CN111471010B - Indoleamine-2, 3-dioxygenase (IDO) inhibitors - Google Patents

Indoleamine-2, 3-dioxygenase (IDO) inhibitors Download PDF

Info

Publication number
CN111471010B
CN111471010B CN202010446383.0A CN202010446383A CN111471010B CN 111471010 B CN111471010 B CN 111471010B CN 202010446383 A CN202010446383 A CN 202010446383A CN 111471010 B CN111471010 B CN 111471010B
Authority
CN
China
Prior art keywords
acid
alkyl
combination
radical
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010446383.0A
Other languages
Chinese (zh)
Other versions
CN111471010A (en
Inventor
李磐
温俏冬
王骥
甘泉
路杨
杨东晖
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xiamen Baotai Biotechnology Co ltd
Original Assignee
Hangzhou Arnold Biomedical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Arnold Biomedical Technology Co ltd filed Critical Hangzhou Arnold Biomedical Technology Co ltd
Priority claimed from CN201880057640.2A external-priority patent/CN111741946B/en
Publication of CN111471010A publication Critical patent/CN111471010A/en
Application granted granted Critical
Publication of CN111471010B publication Critical patent/CN111471010B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/18—Halogen atoms or nitro radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method of a compound shown as a formula I, and the compound prepared by the method has the activity of inhibiting indoleamine 2, 3-dioxygenase。

