EP2785704A1 - Novel combination of n-hydroxy-4-{2-[3-(n,n-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide and folfox - Google Patents

Novel combination of n-hydroxy-4-{2-[3-(n,n-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide and folfox

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Publication number
EP2785704A1
EP2785704A1 EP12743494.2A EP12743494A EP2785704A1 EP 2785704 A1 EP2785704 A1 EP 2785704A1 EP 12743494 A EP12743494 A EP 12743494A EP 2785704 A1 EP2785704 A1 EP 2785704A1
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EP
European Patent Office
Prior art keywords
folfox
treatment
benzamide
ethoxy
administered
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP12743494.2A
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German (de)
French (fr)
Inventor
Stéphane DEPIL
Anne JACQUET-BESCOND
Ioana KLOOS
Anne-Laure SARRY
Sriram Balasubramanian
Joseph Buggy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacyclics LLC
Original Assignee
Laboratoires Servier SAS
Pharmacyclics LLC
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Publication of EP2785704A1 publication Critical patent/EP2785704A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel combination of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide of formula (I):
  • FOLFOX a pharmaceutically acceptable acid or base and FOLFOX for the treatment of cancer, and more particularly for the treatment of colorectal cancer, pancreatic cancer and gastric cancer in patients resistant to a treatment based on FOLFOX.
  • N-Hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzoflu-an-2-ylcarbonylamino] ethoxy ⁇ benzamide is a potent inhibitor of histone deacetylases (HDAC) described in WO2004 / 092,115. It inhibits cell growth and induces apoptosis in tumor cells cultured in vitro, and inhibits tumor growth in vivo in xenograft models (Buggy et al Mol Cancer Ther 2006 5 (5) 1309). Its pharmacological profile gives it a major therapeutic interest in the treatment of cancer.
  • HDAC histone deacetylases
  • the present invention relates to the combination of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide of formula (I) or its addition salts with a acid or a pharmaceutically acceptable base, and FOLFOX, as well as its properties for the treatment of cancer, and more particularly for the treatment of colorectal cancer, pancreatic cancer and gastric cancer in patients resistant to treatment based on FOLFOX.
  • FOLFOX is a chemotherapy protocol used for the treatment of various cancers. It consists of the administration of oxaliplatin, folinic acid and 5-fluorouracil according to a scheme designed to optimize the effectiveness of the treatment. It is commonly used in the treatment of colon cancer (De Gramont A. et al J. Clin, Oncol 2000, 2938). In addition, several phase II or III studies have shown that FOLFOX can induce a partial response rate in patients suffering from gastric cancer (De Vita et al Br. J. Cancer 2005 92 1644). In pancreatic cancer, FOLFOX has also demonstrated efficacy as a second-line treatment following the failure of gemcitabine therapy (Cascinu S.
  • N-hydroxy-4- ⁇ 2- [3 - (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is used in the form of a hydrochloride in the context of the invention.
  • the compounds of the combination according to the invention are administered over 5 consecutive days, this period being followed by 9 consecutive days without any administration. More particularly, N-hydroxy-4- ⁇ 2- [3- (V, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered for 4 consecutive days, while FOLFOX is administered from the third to the fifth day. . Even more preferably, N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered for 4 consecutive days, while oxaliplatin and folinic acid are administered. simultaneously on the third day, infusion at the end of which the 5-fluorouracil is administered continuously until the fifth day.
  • N-hydroxy-4- ⁇ 2- [3- (N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered orally.
  • the appropriate dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the cancer and any associated treatments and ranges from 20 mg to 480 mg of N-hydoxy base equivalent.
  • the doses administered on each 14-day cycle are:
  • a clinical study to test the combination of 7V-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide with the FOLFOX is performed on up to 60 patients. Patients included in the study had colorectal cancer, pancreatic cancer or gastric cancer, and followed, prior to inclusion, FOLFOX-based treatment (ie, alone or in combination). combination with other treatments).
  • the study consists of cycles of 14 days, each of the cycles being carried out as follows: N-hydroxy-4- [2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide (as hydrochloride) is administered for 4 consecutive days, while oxaliplatin and folinic acid are administered simultaneously on the third day, infusion after which 5-fluorouracil is administered continuously to the fifth day.
