WO2013093248A1 - Novel combinations containing n-hydroxy-4-(2-[3-(n, n-dimethylaminomethyl) benzofuran-2-ylcarbonylamino]ethoxy)benzamide in nasopharyngeal carcinoma - Google Patents

Novel combinations containing n-hydroxy-4-(2-[3-(n, n-dimethylaminomethyl) benzofuran-2-ylcarbonylamino]ethoxy)benzamide in nasopharyngeal carcinoma Download PDF

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WO2013093248A1
WO2013093248A1 PCT/FR2012/000550 FR2012000550W WO2013093248A1 WO 2013093248 A1 WO2013093248 A1 WO 2013093248A1 FR 2012000550 W FR2012000550 W FR 2012000550W WO 2013093248 A1 WO2013093248 A1 WO 2013093248A1
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treatment
dimethylaminomethyl
benzofuran
hydroxy
benzamide
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Ioana KLOOS
Anne JACQUET-BESCOND
Laurence Kraus-Berthier
Stéphane DEPIL
Benjamin VERILLAUD
Pierre Busson
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Les Laboratoires Servier
Pharmacyclics, Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to N-hydroxy-4- ⁇ 2- [3- (7V, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide of formula (I):
  • N-hydroxy-4- ⁇ 2- [3- (iV) N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is a potent inhibitor of histone deacetylases (HDAC) is described in the patent application WO2004 / 092115. 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
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide of formula (I) or of its addition salts with a pharmaceutically acceptable acid or base, in combination with a chemotherapy or radiotherapy treatment, is proposed for the treatment of nasopharyngeal carcinoma.
  • Nasopharyngeal carcinoma is a unique pathology in terms of geographical distribution and biological association with the Epstein-Barr virus (Liebowitz D. Semin Oncol 1994; 21: 376-381). It has a low incidence in Europe and the USA, but much higher in China and Southeast Asia. This carcinoma is also characterized by a strong etiological factor associated with genetic predispositions and the consumption of canned or frozen foods.
  • the standard treatment today is the administration of cisplatin in combination with radiotherapy (Ma Brigette et al., Cancer Science 2008; 99 (7): 1311-1318).
  • the effectiveness of the treatment is highly dependent on the stage of disease progression with a cure rate of more than 85% when patients are treated at an early stage, this rate falling below 30% for stadiums.
  • the combination of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide or its salts has been shown addition to a pharmaceutically acceptable acid or base with cisplatin exhibited remarkable synergistic properties in certain tumor cell lines of nasopharyngeal carcinoma.
  • a synergistic effect of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide in combination with radiotherapy in some of these lines was also observed.
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is used in combination with cisplatin.
  • treatments combining N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide can be envisaged at therapeutic doses of cisplatin that are lower than those conventionally used, with an equivalent or even higher tumor response and lower toxicity (especially ototoxicity and neurotoxicity) in nasopharyngeal carcinoma.
  • the invention also covers the use of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide in combination with cisplatin in nasopharyngeal carcinoma in patients resistant to chemotherapy based on platinum derivatives.
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered in combination with cisplatin in cycles.
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered for n + 1 consecutive days, this period being followed by n consecutive days without treatment with the proviso that n is an integer from 1 to 10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered for 4 consecutive days, followed by 3 consecutive days. without treatment for the first two weeks of a three-week cycle. Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle. ⁇ -
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is used in combination with radiation therapy.
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered in combination with cycle radiotherapy.
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered for n + 1 consecutive days, this period being followed by n consecutive days without treatment , it being understood that n is an integer between 1 and 10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. More preferably, n is equal to 3.
  • 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 hydrochloride of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered for 4 consecutive days, followed by 3 consecutive days without treatment for the first two weeks of a three-week cycle. Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle.
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered orally.
  • an oral formulation of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is administered for 4 consecutive days, followed by 3 consecutive days without treatment for the first two weeks of a three-week cycle.