Description

Indoleamine-2, 3-dioxygenase (IDO) inhibitors
The application is a divisional application, and the Chinese application number of the parent case is as follows: 201880057640.2, International application number PCT/CN2018/124110, International application date 12/27 of 2018.
The present invention claims priority from chinese patent applications CN201711478307.2 and CN201810754253.6, and the contents of the specification, drawings and claims of this priority document are incorporated in their entirety into the specification of the present invention and are included as a part of the original description of the present invention. Applicants further claim that applicants have the right to amend the description and claims of this invention based on this priority document.
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of an indoleamine-2, 3-dioxygenase (IDO) inhibitor.
Background
Tryptophan (TRP) is an α -amino acid used in protein biosynthesis. It contains an alpha-amino group, an alpha-carboxylic acid group and a side chain indole. It is essential in humans, who cannot synthesize it, but must be obtained from the diet. Tryptophan is also a precursor in the synthesis of the neurotransmitter 5-hydroxytryptamine (serotonin) and the hormone N-acetyl-5-methoxytryptamine (melatonin). The heme-dependent enzyme indoleamine 2, 3-dioxygenase (also called IDO, or IDO1) is a metabolic enzyme outside the liver responsible for the conversion of tryptophan to N-formyl-kynurenine, which is the first step in the tryptophan metabolism process and is also the rate-limiting step of the overall process. N-formyl-kynurenine is a precursor of the diverse bioactive molecules kynurenine (kynurenine, or Kyn) that has immunomodulatory functions (Schwarcz et al, Nat Rev neurosci.2012; 13(7): 465).
Indoleamine 2, 3-dioxygenase (IDO) is widely expressed in solid tumors (Uyttenhove et al, Nat Med. 2003; 10:1269) and is also expressed in both primary and metastatic cancer cells. IDO is induced in tumors by pro-inflammatory factors, including type I and type II interferons produced by infiltrating lymphocytes (Tnani and Bayard, Biochim biophysis acta.1999; 1451(l): 59; Mellor and Munn, Nat Rev Immunol 2004; 4(10): 762; Munn, Front biosci.2012; 4:734) and transforming growth factor-beta (TGF-beta) (Pallotta et al, Nat immunol.2011; 12(9): 870). In recent years, there has been increasing evidence that IDO plays a major role in immune cell regulation as an inducible enzyme. Decreased tryptophan levels and increased kynurenines suppress immune effector cells and promote adaptive immune suppression by inducing and maintaining regulatory T cells (Tregs; Munn, Front biosci.2012; 4: 734); the concentration of tryptophan in the immune system is positively correlated with T cells. In the tumor immune microenvironment, activated or overexpressed IDO leads to tryptophan depletion, which in turn leads to T cell death, immune system inactivation, and ultimately to the development of tumor immune tolerance and immune escape. The existing research shows that the immune balance disorder caused by IDO is deeply involved in the generation and the progression of tumors. Therefore, IDO receptor has become an important target for immunotherapy such as tumor. IDO is associated with, in addition to tumors, viral infections, depression, organ transplant rejection or autoimmune diseases (Johnson and Munn, Immunol Invest 2012; 41(6-7): 765). Therefore, agents targeting IDO are also of great value for the treatment of the above mentioned diseases. In conclusion, it is necessary to develop an IDO inhibitor having activity and selectivity to effectively treat diseases due to harmful substances in the kynurenine pathway by modulating the kynurenine pathway and maintaining tryptophan levels in the body, either as a single agent or a combination therapy.
Numerous published preclinical data also further confirm the role of IDO in antitumor immune responses. IDO inhibitors may be used to activate T cells, thereby increasing T cell activation when the T cells are suppressed by viruses such as pregnancy, malignancy, or HIV. Forced induction of IDO in cancer cells has proven to be a survival advantage (Uyttenhove et al, Nat Med.2003; 10: 1269). Another in vivo study showed that IDO inhibitors reduce lymphocyte dependence by reducing kynurenine levels in tumor growth (Liu et al, blood.2010; 115(17): 3520). Preclinical studies have also shown that IDO inhibitors have synergistic effects if combined with other tumor drugs, such as radiation therapy, chemotherapy, or vaccines. (Koblish et al, Mol Cancer ther. 2010; 9(2):489, Hou et al, Cancer Res.2007; 67(2): 792; Sharma et al, blood.2009; 113(24):6102).
Research on IDO inhibitor antitumor drugs has currently made significant progress worldwide, such as INCB024360, NLG919 and BMS-986205 all entering the clinic. However, the INCB024360 has the problem of toxic and side effects, so that the dosage (50mg bid or 100mg bid) of the existing clinical research is about 30 percent of the optimal dosage (300mg bid or 600mg bid), and the clinical activity is greatly limited; meanwhile, the toxic group of INCB024360 is a pharmacophore, and the INCB024360 and derivatives thereof have the problem of high toxicity. The safety of NLG919 is good, but the bioactivity of NLG919 is poor. BMS-986205 has already entered the clinic at present, but the clinical data are limited, and based on BMS-986205, the research of novel compounds with high biological activity and high safety is carried out, which has very important practical significance for finding novel IDO tumor immunotherapy drugs with better clinical therapeutic activity, such as possible tumor cure, rather than just tumor inhibition.
Disclosure of Invention
The invention provides a compound shown as a formula I,
Figure BDA0002505919540000041
wherein
Figure BDA0002505919540000042
Represents:
Figure BDA0002505919540000043
or
Figure BDA0002505919540000044
A represents-C (O) -, -S (O)2-or-s (o) -;
wherein each R is1Each independently selected from hydrogen atom, halogen, hydroxyl, nitro, cyano, sulfonic acid group, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy, halo C1-C6Cycloalkyl radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono, hydroxy C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl) phosphono C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6An alkylamino group; or adjacent R1Mutually cyclized to form a 3-8 membered ring, and the ring contains 0, 1,2 and 3 heteroatoms;
