ATE542823T1 - 4,5-dihydro-ä1,2,4ütriazoloä4,3-füpteridine als plk1-proteinkinasehemmer zur behandlung proliferativer erkrankungen - Google Patents

4,5-dihydro-ä1,2,4ütriazoloä4,3-füpteridine als plk1-proteinkinasehemmer zur behandlung proliferativer erkrankungen

Info

Publication number: ATE542823T1
Authority: AT; Austria
Prior art keywords: füpteridine; dihydro; treatment; protein kinase; kinase inhibitor
Prior art date: 2006-04-12

Application number

AT07755318T

Other languages

English (en)

Inventor

Jean-Damien Charrier

David Kay

Ronald Knegtel

Original Assignee

Vertex Pharma

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.)

2006-04-12

Filing date

2007-04-12

Publication date

2012-02-15

2007-04-12 Application filed by Vertex Pharma filed Critical Vertex Pharma

2012-02-15 Application granted granted Critical

2012-02-15 Publication of ATE542823T1 publication Critical patent/ATE542823T1/de

Links

102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 title 1
201000010099 disease Diseases 0.000 title 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
229940043355 kinase inhibitor Drugs 0.000 title 1
108010056274 polo-like kinase 1 Proteins 0.000 title 1
230000002062 proliferating effect Effects 0.000 title 1
239000003909 protein kinase inhibitor Substances 0.000 title 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
- 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
- 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
- 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
- A61P37/08—Antiallergic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Immunology (AREA)
Diabetes (AREA)
Hematology (AREA)
Neurology (AREA)
Pulmonology (AREA)
Neurosurgery (AREA)
Biomedical Technology (AREA)
Obesity (AREA)
Physical Education & Sports Medicine (AREA)
Rheumatology (AREA)
Endocrinology (AREA)
Oncology (AREA)
Cardiology (AREA)
Transplantation (AREA)
Hospice & Palliative Care (AREA)
Heart & Thoracic Surgery (AREA)
Virology (AREA)
Psychiatry (AREA)
Pain & Pain Management (AREA)
Emergency Medicine (AREA)
Orthopedic Medicine & Surgery (AREA)
Communicable Diseases (AREA)
Gastroenterology & Hepatology (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

AT07755318T 2006-04-12 2007-04-12 4,5-dihydro-ä1,2,4ütriazoloä4,3-füpteridine als plk1-proteinkinasehemmer zur behandlung proliferativer erkrankungen ATE542823T1 (de)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US79132706P	2006-04-12	2006-04-12
US83872006P	2006-08-18	2006-08-18
PCT/US2007/009006 WO2007120752A2 (en)	2006-04-12	2007-04-12	4, 5-dihydro- [1, 2, 4] triazolo [4, 3-f] pteridines as protein kinase plk1 inhibitors for the treatment of proliferative disorders

Publications (1)

Publication Number	Publication Date
ATE542823T1 true ATE542823T1 (de)	2012-02-15

Family

ID=38544378

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
AT07755318T ATE542823T1 (de)	2006-04-12	2007-04-12	4,5-dihydro-ä1,2,4ütriazoloä4,3-füpteridine als plk1-proteinkinasehemmer zur behandlung proliferativer erkrankungen

Country Status (16)

Country	Link
US (3)	US7763629B2 (de)
EP (1)	EP2010542B1 (de)
JP (1)	JP5313875B2 (de)
KR (1)	KR101432316B1 (de)
AR (1)	AR060432A1 (de)
AT (1)	ATE542823T1 (de)
AU (1)	AU2007238690B2 (de)
CA (1)	CA2649324A1 (de)
ES (1)	ES2381212T3 (de)
IL (1)	IL194699A (de)
MX (1)	MX2008013110A (de)
NO (1)	NO20084747L (de)
NZ (1)	NZ571969A (de)
RU (1)	RU2441006C2 (de)
TW (1)	TW200808805A (de)
WO (1)	WO2007120752A2 (de)

