[go: up one dir, main page]

MA32064B1 - Nouvelles pyridinones et pyridazinones - Google Patents

Nouvelles pyridinones et pyridazinones

Info

Publication number
MA32064B1
MA32064B1 MA33066A MA33066A MA32064B1 MA 32064 B1 MA32064 B1 MA 32064B1 MA 33066 A MA33066 A MA 33066A MA 33066 A MA33066 A MA 33066A MA 32064 B1 MA32064 B1 MA 32064B1
Authority
MA
Morocco
Prior art keywords
phenyl
iii
diseases associated
pyridinones
pyridazinones
Prior art date
Application number
MA33066A
Other languages
Arabic (ar)
English (en)
Inventor
Nolan James Dewdney
Joshua Kennedy-Smith
Rama K Kondru
Bradley E Loe
Yan Lou
Joel Mcintosh
Timothy D Owens
Michael Soth
Zachary Kevin Sweeney
Joshua Paul Gergely Taygerly
Original Assignee
Hoffmann La Roche
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 Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of MA32064B1 publication Critical patent/MA32064B1/fr

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
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention porte sur des dérivés de 5-phényl-1h-pyridin-2-one et de 6-phényl-2h-pyridazin-3-one selon les formules génériques i-iii : dans lesquelles les variables r, x, y1, y2, y3, y4, n et m sont définies comme décrit dans la description, les dérivés inhibant btk. Les composés décrits dans la description sont utiles pour moduler l'activité de btk et traiter des maladies associées à une activité de btk excessive. Les composés sont encore utiles pour traiter des maladies inflammatoires et auto-immunes associées à une prolifération aberrante des lymphocytes b telles que la polyarthrite rhumatoïde. L'invention porte également sur des compositions contenant des composés représentés par les formules i-iii et au moins un support, diluent ou excipient.
MA33066A 2008-02-05 2010-08-06 Nouvelles pyridinones et pyridazinones MA32064B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2620408P 2008-02-05 2008-02-05
US12251008P 2008-12-15 2008-12-15
PCT/EP2009/050875 WO2009098144A1 (fr) 2008-02-05 2009-01-27 Nouvelles pyridinones et pyridazinones

Publications (1)

Publication Number Publication Date
MA32064B1 true MA32064B1 (fr) 2011-02-01

Family

ID=40413736

Family Applications (1)

Application Number Title Priority Date Filing Date
MA33066A MA32064B1 (fr) 2008-02-05 2010-08-06 Nouvelles pyridinones et pyridazinones

Country Status (29)

Country Link
EP (1) EP2242749B1 (fr)
JP (1) JP5259739B2 (fr)
KR (1) KR101308803B1 (fr)
CN (1) CN101932573B (fr)
AR (1) AR070408A1 (fr)
AU (1) AU2009211514B2 (fr)
BR (1) BRPI0907915A2 (fr)
CA (1) CA2710462C (fr)
CL (1) CL2009000229A1 (fr)
CO (1) CO6290767A2 (fr)
CR (1) CR11598A (fr)
CY (1) CY1114114T1 (fr)
DK (1) DK2242749T3 (fr)
EC (1) ECSP10010384A (fr)
ES (1) ES2420846T3 (fr)
HR (1) HRP20130615T1 (fr)
IL (1) IL206357A (fr)
MA (1) MA32064B1 (fr)
MX (1) MX2010008197A (fr)
MY (1) MY158411A (fr)
NZ (1) NZ586916A (fr)
PE (1) PE20091484A1 (fr)
PL (1) PL2242749T3 (fr)
PT (1) PT2242749E (fr)
RU (1) RU2505538C2 (fr)
SI (1) SI2242749T1 (fr)
TW (1) TWI382024B (fr)
WO (1) WO2009098144A1 (fr)
ZA (1) ZA201005539B (fr)