Cy1selected from 5-15 membered bridged ring group, 5-15 membered spiro ring group, 5-15 membered bridged heterocyclic group, or 5-15 membered spiro heterocyclic group substituted by any substituent group: halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano;
Ra、Rb、R2each independently selected from hydrogen and C1-C6Alkyl or C3-6A cycloalkyl group;
Cy2is C containing one or more substituents5-C10Aryl radical, C5-C10Heteroaryl group, C5-C10Cycloalkyl radical, C5-C10A heterocycloalkyl group; the substituent can be selected from halogen, hydroxyl, nitro, cyano, sulfonic acid group and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono, hydroxy C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl) phosphono C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6Alkylamino, -S (O) C1-6An alkyl group; or when two substituents are adjacent, can form a 3-8 membered ring, which 3-8 membered ring may contain 0, 1,2, 3O, S, N atoms; m and n are 0, 1,2, 3 and 4.
In another embodiment of the present invention, Cy is1Selected from the group consisting of8-12 membered spiro ring group or 8-12 membered spiro ring group, 8-12 membered bridged heterocyclic group, or 8-12 membered spiro heterocyclic group, the substituent is: halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano.
In another embodiment of the present invention, Cy is1Selected from the following groups:
Figure BDA0002505919540000061
the above groups may be selected from halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano.
In another embodiment of the present invention, Cy is1Selected from the following groups:
Figure BDA0002505919540000062
Figure BDA0002505919540000071
the above groups may be selected from halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano.
The invention provides a compound shown as a formula (II),
Figure BDA0002505919540000072
wherein R is1、R2、Ra、Rb、Cy2M, n, A are as defined for formula I; x is selected from (CR)cRd)oWherein is optionally CRcRdMay be substituted by O or NReReplacing; y is selected from CRfOr N; wherein R isc、Rd、Re、RfEach independently selected from hydrogen or C1-6An alkyl group; o is selected from 0, 1,2, 3, 4, 5.
The invention provides a compound shown as a formula (III),
Figure BDA0002505919540000081
wherein W and Q are selected from CRcRdOr NReOr O; A. r1、R2、Ra、Rb、Rc、Rd、Re、Cy2M, n and Y are as defined above for formula (II).
The invention also provides a compound shown as a formula (IV),
Figure BDA0002505919540000082
wherein R is1、R2、Ra、Rb、Cy2M, n, X, Y, A are as defined above for formula (II); z is selected from (CR)g)pWherein CR is arbitrarygMay be replaced by N; rgEach independently selected from hydrogen or C1-6An alkyl group; p is selected from 0, 1,2, 3, 4, 5.
In the preferred technical scheme of the invention, the structure of the compound has the formula (V):
Figure BDA0002505919540000091
wherein R is1、R2、Rc、Rd、Rf、Cy2M, A are as defined in the above formula (II)And (5) defining.
In the preferred technical scheme of the invention, the structure of the compound has the formula (VI):
Figure BDA0002505919540000092
wherein R is1、R2、Rc、Rd、Cy2M and A are as defined above for formula (II).
In a preferred embodiment of the present invention, the compound has a structure represented by formula (VII):
Figure BDA0002505919540000093
wherein R is1、R2、Re、Rf、Cy2M and A are as defined above for formula (II).
In a preferred technical scheme of the invention, the compound has a structure as shown in a formula (VIII):
Figure BDA0002505919540000101
wherein R is1、R2、Rc、Rd、Rf、Cy2M and A are as defined above for formula (II).
In a preferred technical scheme of the invention, the compound has a structure as shown in a formula (IX):
Figure BDA0002505919540000102
wherein R is1、R2、Rc、Rd、Re、Rf、Cy2M and A are as defined above for formula (II).
In the technical scheme of the invention, the air conditioner is provided with a fan,
Figure BDA0002505919540000103
to represent
Figure BDA0002505919540000104
Or
Figure BDA0002505919540000105
In the technical scheme of the invention, the air conditioner is provided with a fan,
Figure BDA0002505919540000106
preferably, it is
Figure BDA0002505919540000107
In the technical scheme of the invention, A is selected from-C (O) -or S (O)2-。
The invention also provides a preparation method of the compound with the structure of the formula (X):
Figure BDA0002505919540000111
in the route I reaction:
wherein the base used in step (1) is selected from inorganic bases or organic bases, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, potassium tert-butoxide, lithium diisopropylamide, barium hydroxide, or any combination thereof;
wherein the organic solvent used in step (1) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof;
wherein the ylide used in step (2) is selected from the group consisting of a sulfur ylide and a phosphorus ylide;
wherein the Grignard reagent used in step (3) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr, or any combination thereof.
The invention also provides a preparation method of the compound with the structure of the formula (XI):
Figure BDA0002505919540000112
in the route II reaction:
wherein the catalyst used in step (1) is selected from methyl titanate, ethyl titanate, n-propyl titanate, isopropyl titanate, butyl titanate or any combination thereof;
wherein the base used in step (2) is selected from inorganic bases or organic bases, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, potassium tert-butoxide, lithium diisopropylamide, barium hydroxide, or any combination thereof;
wherein the organic solvent used in step (2) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof;
wherein the ylide used in step (2) is selected from the group consisting of a sulfur ylide and a phosphorus ylide;
wherein the hydrolysis of step (3) is carried out under acidic conditions, said acid being selected from, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid or any combination thereof;
wherein the organic solvent used in step (4) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof.
The invention also provides a preparation method of the compound with the structure of the formula (XII):
Figure BDA0002505919540000121
in path III:
wherein the catalyst used in step (1) is selected from methyl titanate, ethyl titanate, n-propyl titanate, isopropyl titanate, butyl titanate or any combination thereof;
wherein the step (2) is carried out under the action of non-nucleophilic strong base selected from the group consisting of but not limited to lithium diisopropylamide, lithium diethylamide, lithium isopropylcyclohexylamide, lithium dicyclohexylamide, lithium 2,2,6, 6-tetramethylpiperidino and lithium hexamethyldisilazide;
