MA27247A1 - Utilisation combinee de derive indolopyrrolocarbazole antitumoral et autre agent antitumoral - Google Patents

Utilisation combinee de derive indolopyrrolocarbazole antitumoral et autre agent antitumoral

Info

Publication number
MA27247A1
MA27247A1 MA27853A MA27853A MA27247A1 MA 27247 A1 MA27247 A1 MA 27247A1 MA 27853 A MA27853 A MA 27853A MA 27853 A MA27853 A MA 27853A MA 27247 A1 MA27247 A1 MA 27247A1
Authority
MA
Morocco
Prior art keywords
tumor
pharmaceutically acceptable
antitumor
preparation
combined
Prior art date
Application number
MA27853A
Other languages
English (en)
Inventor
Hiroharu Arakawa
Yoko Nakatsuru
Yoshiaki Monden
Tsutomu Kodera
Original Assignee
Banyu Pharma 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 Banyu Pharma Co Ltd filed Critical Banyu Pharma Co Ltd
Publication of MA27247A1 publication Critical patent/MA27247A1/fr

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/28Compounds containing heavy metals
    • A61K31/282Platinum compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/243Platinum; Compounds thereof
    • 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
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention se rapporte à une préparation combinée pour administration simultanée, séparée ou séquentielle dans le traitement du cancer, comprenant deux préparations séparées: * une préparation comprenant, en combinaison avec un support ou diluant pharmaceutiquement acceptable, au moins un composé de la formule générale I : dans laquelle R1 et R2 représentent chacun indépendamment un atome d'hydrogène, alkyle inférieur, ou du même genre, et G représente un pentosyle ou du même genre, X1 et X2 représentent chacun indépendamment un atome d'hydrogène, un atome d'halogène, ou du même genre ou un de leurs sels pharmaceutiquement acceptables; et * une préparation, en combinaison avec un support ou diluant pharmaceutiquement acceptable, telle que des agents alcoylants antitumoraux, des antimétabolites antitumoraux, des antibiotiques antitumoraux, ou des agents antitumoraux issus de végétaux (une préparation comprenant au moins un composé de la formule générale I ou un de ses sels pharmaceutiquement acceptables peut être combinée avec deux ou plusieurs autres agents antitumoraux), et une méthode pour le traitement du cancer comprenant l'administration de ces préparations combinées.
MA27853A 2002-03-26 2004-09-10 Utilisation combinee de derive indolopyrrolocarbazole antitumoral et autre agent antitumoral MA27247A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2002084677 2002-03-26

Publications (1)

Publication Number Publication Date
MA27247A1 true MA27247A1 (fr) 2005-03-01

Family

ID=28449220

Family Applications (1)

Application Number Title Priority Date Filing Date
MA27853A MA27247A1 (fr) 2002-03-26 2004-09-10 Utilisation combinee de derive indolopyrrolocarbazole antitumoral et autre agent antitumoral

Country Status (25)

