PT1235824E - Analogos da vitamina d - Google Patents

Analogos da vitamina d

Info

Publication number
PT1235824E
PT1235824E PT00985303T PT00985303T PT1235824E PT 1235824 E PT1235824 E PT 1235824E PT 00985303 T PT00985303 T PT 00985303T PT 00985303 T PT00985303 T PT 00985303T PT 1235824 E PT1235824 E PT 1235824E
Authority
PT
Portugal
Prior art keywords
analogs
vitamin
Prior art date
Application number
PT00985303T
Other languages
English (en)
Inventor
Jean-Michel Bernardon
Original Assignee
Galderma Res & Dev
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 Galderma Res & Dev filed Critical Galderma Res & Dev
Publication of PT1235824E publication Critical patent/PT1235824E/pt

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67Vitamins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/08Antiseborrheics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/10Anti-acne agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/14Drugs for dermatological disorders for baldness or alopecia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/02Nutrients, e.g. vitamins, minerals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/14Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00Preparations for affecting hair growth
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Obesity (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Virology (AREA)
  • Vascular Medicine (AREA)
  • Transplantation (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Neurosurgery (AREA)
  • Ophthalmology & Optometry (AREA)
PT00985303T 1999-11-24 2000-11-22 Analogos da vitamina d PT1235824E (pt)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR9914783A FR2801307B1 (fr) 1999-11-24 1999-11-24 Analogues de la vitamine d

Publications (1)

Publication Number Publication Date
PT1235824E true PT1235824E (pt) 2004-10-29

Family

ID=9552485

Family Applications (1)

Application Number Title Priority Date Filing Date
PT00985303T PT1235824E (pt) 1999-11-24 2000-11-22 Analogos da vitamina d

Country Status (20)

Country Link
US (1) US6706725B1 (pt)
EP (1) EP1235824B1 (pt)
JP (1) JP4003210B2 (pt)
KR (1) KR100554555B1 (pt)
CN (1) CN1214022C (pt)
AR (1) AR043280A1 (pt)
AT (1) ATE267190T1 (pt)
AU (1) AU767427B2 (pt)
BR (1) BR0015770B1 (pt)
CA (1) CA2392168C (pt)
DE (1) DE60010925T2 (pt)
DK (1) DK1235824T3 (pt)
ES (1) ES2222260T3 (pt)
FR (1) FR2801307B1 (pt)
MX (1) MXPA02005118A (pt)
PL (1) PL212711B1 (pt)
PT (1) PT1235824E (pt)
RU (1) RU2234503C2 (pt)
WO (1) WO2001038320A1 (pt)
ZA (1) ZA200203390B (pt)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101978A1 (en) * 2002-05-29 2003-12-11 Eli Lilly And Company Phenyl-thiophene type vitamin d receptor modulators
ES2275106T3 (es) * 2002-08-27 2007-06-01 GALDERMA RESEARCH & DEVELOPMENT, S.N.C. Analogos de la vitamina d.
US7582775B2 (en) 2003-11-20 2009-09-01 Eli Lilly And Company Vitamin D receptor modulators
WO2005051898A2 (en) * 2003-11-20 2005-06-09 Eli Lilly And Company Vitamin d receptor modulators
JP4717005B2 (ja) * 2003-11-20 2011-07-06 イーライ リリー アンド カンパニー ビタミンd受容体モジュレータ
EP1686972B1 (en) 2003-11-21 2008-03-12 Galderma Research & Development Sprayable composition for the administration of vitamin d derivatives
EP1748784A4 (en) * 2004-05-26 2008-02-13 Cedars Sinai Medical Center INDUCTION OF IMMUNITY IN VITAMIN D3 AND ITS ANALOGUES
PT1836151E (pt) * 2004-12-21 2009-04-20 Lilly Co Eli Moduladores do receptor da vitamina d
CA2717362A1 (en) * 2008-03-10 2009-09-17 Wisconsin Alumni Research Foundation Vitamin d compounds and methods for reducing ocular hypertension (oht)
SG173119A1 (en) 2009-01-27 2011-08-29 Berg Biosystems Llc Vitamin d3 and analogs thereof for alleviating side effects associated with chemotherapy
US8470304B2 (en) * 2009-08-04 2013-06-25 Avidas Pharmaceuticals Llc Therapeutic vitamin D sun-protecting formulations and methods for their use
EP3603646B1 (en) 2009-08-14 2024-04-03 BPGbio, Inc. Vitamin d3 and analogs thereof for treating alopecia
US20120015913A1 (en) * 2010-07-15 2012-01-19 Delansorne Remi Formulations of 14-EPI-Analogues of Vitamin D
EP3505180B1 (en) * 2011-09-30 2022-08-03 Allergan Pharmaceuticals International Limited In vivo synthesis of elastic fiber
CN112156097A (zh) 2013-05-29 2021-01-01 博格有限责任公司 使用维生素d预防或减轻化疗诱发的脱发
CN107954927A (zh) * 2017-10-30 2018-04-24 广东莱佛士制药技术有限公司 一种3-溴-5-(丙炔-1-基)吡啶的制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0507488A1 (en) * 1991-03-27 1992-10-07 Merck & Co. Inc. Inhibitors of HIV-1 reverse transcriptase
FR2741876B1 (fr) * 1995-12-01 1998-01-09 Cird Galderma Composes biaromatiques portant un groupement adamantyl en para, compositions pharmaceutiques et cosmetiques les contenant et utilisations
FR2746098B1 (fr) * 1996-03-14 1998-04-30 Composes propynyl biaromatiques
FR2746101B1 (fr) * 1996-03-14 1998-04-30 Composes bicycliques-aromatiques
FR2757852B1 (fr) * 1996-12-31 1999-02-19 Cird Galderma Composes stilbeniques a groupement adamantyl, compositions les contenant et utilisations
FR2759368B1 (fr) * 1997-02-10 2001-06-01 Galderma Rech Dermatologique Composes biaromatiques, compositions les contenant et utilisations
FR2785284B1 (fr) * 1998-11-02 2000-12-01 Galderma Res & Dev Analogues de la vitamine d

Also Published As

Publication number Publication date
CN1214022C (zh) 2005-08-10
DK1235824T3 (da) 2004-06-28
BR0015770A (pt) 2002-08-06
ES2222260T3 (es) 2005-02-01
PL355432A1 (en) 2004-04-19
FR2801307B1 (fr) 2002-12-06
AU767427B2 (en) 2003-11-13
ZA200203390B (en) 2004-02-11
PL212711B1 (pl) 2012-11-30
CN1423645A (zh) 2003-06-11
RU2234503C2 (ru) 2004-08-20
FR2801307A1 (fr) 2001-05-25
KR20020069187A (ko) 2002-08-29
KR100554555B1 (ko) 2006-03-03
JP2004501059A (ja) 2004-01-15
DE60010925T2 (de) 2005-06-16
EP1235824B1 (fr) 2004-05-19
AR043280A1 (es) 2005-07-27
WO2001038320A1 (fr) 2001-05-31
EP1235824A1 (fr) 2002-09-04
BR0015770B1 (pt) 2013-07-30
AU2176501A (en) 2001-06-04
US6706725B1 (en) 2004-03-16
CA2392168A1 (fr) 2001-05-31
MXPA02005118A (es) 2003-01-28
JP4003210B2 (ja) 2007-11-07
CA2392168C (fr) 2008-01-22
ATE267190T1 (de) 2004-06-15
DE60010925D1 (de) 2004-06-24

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