  • Cisplatin is administered on the third day of each treatment cycle. No treatment is given during the third week of the cycle.
  • an oral formulation of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide hydrochloride is administered for 4 consecutive days, followed by 3 consecutive days without treatment for the first two weeks of a three-week cycle.
  • Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle.
  • 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 360 mg of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide per day.
  • the dose administered varies between 50 and 100 mg / m.
  • the preferred dose is 75 mg / m.
  • the cells are cultured in the presence of test compounds for 48 hours.
  • the cell viability is then quantified by a colorimetric assay, the "Microculture Tetrazolium assay” (MTT assay).
  • MTT assay Microculture Tetrazolium assay
  • the combined treatment of N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide (also called compound 1) and cisplatin (also called CDDP) shows a significant increase in inhibition of growth cells exposed to the combination of the two compounds compared to the effect observed for each of the products alone (see Figure 1).
  • N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide hydrochloride used alone or in combination with radiotherapy, has been evaluated on the tumor cell line Cl 7.
  • the cells are cultured in the presence of compound 1 and irradiated at 2 Gy 24 hours later.
  • the cell viability is then quantified after 48 hours of culture by the MTT test (see Figure 2).
  • the antitumor activity of the compounds of the invention is evaluated in two models of nasopharyngeal carcinoma cell xenografts described above, Cl 5 and Cl 7.
  • Cl 5 or Cl 7 tumor fragments are grafted subcutaneously into immunocompromised (Swiss Nude) mice. When the tumor volume reaches between 100 and 150 mm 3 , the different treatments begin. The animals are treated for three consecutive weeks.
  • N-hydroxy-4- ⁇ 2- [3- (N ) N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide hydrochloride with cisplatin in the treatment of carcinoma nasopharynx is performed on approximately 40 patients. Patients receive a maximum of six cycles of combination therapy, each of which is conducted in the following manner: N-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ Benzamide is administered for 4 consecutive days, followed by 3 consecutive days without treatment, during the first two weeks of a three-week cycle. Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle.
  • the daily dose of 7V-hydroxy-4- ⁇ 2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy ⁇ benzamide is between 80 and 280 mg, with two doses in between 4 hrs.
  • Cisplatin is administered at a fixed dose of 75 mg / m 2 .
  • the patient continues the combination treatment for up to six cycles.
  • the effectiveness of the treatment is assessed via the evaluation of the tumor response (CT-scan, MRI, .

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Abstract

The invention relates to the N-hydroxy-4-(2-[3-(N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino]ethoxy)benzamide of formula (I), or to one of the acid or pharmaceutically acceptable base addition salts thereof, combined with a chemotherapy or radiotherapy treatment, for the use thereof in treating nasopharyngeal carcinoma.

Description

NOUVELLES ASSOCIATIONS A BASE DE N- HYDROXY - 4 - { 2 - [3 - (N, - DIMETHYLAMINOMETHYL) BENZOFURAN- 2 -YLCARB ONYLAMINO] ΕΤΗΟΧΥ} BENZAMIDE DANS LE CARCINOME DU NASOPHARYNX NOVEL N-HYDROXY-4 - {2 - [3 - (N, - DIMETHYLAMINOMETHYL) BENZOFURAN-2-YLCARB ONYLAMINO] ΕΤΗΟΧΥ} BENZAMIDE ASSOCIATIONS IN NASOPHARYNX CARCINOMA
La présente invention concerne le N-hydroxy-4-{2-[3-(7V,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide de formule (I) : The present invention relates to N-hydroxy-4- {2- [3- (7V, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide of formula (I):
Figure imgf000003_0001
Figure imgf000003_0001
ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, en association avec un traitement de chimiothérapie ou de radiothérapie, pour son utilisation dans le traitement du carcinome du nasopharynx.  or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with a chemotherapy or radiotherapy treatment, for use in the treatment of nasopharyngeal carcinoma.