  • the daily dose of N " -hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzoylaman-2-ylcarbonylamino] ethoxy ⁇ benzamide hydrochloride is between 160 and 360 mg, at a rate of two doses in 4 hours, and the components of FOLFOX are given at each cycle:
  • the toxicity of the protocol associating N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide and FOLFOX is evaluated. If no unacceptable toxicity is observed, the patient continues the treatment. Every four cycles, the effectiveness of the treatment is appreciated via the evaluation of the tumor response (CT-scan, MRI, ). The acceptability profile is also evaluated (haematological and cardiac toxicities in particular).

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  • General Health & Medical Sciences (AREA)
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Abstract

The invention relates to a combination of N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide with formula (I): or one of the pharmaceutically acceptable base or acid addition salts thereof and FOLFOX for cancer treatment.

Description

NOUVELLE ASSOCIATION ENTRE LE  NEW ASSOCIATION BETWEEN THE
iV-HYDROXY-4-{2-[3-(7V)Ar-DIMETHYLAMINOMETHYL)BENZOFURAN-2- YLCARBONYLAMINO]ETHOXY}BENZAMIDE N-HYDROXY-4- {2- [3- (7V) A r -DIMETHYLAMINOMETHYL) benzofuran-2-ylcarbonylamino] ethoxy} BENZAMIDE
ET LE FOLFOX  AND THE FOLFOX
La présente invention concerne une nouvelle association entre le N-hydiOxy-4-{2-[3-(JV,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide de formule (I) : The present invention relates to a novel combination of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide of formula (I):
ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable et le FOLFOX pour le traitement du cancer, et plus particulièrement pour le traitement du cancer colo-rectal, du cancer pancréatique et du cancer gastrique chez les patients résistants à un traitement basé sur le FOLFOX. or an addition salt thereof to a pharmaceutically acceptable acid or base and FOLFOX for the treatment of cancer, and more particularly for the treatment of colorectal cancer, pancreatic cancer and gastric cancer in patients resistant to a treatment based on FOLFOX.
Le N-hydiOxy-4-{2-[3-(N,N-diméthylaminométhyl)benzofui-an-2-ylcarbonylamino] éthoxy}benzamide est un inhibiteur puissant des histones-déacétylases (HDAC) décrit dans la demande de brevet WO2004/092115. Il permet d'inhiber la croissance cellulaire et induit l'apoptose dans des cellules tumorales cultivées in vitro, et inhibe la croissance tumorale in vivo dans des modèles de xénogreffes (Buggy et al Mol. Cancer Ther 2006 5(5) 1309). Son profil pharmacologique lui confère un intérêt thérapeutique majeur dans le traitement du cancer. N-Hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzoflu-an-2-ylcarbonylamino] ethoxy} benzamide is a potent inhibitor of histone deacetylases (HDAC) described in WO2004 / 092,115. It inhibits cell growth and induces apoptosis in tumor cells cultured in vitro, and inhibits tumor growth in vivo in xenograft models (Buggy et al Mol Cancer Ther 2006 5 (5) 1309). Its pharmacological profile gives it a major therapeutic interest in the treatment of cancer.
La présente invention concerne l'association entre le N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide de formule (I) ou ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, et le FOLFOX, ainsi que ses propriétés pour le traitement du cancer, et plus particulièrement pour le traitement du cancer colo-rectal, du cancer pancréatique et du cancer gastrique chez les patients résistants à un traitement basé sur le FOLFOX. The present invention relates to the combination of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide of formula (I) or its addition salts with a acid or a pharmaceutically acceptable base, and FOLFOX, as well as its properties for the treatment of cancer, and more particularly for the treatment of colorectal cancer, pancreatic cancer and gastric cancer in patients resistant to treatment based on FOLFOX.