wherein the hydrolysis reaction of step (3) is carried out under acidic conditions, and the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid, or any combination thereof;
wherein the Grignard reagent used in step (4) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr or any combination thereof;
wherein, when the alkylation reaction in the step (5) is performed, the alkylation reaction reagent is selected from halogenated alkyl, the reaction is performed under the condition of Lewis acid as a catalyst, and the Lewis acid is preferably AlCl3、FeCl2、CuCl2。
The invention also provides a preparation method of the compound with the structure of the formula (XIII):
Figure BDA0002505919540000131
in path IV
Wherein the base used in step (1) and step (3) is selected from inorganic bases or organic bases, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, potassium tert-butoxide, lithium diisopropylamide, barium hydroxide, or any combination thereof;
wherein the organic solvent used in steps (1) to (3) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof;
wherein the oxidant used in step (2) is selected from but not limited to m-chloroperoxybenzoic acid, CrO3、KMnO4、MnO2、NaCr2O7、HIO4、PbAc4、OsO4Hydrogen peroxide or any combination thereof;
wherein the hydrolysis reaction of step (4) is carried out under acidic conditions, and the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid, or any combination thereof;
wherein the Grignard reagent used in step (5) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr, or any combination thereof.
The invention also provides a preparation method of the compound with the structure of the formula (XIV):
Figure BDA0002505919540000141
in path V:
wherein step (1) is carried out in the presence of an alkali metal fluoride selected from, but not limited to, LiF, NaF, KF, MgF, or an alkaline earth metal fluoride2、CaF2；
Wherein the reduction reaction in the step (2) can be palladium carbon catalytic hydrogenation reduction or Na/liquid ammonia reduction;
wherein the Grignard reagent used in step (3) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr or any combination thereof;
wherein, when the alkylation reaction in step (4) is carried out, the alkylation reaction reagent is selected from a haloalkyl group, and theThe reaction is carried out with a Lewis acid, preferably AlCl, as catalyst3、FeCl2、CuCl2。
Detailed Description
Design and reaction examples
The compound of the present invention can be synthesized by known procedures with reference to the following descriptions. All solvents and reagents purchased were used directly without treatment. All synthesized compounds can be analytically validated by, but not limited to, the following methods: LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). Nuclear Magnetic Resonance (NMR) was measured by Bruker AVANCE-500 NMR spectrometer using deuterated dimethyl sulfoxide (d)6-DMSO), deuterated chloroform (CDCl)3) Tetramethylsilane (TMS) was used as an internal standard. The following abbreviations represent various types of split peaks: singlet(s), doublet (d), triplet (t), multiplet (m), broad (br). Mass Spectrometry (MS) was measured using a Thermo Fisher-MSQ Plus LC Mass spectrometer. General synthetic analysis and examples are described below:
example 1
N- (4-chlorophenylyl) -6- (6-fluoroquinolin-4-yl) spiro [2.5] octane-1-carboxamid eN- (4-chlorophenyl) -6- (6-fluoroquinolin-4-yl) spiro [2.5] octane-1-carboxamide
Figure BDA0002505919540000161
The first step is as follows: 1, 4-cyclohexanedione monoethylene glycol ketal (10.0g,64.03mmol) was dissolved in 250mL of methyl tert-butyl ether and N-phenylbis (trifluoromethanesulfonyl) imide (22.9g,64.03mmol) was added. The reaction mixture was cooled to-78 ℃ and sodium bis (trimethylsilyl) amide (2mol/L tetrahydrofuran solution) (32mL,64.03mmol) was added dropwise to the reaction mixture under a nitrogen atmosphere. After the completion of the dropwise addition, the reaction mixture was stirred at that temperature for 60 minutes, then allowed to warm to room temperature and stirred overnight until the reaction material was completely consumed by TLC. The reaction solution was quenched with 3mL of an aqueous potassium hydrogen sulfate solution, filtered to remove solids, and the filtrate was concentrated. To the residue was added 3mL of methyl tert-butyl etherButyl ether, the organic layer was washed three times with 45mL of sodium hydroxide (5%) solution and once with 50mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1a (17.23g) as an orange oily liquid in 93% yield.1H NMR(500MHz,CDCl3)δ5.66(J＝4.0Hz,1H),4.01–3.96(m,4H),2.56–2.52(m,2H),2.42–2.40(m,2H),1.90(t,J＝6.5Hz,2H).
The second step is that: compound 1a (13g,45.1mmol) was dissolved in 100mL dioxane, and pinacol diboron (14.9g,58.64mmol), potassium acetate (13.3g,135.3mmol) and Pd (dppf) Cl were added sequentially2(1.65g,2.26 mmol). The reaction mixture was refluxed overnight under nitrogen atmosphere. Then the reaction solvent dioxane was evaporated to dryness, ethyl acetate was added, celite was filtered, the filtrate was concentrated and then separated by flash column chromatography to give compound 1b (7.6g) as a pale yellow solid in 63% yield.1HNMR(500MHz,CDCl3)δ6.48–6.45(m,1H),3.98(s,4H),2.40–2.34(m,4H),1.73(t,J＝6.5Hz,2H),1.25(s,12H).
The third step: compound 1b (5.7g,21.48mmol) was dissolved in 60mL/15mL dioxane/water and 4-chloro-6-fluoroquinoline (3.0g,16.53mmol), potassium carbonate (6.8g,49.56mmol) and Pd (PPh3)4(954mg,0.83mmol) were added sequentially. The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction was then concentrated, extracted with ethyl acetate, and the organic phase was concentrated and then separated by flash column chromatography to give compound 1c (2.42g) as a pale yellow liquid in 51% yield. MS (ESI) M/z 286.1(M + H)+.1H NMR(500MHz,CDCl3)δ8.81(d,J＝4.5Hz,1H),8.15(dd,J＝9.0,5.5Hz,1H),7.65(dd,J＝10.0,2.5Hz,1H),7.49(td,J＝9.0,2.5Hz,1H),7.26(d,J＝4.5Hz,1H),5.77(t,J＝3.5Hz,1H),4.08–40.6(m,4H),2.65–2.60(m,2H),2.56–2.53(m,2H),2.00(t,J＝6.5Hz,2H).
The fourth step: compound 1c (2.42g,8.49mmol) was dissolved in 45mL of isopropanol and 10% palladium on carbon (300mg) was added. The reaction mixture was heated to 55 ℃ under hydrogen atmosphere for overnight reaction. The palladium on carbon was then filtered off with celite and the filtrate was concentrated to give crude compound 1d (2.04g) as a slurry in 84% yield, which was used directly in the next reaction. MS (ESI) M/z 288.1(M + H)+.