Le N-hydroxy-4-{2-[3-(iV)N-diméthylaminométhyl)benzofuran-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- (iV) N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is a potent inhibitor of histone deacetylases (HDAC) is described in the patent application WO2004 / 092115. 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.
Dans la présente invention, l'utilisation du N-hydroxy-4-{2-[3-(JV,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide de formule (I) ou de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, en association avec un traitement de chimiothérapie ou de radiothérapie, est proposée pour le traitement du carcinome du nasopharynx. In the present invention, the use of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide of formula (I) or of its addition salts with a pharmaceutically acceptable acid or base, in combination with a chemotherapy or radiotherapy treatment, is proposed for the treatment of nasopharyngeal carcinoma.
Le carcinome du nasopharynx est une pathologie unique en terme de distribution géographique et d'association biologique avec le virus d'Epstein-Barr (Liebowitz D. Semin Oncol 1994 ;21 : 376-381). Il présente une incidence faible en Europe et aux USA, mais bien plus élevée en Chine et en Asie du Sud-Est. Ce carcinome est également caractérisé par un fort facteur étiologique associé à des prédispositions génétiques et à la consommation d'aliments en conserve ou surgelés. Le traitement de référence consiste aujourd'hui en l'administration de cisplatine en association avec la radiothérapie (Ma Brigette et al. Cancer Science 2008 ; 99(7) : 1311-1318). Cependant, l'efficacité du traitement dépend fortement du stade de l'évolution de la maladie avec un taux de guérison de plus de 85% lorsque les patients sont traités à un stade précoce, ce taux tombant en- dessous de 30% pour les stades les plus avancés (Lee AW et al. Int. J. Radiât. Oncol. Biol. Phys. 1992 ; 23(2) :261-270). De plus, les complications consécutives au traitement posent de sérieux problèmes ; l'irradiation conduit souvent à de sévères séquelles fonctionnelles. On observe également que les lésions métastatiques deviennent résistantes aux chimiothérapies basées sur des dérivés du platine au bout de quelques mois de traitement. Dans ce contexte, la recherche de nouvelles alternatives thérapeutiques en oncologie reste toujours d'actualité. En particulier, re-sensibiliser les patients résistants aux chimiothérapies déjà validées cliniquement constitue une stratégie thérapeutique à explorer. Nasopharyngeal carcinoma is a unique pathology in terms of geographical distribution and biological association with the Epstein-Barr virus (Liebowitz D. Semin Oncol 1994; 21: 376-381). It has a low incidence in Europe and the USA, but much higher in China and Southeast Asia. This carcinoma is also characterized by a strong etiological factor associated with genetic predispositions and the consumption of canned or frozen foods. The standard treatment today is the administration of cisplatin in combination with radiotherapy (Ma Brigette et al., Cancer Science 2008; 99 (7): 1311-1318). However, the effectiveness of the treatment is highly dependent on the stage of disease progression with a cure rate of more than 85% when patients are treated at an early stage, this rate falling below 30% for stadiums. the most advanced (Lee AW et al., J. Radiat Oncol Biol Phys 1992, 23 (2): 261-270). In addition, complications following treatment pose serious problems; Irradiation often leads to severe functional sequelae. It is also observed that metastatic lesions become resistant to chemotherapy based on platinum derivatives after a few months of treatment. In this context, the search for new therapeutic alternatives in oncology is still relevant today. In particular, re-sensitizing patients resistant to chemotherapy already clinically validated is a therapeutic strategy to explore.