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2728016C (fr) 2008-06-24 2017-02-28 F. Hoffmann-La Roche Ag Nouvelles pyridine-2-ones et pyridazine-3-ones substituees
US8299077B2 (en) * 2009-03-02 2012-10-30 Roche Palo Alto Llc Inhibitors of Bruton's tyrosine kinase
SG175287A1 (en) * 2009-04-24 2011-11-28 Hoffmann La Roche Inhibitors of bruton's tyrosine kinase
EP3461824B1 (fr) 2009-09-04 2021-08-25 Biogen MA Inc. Inhibiteurs de tyrosine kinase de bruton
ES2573716T3 (es) * 2010-05-07 2016-06-09 Gilead Connecticut, Inc. Compuestos de piridona y aza-piridona y métodos de utilización
EP2394998A1 (fr) * 2010-05-31 2011-12-14 Almirall, S.A. Dérivés de 3-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-biphenyl en tant qu'inhibiteurs de la PDE4
AR082590A1 (es) 2010-08-12 2012-12-19 Hoffmann La Roche Inhibidores de la tirosina-quinasa de bruton
KR101585753B1 (ko) * 2011-05-17 2016-01-14 에프. 호프만-라 로슈 아게 브루톤 티로신 키나아제의 억제제
WO2013024078A1 (fr) * 2011-08-17 2013-02-21 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
UA111756C2 (uk) * 2011-11-03 2016-06-10 Ф. Хоффманн-Ля Рош Аг Сполуки гетероарилпіридону та азапіридону як інгібітори тирозинкінази брутона
WO2013148603A1 (fr) 2012-03-27 2013-10-03 Takeda Pharmaceutical Company Limited Dérivés de cinnoline en tant qu'en tant qu'inhibiteurs de la btk
US9822058B2 (en) 2012-04-05 2017-11-21 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
AU2013250726B2 (en) 2012-04-20 2017-01-05 Advinus Therapeutics Limited Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof
AR091273A1 (es) * 2012-06-08 2015-01-21 Biogen Idec Inc Inhibidores de pirimidinil tirosina quinasa
RU2015111133A (ru) * 2012-09-13 2016-11-10 Ф. Хоффманн-Ля Рош Аг Ингибиторы тирозинкиназы брутона
MX2015006162A (es) * 2012-11-16 2015-08-14 Hoffmann La Roche Inhibidores de la tirosina-cinasa de bruton.
CA2891634A1 (fr) * 2012-11-30 2014-06-05 F. Hoffmann-La Roche Ag Inhibiteur de tyrosine kinase de bruton
KR101737724B1 (ko) * 2013-03-05 2017-05-29 에프. 호프만-라 로슈 아게 브루톤 티로신 키나아제의 억제제
EP2964642B1 (fr) * 2013-03-05 2017-11-15 F. Hoffmann-La Roche AG Inhibiteurs de la tyrosine kinase de bruton
JO3377B1 (ar) 2013-03-11 2019-03-13 Takeda Pharmaceuticals Co مشتقات بيريدينيل وبيريدينيل مندمج
EA028756B1 (ru) 2013-04-25 2017-12-29 Бэйджин, Лтд. Конденсированные гетероциклические соединения в качестве ингибиторов протеинкиназы
CN104177338B (zh) * 2013-05-22 2018-04-03 南京勇山生物科技有限公司 一类布鲁顿激酶抑制剂
JP6165977B2 (ja) * 2013-07-03 2017-07-19 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト ヘテロアリールピリドン及びアザ−ピリドンアミド化合物
PT3702373T (pt) 2013-09-13 2022-09-27 Beigene Switzerland Gmbh Anticorpos anti-pd1 e a sua utilização como agentes terapêuticos e de diagnóstico
RU2646758C2 (ru) * 2013-12-05 2018-03-07 Ф. Хоффманн-Ля Рош Аг Гетероарил пиридоны и азапиридоны с электрофильной функциональностью
JP6526189B2 (ja) 2014-07-03 2019-06-05 ベイジーン リミテッド 抗ｐｄ−ｌ１抗体並びにその治療及び診断のための使用
JP6507234B2 (ja) * 2014-10-02 2019-04-24 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ブルトンチロシンキナーゼ（ｂｔｋ）によって介入される障害の処置における使用のためのピラゾールカルボキサミド化合物
JP6916185B2 (ja) * 2016-01-13 2021-08-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｂｔｋ阻害剤としてのイソキノロン類
JP7305352B2 (ja) 2016-03-31 2023-07-10 武田薬品工業株式会社 イソキノリニルトリアゾロン錯体
CN109475536B (zh) 2016-07-05 2022-05-27 百济神州有限公司 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合
US11174243B2 (en) 2016-07-21 2021-11-16 Sunesis Pharmaceuticals, Inc. Succinate forms and compositions of Bruton's tyrosine kinase inhibitors
SG11201901141WA (en) 2016-08-16 2019-03-28 Beigene Ltd Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof
CN118252927A (zh) 2016-08-19 2024-06-28 百济神州有限公司 使用包含btk抑制剂的组合产品治疗癌症
CA3037364A1 (fr) 2016-09-19 2018-03-22 Mei Pharma, Inc. Polytherapie
WO2018137681A1 (fr) 2017-01-25 2018-08-02 Beigene, Ltd. Formes cristallines de (s) -7- (1- (but-2-ynoyl) pipéridin-4-yl) -2- (4-phénoxyphényl) -4, 5, 6, 7-tétrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, préparation et utilisations associées
CN106967073A (zh) * 2017-04-24 2017-07-21 刘双伟 一种治疗类风湿性关节炎的药物
CN106946891B (zh) * 2017-05-08 2018-07-13 宿州市徽腾知识产权咨询有限公司 一种用于治疗类风湿性关节炎的药物
JP2020525411A (ja) 2017-06-26 2020-08-27 ベイジーン リミテッド 肝細胞癌のための免疫療法
WO2019034009A1 (fr) 2017-08-12 2019-02-21 Beigene, Ltd. Inhibiteur de btk ayant une double sélectivité améliorée
WO2019108795A1 (fr) 2017-11-29 2019-06-06 Beigene Switzerland Gmbh Traitement de lymphomes à cellules b indolentes ou agressives au moyen d'une combinaison comprenant des inhibiteurs de btk
BR122023024103A2 (pt) 2018-10-15 2024-02-20 Nurix Therapeutics, Inc. Compostos bifuncionais para degradação de btk por meio da via de proteossoma de ubiquitina, composição farmacêutica compreendendo os mesmos, e seus usos
JP2022526713A (ja) 2019-03-21 2022-05-26 オンクセオ がんの処置のための、キナーゼ阻害剤と組み合わせたＤｂａｉｔ分子
WO2020210508A1 (fr) 2019-04-09 2020-10-15 Nurix Therapeutics, Inc. Composés de pipéridine substitués en position 3 pour l'inhibition de cbl-b, et utilisation d'un inhibiteur de cbl-b en combinaison avec un vaccin contre le cancer et/ou un virus oncolytique
US11530229B2 (en) 2019-05-17 2022-12-20 Nurix Therapeutics, Inc. Cyano cyclobutyl compounds for CBL-B inhibition and uses thereof
US20220249491A1 (en) 2019-06-10 2022-08-11 Beigene Switzerland Gmbh Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor
US11401267B2 (en) 2019-06-26 2022-08-02 Nurix Therapeutics, Inc. Substituted benzyl-triazole compounds for Cbl-b inhibition, and further uses thereof
KR20220098759A (ko) 2019-11-08 2022-07-12 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) 키나제 억제제에 대해 내성을 획득한 암의 치료 방법
EP4055019B1 (fr) * 2019-11-08 2025-01-22 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
WO2021113557A1 (fr) 2019-12-04 2021-06-10 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de la btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
US12016860B2 (en) 2021-04-08 2024-06-25 Nurix Therapeutics, Inc. Combination therapies with Cbl-b inhibitor compounds
CA3236073A1 (fr) 2021-10-26 2023-05-04 Robert J. Brown Composes de piperidinylpyrazine-carboxamide pour le traitement et la prevention du cancer et pour la degradation de btk
US11786531B1 (en) 2022-06-08 2023-10-17 Beigene Switzerland Gmbh Methods of treating B-cell proliferative disorder