The fifth step: compound 1d (2.04g,7.11mmol) was dissolved in 36mL of acetone, and 9mL of 4mol/L hydrochloric acid was added. The reaction mixture was heated to 45 ℃ and reacted overnight. The solvent was then evaporated off, the aqueous solution was neutralized with 6mol/L sodium hydroxide to pH 9 and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by flash column chromatography to give compound 1e (1.17g) as a pale yellow solid in 67% yield. MS (ESI) M/z 244.3(M + H)+.1H NMR(500MHz,CDCl3)δ8.85(d,J＝4.5Hz,1H),8.22(dd,J＝9.0,5.5Hz,1H),7.74(dd,J＝10.0,2.5Hz,1H),7.57–7.50(m,1H),7.33(d,J＝4.5Hz,1H),3.74–3.66(m,1H),2.72–2.58(m,4H),2.41–2.34(m,2H),2.11–2.00(m,2H).
And a sixth step: triethyl phosphonoacetate (968mg,4.32mmol) was dissolved in 16mL of ultra dry tetrahydrofuran and sodium tert-butoxide (415mg,4.32mmol) was added at 0 ℃ in an ice bath. After 10 minutes, a solution of compound 1e (1g,4.12mmol) in tetrahydrofuran (4mL) was added to the reaction. After 2 hours of reaction, quench with water. The aqueous solution was extracted three times with 20mL of ethyl acetate, the organic phases were combined, washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by flash column chromatography to give compound 1f (1.18g) as a white solid in 92% yield. MS (ESI) M/z 314.0(M + H)+.1H NMR(500MHz,CDCl3)δ8.81(d,J＝4.5Hz,1H),8.17(dd,J＝9.0,5.5Hz,1H),7.72(dd,J＝10.0,2.5Hz,1H),7.53–7.47(m,1H),7.28(d,J＝4.5Hz,1H),5.75(s,1H),4.19(q,J＝7.0Hz,2H),3.52–3.42(m,1H),2.54–2.48(m,2H),2.26–2.11(m,4H),1.80–1.68(m,2H),1.30(t,J＝7.0Hz,3H).
The seventh step: NaH (383mg,9.57mmol) was added to 15mL of dimethyl sulfoxide, and trimethyl sulfoxide iodide (2.11g,9.57mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. Then, a solution of compound 1f (1.0g,3.19mmol) in dimethyl sulfoxide (5mL) was added to the reaction solution. The reaction was stirred at room temperature overnight. Then quenched with water, extracted with ethyl acetate, and isolated by flash column chromatography to give 1g (820mg) of the compound as a colorless oily liquid in 78% yield. MS (ESI) M/z 328.1(M + H)+.1HNMR(500MHz,CDCl3)δ8.83(d,J＝4.5Hz,1H),8.24(dd,J＝9.0,5.5Hz,1H),7.71(dd,J＝10.0,2.5Hz,1H),7.55–7.49(m,1H),7.35(d,J＝4.5Hz,1H),4.19(q,J＝7.0Hz,2H),3.32–3.24(m,1H),2.17(td,J＝13.0,3.5Hz,1H),2.07–1.90(m,4H),1.87–1.78(m,1H),1.58(dd,J＝8.0,5.5Hz,1H),1.46–1.37(m,1H),1.30(t,J＝7.0Hz,3H),1.28–1.24(m,2H),1.16–1.11(m,1H),1.00(dd,J＝8.0,4.5Hz,1H).
Eighth step: 4-chloroaniline (94mg,0.73mmol) was dissolved in 5mL tetrahydrofuran and a 2mol/L solution of isopropyl magnesium chloride in tetrahydrofuran (0.4mL,0.73mmol) was added at 0 deg.C in an ice bath. The mixture was stirred at room temperature for 5 minutes, and a solution of compound 1g (60mg,0.18mmol) in tetrahydrofuran (2mL) was added to the mixture. The reaction was stirred at room temperature overnight, then quenched with saturated ammonium chloride solution and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative chromatography to give compound 1(16.04mg) as a white solid in 21% yield. MS (ESI) M/z 408.9(M + H)+.1H NMR(500MHz,d6-DMSO)δ10.37(s,1H),8.81(s,1H),8.11–8.05(m,1H),8.02(d,J＝11.0Hz,1H),7.69–7.63(m,3H),7.38–7.31(m,3H),3.48–3.40(m,1H),2.20(t,J＝12.0Hz,1H),1.97–1.84(m,4H),1.78(d,J＝12.5Hz,1H),1.72(t,J＝6.5Hz,1H),1.35–1.26(m,1H),1.17–1.08(m,2H),0.96–0.90(m,1H).
Example 32
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)spiro[3.5]nonane-1-carboxamide
N- (4-chlorophenyl) -7- (6-fluoroquinolin-4-yl) spiro [3.5] nonane-1-carboxamide
Figure BDA0002505919540000201
Synthesis of compound 32 starting from intermediate 1e in example 1, was prepared via the following steps: the first step is as follows: (cyclopropylmethyl) triphenylphosphine bromide (2.0eq) was added to the ultra-dry tetrahydrofuran, and NaH (2.0eq) was added to the suspension, followed by stirring at room temperature for 2 hours. Further, compound 1e (1.0eq) and tris (3, 6-dioxaheptyl) amine (0.1eq) were added to the reaction solution. The reaction mixture isStirred at room temperature for 10 minutes and then heated to 62 ℃ for 4 hours. The reaction solvent was dried by spinning and the residue was isolated by flash column chromatography to give compound 32a in 75% yield. MS (ESI) M/z 268.3(M + H)+.
The second step is that: compound 32a (1.0eq) was dissolved in dichloromethane and m-chloroperoxybenzoic acid (1.4eq) was added in portions at 0-5 ℃. The reaction mixture was reacted at 0-5 ℃ for 40 minutes and then warmed to room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, and the organic phase was washed successively with a 10% aqueous sodium hydroxide solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash column chromatography to give compound 32b in 35% yield. MS (ESI) M/z284.3(M + H)+.
The third step: compound 32b (1.0eq) and p-toluenesulfonylmethylisocyanitrile (2.0eq) were dissolved in 1, 2-dimethoxyethane and methanol (v/v:16/1), and potassium tert-butoxide (3.0eq) was added at 0-5 ℃. The reaction mixture was stirred at room temperature for 4 hours, then poured into water and neutralized with 1M hydrochloric acid solution to pH 6-7. The aqueous solution was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash column chromatography to give compound 32c in 20% yield. MS (ESI) M/z 295.3(M + H)+.
The fourth step: compound 32c (1.0eq) was dissolved in ethanol, 40% sodium hydroxide solution (10.0eq) was added, and the mixture was heated at 95 ℃ for reaction for 3 hours. The reaction was diluted with water and neutralized with 4M hydrochloric acid solution to pH 1-2. The aqueous phase was extracted with ethyl acetate, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 32d in 82% yield, which was used in the next step without purification. MS (ESI) M/z 314.3(M + H)+.
The fifth step: compound 32d (1.0eq) was dissolved in ethyl acetate, and pyridine (3.0eq) and tripropyl phosphoric anhydride (2.5eq) were added in this order and stirred at room temperature for 10 minutes. 4-chloroaniline (3.0eq) was then added and the reaction was continued at room temperature with stirring overnight. To the reaction solution was added 2M sodium hydroxide solution, and diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative chromatography to give compound 32 as a white solid.
Synthesis of compounds 33,34,35,36,37 and compound 32.
Figure BDA0002505919540000221
Figure BDA0002505919540000231
Figure BDA0002505919540000241
Figure BDA0002505919540000251