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AU2008287339A1 (en) *	2007-08-15	2009-02-19	Vertex Pharmaceuticals Incorporated	4-(9-(3, 3-difluorocyclopentyl) -5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-b][1, 4] diazepin-2-ylamino)-3-methoxybenzamide Derivatives as Inhibitors of the Human Protein Kinases PLK1 to PLK4 for the Treatment of Proliferative Diseases
EA201001030A1 (ru)	2007-12-19	2011-02-28	Амген Инк.	Конденсированные соединения пиридина, пиримидина и триазина в качестве ингибиторов клеточного цикла
US8389533B2 (en)	2008-04-07	2013-03-05	Amgen Inc.	Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors
MX2011000021A (es) *	2008-06-23	2011-02-24	Vertex Pharma	Inhibidores de proteina cinasas.
AU2009271658B2 (en) *	2008-06-23	2014-04-10	Vertex Pharmaceuticals Incorporated	Protein kinase inhibitors
CN102548994A (zh)	2009-09-25	2012-07-04	沃泰克斯药物股份有限公司	用于制备用作蛋白激酶抑制剂的嘧啶衍生物的方法
CN103492391A (zh) *	2009-09-25	2014-01-01	沃泰克斯药物股份有限公司	用于制备用作蛋白激酶抑制剂的嘧啶衍生物的方法
RU2012131124A (ru)	2009-12-23	2014-01-27	Элан Фармасьютикалз, Инк.	Птеридиноны как ингибиторы polo-подобных киназ
WO2011099502A1 (ja) *	2010-02-10	2011-08-18	公立大学法人横浜市立大学	神経選択的転写抑制因子NRSFに特異的に結合するmSin3B に結合する化合物の利用
ES2706066T3 (es)	2010-07-02	2019-03-27	Univ Health Network	Procedimiento dirigido a enfermedades mutantes con PTEN y composiciones para las mismas
CN103403010A (zh) *	2010-10-08	2013-11-20	依兰制药公司	Polo样激酶的抑制剂
WO2012061342A2 (en)	2010-11-01	2012-05-10	Arqule, Inc.	Substituted benzo-imidazo-pyrido-diazepine compounds
EP2937349B1 (de)	2011-03-23	2016-12-28	Amgen Inc.	Fusionierte tricyclische duale inhibitoren von cdk 4/6 und flt3
MD4300C1 (ro) *	2012-12-28	2015-03-31	Государственный Университет Молд0	Inhibitor al proliferării celulelor HepG2 în cancerul hepatic în bază de cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]nichel
US9840503B2 (en)	2015-05-11	2017-12-12	Incyte Corporation	Heterocyclic compounds and uses thereof
US9708333B2 (en)	2015-08-12	2017-07-18	Incyte Corporation	Fused bicyclic 1,2,4-triazine compounds as TAM inhibitors
WO2017035366A1 (en)	2015-08-26	2017-03-02	Incyte Corporation	Pyrrolopyrimidine derivatives as tam inhibitors
KR102483020B1 (ko)	2016-03-28	2023-01-04	인사이트 코포레이션	Tam 저해제로서의 피롤로트리아진 화합물
MA50655B1 (fr)	2017-09-27	2021-11-30	Incyte Corp	Sels de dérivés de pyrrolotriazine utiles en tant qu'inhibiteurs de tam
AR117600A1 (es)	2018-06-29	2021-08-18	Incyte Corp	Formulaciones de un inhibidor de axl / mer
CN109734809A (zh) *	2019-02-27	2019-05-10	南方科技大学	治疗性的人Plk1蛋白单克隆抗体及其制备方法
WO2021178779A1 (en)	2020-03-06	2021-09-10	Incyte Corporation	Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors
CN121537408A (zh)	2021-02-08	2026-02-17	上海复星医药产业发展有限公司	5，6-二氢噻吩并[3，4-h]喹唑啉类化合物
PE20240894A1 (es) *	2021-08-10	2024-04-24	Uppthera Inc	Compuesto inductor de la degradacion de plk1 novedoso