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3951395B2 (ja) * 1996-12-13 2007-08-01 田辺製薬株式会社 ピリジン誘導体、その製法及びその合成中間体
ID30176A (id) * 1999-03-12 2001-11-08 Boehringer Ingelheim Pharma Senyawa-senyawa yang bermanfaat sebagai zat anti-inflamasi
ES2232306B1 (es) * 2003-11-10 2006-08-01 Almirall Prodesfarma, S.A. Nuevos derivados de piridazin-3(2h)-ona.
US8101770B2 (en) * 2004-12-16 2012-01-24 Vertex Pharmaceuticals Incorporated Pyridones useful as inhibitors of kinases
RU2396259C2 (ru) * 2004-12-24 2010-08-10 Астразенека Аб Амидные производные
TW200716551A (en) * 2005-03-10 2007-05-01 Cgi Pharmaceuticals Inc Certain substituted amides, method of making, and method of use thereof
WO2006124731A2 (fr) * 2005-05-12 2006-11-23 Irm Llc Composes et compositions utilise(e)s en tant qu'inhibiteurs de proteines-kinases
ES2351939T3 (es) * 2005-08-09 2011-02-14 Irm Llc Compuestos y composiciones como inhibidores de proteínas cinasas.
ATE548363T1 (de) * 2005-08-29 2012-03-15 Vertex Pharma 3,5-disubstituierte pyrid-2-one, die sich als inhibitoren der tec-familie von nicht-rezeptor- tyrosinkinasen eignen
BRPI0711628A2 (pt) * 2006-05-15 2011-12-06 Irm Llc composto, composição farmacêutica, uso e processo para preparação do composto

