WO1993023389A1 - Novel taxane derivatives, their preparation and compositions containing same - Google Patents

Novel taxane derivatives, their preparation and compositions containing same Download PDF

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Publication number
WO1993023389A1
WO1993023389A1 PCT/FR1993/000477 FR9300477W WO9323389A1 WO 1993023389 A1 WO1993023389 A1 WO 1993023389A1 FR 9300477 W FR9300477 W FR 9300477W WO 9323389 A1 WO9323389 A1 WO 9323389A1
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Prior art keywords
carbon atoms
radical
alkyl
atoms
radicals
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PCT/FR1993/000477
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French (fr)
Inventor
Jean-Dominique Bourzat
Alain Commerçon
Original Assignee
Rhone-Poulenc Rorer S.A.
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Application filed by Rhone-Poulenc Rorer S.A. filed Critical Rhone-Poulenc Rorer S.A.
Priority to JP5519950A priority Critical patent/JPH07506586A/en
Priority to EP93910129A priority patent/EP0641334A1/en
Priority to SK1399-94A priority patent/SK139994A3/en
Publication of WO1993023389A1 publication Critical patent/WO1993023389A1/en
Priority to NO944141A priority patent/NO944141D0/en
Priority to FI945439A priority patent/FI945439A0/en
Priority to KR1019940704156A priority patent/KR950701629A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D305/00Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Definitions

  • the present invention relates to new taxane derivatives of general formula
  • Ar represents an aryl radical
  • Ri represents a hydrogen atom or an acetyl radical or a radical of general formula: o
  • R ⁇ and R.2, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, or else R j and R2 form together with the nitrogen atom to which they are linked a heterocycle, saturated or unsaturated, with 5 or 6 links optionally containing a second heteroatom chosen from nitrogen atoms (optionally substituted by an alkyl radical containing 1 to 4 carbon or benzyl atoms), oxygen and of sulfur, n is 2 or 3, and R represents
  • alkyl radical containing 1 to 8 carbon atoms alkenyl containing 3 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radi ⁇ cals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 with 4 carbon atoms, piperidino, morpholino, pifugrazinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms
  • cycloalkyl, cycloalkenyl or bicycloalkyl radicals can optionally be substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.
  • Ar represents a phenyl or a- or ⁇ -naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl radicals, aryls, arylalkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, carbamoyl, dialkoyl, carbamoyl understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms
  • the new taxane derivatives of general formula (I) can be obtained by heating a derivative of general formula:
  • OCOC 6 H 5 in which R, R ⁇ and Ar are defined as above, in solution in an aliphatic alcohol containing 1 to 4 carbon atoms (methanol, ethanol, propanol, isopropanol) at a temperature between 20 ° C and 97 ° C in the presence of 'a catalytic amount of Lewis acid such as zinc bromide.
  • the duration of the heating can vary from 6 hours to 8 days.
  • R is defined as above and X represents a halogen atom (fluorine, chlorine) or a residue -OR or -O-CO-OR, on a derivative of baccatin III or of 10-deacetyl baccatin III of general formula:
  • G represents a protective group for the hydroxy function such as a 2,2,2-trichloroethoxycarbonyl or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radical in which each alkyl part contains 1 to 4 carbon atoms and each aryl part preferably represents a phenyl radical and G2 represents an acetyl radical or a protecting group for the hydroxy function such as a 2,2,2,2-trichloroethoxycarbonyl radical, to give a product of general formula:
  • the derivative of baccatin DI or of desacetyl-10 baccatin III of general formula (V) can be obtained by the action of a mineral or organic acid, under conditions which have no effect on the protective groups G and G2, on a product of general formula:
  • Boc represents the tert-butoxycarbonyl radical and R2 and R3, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by one or two aryl (phenyl) or aryl (phenyl) radicals or else R2 and R3 form together with the carbon atom to which they are linked a ring having from 4 to 7 members.
  • the product of formula (Vu) can be obtained by the action of an oxazolidine derivative of general formula:
  • oxa-zolidine derivative of general formula (NUI) can be obtained by saponification in basic medium of the corresponding ester which is itself obtained by the action of a methoxyalkene optionally substituted by one or more aryl radicals, of a gem-dimethoxyalkane optionally substituted by tm or more aryl radi ⁇ or a gem-dimethoxycycloalkane containing 4 to 7 carbon atoms on a phenylisoserine derivative of general formula:
