ° C for 1 hour.
  • the anti-complement C3 component, the C4 component or the C9 component primary antibody and the HRP-conjugated secondary antibody were separately added, and TMB was developed for 30 minutes, and the OD value was measured at a wavelength of 450 nm.
  • Fig. 1 is the OD value at 450 nm of the compound 11 of the classical route C4 component
  • Fig. 2 is the OD value at 450 nm of the compound 11 of the classical route C3 component
  • 3 is the OD value at 450 nm of the compound 11 of the classical route C9 component
  • FIG. 4 is the OD value at 450 nm of the compound 11 of the classical route C5b-9 component
  • FIG. 5 is the 450 of the compound 11 of the mannose pathway C4 component.
  • OD value at nm Figure 6 is the OD value at 450 nm of Compound 11 of the mannose pathway C3 component; Figure 7 is the OD value at 450 nm of Compound 11 of the mannose pathway C9 component; Figure 8 is the mannose pathway The OD value at 450 nm of compound 11 of the C5b-9 component; Figure 9 is the OD value at 450 nm of compound 11 of the C3 component of the alternative pathway; Figure 10 is the 450 nm of compound 11 of the C9 component of the alternative pathway. OD value; Figure 11 is the OD value at 450 nm of compound 11 of the alternative pathway C5b-9 component.
  • the compounds have little inhibitory effect on the activation of C4/C3 by any means, but have inhibitory effects on the terminal pathways of the three activation pathways, indicating that the target of the compound is C9, which can be prepared. It has new targets for the treatment of inflammatory response, hyperthyroidism and organ transplant rejection.

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  • Organic Chemistry (AREA)
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  • Pain & Pain Management (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur un composé de l'urée ayant une structure telle que représentée par la formule générale (I), sur son procédé de préparation, sur une composition pharmaceutique contenant le composé et sur ses utilisations dans la préparation de médicaments pour le traitement d'une réponse inflammatoire, d'une hyperactivité du système immunitaire et d'un rejet de greffe d'organe. Dans la formule générale (I), R1-R7, X, Y et n sont tels que définis dans la description et les revendications.
PCT/CN2012/001719 2011-12-21 2012-12-21 Composé de l'urée, son procédé de préparation et son utilisation WO2013091285A1 (fr)

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CN103694144B (zh) * 2013-12-11 2015-04-08 华东师范大学 一种3-烯基取代脲类衍生物及其制备方法
CN105985293B (zh) * 2015-03-04 2018-04-03 埃斯特维华义制药有限公司 尼洛替尼中间体的制备方法
CN109776244A (zh) * 2019-01-28 2019-05-21 浙江大学 一种脲类化合物的合成方法及应用

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