Claims (6)

1. A method of preparing a compound having the structure of formula (XIII):
Figure FDA0003177857880000011
wherein, among others,
Figure FDA0003177857880000012
represents: - (O) b,
Figure FDA0003177857880000013
Or
Figure FDA0003177857880000014
Wherein each R is1Each independently selected from a hydrogen atom or a halogen;
wherein R is2Each independently selected from hydrogen;
wherein R isc、RdEach independently selected from hydrogen;
wherein, Cy2Is C containing one or two substituents5-C10An aryl group; the substituent is selected from halogen, hydroxyl, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-C6An alkyl group; wherein m is 1.
2. The process of claim 1, wherein the base used in step (1) and step (3) is selected from inorganic or organic bases including sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, lithium diisopropylamide, barium hydroxide or any combination thereof.
3. The method according to claim 1 or 2, wherein the organic solvent used in the steps (1) to (3) comprises 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol or any combination thereof.
4. The process of claim 1, wherein the oxidizing agent used in step (2) is selected from m-chloroperoxybenzoic acid, CrO3、KMnO4、MnO2、NaCr2O7、HIO4、PbAc4、OsO4Hydrogen peroxide or any combination thereof.
5. The process of claim 1, wherein the hydrolysis reaction of step (4) is carried out under acidic conditions, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid, or any combination thereof.
6. The method according to claim 1, wherein the Grignard reagent used in step (5) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr, or any combination thereof.
CN202010446383.0A 2017-12-29 2018-12-27 Indoleamine-2, 3-dioxygenase (IDO) inhibitors Active CN111471010B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CN2017114783072 2017-12-29
CN201711478307 2017-12-29
CN2018107542536 2018-06-29
CN201810754253 2018-06-29
CN201880057640.2A CN111741946B (en) 2017-12-29 2018-12-27 Indoleamine 2, 3-dioxygenase inhibitors and their use in medicine