Le FOLFOX est un protocole de chimiothérapie utilisé pour le traitement de divers cancers. Il consiste en l'administration d'oxaliplatine, d'acide folinique et de 5-fluorouracil selon un schéma destiné à optimiser l'efficacité du traitement. Il est couramment utilisé dans le traitement du cancer du colon (De Gramont A. et al J. Clin. Oncol. 2000 18 2938). Par ailleurs, plusieurs études de phase II ou III ont montré que le FOLFOX pouvait induire un taux de réponse partiel chez les patients souffrant d'un cancer gastrique (De Vita et al Br. J. Cancer 2005 92 1644). Dans le cancer du pancréas, le FOLFOX a également fait preuve d'efficacité en tant que traitement de seconde intention suite à l'échec d'une thérapie à la gemcitabine (Cascinu S. et al Annals of Oncology 2010 21(Suppl 5) v55 ; Gebbia V. et al Annals of Oncol 2007 18(Suppl 6) vil 24 ; Li J. et al J. Pancréas (Online) 2009 10(4) 361). Cependant, la recherche de nouvelles alternatives thérapeutiques en oncologie reste toujours d'actualité. En particulier, sensibiliser les patients résistants aux chimiothérapies déjà validées cliniquement constitue une stratégie thérapeutique à explorer. FOLFOX is a chemotherapy protocol used for the treatment of various cancers. It consists of the administration of oxaliplatin, folinic acid and 5-fluorouracil according to a scheme designed to optimize the effectiveness of the treatment. It is commonly used in the treatment of colon cancer (De Gramont A. et al J. Clin, Oncol 2000, 2938). In addition, several phase II or III studies have shown that FOLFOX can induce a partial response rate in patients suffering from gastric cancer (De Vita et al Br. J. Cancer 2005 92 1644). In pancreatic cancer, FOLFOX has also demonstrated efficacy as a second-line treatment following the failure of gemcitabine therapy (Cascinu S. et al Annals of Oncology 2010 21 (Suppl 5) v55 Gebbia V. et al Annals of Oncol 2007 18 (Suppl 6) vil 24, Li J. et al J. Pancreas (Online) 2009 10 (4) 361). However, the search for new therapeutic alternatives in oncology is still relevant today. In particular, sensitizing patients resistant to chemotherapy already clinically validated is a therapeutic strategy to explore.
Dans un autre aspect de l'invention, il a été montré que les effets du N-hydroxy-4-{2-[3- (N,N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide ou de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable permettaient d'inverser la résistance au FOLFOX chez les patients préalablement traités par ce protocole chimiothérapeutique. In another aspect of the invention, the effects of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide or its salts thereof have been shown to be effective. addition to a pharmaceutically acceptable acid or base permitted reversal of FOLFOX resistance in patients previously treated with this chemotherapeutic protocol.
Cet effet permet d'envisager l'utilisation de l'association du N-hydi xy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide et du FOLFOX dans le traitement des cancers traités en premier lieu par le FOLFOX chez des patients pour lesquels une progression de la maladie a été observée malgré le traitement, et plus particulièrement dans le traitement du cancer colo-rectal, du cancer pancréatique et du cancer gastrique chez les patients résistants à un traitement basé sur le FOLFOX. Préférentiellement, le N-hydroxy-4- {2- [3 -(N, N-diméthylaminométhyl)benzofuran-2- ylcarbonylamino]éthoxy}benzamide est utilisé sous la forme d'un chlorhydrate dans le cadre de l'invention. This effect makes it possible to envisage the use of the combination of N-hydrazy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide and FOLFOX in the treatment of cancers first treated with FOLFOX in patients for whom disease progression was observed despite treatment, and more specifically in the treatment of colorectal cancer, pancreatic cancer and gastric cancer in patients resistant to treatment based on FOLFOX. Preferentially, N-hydroxy-4- {2- [3 - (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is used in the form of a hydrochloride in the context of the invention.
Dans le schéma d'administration préféré, les composés de l'association selon l'invention sont administrés sur 5 jours consécutifs, cette période étant suivie de 9 jours consécutifs sans aucune administration. Plus particulièrement, le N-hydroxy-4-{2-[3-( V,jV- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant 4 jours consécutifs, tandis que le FOLFOX est administré du troisième au cinquième jour. Plus préférentiellement encore, le N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant 4 jours consécutifs, tandis que Poxaliplatine et l'acide folinique sont administrés simultanément le troisième jour, infusion au bout de laquelle le 5-fluorouracil est administré de manière continue jusqu'au cinquième jour. In the preferred administration scheme, the compounds of the combination according to the invention are administered over 5 consecutive days, this period being followed by 9 consecutive days without any administration. More particularly, N-hydroxy-4- {2- [3- (V, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for 4 consecutive days, while FOLFOX is administered from the third to the fifth day. . Even more preferably, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for 4 consecutive days, while oxaliplatin and folinic acid are administered. simultaneously on the third day, infusion at the end of which the 5-fluorouracil is administered continuously until the fifth day.