Also Published As

Publication number Publication date
MY158411A (en) 2016-10-14
PL2242749T3 (pl) 2013-09-30
TW200938538A (en) 2009-09-16
CO6290767A2 (es) 2011-06-20
AU2009211514A1 (en) 2009-08-13
AU2009211514B2 (en) 2014-02-20
RU2505538C2 (ru) 2014-01-27
HRP20130615T1 (en) 2013-08-31
HK1146826A1 (en) 2011-07-15
ES2420846T3 (es) 2013-08-27
IL206357A0 (en) 2010-12-30
PE20091484A1 (es) 2009-10-03
RU2010136665A (ru) 2012-03-20
TWI382024B (zh) 2013-01-11
ECSP10010384A (es) 2010-09-30
EP2242749A1 (fr) 2010-10-27
NZ586916A (en) 2012-06-29
CA2710462A1 (fr) 2009-08-13
MX2010008197A (es) 2010-08-23
CN101932573B (zh) 2014-06-11
CA2710462C (fr) 2015-11-24
JP2011511027A (ja) 2011-04-07
CN101932573A (zh) 2010-12-29
CY1114114T1 (el) 2016-07-27
CR11598A (es) 2010-10-27
ZA201005539B (en) 2011-04-28
KR20100093130A (ko) 2010-08-24
AR070408A1 (es) 2010-04-07
CL2009000229A1 (es) 2010-06-04
KR101308803B1 (ko) 2013-09-13
DK2242749T3 (da) 2013-06-17
IL206357A (en) 2013-12-31
BRPI0907915A2 (pt) 2015-07-28
JP5259739B2 (ja) 2013-08-07
EP2242749B1 (fr) 2013-04-10
PT2242749E (pt) 2013-07-16
SI2242749T1 (sl) 2013-07-31
WO2009098144A1 (fr) 2009-08-13

Similar Documents

Publication Publication Date Title
MA32064B1 (fr) Nouvelles pyridinones et pyridazinones
MA32487B1 (fr) Nouvelles pyridine-2-ones et pyridazine-3-ones substituees
MA34465B1 (fr) Inhibiteurs de tyrosine kinase de bruton
MA35112B1 (fr) Inhibiteurs de tyrosine kinase de bruton
MA35419B1 (fr) Inhibiteurs de la tyrosine kinase de bruton
MA29140B1 (fr) Dérivés de quinoléine hétéroaromatiques et leur utilisation comme inhibiteurs de PDE10
TNSN06369A1 (fr) Derives de tetrahydronaphtyridine utiles comme ligands du recepteur d'histamine h3
MA33178B1 (fr) Pipéridines substituées comme antagonistes de ccr3
TN2009000112A1 (fr) Derives de sulfonamides servant d'agonistes adrenergiques et d'antagonistes muscariniques
MA31763B1 (fr) Inhibiteurs de kinase de type polo
MA29335B1 (fr) Derives de n-(n-sulfonylaminomethyl) cyclopropanecarboxamide utiles pour le traitement de la douleur
TNSN07248A1 (fr) Derive de pyrrolidyle de composes heteroaromatiques servant d'inhibiteurs de phosphodiesterases
TNSN08359A1 (fr) Derives d'amines
ATE513828T1 (de) Phenyl-ä3-ä3-(1h-pyrrol-2-yl)-ä1,2,4üoxadiazol- - ylüpiperidin-1-ylü-methanon-derivate und verwandte verbindungen als positive allosterische modulatoren metabotroper glutamatrezeptoren
EA017914B8 (ru) 1,4-ДВУЗАМЕЩЕННЫЕ 3-ЦИАНОПИРИДОНОВЫЕ ПРОИЗВОДНЫЕ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ПОЗИТИВНЫХ МОДУЛЯТОРОВ РЕЦЕПТОРОВ mGluR2
UA87856C2 (ru) Алкильные производные как модуляторы метаботропных рецепторов глутамата
TNSN06358A1 (fr) Methyl-aryl-ou-heteroaryl-amides substitues
TW200634016A (en) Novel thieno-pyridine and thieno-pyrimidine derivatives and their use as positive allosteric modulators of mglur2-receptors
MA28269A1 (fr) Arylpyrazoles substitués servant d'agents parasiticides
MA31766B1 (fr) Composés organiques
TW200633982A (en) Novel pyridinone derivatives and their use as positive allosteric modulators of mglur2-receptors
ATE423769T1 (de) Fluor- und sulfonylaminohaltige, 3,6- disubstituierte azabicyclo 3.1.0 hexanderivate als muscarinrezeptorantagonisten
MA27926A1 (fr) Derives de quinoline et de quinazoline presentant une affinite vis-a-vis des recepteurs du type 5ht1
MA27452A1 (fr) Derives d'indole servant d'agonistes beta-2
ATE427992T1 (de) Dna-synthesepromotoren, mit dna-polymerase assoziierte faktoren und nutzung davon