AR123788A1 - Proteínas de fusión que comprenden enzimas sulfoglucosamina sulfohidrolasa y métodos de estas - Google Patents

Proteínas de fusión que comprenden enzimas sulfoglucosamina sulfohidrolasa y métodos de estas

Info

Publication number
AR123788A1
AR123788A1 ARP210102838A ARP210102838A AR123788A1 AR 123788 A1 AR123788 A1 AR 123788A1 AR P210102838 A ARP210102838 A AR P210102838A AR P210102838 A ARP210102838 A AR P210102838A AR 123788 A1 AR123788 A1 AR 123788A1
Authority
AR
Argentina
Prior art keywords
polypeptide
acid sequence
amino acid
sgsh
catalytically active
Prior art date
Application number
ARP210102838A
Other languages
English (en)
Spanish (es)
Inventor
Tina Giese
Gunasekaran Kannan
Mihalis Kariolis
Cathal Mahon
Original Assignee
Denali Therapeutics Inc
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 Denali Therapeutics Inc filed Critical Denali Therapeutics Inc
Publication of AR123788A1 publication Critical patent/AR123788A1/es

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2881Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD71
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62DNA sequences coding for fusion proteins
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y310/00Hydrolases acting on sulfur-nitrogen bonds (3.10)
    • C12Y310/01Hydrolases acting on sulfur-nitrogen bonds (3.10) acting on sulfur-nitrogen bonds (3.10.1)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y310/00Hydrolases acting on sulfur-nitrogen bonds (3.10)
    • C12Y310/01Hydrolases acting on sulfur-nitrogen bonds (3.10) acting on sulfur-nitrogen bonds (3.10.1)
    • C12Y310/01001N-Sulfoglucosamine sulfohydrolase (3.10.1.1)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/40Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41Glycosylation, sialylation, or fucosylation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/30Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
ARP210102838A 2020-10-14 2021-10-14 Proteínas de fusión que comprenden enzimas sulfoglucosamina sulfohidrolasa y métodos de estas AR123788A1 (es)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US202063091800P 2020-10-14 2020-10-14

Publications (1)

Publication Number Publication Date
AR123788A1 true AR123788A1 (es) 2023-01-11

Family

ID=78725609

Family Applications (1)

Application Number Title Priority Date Filing Date
ARP210102838A AR123788A1 (es) 2020-10-14 2021-10-14 Proteínas de fusión que comprenden enzimas sulfoglucosamina sulfohidrolasa y métodos de estas

Country Status (18)

Country Link
US (2) US11884944B2 (https=)
EP (1) EP4229192A1 (https=)
JP (1) JP2023545707A (https=)
KR (1) KR20230086703A (https=)
CN (1) CN116916947A (https=)
AR (1) AR123788A1 (https=)
AU (1) AU2021362209B2 (https=)
CA (1) CA3197506A1 (https=)
CL (1) CL2023001034A1 (https=)
CO (1) CO2023005260A2 (https=)
CR (1) CR20230178A (https=)
EC (1) ECSP23035251A (https=)
IL (1) IL302029A (https=)
MA (1) MA71661A (https=)
MX (1) MX2023004335A (https=)
PE (1) PE20231931A1 (https=)
TW (1) TW202229547A (https=)
WO (1) WO2022081765A1 (https=)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110506055A (zh) 2017-02-17 2019-11-26 戴纳立制药公司 工程改造的转铁蛋白受体结合多肽
CR20200129A (es) 2017-10-02 2020-08-22 Denali Therapeutics Inc Proteínas de fusión que comprenden enzimas de terapia de reemplazo de enzimas
BR112021015656A2 (pt) 2019-02-20 2021-10-05 Denali Therapeutics Inc. Anticorpos anti-trem2 e métodos de uso dos mesmos
PH12022551598A1 (en) 2019-12-23 2023-11-20 Denali Therapeutics Inc Progranulin variants
TW202542190A (zh) 2023-12-20 2025-11-01 美商戴納立製藥公司 包含酸性α—葡萄糖苷酶之融合蛋白及其方法