Dans un mode de réalisation préféré, le N-hydroxy-4-{2-[3-(/^N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré sous forme orale. In a preferred embodiment, N-hydroxy-4- {2- [3- (N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered orally.
La posologie utile varie selon le sexe, l'âge et le poids du patient, la voie d'administration, la nature du cancer et des traitements éventuellement associés et s'échelonne entre 20 mg et 480 mg d'équivalent base de N-hydiOxy-4-{2-[3-(N,iV- diméthylaminométhyl)benzofuran-2-yIcarbonylamino]éthoxy}benzamide par jour. Quant aux composants du FOLFOX, les doses administrées sur chaque cycle de 14 jours sont : The appropriate dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the cancer and any associated treatments and ranges from 20 mg to 480 mg of N-hydoxy base equivalent. 4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide per day. As for the components of FOLFOX, the doses administered on each 14-day cycle are:
85 mg/m2 pour l'oxaliplatine, 85 mg / m 2 for oxaliplatin,
- 400 mg/m2 pour l'acide folinique, 400 mg / m 2 for folinic acid,
- 2400 mg/m2 pour le 5-fluorouracil. - 2400 mg / m 2 for 5-fluorouracil.
Etude clinique : Clinical study :
Une étude clinique pour tester l'association du 7V-hydroxy-4- {2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide avec le FOLFOX est réalisée sur 60 patients au maximum. Les patients inclus dans l'étude sont atteints d'un cancer colo-rectal, d'un cancer pancréatique ou d'un cancer gastrique, et ont suivi, préalablement à leur inclusion, un traitement basé sur le FOLFOX (i.e., seul ou en association à d'autres traitements). Plus précisément, l'étude consiste en cycles de 14 jours, chacun des cycles se déroulant de la manière suivante : le N-hydiOxy-4-{2-[3-(N,jV- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide (sous forme de chlorhydrate) est administré pendant 4 jours consécutifs, tandis que l'oxaliplatine et l'acide folinique sont administrés simultanément le troisième jour, infusion au bout de laquelle le 5-fluorouracil est administré de manière continue jusqu'au cinquième jour. Dans un premier temps, la dose journalière de chlorhydrate de N"-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzoi\iran-2-ylcarbonylamino]éthoxy}benzamide est comprise entre 160 et 360 mg, à raison de deux prises p.o. espacées de 4 h. Quant aux composants du FOLFOX, les doses administrées lors de chaque cycle sont : A clinical study to test the combination of 7V-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide with the FOLFOX is performed on up to 60 patients. Patients included in the study had colorectal cancer, pancreatic cancer or gastric cancer, and followed, prior to inclusion, FOLFOX-based treatment (ie, alone or in combination). combination with other treatments). More precisely, the study consists of cycles of 14 days, each of the cycles being carried out as follows: N-hydroxy-4- [2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy } benzamide (as hydrochloride) is administered for 4 consecutive days, while oxaliplatin and folinic acid are administered simultaneously on the third day, infusion after which 5-fluorouracil is administered continuously to the fifth day. In a first step, the daily dose of N " -hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzoylaman-2-ylcarbonylamino] ethoxy} benzamide hydrochloride is between 160 and 360 mg, at a rate of two doses in 4 hours, and the components of FOLFOX are given at each cycle:
85 mg/m2 pour l'oxaliplatine, 85 mg / m 2 for oxaliplatin,
- 400 mg/m pour l'acide folinique,  - 400 mg / m for folinic acid,
- 2400 mg/m pour le 5-fluorouracil.  - 2400 mg / m for 5-fluorouracil.