Dans un aspect de l'invention, il a été montré que l'association 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, avec le cisplatine présentait des propriétés synergiques remarquables dans certaines lignées cellulaires tumorales de carcinome du nasopharynx. De plus, un effet synergique du N-hydroxy-4-{2- [3-(N,N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide en association avec la radiothérapie dans certaines de ces lignées a également été observé. Ces résultats mettent en évidence un possible intérêt thérapeutique du N-hydroxy-4-{2-[3- (N,N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide dans le traitement du carcinome du nasopharynx, et plus particulièrement lorsqu'il est utilisé en association avec un traitement de chimiothérapie ou de radiothérapie. In one aspect of the invention, the combination of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide or its salts has been shown addition to a pharmaceutically acceptable acid or base with cisplatin exhibited remarkable synergistic properties in certain tumor cell lines of nasopharyngeal carcinoma. In addition, a synergistic effect of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide in combination with radiotherapy in some of these lines was also observed. These results demonstrate a possible therapeutic interest of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide in the treatment of nasopharyngeal carcinoma, and more particularly when it is used in combination with a chemotherapy or radiotherapy treatment.
De manière préférentielle, le N-hydroxy-4-{2-[3-(N,N-diméthylaminométhyl)benzofuran- 2-ylcarbonylamino]éthoxy}benzamide est utilisé en association avec le cisplatine. Ainsi, on peut envisager des traitements associant le N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide à des doses thérapeutiques de cisplatine inférieures à celles classiquement utilisées, avec une réponse tumorale équivalente voire supérieure et une toxicité moindre (en particulier l'ototoxicité et la neurotoxicité) dans le carcinome du nasopharynx. Preferably, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is used in combination with cisplatin. Thus, treatments combining N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide can be envisaged at therapeutic doses of cisplatin that are lower than those conventionally used, with an equivalent or even higher tumor response and lower toxicity (especially ototoxicity and neurotoxicity) in nasopharyngeal carcinoma.
L'invention couvre également l'utilisation du N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide en association avec le cisplatine dans le carcinome du nasopharynx chez les patients résistants aux chimiothérapies basées sur des dérivés du platine. The invention also covers the use of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide in combination with cisplatin in nasopharyngeal carcinoma in patients resistant to chemotherapy based on platinum derivatives.
Dans un schéma d'administration clinique selon l'invention, le N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré en association avec le cisplatine par cycles dans lesquels le N-hydroxy-4-{2-[3-(N,iV- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant n+1 jours consécutifs, cette période étant suivie de n jours consécutifs sans traitement, étant entendu que n est un nombre entier compris entre 1 et 10, par exemple, 1 , 2, 3, 4, 5, 6, 7, 8, 9, ou 10. In a clinical administration scheme according to the invention, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered in combination with cisplatin in cycles. wherein N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for n + 1 consecutive days, this period being followed by n consecutive days without treatment with the proviso that n is an integer from 1 to 10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
Dans le schéma d'administration clinique préféré, le jV-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant 4 jours consécutifs, suivis de 3 jours consécutifs sans traitement, et ce pendant les deux premières semaines d'un cycle constitué de trois semaines. Le cisplatine est administré le troisième jour de chaque cycle de traitement. Aucun traitement n'est administré pendant la troisième semaine du cycle. Λ- In the preferred clinical administration scheme, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for 4 consecutive days, followed by 3 consecutive days. without treatment for the first two weeks of a three-week cycle. Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle. Λ-
Dans un autre mode de réalisation préféré de l'invention, le N-hydroxy-4-{2-[3-(N,iV- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est utilisé en association avec la radiothérapie. In another preferred embodiment of the invention, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is used in combination with radiation therapy.
Dans un schéma d'administration clinique selon l'invention, le N-hydroxy-4-{2-[3-(jV,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré en association avec la radiothérapie par cycles dans lesquels le N-hydroxy-4-{2-[3-(N,iV- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant n+1 jours consécutifs, cette période étant suivie de n jours consécutifs sans traitement, étant entendu que n est un nombre entier compris entre 1 et 10, par exemple, 1 , 2, 3, 4, 5, 6, 7, 8, 9, ou 10. Plus préférentiellement, n est égal à 3. In a clinical administration scheme according to the invention, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered in combination with cycle radiotherapy. wherein N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for n + 1 consecutive days, this period being followed by n consecutive days without treatment , it being understood that n is an integer between 1 and 10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. More preferably, n is equal to 3.