Family Cites Families (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5863782A (en) 1995-04-19 1999-01-26 Women's And Children's Hospital Synthetic mammalian sulphamidase and genetic sequences encoding same
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
WO2003057179A2 (en) 2002-01-11 2003-07-17 Biomarin Pharmaceutical, Inc. Use of p97 as an enzyme delivery system for the delivery of therapeutic lysosomal enzymes
US20050142141A1 (en) 2002-11-27 2005-06-30 Pardridge William M. Delivery of enzymes to the brain
AU2003286870A1 (en) 2003-06-05 2005-01-04 Salk Institute For Biological Studies Targeting polypeptides to the central nervous system
CA2711590C (en) 2008-01-18 2021-03-23 Biomarin Pharmaceutical Inc. Manufacture of active highly phosphorylated human lysosomal sulfatase enzymes and uses thereof
EP2394667A1 (en) 2010-06-10 2011-12-14 Laboratorios Del Dr. Esteve, S.A. Vectors and sequences for the treatment of diseases
PT3103469T (pt) 2010-06-25 2021-03-04 Shire Human Genetic Therapies Administração de agentes terapêuticos no snc
JP6073783B2 (ja) 2010-06-25 2017-02-01 シャイアー ヒューマン ジェネティック セラピーズ インコーポレイテッド ヘパランn−スルファターゼのcns送達のための方法および組成物
ES2692268T5 (en) 2011-03-29 2025-02-26 Roche Glycart Ag Antibody fc variants
AU2012294673B2 (en) 2011-08-05 2015-11-26 Bioasis Technologies Inc. p97 fragments with transfer activity
CA3140358A1 (en) 2012-07-31 2014-02-06 Bioasis Technologies, Inc. Dephosphorylated lysosomal storage disease proteins and methods of use thereof
HUE045144T2 (hu) 2012-08-29 2019-12-30 Hoffmann La Roche Véragygát-shuttle
AU2014243816B2 (en) 2013-03-13 2019-01-31 Bioasis Technologies Inc. Fragments of p97 and uses thereof
EP2970940B1 (en) 2013-03-14 2018-07-25 Translate Bio, Inc. Mrna therapeutic compositions and use to treat diseases and disorders
JP6692293B2 (ja) 2013-07-22 2020-05-13 アーマジェン・インコーポレイテッドArmagen, Inc. Cnsにおける酵素活性を増大するための方法および組成物
SI2970413T1 (sl) 2014-04-01 2018-10-30 Swedish Orphan Biovitrum Ab (Publ) Modificirana sulfamidaza in proizvodja le-te
DK3215528T3 (da) 2014-11-06 2019-10-07 Hoffmann La Roche Fc-regionvarianter med modificeret FcRn-binding og anvendelsesfremgangsmåder
WO2016081640A1 (en) 2014-11-19 2016-05-26 Genentech, Inc. Anti-transferrin receptor / anti-bace1 multispecific antibodies and methods of use
EA039366B1 (ru) 2015-06-24 2022-01-19 Джей Си Ар ФАРМАСЬЮТИКАЛЗ КО., ЛТД. Антитело к рецептору трансферрина человека, проникающее через гематоэнцефалический барьер
HUE057952T2 (hu) 2015-06-24 2022-06-28 Hoffmann La Roche Anti-transzferrin receptor antitestek testreszabott affinitással
DK3386534T3 (da) 2015-12-08 2020-11-30 Regeneron Pharma Sammensætninger og fremgangsmåder til internalisering af enzymer
AR107483A1 (es) 2016-01-29 2018-05-02 Hanmi Pharm Ind Co Ltd Conjugado de enzimas terapéuticas
MX2018010196A (es) 2016-02-24 2018-11-19 Biomarin Pharm Inc Proteinas de fusion de enzimas lisosomales terapeuticas dirigidas, formulaciones asociadas y usos de las mismas.