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201880057640.2A Division CN111741946B (en) 2017-12-29 2018-12-27 Indoleamine 2, 3-dioxygenase inhibitors and their use in medicine

Publications (2)

Publication Number Publication Date
CN111471010A CN111471010A (en) 2020-07-31
CN111471010B true CN111471010B (en) 2021-09-28

Family

ID=71780139

Family Applications (4)

Application Number Title Priority Date Filing Date
CN202010446396.8A Pending CN111574442A (en) 2017-12-29 2018-12-27 Preparation method of indoleamine 2, 3-dioxygenase inhibitor
CN202010446382.6A Active CN111471035B (en) 2017-12-29 2018-12-27 Preparation method of IDO inhibitor
CN202010446435.4A Active CN111471011B (en) 2017-12-29 2018-12-27 Preparation method of high-activity indoleamine 2, 3-dioxygenase inhibitor
CN202010446383.0A Active CN111471010B (en) 2017-12-29 2018-12-27 Indoleamine-2, 3-dioxygenase (IDO) inhibitors

Family Applications Before (3)

Application Number Title Priority Date Filing Date
CN202010446396.8A Pending CN111574442A (en) 2017-12-29 2018-12-27 Preparation method of indoleamine 2, 3-dioxygenase inhibitor
CN202010446382.6A Active CN111471035B (en) 2017-12-29 2018-12-27 Preparation method of IDO inhibitor
CN202010446435.4A Active CN111471011B (en) 2017-12-29 2018-12-27 Preparation method of high-activity indoleamine 2, 3-dioxygenase inhibitor

Country Status (1)

Country Link
CN (4) CN111574442A (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110156674A (en) * 2018-02-13 2019-08-23 中国科学院上海有机化学研究所 A kind of spiro-compound as indoles amine -2,3- dioxygenase inhibitor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1678586A (en) * 2002-06-27 2005-10-05 舍林股份公司 Substituted quinoline CCR5 receptor antagonists
CN101479249A (en) * 2006-06-29 2009-07-08 霍夫曼-拉罗奇有限公司 Benzimidazole derivatives, method for the production thereof, their use as FXR agonists and pharmaceutical preparations containing the same
WO2013134518A1 (en) * 2012-03-09 2013-09-12 Amgen Inc. Sulfamide sodium channel inhibitors

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4567265A (en) * 1984-01-16 1986-01-28 Loyola University Of Chicago Cyclopropanoid cyanoesters and method of making same
US8415354B2 (en) * 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
CN102140104B (en) * 2010-02-03 2014-11-12 中国科学院上海药物研究所 1-(3-(S)-amino propyl)-piperidine-4-aminoacid amide compound and pharmaceutical composition thereof as well as preparation methods and applications of compound and pharmaceutical composition
GB201419579D0 (en) * 2014-11-03 2014-12-17 Iomet Pharma Ltd Pharmaceutical compound
UY36390A (en) * 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CN105732636B (en) * 2014-12-30 2020-04-21 广东东阳光药业有限公司 Heteroaromatic compounds and their use in medicine
CN107021929A (en) * 2016-01-29 2017-08-08 苏州国匡医药科技有限公司 One class Novel IDO inhibitor, preparation method, medical composition and its use
KR20190003686A (en) * 2016-05-04 2019-01-09 브리스톨-마이어스 스큅 컴퍼니 Inhibitors of indoleamine 2,3-dioxygenase and methods of use thereof
CN108017639B (en) * 2016-11-01 2020-09-15 南京华威医药科技集团有限公司 IDO inhibitor and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1678586A (en) * 2002-06-27 2005-10-05 舍林股份公司 Substituted quinoline CCR5 receptor antagonists
CN101479249A (en) * 2006-06-29 2009-07-08 霍夫曼-拉罗奇有限公司 Benzimidazole derivatives, method for the production thereof, their use as FXR agonists and pharmaceutical preparations containing the same
WO2013134518A1 (en) * 2012-03-09 2013-09-12 Amgen Inc. Sulfamide sodium channel inhibitors