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. Preferably, 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 un schéma d'administration clinique préféré, le chlorhydrate du N-hydroxy-4-{2-[3- (iV,iV-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant 4 jours consécutifs, suivis de 3 jours consécutifs sans traitement, et ce pendant les deux premières semaines d'un cycle constitué de trois semaines. Le cisplatine est administré le troisième jour de chaque cycle de traitement. Aucun traitement n'est administré pendant la troisième semaine du cycle. Dans un mode de réalisation préféré, le N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy } benzamide est administré sous forme orale. In a preferred clinical administration scheme, the hydrochloride of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for 4 consecutive days, followed by 3 consecutive days without treatment for the first two weeks of a three-week cycle. Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle. In a preferred embodiment, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered orally.
Dans un schéma d'administration clinique préféré, une formulation orale du N-hydroxy-4- {2-[3-(N,N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administrée pendant 4 jours consécutifs, suivis de 3 jours consécutifs sans traitement, et ce pendant les deux premières semaines d'un cycle constitué de trois semaines. Le cisplatine est administré le troisième jour de chaque cycle de traitement. Aucun traitement n'est administré pendant la troisième semaine du cycle. In a preferred clinical administration scheme, an oral formulation of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for 4 consecutive days, followed by 3 consecutive days without treatment for the first two weeks of a three-week cycle. Cisplatin is administered on the third day of each treatment cycle. No treatment is given during the third week of the cycle.
Dans un schéma d'administration clinique préféré, une formulation orale du chlorhydrate de N-hydroxy-4-{2-[3-(NN-diméthylaminométhyl)benzofuran-2-ylcarbonylamino] éthoxy}benzamide est administrée pendant 4 jours consécutifs, suivis de 3 jours consécutifs sans traitement, et ce pendant les deux premières semaines d'un cycle constitué de trois semaines. Le cisplatine est administré le troisième jour de chaque cycle de traitement. Aucun traitement n'est administré pendant la troisième semaine du cycle. In a preferred clinical administration scheme, an oral formulation of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide hydrochloride is administered for 4 consecutive days, followed by 3 consecutive days without treatment for the first two weeks of a three-week cycle. Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle.
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 360 mg de N-hydroxy-4-{2-[3-(N,N-diméthylaminométhyl)benzofuran-2- ylcarbonylamino]éthoxy}benzamide par jour. Quant au cisplatine, la dose administrée varie entre 50 et 100 mg/m . La dose préférée est de 75 mg/m . 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 360 mg of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide per day. As for cisplatin, the dose administered varies between 50 and 100 mg / m. The preferred dose is 75 mg / m.
Etude pré-clinique : Activité antitumorale in vitro Pre-clinical study: In vitro antitumor activity
L'ef et antiprolifératif du chlorhydrate de N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide, utilisé seul ou en association avec le cisplatine, a été évalué sur quatre lignées cellulaires tumorales humaines : The ef and antiproliferative effect of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide hydrochloride, used alone or in combination with cisplatin, was evaluated on four human tumor cell lines:
- 1 carcinome du nasopharynx positif au virus d'Epstein-Barr, C666- 1 , C 15 et C 17, 1 nasopharyngeal carcinoma positive for Epstein-Barr virus, C666-1, C15 and C17,
1 carcinome du nasopharynx négatif au virus d'Epstein-Barr, HONE1. 1 nasopharyngeal carcinoma negative to Epstein-Barr virus, HONE1.