EP3494216B1 (en) 2016-08-06 2025-10-15 Ossianix, Inc. In vivo methods for selecting peptides that cross the blood brain barrier, related compositions and methods of use
SG11201901495YA (en) 2016-08-25 2019-03-28 Jcr Pharmaceuticals Co Ltd Method for producing antibody fusion protein
US20190352335A1 (en) 2016-12-19 2019-11-21 Hanmi Pharm. Co., Ltd. Brain targeting long-acting protein conjugate
KR102497564B1 (ko) 2016-12-26 2023-02-07 제이씨알 파마 가부시키가이샤 혈액뇌관문을 통과하는 신규한 항인간 트랜스페린 수용체 항체
AU2017386888B2 (en) 2016-12-28 2024-08-08 Jcr Pharmaceuticals Co., Ltd. Lyophilized preparation
WO2018152285A1 (en) 2017-02-17 2018-08-23 Denali Therapeutics Inc. Transferrin receptor transgenic models
CN110506055A (zh) 2017-02-17 2019-11-26 戴纳立制药公司 工程改造的转铁蛋白受体结合多肽
SG11201907422RA (en) 2017-02-17 2019-09-27 Denali Therapeutics Inc Anti-tau antibodies and methods of use thereof
GB201702863D0 (en) 2017-02-22 2017-04-05 Evox Therapeutics Ltd Improved loading of EVs with therapeutic proteins
AU2018295994B2 (en) 2017-07-07 2025-02-06 Hanmi Pharm. Co., Ltd. Novel therapeutic enzyme fusion protein and use thereof
EP3665194A4 (en) 2017-08-10 2021-07-07 Denali Therapeutics Inc. AFFINITY BASED METHODS OF USING TRANSFERRIN RECEPTOR BINDING PROTEINS
CR20200129A (es) 2017-10-02 2020-08-22 Denali Therapeutics Inc Proteínas de fusión que comprenden enzimas de terapia de reemplazo de enzimas
WO2019094608A1 (en) 2017-11-08 2019-05-16 Denali Therapeutics Inc. Anti-bace1 antibodies and methods of use thereof
CN111511910B (zh) 2017-12-22 2024-11-08 韩美药品株式会社 具有新颖结构的治疗酶融合蛋白及其用途
TW201934573A (zh) 2018-01-10 2019-09-01 美商戴納立製藥公司 轉鐵蛋白受體結合性多肽及其用途
WO2019145500A1 (en) 2018-01-26 2019-08-01 Swedish Orphan Biovitrum Ab (Publ) Method of treatment
JP7337099B2 (ja) * 2018-05-25 2023-09-01 アレクトル エルエルシー 抗sirpa抗体およびその使用法
WO2019246071A1 (en) 2018-06-18 2019-12-26 Denali Therapeutics Inc. Fusion proteins comprising progranulin
WO2020037150A2 (en) 2018-08-16 2020-02-20 Denali Therapeutics Inc. Engineered bispecific proteins
JP2021534220A (ja) 2018-08-22 2021-12-09 デナリ セラピューティクス インコーポレイテッドDenali Therapeutics Inc. 抗her2ポリペプチド及びそれらの使用の方法
CR20210155A (es) * 2018-08-31 2021-05-10 Alector Llc Anticuerpos anti-cd33 y métodos para usarlos
CA3134538A1 (en) 2019-04-03 2020-10-08 Denali Therapeutics Inc. Formulations of protein molecules comprising iduronate 2-sulfatase
WO2021133907A1 (en) 2019-12-23 2021-07-01 Denali Therapeutics Inc. Progranulin variants
PH12022551598A1 (en) 2019-12-23 2023-11-20 Denali Therapeutics Inc Progranulin variants
WO2021146256A1 (en) 2020-01-13 2021-07-22 Denali Therapeutics Inc. Anti-trem2 antibodies and methods of use thereof
JP2023512450A (ja) 2020-01-13 2023-03-27 デナリ セラピューティクス インコーポレイテッド 抗trem2抗体及びその使用方法
WO2021158986A1 (en) 2020-02-07 2021-08-12 Denali Therapeutics Inc. Methods for the treatment of hunter syndrome
AU2021224200A1 (en) 2020-02-19 2022-09-08 Denali Therapeutics Inc. Engineered anti-HER2 bispecific proteins