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WO2002076985A1 (en) *	2001-03-23	2002-10-03	Smithkline Beecham Corporation	Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases
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2007
- 2007-04-12 AU AU2007238690A patent/AU2007238690B2/en not_active Ceased
- 2007-04-12 NZ NZ571969A patent/NZ571969A/en not_active IP Right Cessation
- 2007-04-12 EP EP07755318A patent/EP2010542B1/de not_active Not-in-force
- 2007-04-12 US US11/786,578 patent/US7763629B2/en not_active Expired - Fee Related
- 2007-04-12 AR ARP070101560A patent/AR060432A1/es unknown
- 2007-04-12 KR KR1020087027593A patent/KR101432316B1/ko not_active Expired - Fee Related
- 2007-04-12 JP JP2009505472A patent/JP5313875B2/ja not_active Expired - Fee Related
- 2007-04-12 ES ES07755318T patent/ES2381212T3/es active Active
- 2007-04-12 WO PCT/US2007/009006 patent/WO2007120752A2/en not_active Ceased
- 2007-04-12 MX MX2008013110A patent/MX2008013110A/es active IP Right Grant
- 2007-04-12 CA CA002649324A patent/CA2649324A1/en not_active Abandoned
- 2007-04-12 RU RU2008144584/04A patent/RU2441006C2/ru not_active IP Right Cessation
- 2007-04-12 AT AT07755318T patent/ATE542823T1/de active
- 2007-04-12 TW TW096112918A patent/TW200808805A/zh unknown
2008
- 2008-10-12 IL IL194699A patent/IL194699A/en not_active IP Right Cessation
- 2008-11-10 NO NO20084747A patent/NO20084747L/no not_active Application Discontinuation
2010
- 2010-06-08 US US12/796,174 patent/US8067417B2/en not_active Expired - Fee Related
2011
- 2011-10-05 US US13/253,196 patent/US8524902B2/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
US8067417B2 (en)	2011-11-29
WO2007120752A3 (en)	2008-05-08
NZ571969A (en)	2011-10-28
AU2007238690B2 (en)	2013-05-02
CA2649324A1 (en)	2007-10-25
EP2010542B1 (de)	2012-01-25
AR060432A1 (es)	2008-06-18
ES2381212T3 (es)	2012-05-24
MX2008013110A (es)	2009-03-06
WO2007120752A2 (en)	2007-10-25
JP5313875B2 (ja)	2013-10-09
RU2441006C2 (ru)	2012-01-27
US20110021519A1 (en)	2011-01-27
NO20084747L (no)	2008-11-25
US20120277425A1 (en)	2012-11-01
US20090062292A1 (en)	2009-03-05
KR101432316B1 (ko)	2014-08-29
IL194699A (en)	2014-07-31
KR20080109919A (ko)	2008-12-17
HK1134486A1 (en)	2010-04-30
IL194699A0 (en)	2009-08-03
EP2010542A2 (de)	2009-01-07
US7763629B2 (en)	2010-07-27
US8524902B2 (en)	2013-09-03
TW200808805A (en)	2008-02-16
RU2008144584A (ru)	2010-05-20
AU2007238690A1 (en)	2007-10-25
JP2009536155A (ja)	2009-10-08

Publication	Publication Date	Title
ATE542823T1 (de)	2012-02-15	4,5-dihydro-ä1,2,4ütriazoloä4,3-füpteridine als plk1-proteinkinasehemmer zur behandlung proliferativer erkrankungen
DE602007004092D1 (de)	2010-02-11	C-met-proteinkinasehemmer zur behandlung proliferativer erkrankungen
IL284991A (en)	2021-08-31	Antibodies against cd38 for treatment of multiple myeloma
ATE434620T1 (de)	2009-07-15	Dihydrothienopyrimidine zur behandlung von entzündlichen erkrankungen
BRPI0716844A2 (pt)	2013-10-22	Inidores de quinase úteis para o tratamento de doenças proliferativas
ATE550338T1 (de)	2012-04-15	Spiropiperidininhibitoren von beta-secretase zur behandlung von alzheimer-krankheit
NO20083002L (no)	2008-08-14	Fremgangsmate for anvendelse av CD40-bindende forbindelser
DE602005007717D1 (de)	2008-08-07	Imidazolverbindungen zur behandlung von neurodegenerativen erkrankungen
EP2063897A4 (de)	2010-09-29	Kinasehemmer zur behandlung proliferativer krankheiten
DE602005023172D1 (de)	2010-10-07	Hydantoinderivate zur behandlung von entzündlichen erkrankungen
ATE534633T1 (de)	2011-12-15	Indazolderivate zur behandlung von hsp90- induzierten krankheiten
ATE557021T1 (de)	2012-05-15	Zur behandlung von erkrankungen des zns geeignete derivate des 4-piperazin-1-yl-4-benzoäbüthiophens
ATE527241T1 (de)	2011-10-15	Pyridiazinonderivate zur behandlung von tumoren
DE602006019560D1 (de)	2011-02-24	2-cyanobenzolsulfonamidverbindungen zur behandlung von samen
DE602005005810D1 (de)	2008-05-15	Verwendung von substituierten chinolin-derivaten zur behandlung von arzneimittelresistenten mycobakteriellen erkrankungen
ATE476414T1 (de)	2010-08-15	Biphenyloxyessigsäurederivate zur behandlung von atemwegserkrankungen
EP2135858A4 (de)	2012-02-08	Zusammensetzung zur behandlung von infektionserkrankungen
FI20095600L (fi)	2009-06-09	Koostumus ihosairauksien hoitoa varten
DK1847524T3 (da)	2010-01-11	Terphenylderivater til behandling af Alzheimers sygdom
ATE525355T1 (de)	2011-10-15	1-ä(4-äbenzoyl(methyl)aminoü-3- (phenyl)butylüazetidinderivate zur behandlung von gastrointestinalen erkrankungen 1
DE502006008804D1 (de)	2011-03-10	Neue, langwirksame betamimetika zur behandlung von atemwegserkrankungen
DE602006003094D1 (de)	2008-11-20	4-phenyl-5-oxo-1,4,5,6,7,8-hexahydrochinolin-derivate zur behandlung von unfruchtbarkeit
ITRM20050179A1 (it)	2006-10-14	Composizione impiegabile per il trattamento delle patologie paradontali.
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