Les cellules sont mises en culture en présence des composés à tester pendant 48 heures. La viabilité cellulaire est ensuite quantifiée par un essai colorimétrique, le « Microculture Tetrazolium assay » (MTT assay). Le traitement combiné du N-hydroxy-4-{2-[3-(NN-diméthylaminométhyl)benzofuran-2- ylcarbonylamino]éthoxy}benzamide (aussi appelé composé 1) et du cisplatine (aussi appelé CDDP) montre une augmentation significative de l'inhibition de croissance des cellules exposées à l'association des deux composés par comparaison avec l'effet observé pour chacun des produits seuls (voir Figure 1). The cells are cultured in the presence of test compounds for 48 hours. The cell viability is then quantified by a colorimetric assay, the "Microculture Tetrazolium assay" (MTT assay). The combined treatment of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide (also called compound 1) and cisplatin (also called CDDP) shows a significant increase in inhibition of growth cells exposed to the combination of the two compounds compared to the effect observed for each of the products alone (see Figure 1).
En outre, l'effet antiprolifératif du chlorhydrate de N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide, utilisé seul ou en association avec la radiothérapie, a été évalué sur la lignée cellulaire tumorale Cl 7. Les cellules sont mises en culture en présence du composé 1 et irradiées à 2 Gy 24 heures plus tard. La viabilité cellulaire est ensuite quantifiée après 48 heures de culture par le test MTT (voir Figure 2). In addition, the antiproliferative effect of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide hydrochloride, used alone or in combination with radiotherapy, has been evaluated on the tumor cell line Cl 7. The cells are cultured in the presence of compound 1 and irradiated at 2 Gy 24 hours later. The cell viability is then quantified after 48 hours of culture by the MTT test (see Figure 2).
Les résultats mettent clairement en évidence que l'administration du N-hydroxy-4-{2-[3- (N,N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide en association avec le cisplatine ou la radiothérapie permet d'obtenir un effet synergique remarquable. The results clearly demonstrate that the administration of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide in combination with cisplatin or radiotherapy allows achieve a remarkable synergistic effect.
Activité antitumorale in vivo Antitumor activity in vivo
L'activité antitumorale des composés de l'invention est évaluée dans deux modèles de xénogreffes de cellules de carcinome du nasopharynx décrits ci-dessus, Cl 5 et Cl 7. The antitumor activity of the compounds of the invention is evaluated in two models of nasopharyngeal carcinoma cell xenografts described above, Cl 5 and Cl 7.
Des fragments de tumeur Cl 5 ou Cl 7 sont greffés par voie sous-cutanée dans des souris immunodéprimées (Swiss Nude). Lorsque le volume tumoral atteint entre 100 et 150 mm3, les différents traitements débutent. Les animaux sont traités pendant trois semaines consécutives. Cl 5 or Cl 7 tumor fragments are grafted subcutaneously into immunocompromised (Swiss Nude) mice. When the tumor volume reaches between 100 and 150 mm 3 , the different treatments begin. The animals are treated for three consecutive weeks.
Dans le cas de l'association du jV-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide et du cisplatine, les produits sont administrés par voie intra-péritonéale : In the case of the combination of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide and cisplatin, the products are administered intraperitoneally:
• deux fois par jour, 4 jours par semaine (J1-J4) à la dose de 12,5 mg/kg/injection pendant 3 semaines en ce qui concerne le N-hydroxy-4-{2-[3-(NN- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide, • twice daily, 4 days per week (D1-D4) at the dose of 12.5 mg / kg / injection for 3 weeks for N-hydroxy-4- {2- [3- (NN dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide,
• une fois par semaine (J3) à la dose de 2 mg/kg/injection en ce qui concerne le cisplatine. Les animaux sont pesés et leur volume tumoral est mesuré deux fois par semaine à partir du premier jour de traitement. • once a week (D3) at a dose of 2 mg / kg / injection for cisplatin. The animals are weighed and their tumor volume is measured twice a week from the first day of treatment.
Les résultats présentés dans la Figure 3 montrent que le traitement associant le N-hydroxy- 4-{2-[3-(N, N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]ét oxy}benzamide et le cisplatine inhibe significativement la croissance tumorale dans les deux modèles évalués (Cl 5 et Cl 7) avec un effet synergique. L'effet de l'association est supérieur dans les deux modèles à l'effet des produits seuls. The results presented in Figure 3 show that treatment combining N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] oxy} benzamide and cisplatin significantly inhibits tumor growth. in both evaluated models (Cl 5 and Cl 7) with a synergistic effect. The effect of the association is greater in both models to the effect of the products alone.