  • R4 represents an alkyl radi ⁇ cal containing 1 to 4 carbon atoms optionally substituted by t radi ⁇ phenyl.
  • the product of general formula (X) can be obtained by acylation of a ⁇ -phenylisoserine derivative of general formula:
  • the ⁇ -phenylisoserine derivative of general formula (XI) can be obtained according to known methods and in particular from ⁇ -phenylglycidic acid under the conditions described by JN. Denis et al., J. Org. Chem., 5L 46-50 (1986).
  • the derivatives of general formula (DI) in which Rj represents a radical of general formula (H) in which Rj, R2 and n are defined as above can be obtained by the action of an amine of general formula:
  • a white meringue 2.5 g of a white meringue are obtained which is purified by chromatography on 60 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter [eluent: dichloromethane-methanol (98-2 by volume)] by collecting fractions of 20 cm3. Fractions 19 to 35 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1.2 g of a white meringue are thus obtained, which is again purified by a second chromatography on 60 g of silica.
  • the new products of general formula (I) present particularly interesting biological activities.
  • the new products of general formula (I) demonstrate a significant inhibitory activity against abnormal cell proliferation and have therapeutic properties allowing the treatment of patients with pathological conditions associated with abnormal cell proliferation.
  • Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, lymphatic or renal systems, mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands.
  • pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas.
  • the new products according to the invention are particularly useful for the treatment of ovarian cancer.
  • the products according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.
  • the products according to the invention can be administered to a patient in different forms adapted to the chosen route of administration which, preferably, is the parenteral route.
  • Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.
  • the present invention also comprises the pharmaceutical compositions which contain at least one product of general formula (Ia) in a sufficient quantity suitable for use in human or veterinary therapy.
  • the compositions can be prepared according to the usual methods using one or more adjuvants, carriers or pharmaceutically acceptable excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
  • Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
  • the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifying agents, dyes, preservatives or stabilizers.
  • adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices.
  • aqueous or non-aqueous sterile solutions or suspensions are used.
  • non-aqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate .
  • the sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water.
  • the aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.
  • compositions according to the invention can contain at least 0.01% of therapeutically active product.
  • the amount of active ingredient in a composition is such that a suitable dosage can be prescribed.
  • the compositions are prepared in such a way that a unit dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.
  • Therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses.
  • Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons ( ⁇ , ⁇ or ⁇ ) and TNF.
  • chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogues such as fluorouracil and cytarabine, purine analogs such as mercaptopurine and tWoguanine, natural products such as vinca alkaloids such as vinblastine, vincristine and vendesin, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin
  • the doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response.
  • the doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation.
  • the products according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to relatively large or low doses and may require low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasing doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient considered. It is also possible that for some patients it is necessary to use only one or two daily administrations.
  • the doses are generally between 0.01 and 200 mg kg. Intraperitoneally, the doses will generally be between 0.1 and 100 mg kg and, preferably between 0.5 and 50 mg / kg and, even more specifically between 1 and 10 mg / kg. Intravenously, the doses are generally between 0.1 and 50 mg / kg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the efficacy must be taken into account. of treatment.
  • Example 2 40 mg of the product obtained in Example 1 are dissolved in 1 cm 3 of Emulphor EL 620 and 1 cm 3 of ethanol then the solution is diluted by adding 18 cm 3 of physiological saline.
  • composition is administered by introduction into an infusion of a physiological solution for 1 hour.