Au bout d'un cycle de traitement, la toxicité du protocole associant le N-hydroxy-4-{2-[3- (N,N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide et le FOLFOX est évaluée. Si aucune toxicité rédhibitoire n'est observée, le patient continue le traitement. Tous les quatre cycles, l'efficacité du traitement est appréciée via l'évaluation de la réponse tumorale (CT-scan, IRM,...). Le profil d'acceptabilité est également évalué (toxicités hématologiques et cardiaques en particulier). After one treatment cycle, the toxicity of the protocol associating N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide and FOLFOX is evaluated. If no unacceptable toxicity is observed, the patient continues the treatment. Every four cycles, the effectiveness of the treatment is appreciated via the evaluation of the tumor response (CT-scan, MRI, ...). The acceptability profile is also evaluated (haematological and cardiac toxicities in particular).
Les résultats montrent que l'utilisation du 7V-hydroxy-4-{2-[3-(NJN- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy } benzamide en association avec le FOLFOX est encourageante pour le traitement du cancer, et plus particulièrement pour le traitement du cancer colo-rectal, du cancer pancréatique ou du cancer gastrique chez les patients résistants à un traitement basé sur le FOLFOX. The results show that the use of 7V-hydroxy-4- {2- [3- (N J N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide in association with the FOLFOX is encouraging for the treatment of cancer, and especially for the treatment of colorectal cancer, pancreatic cancer or gastric cancer in patients resistant to a treatment based on FOLFOX.

Claims

REVENDICATIONS
1- Association entre le N-hydroxy-4-{2-[3-(N,jV-diméthylaminométhyl)benzofui-an-2- ylcarbonylamino]éthoxy}benzamide de formule (I) : 1- Association between N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzoful-an-2-ylcarbonylamino] ethoxy} benzamide of formula (I):
ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable et le FOLFOX.  or an addition salt thereof with a pharmaceutically acceptable acid or base and FOLFOX.
2 Association selon la revendication î caractérisée en ce que le -V-hydroxy-4-{2-[3-(NtN- diméthylaminométhyI)benzofuran-2-ylcarbonylamino]éthoxy } benzamide est utilisé sous la forme d'un chlorhydrate. ^ Association selon la revendication 1 ou 2 pour son utilisation dans le traitement du cancer. ; Association selon l'une des revendications 1 à 3 pour son utilisation dans le traitement du cancer colo-rectal chez les patients résistants à un traitement basé sur le FOLFOX. 5; Association selon l'une des revendications 1 à 3 pour son utilisation dans le traitement du cancer pancréatique chez les patients résistants à un traitement basé sur le FOLFOX. Association selon l'une des revendications 1 à 3 pour son utilisation dans le traitement du cancer gastrique chez les patients résistants à un traitement basé sur le FOLFOX. Combination according to Claim 2 î characterized in that the -V-hydroxy-4- {2- [3- (N t N diméthylaminométhyI) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is used in the form of a hydrochloride. Association according to claim 1 or 2 for its use in the treatment of cancer. ; Association according to one of claims 1 to 3 for its use in the treatment of colorectal cancer in patients resistant to treatment based on FOLFOX. 5; Association according to one of claims 1 to 3 for its use in the treatment of pancreatic cancer in patients resistant to treatment based on FOLFOX. Association according to one of claims 1 to 3 for its use in the treatment of gastric cancer in patients resistant to treatment based on FOLFOX.
2 Association selon l'une des revendications 4 à 6 caractérisée en ce que les composés de l'association sont administrés sur 5 jours consécutifs, cette période étant suivie de 9 jours consécutifs sans aucune administration. 2 Association according to one of claims 4 to 6 characterized in that the compounds of the combination are administered over 5 consecutive days, this period being followed by 9 consecutive days without any administration.
8; Association selon l'une des revendications 4 à 6 caractérisée en ce que le N-hydroxy~4- {2-[3-(N,7V-diméthylaminométhyl)benzofuran-2-yicarbonylamino]éthoxy}benzamide est administré pendant 4 jours consécutifs, tandis que le FOLFOX est administré du troisième au cinquième jour. Association selon l'une des revendications 4 à 6 caractérisée en ce que le N-hydroxy-4- {2- [3 -(7V, JV-diméthyl aminométhy 1) benzofuran-2-ylcarbony lamino] éthoxy } benzamide est administré pendant 4 jours consécutifs, tandis que l'oxaliplatine et l'acide folinique sont administrés simultanément le troisième jour, infusion au bout de laquelle le 5- fiuorouracil est administré de manière continue jusqu'au cinquième jour. 8; Association according to one of Claims 4 to 6, characterized in that N-hydroxy-4- {2- [3- (N, 7-dimethylaminomethyl) benzofuran-2-yicarbonylamino] ethoxy} benzamide is administered for 4 consecutive days, while FOLFOX is administered from the third to the fifth day. Combination according to one of Claims 4 to 6, characterized in that N-hydroxy-4- {2- [3- (7V, N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for 4 hours. consecutive days, while oxaliplatin and folinic acid are administered simultaneously on the third day, infusion after which 5-fluorouracil is administered continuously until the fifth day.