Ktudc clinique : Clinical Ktudc:
Une étude clinique de phase I pour tester l'association du chlorhydrate de N-hydroxy-4-{2- [3-(N)N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide avec le cisplatine dans le traitement du carcinome du nasopharynx est réalisée sur environ 40 patients. Les patients reçoivent au maximum six cycles de traitement en association, chacun des cycles se déroulant de la manière suivante : le N-hydroxy-4-{2-[3-(N,jV- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant 4 jours consécutifs, suivis de 3 jours consécutifs sans traitement, et ce pendant les deux premières semaines d'un cycle de trois semaines. Le cisplatine est administré le troisième jour de chaque cycle de traitement. Aucun traitement n'est administré pendant la troisième semaine du cycle. A phase I clinical trial to test the combination of N-hydroxy-4- {2- [3- (N ) N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide hydrochloride with cisplatin in the treatment of carcinoma nasopharynx is performed on approximately 40 patients. Patients receive a maximum of six cycles of combination therapy, each of which is conducted in the following manner: N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} Benzamide is administered for 4 consecutive days, followed by 3 consecutive days without treatment, during the first two weeks of a three-week cycle. Cisplatin is given on the third day of each treatment cycle. No treatment is given during the third week of the cycle.
Les jours concernés, la dose journalière de 7V-hydroxy-4-{2-[3-(NN- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy} benzamide est comprise entre 80 et 280 mg, à raison de deux prises p.o. espacées de 4 h. Le cisplatine est administré à la dose fixe de 75 mg/m2. On the days concerned, the daily dose of 7V-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is between 80 and 280 mg, with two doses in between 4 hrs. Cisplatin is administered at a fixed dose of 75 mg / m 2 .
Le patient continue le traitement en combinaison pendant six cycles au maximum. A la fin du deuxième cycle, l'efficacité du traitement est appréciée via l'évaluation de la réponse tumorale (CT-scan, IRM,...).  The patient continues the combination treatment for up to six cycles. At the end of the second cycle, the effectiveness of the treatment is assessed via the evaluation of the tumor response (CT-scan, MRI, ...).

Claims

REVENDICATIONS
I2 jV-hydroxy-4- {2- [3 -(N, N-diméthylaminométhyl)benzofuran-2-ylcarbonyl 12-hydroxy-4- {2- [3 - (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonyl}
éthoxy}benzamide de formule (I) :  ethoxy} benzamide of formula (I):
Figure imgf000011_0001
Figure imgf000011_0001
ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, en association avec un traitement de chimiothérapie ou de radiothérapie, pour son utilisation dans le traitement du carcinome du nasopharynx.  or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with a chemotherapy or radiotherapy treatment, for use in the treatment of nasopharyngeal carcinoma.
2 Composé de formule (I) selon la revendication l .tel qu'il est utilisé sous la forme d'un chlorhydrate. Compound of formula (I) according to claim 1, which is used in the form of a hydrochloride.
3; Composé de formule (I) selon la revendication 1 ou 2 en association avec le cisplatine, pour son utilisation dans le traitement du carcinome du nasopharynx. ; Composé de formule (I) selon la revendication 3 pour son utilisation dans le traitement du carcinome du nasopharynx chez les patients résistants aux chimiothérapies basées sur des dérivés du platine. 3; Compound of formula (I) according to claim 1 or 2 in combination with cisplatin for its use in the treatment of nasopharyngeal carcinoma. ; Compound of formula (I) according to claim 3 for use in the treatment of nasopharyngeal carcinoma in patients resistant to chemotherapy based on platinum derivatives.