Also Published As

Publication number Publication date
CN111471035A (en) 2020-07-31
CN111471011A (en) 2020-07-31
CN111471011B (en) 2021-06-01
CN111471035B (en) 2021-02-26
CN111574442A (en) 2020-08-25
CN111471010A (en) 2020-07-31

Similar Documents

Publication Publication Date Title
KR102445288B1 (en) Synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine
CN111518077B (en) Preparation method of novel anti-tumor IDO inhibitor
ES2859510T3 (en) Pyridazinone fused tricyclic compounds useful for treating orthomyxovirus infections
EP3305769B1 (en) Method for preparation of (7-phenoxy-4-hydroxy-1-methyl-isoquinoline-3-carbonyl)-glycine (roxedustat) and its intermediates based on simultaneous opening of oxazolic ring, fission of ether and creation of imine
KR102073181B1 (en) Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals
CN112608298A (en) Process and intermediates for the preparation of a medicament
CN111471010B (en) Indoleamine-2, 3-dioxygenase (IDO) inhibitors
Charette et al. A new method for the conversion of secondary and tertiary amides to bridged orthoesters
AU2021321905A1 (en) ATR inhibitors and uses thereof
EP3164393A1 (en) Flavagline derivatives
CN111741946B (en) Indoleamine 2, 3-dioxygenase inhibitors and their use in medicine
Goryaeva et al. Reaction of 2-(ethoxymethylidene)-3-oxo carboxylic acid esters with tetrazol-5-amine
WO2010141494A2 (en) Synthesis of ezetimibe
Mikhaylov et al. 3-Halomethylated cyclic nitronates: synthesis and nucleophilic substitution
Luk’yanov et al. 3-Amino-4-(α-nitroalkyl-ONN-azoxy) furazans and some of their derivatives
RU2006141393A (en) 7H-PYRROL [2,3-D] PYRIMIDINE DERIVATIVES, THEIR PHARMACEUTALLY ACCEPTABLE SALTS CONTAINING THEIR PHARMACEUTICAL COMPOSITIONS AND METHOD FOR PRODUCING THEM
US11505534B2 (en) Highly diastereoselective construction of the 4,5-spirocycle via palladium-catalyzed intramolecular alkenylation
ES2761050T3 (en) Substituted heteropentadiene-pyrrolopyrimidine ribonucleosides for therapeutic use
ES2468020T3 (en) Method for producing N-substituted 2-amino-4- (hydroxymethylphosphinyl) -2-butenoic acid
WO2012157504A1 (en) β-LACTAM COMPOUND AND METHOD FOR PRODUCING SAME
Riva et al. A new diversity oriented and metal-free approach to highly functionalized 3 H-pyrimidin-4-ones
CN111747956A (en) Process for preparing tricyclic lactam compounds
AU2020101059A4 (en) Preparation method of indoleamine 2,3-dioxygenase inhibitor
Birnberg et al. The synthesis of 5‐arylpyrrolo [3, 2‐b] pyridines and 7‐arylpyrrolo [3, 2‐b] pyridines: Addition of 3‐aminopyrroles to aryl enaminones
WO2002079185A1 (en) Process for producing (dioxolenon-4-yl)methyl ester derivative

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information
CB02 Change of applicant information

Address after: 311100 Building 8, 1008 Xiangxiang street, Cangqian street, Yuhang District, Hangzhou City, Zhejiang Province

Applicant after: Hangzhou Arnold Biomedical Technology Co.,Ltd.

Address before: 310018 21 / F, building 2, high tech incubator, 452, No.6 street, Qiantang New District, Hangzhou City, Zhejiang Province

Applicant before: Hangzhou Arnold Biomedical Technology Co.,Ltd.

GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20211129

Address after: 361000 floor 3-5, No. 188, Pingcheng South Road, Haicang street, Haicang District, Xiamen City, Fujian Province

Patentee after: Xiamen Baotai Biotechnology Co.,Ltd.

Address before: 311100 Building 8, 1008 Xiangxiang street, Cangqian street, Yuhang District, Hangzhou City, Zhejiang Province

Patentee before: Hangzhou Arnold Biomedical Technology Co.,Ltd.