10- Utilisation d'une association selon la revendication 1 ou 2 pour le traitement du cancer. 10- Use of a combination according to claim 1 or 2 for the treatment of cancer.
11- Utilisation d'une association selon la revendication 1 ou 2 pour le traitement du cancer colo-rectal chez les patients résistants à un traitement basé sur le FOLFOX. 11- Use of a combination according to claim 1 or 2 for the treatment of colorectal cancer in patients resistant to treatment based on FOLFOX.
12- Utilisation d'une association selon la revendication 1 ou 2 pour le traitement du cancer pancréatique chez les patients résistants à un traitement basé sur le FOLFOX. 12- Use of a combination according to claim 1 or 2 for the treatment of pancreatic cancer in patients resistant to treatment based on FOLFOX.
13- Utilisation d'une association selon la revendication 1 ou 2 pour le traitement du cancer gastrique chez les patients résistants à un traitement basé sur le FOLFOX. 14- Utilisation d'une association selon l'une des revendications 1 1 à 13 caractérisée en ce que les composés de l'association sont administrés sur 5 jours consécutifs, cette période étant suivie de 9 jours consécutifs sans aucune administration. 13- Use of a combination according to claim 1 or 2 for the treatment of gastric cancer in patients resistant to a treatment based on FOLFOX. 14- Use of an association according to one of claims 1 1 to 13 characterized in that the compounds of the combination are administered over 5 consecutive days, this period being followed by 9 consecutive days without any administration.
15- Utilisation d'une association selon l'une des revendications 1 1 à 13 caractérisée en ce que le N-hydroxy-4-{2-[3-(N,N-diméthylaminométhyl)benzofuran-2- ylcarbonylaminojëthoxy} benzamide est administré pendant 4 jours consécutifs, tandis que le FOLFOX est administré du troisième au cinquième jour. 15- Use of a combination according to one of claims 1 1 to 13 characterized in that N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino} ethoxy} benzamide is administered for 4 consecutive days, while FOLFOX is administered from the third to the fifth day.
16- Utilisation d'une association selon l'une des revendications 1 1 à 13 caractérisée en ce que le N-hydroxy-4-{2-[3-(N)N-diméthylaminométhyl)benzofuran-2- ylcarbonylaminojéthoxy} benzamide est administré pendant 4 jours consécutifs, tandis que l'oxaliplatine et l'acide folinique sont administrés simultanément le troisième jour, infusion au bout de laquelle le 5-fluorouracil est administré de manière continue jusqu'au cinquième jour. 16- Use of a combination according to one of claims 1 1 to 13 characterized in that N-hydroxy-4- {2- [3- (N ) N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino} ethoxy} benzamide is administered for 4 consecutive days, while oxaliplatin and folinic acid are administered simultaneously on the third day, infusion after which 5-fluorouracil is administered continuously until the fifth day.
EP12743494.2A 2011-07-04 2012-07-03 Novel combination of n-hydroxy-4-{2-[3-(n,n-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide and folfox Withdrawn EP2785704A1 (en)

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FR1102087A FR2977492B1 (en) 2011-07-04 2011-07-04 NOVEL ASSOCIATION BETWEEN N-HYDROXY-4- {2- [3- (N, N-DIMETHYLAMINOMETHYL) BENZOFURAN-2-YLCARBONYLAMINO] ETHOXY} BENZAMIDE AND FOLFOX
US201161571789P 2011-07-05 2011-07-05
PCT/FR2012/051540 WO2013004965A1 (en) 2011-07-04 2012-07-03 Novel combination of n-hydroxy-4-{2-[3-(n,n-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide and folfox

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