5; Composé de formule (I) selon la revendication 3 ou 4 pour son utilisation dans le traitement du carcinome du nasopharynx, dans laquelle le N-hydroxy-4-{2-[3-(N,N- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est administré pendant 4 jours consécutifs, suivis de 3 jours consécutifs sans traitement pendant les deux premières semaines d'un cycle constitué 'de trois semaines, tandis que le cisplatine est administré au troisième jour de chaque cycle de traitement. ; Composé de formule (I) selon la revendication 1 ou 2 en association avec la radiothérapie pour son utilisation dans le traitement du carcinome du nasopharynx. 5; Compound of formula (I) according to claim 3 or 4 for use in the treatment of nasopharyngeal carcinoma, wherein N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino ] ethoxy} benzamide is administered for 4 consecutive days, followed by 3 consecutive days without treatment during the first two weeks of a three-week cycle, while cisplatin is administered on the third day of each treatment cycle. ; Compound of formula (I) according to claim 1 or 2 in combination with radiotherapy for use in the treatment of nasopharyngeal carcinoma.
Utilisation du N-hydroxy-4-{2-[3-(N,N-diméthylaminométhyl)benzofuran-2-yl carbonylamino]éthoxy}benzamide de formule (I) : Use of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide of formula (I):
Figure imgf000012_0001
ou d'un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, en association avec un traitement de chimiothérapie ou de radiothérapie, pour la fabrication d'un médicament destiné au traitement du carcinome du nasopharynx. ; Utilisation selon la revendication 7 dans laquelle le N-hydroxy-4-{2-[3-(NN- diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy}benzamide est utilisé sous la forme d'un chlorhydrate. z Utilisation du composé de formule (I) selon la revendication 7 ou 8 en association avec le cisplatine pour la fabrication d'un médicament destiné au traitement du carcinome du nasopharynx. -I L
Figure imgf000012_0001
or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with a chemotherapy or radiotherapy treatment, for the manufacture of a medicament for the treatment of nasopharyngeal carcinoma. ; Use according to claim 7 wherein N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is used in the form of a hydrochloride. Use of the compound of formula (I) according to claim 7 or 8 in combination with cisplatin for the manufacture of a medicament for the treatment of nasopharyngeal carcinoma. -HE
10- Utilisation du composé de formule (I) selon la revendication 9 en association avec le cisplatine pour la fabrication d'un médicament destiné au traitement du carcinome du nasopharynx chez les patients résistants aux chimiothérapies basées sur des dérivés du platine. 10- Use of the compound of formula (I) according to claim 9 in combination with cisplatin for the manufacture of a medicament for the treatment of nasopharyngeal carcinoma in patients resistant to chemotherapy based on platinum derivatives.
11- Utilisation d'une association selon la revendication 9 ou 10 telle que le N-hydroxy- 4- { 2- [3 -(N, N-diméthylaminométhyl)benzofuran-2-ylcarbonylamino]éthoxy } benzamide est administré pendant 4 jours consécutifs, suivis de 3 jours consécutifs sans traitement pendant les deux premières semaines d'un cycle constitué de trois semaines, tandis que le cisplatine est administré au troisième jour de chaque cycle de traitement. 11- Use of a combination according to claim 9 or 10 such that N-hydroxy-4- {2- [3 - (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide is administered for 4 consecutive days followed by 3 consecutive days without treatment during the first two weeks of a three-week cycle, while cisplatin is given on the third day of each treatment cycle.
12- Utilisation du composé de formule (I) selon la revendication 7 ou 8 en association avec la radiothérapie pour la fabrication d'un médicament destiné au traitement du carcinome du nasopharynx. 12- Use of the compound of formula (I) according to claim 7 or 8 in combination with radiotherapy for the manufacture of a medicament for the treatment of carcinoma of the nasopharynx.
PCT/FR2012/000550 2011-12-23 2012-12-21 Novel combinations containing n-hydroxy-4-(2-[3-(n, n-dimethylaminomethyl) benzofuran-2-ylcarbonylamino]ethoxy)benzamide in nasopharyngeal carcinoma WO2013093248A1 (en)

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