Also Published As

Publication number Publication date
IL302029A (en) 2023-06-01
MX2023004335A (es) 2023-05-04
MA71661A (fr) 2025-05-30
TW202229547A (zh) 2022-08-01
AU2021362209B2 (en) 2026-02-12
CN116916947A (zh) 2023-10-20
US11884944B2 (en) 2024-01-30
JP2023545707A (ja) 2023-10-31
CR20230178A (es) 2023-07-26
WO2022081765A1 (en) 2022-04-21
US20240150736A1 (en) 2024-05-09
AU2021362209A1 (en) 2023-05-18
US20230062800A1 (en) 2023-03-02
EP4229192A1 (en) 2023-08-23
KR20230086703A (ko) 2023-06-15
ECSP23035251A (es) 2023-10-31
CL2023001034A1 (es) 2023-10-06
CA3197506A1 (en) 2022-04-21
CO2023005260A2 (es) 2023-05-19
PE20231931A1 (es) 2023-12-01

Similar Documents

Publication Publication Date Title
AR123788A1 (es) Proteínas de fusión que comprenden enzimas sulfoglucosamina sulfohidrolasa y métodos de estas
JP5232021B2 (ja) Peg化変異クロストリジウム・ボツリヌム毒素
US11229694B2 (en) Vaccine against RSV
MX2024015050A (es) L-asparaginasa modificada
CL2021000550A1 (es) Péptido asociado a tumor (tumap); ácido nucleico; vector de expresión; célula hospedadora recombinante que comprende el péptido; método para producir el péptido; composición farmaceutica; uso para preparar un medicamento útil para tratar el cáncer; kit farmacéutico (divisional de la solicitud no. 201900460)
US11274141B2 (en) Enveloped virus resistant to complement inactivation for the treatment of cancer
AR107020A2 (es) Vacuna de pcsk9 (proteína convertasa subtilisina-kexina tipo 9)
CN101184770A (zh) 用于靶向神经细胞的载体
AR087091A1 (es) Polipeptidos quimericos e hibridos del factor viii, y sus metodos de uso
DE69834824D1 (de) Nukleinsäure, welche einen von lektin abstammenden faktor zur präservierung von progenitorzellen kodiert
RU2013112616A (ru) Пептид cdca1 и включающее его фармацевтическое средство
CN107438670A (zh) 嵌合多肽
AR123187A1 (es) Vacuna de múltiples epítopos para el tratamiento de la enfermedad de alzheimer
CL2009001249A1 (es) Uso de una enzima pectonilitica endopoligalacturonasa para tratar pure de frutas o verduras; procedimiento para tratamiento enzimatico; molecula de adn que codifica un polipeptido con actividad endopoligalacturonasa; polipeptido, vector de expresion y celula huesped que comprende dicha secuencia.
Portaro et al. The Mycobacterium leprae hsp65 displays proteolytic activity. Mutagenesis studies indicate that the M. leprae hsp65 proteolytic activity is catalytically related to the HslVU protease
CA2692358A1 (en) Recombinant human interferon-like proteins
WO2022032140A3 (en) Vesicle targeting proteins and uses of same
JP2017513849A5 (https=)
MX2022007546A (es) Interferon-alfa-2 modificado que tiene inmunogenicidad reducida.
AR126877A1 (es) PARTÍCULAS DE AAV QUE COMPRENDEN UNA PROTEÍNA DE LA CÁPSIDE HEPATOTRÓPICA Y a-GLUCOSIDASA ÁCIDA (GAA) Y SU USO PARA TRATAR LA ENFERMEDAD DE POMPE
JP2021525711A5 (https=)
Choi et al. Construction and characterization of cell-penetrating peptide-fused fibroblast growth factor and vascular endothelial growth factor for an enhanced percutaneous delivery system
AR128003A1 (es) PROTEÍNAS DE FUSIÓN QUE COMPRENDEN ENZIMAS DE a-L-IDURONIDASA Y MÉTODOS PARA LAS MISMAS
AR132194A1 (es) PROTEÍNAS DIRIGIDAS A Ab Y MÉTODOS DE USO
CN107365784A (zh) 一种用于递送至中枢神经系统的融合蛋白及合成方法