Country Link
US (1) US20050171036A1 (fr)
EP (1) EP1498127A4 (fr)
JP (1) JPWO2003080077A1 (fr)
KR (1) KR20040097237A (fr)
CN (1) CN100490817C (fr)
AP (1) AP2004003120A0 (fr)
AU (1) AU2002335472B8 (fr)
BR (1) BR0215650A (fr)
CA (1) CA2480335A1 (fr)
CO (1) CO5611155A2 (fr)
EA (1) EA008302B1 (fr)
EC (1) ECSP045301A (fr)
IL (1) IL164193A0 (fr)
IS (1) IS7379A (fr)
MA (1) MA27247A1 (fr)
MX (1) MXPA04009324A (fr)
NO (1) NO20044030L (fr)
NZ (1) NZ534914A (fr)
OA (1) OA12794A (fr)
PL (1) PL370866A1 (fr)
RS (1) RS84904A (fr)
TN (1) TNSN04185A1 (fr)
UA (1) UA80552C2 (fr)
WO (1) WO2003080077A1 (fr)
ZA (1) ZA200406716B (fr)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO20014256D0 (no) 2001-09-03 2001-09-03 Bjoern Kristiansen Fremstilling av immunstimulerende forbindelse
AU2004222439B2 (en) * 2003-03-20 2008-08-21 Nanocarrier Kabushiki Kaisha Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
US7514085B2 (en) 2004-07-16 2009-04-07 Medimush A/S Immune modulating compounds from fungi
DK1792927T3 (da) * 2004-09-22 2013-06-10 Nippon Kayaku Kk Ny blokcopolymer, micelletilberedning og anticancermiddel indeholdende samme som aktiv ingrediens
KR100968818B1 (ko) * 2004-12-03 2010-07-08 현대자동차주식회사 차량용 리어 쇽업쇼버의 보호 커버 구조
WO2006071955A2 (fr) * 2004-12-23 2006-07-06 Threshold Pharmaceuticals, Inc. Polytherapie a base de glufosfamide
CN100358482C (zh) * 2005-01-31 2008-01-02 武汉理工大学 多功能医用金属支架及制备方法
CN100431607C (zh) * 2005-02-03 2008-11-12 山东蓝金生物工程有限公司 一种抗实体肿瘤的药物组合物
WO2006133707A2 (fr) 2005-06-15 2006-12-21 Medimush A/S Polytherapie contre le cancer et kit de composants associe
NZ565654A (en) * 2005-07-18 2010-10-29 Bipar Sciences Inc Use of iodonitrobenzamide compounds for the treatment of ovarian cancer
CN101448875A (zh) * 2006-05-18 2009-06-03 日本化药株式会社 鬼臼毒素类的高分子量结合体
CA2662337A1 (fr) 2006-09-05 2008-03-13 Bipar Sciences, Inc. Inhibition de la synthese d'acides gras au moyen d'inhibiteurs parp et methodes de traitement associees
WO2008030883A2 (fr) 2006-09-05 2008-03-13 Bipar Sciences, Inc. Traitement du cancer
ES2584840T3 (es) * 2006-10-03 2016-09-29 Nippon Kayaku Kabushiki Kaisha Compuesto de un derivado de resorcinol con un polímero
CN100571709C (zh) * 2007-06-01 2009-12-23 中国医学科学院医药生物技术研究所 一种有抗肿瘤协同增效作用的药物组合物
JP5349318B2 (ja) 2007-09-28 2013-11-20 日本化薬株式会社 ステロイド類の高分子結合体
CN101903025A (zh) * 2007-10-19 2010-12-01 彼帕科学公司 利用苯并吡喃酮-型parp抑制剂治疗癌症的方法和组合物
JP2011503111A (ja) 2007-11-12 2011-01-27 バイパー サイエンシズ,インコーポレイティド Parp阻害剤単独又は抗腫瘍剤との組み合わせによる乳がんの治療
ES2402138T3 (es) * 2007-12-28 2013-04-29 Deutsches Krebsforschungszentrum, Stiftung Des Öffentlichen Rechts Terapia contra el cáncer con un parvovirus combinado con quimioterapia
JP5687899B2 (ja) * 2008-03-18 2015-03-25 日本化薬株式会社 生理活性物質の高分子結合体
US9149540B2 (en) 2008-05-08 2015-10-06 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of folic acid or folic acid derivative
EP2431403B1 (fr) 2009-05-15 2016-09-28 Nipponkayaku Kabushikikaisha Conjugue polymere de substance bioactive comprenant un groupe hydroxy
CN102198150B (zh) * 2010-03-26 2013-11-06 中国医学科学院医药生物技术研究所 双活性成分抗肿瘤药物及其应用
TW201304805A (zh) 2010-11-17 2013-02-01 Nippon Kayaku Kk 新穎之胞核苷系代謝拮抗劑之高分子衍生物
CN102178676B (zh) * 2011-04-29 2012-07-25 山东大学 一种治疗脑胶质瘤的药物组合物
WO2013035641A1 (fr) 2011-09-11 2013-03-14 日本化薬株式会社 Procédé de préparation de copolymère à blocs
CN117486782A (zh) * 2023-12-29 2024-02-02 中国医学科学院药用植物研究所 一种n-取代咔唑衍生物及其制备方法和应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ245203A (en) * 1991-11-29 1997-07-27 Banyu Pharma Co Ltd 5h-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6h)-dione derivatives substituted in position-13 by a pentose or hexose group; corresponding indolo-furano(anhydride)intermediates
PL172316B1 (en) * 1991-11-29 1997-09-30 Banyu Pharma Co Ltd Method of obtaining novel derivatives of indolopyrrole carbazole
US5589365A (en) * 1991-11-29 1996-12-31 Banyu Pharmaceutical Co., Ltd. Process for producing glycosylated indolopyrrolocarbazole derivatives by culturing certain microorganisms
CN1035878C (zh) * 1992-02-18 1997-09-17 万有制药株式会社 吲哚并吡咯并咔唑衍生物
US5922860A (en) * 1994-05-09 1999-07-13 Banyu Pharmaceutical Co., Ltd. Antitumor indolopyrrolocarbazole derivatives
JP3536574B2 (ja) 1997-02-28 2004-06-14 萬有製薬株式会社 抗腫瘍性インドロピロロカルバゾール誘導体
FR2772763B1 (fr) * 1997-12-24 2004-01-23 Sod Conseils Rech Applic Nouveaux analogues tetracycliques de camptothecines, leurs procedes de preparation, leur application comme medicaments et les compositions pharmaceutiques les contenant
DE60118571T2 (de) * 2000-05-15 2007-02-01 Celgene Corp. Pharmazeutische zusammensetzungen zur behandlung von krebs welche thalidomid und topoisomerase inhibitoren enthalten

Also Published As

Publication number Publication date
AU2002335472A1 (en) 2003-10-08
AU2002335472B2 (en) 2007-12-13
BR0215650A (pt) 2005-01-04
IL164193A0 (en) 2005-12-18
UA80552C2 (en) 2007-10-10
NZ534914A (en) 2007-01-26
CA2480335A1 (fr) 2003-10-02
OA12794A (en) 2006-07-10
WO2003080077A1 (fr) 2003-10-02
US20050171036A1 (en) 2005-08-04
AU2002335472B8 (en) 2007-12-20
RS84904A (sr) 2006-12-15
ECSP045301A (es) 2004-11-26
EA200401254A1 (ru) 2005-02-24
EP1498127A1 (fr) 2005-01-19
KR20040097237A (ko) 2004-11-17
EA008302B1 (ru) 2007-04-27
CO5611155A2 (es) 2006-02-28
AP2004003120A0 (en) 2004-09-30
TNSN04185A1 (en) 2007-03-12
MXPA04009324A (es) 2005-01-25
JPWO2003080077A1 (ja) 2005-07-21
PL370866A1 (en) 2005-05-30
EP1498127A4 (fr) 2008-02-06
CN100490817C (zh) 2009-05-27
ZA200406716B (en) 2006-07-26
IS7379A (is) 2004-07-29
CN1622814A (zh) 2005-06-01
NO20044030L (no) 2004-12-16

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