Abstract

Novel taxane derivatives of formula (I), their preparation and pharmaceutical compositions containing same. In general formula (I), Ar is an aryl radical, R1? is a hydrogen atom or an acetyl radical or a radical according to formula (II) (wherein R1? and R2? denote hydrogen, alkyl or together form a heterocycle, n is equal to 2 or 3), R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl. The novel products of general formula (I) have outstanding tumour prevention activity.

Description

NOUVEAUX DERIVES DU TAXANE. LEUR PREPARATION ET LES COMPOSITIONS OUI LES CONTIENNENT NEW TAXANE DERIVATIVES. THEIR PREPARATION AND THE COMPOSITIONS YES CONTAINING THEM
La présente invention concerne de nouveaux dérivés du taxane de formule généraleThe present invention relates to new taxane derivatives of general formula
Figure imgf000003_0001
OCOC6H5 leur préparation et les compositions pharmaceutiques qui les contiennent.
Figure imgf000003_0001
OCOC 6 H 5 their preparation and the pharmaceutical compositions which contain them.
Dans la formule générale (I), Ar représente un radical aryle, Ri représente un atome d'hydrogène ou un radical acétyle ou un radical de formule générale : oIn the general formula (I), Ar represents an aryl radical, Ri represents a hydrogen atom or an acetyl radical or a radical of general formula: o
*κ N-(CH?)n-NH-C II- (II)* κ N- (CH ? ) n-NH-C II- (II)
/ R2 dans laquelle :/ R 2 in which:
R\ et R.2, identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle contenant 1 à 4 atomes de carbone en chaîne droite ou ramifiée, ou bien Rj et R2 forment ensemble avec l'atome d'azote auquel ils sont liés un heterocycle, saturé ou non saturé, à 5 ou 6 chaînons contenant éventuellement un second hétéroatome choisi parmi les atomes d'azote (éventuellement substitué par un radical alkyle contenant 1 à 4 atomes de carbone ou benzyle), d'oxygène et de soufre, n est égal à 2 ou 3, et R représenteR \ and R.2, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, or else R j and R2 form together with the nitrogen atom to which they are linked a heterocycle, saturated or unsaturated, with 5 or 6 links optionally containing a second heteroatom chosen from nitrogen atoms (optionally substituted by an alkyl radical containing 1 to 4 carbon or benzyl atoms), oxygen and of sulfur, n is 2 or 3, and R represents
- un radical alcoyle droit ou ramifié contenant 1 à 8 atomes de carbone, alcényle contenant 3 à 8 atomes de carbone, alcynyle contenant 3 à 8 atomes de carbone, cycloalcoyle contenant 3 à 6 atomes de carbone, cycloalcényle contenant 4 à 6 atomes de carbone ou bicycloalcoyle contenant 7 à 10 atomes de carbone, ces radi¬ caux étant éventuellement substitués par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux hydroxy, alcoyloxy contenant 1 à 4 atomes de carbone, dialcoylamino dont chaque partie alcoyle contient 1 à 4 atomes de carbone, pipéridino, morpholino, pipérazinyl-1 (éventuellement substitué en -4 par un radical alcoyle contenant 1 à 4 atomes de carbone ou par un radical phénylalcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone), cycloalcoyle contenant 3 à 6 atomes de carbone, cycloalcényle contenant 4 à 6 atomes de carbone, phényle, cyano, carboxy ou alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone,- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 3 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radi¬ cals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 with 4 carbon atoms, piperidino, morpholino, pipérazinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms , cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl in which the alkyl part contains 1 to 4 carbon atoms,
- ou un radical phényle éventuellement substitué par un ou plusieurs atomes ou radi¬ caux choisis parmi les atomes d'halogène et les radicaux alcoyles contenant 1 à 4 atomes de carbone, alcoyloxy contenant 1 à 4 atomes de carbone, - ou un radical hétérocyclyle azoté saturé ou non saturé contenant 5 ou 6 chaînons et éventuellement substitué par un ou plusieurs radicaux alcoyles contenant 1 à 4 atomes de carbone, étant entendu que les radicaux cycloalcoyles, cycloalcényles ou bicycloalcoyles peu¬ vent être éventuellement substitués par un ou plusieurs radicaux alcoyles contenant 1 à 4 atomes de carbone.- or a phenyl radical optionally substituted by one or more atoms or radiols chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, - or a heterocyclyl nitrogen radical saturated or unsaturated containing 5 or 6 links and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can optionally be substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.
De préférence Ar représente un radical phényle ou a- ou β-naphtyle éven¬ tuellement substitué par un ou plusieurs atomes ou radicaux choisis parmi les atomes d'halogène (fluor, chlore, brome, iode) et les radicaux alcoyles, alcényles, alcynyles, aryles, arylalcoyles, alcoxy, alcoylthio, aryloxy, arylthio, hydroxy, hydroxyalcoyle, mercapto, formyle, acyle, acylamino, aroylamino, alcoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alcoxycarbonyle, carbamoyle, dialcoylcarba- moyle, cyano, nitro ettrifluorométhyle, étant entendu que les radicaux alcoyles et les portions alcoyles des autres radicaux contiennent 1 à 4 atomes de carbone que les radicaux alcényles et alcynyles contiennent 3 à 8 atomes de carbone et que les radi- eaux aryles sont des radicaux phényles ou a- ou β-naphtyles.Preferably Ar represents a phenyl or a- or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl radicals, aryls, arylalkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, carbamoyl, dialkoyl, carbamoyl understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms and that the aryl radicals are phenyl or a- or β-naphthyl radicals .
Selon la présente invention, les nouveaux dérivés du taxane de formule générale (I) peuvent être obtenus par chauffage d'un dérivé de formule générale :According to the present invention, the new taxane derivatives of general formula (I) can be obtained by heating a derivative of general formula:
Figure imgf000004_0001
Figure imgf000004_0001
OCOC6H5 dans laquelle R, R^ et Ar sont définis comme précédemment, en solution dans un alcool aliphatique contenant 1 à 4 atomes de carbone (méthanol, éthanol, propanol, isopropanol) à une température comprise entre 20°C et 97°C en présence d'une quantité catalytique d'acide de Lewis tel que le bromure de zinc. La durée du chauffage peut varier de 6 heures à 8 jours.OCOC 6 H 5 in which R, R ^ and Ar are defined as above, in solution in an aliphatic alcohol containing 1 to 4 carbon atoms (methanol, ethanol, propanol, isopropanol) at a temperature between 20 ° C and 97 ° C in the presence of 'a catalytic amount of Lewis acid such as zinc bromide. The duration of the heating can vary from 6 hours to 8 days.
Les dérivés du taxane de formule générale (III) dans laquelle Rj représente un atome d'hydrogène ou un radical acétyle peuvent être obtenus par action d'un dérivé réactif de formule générale :The taxane derivatives of general formula (III) in which Rj represents a hydrogen atom or an acetyl radical can be obtained by the action of a reactive derivative of general formula:
R-O-CO-X (IN)R-O-CO-X (IN)
dans laquelle R est défini comme précédemment et X représente tm atome d'halo¬ gène (fluor, chlore) ou un reste -O-R ou -O-CO-OR, sur un dérivé de la baccatine III ou de la désacétyl-10 baccatine III de formule générale :in which R is defined as above and X represents a halogen atom (fluorine, chlorine) or a residue -OR or -O-CO-OR, on a derivative of baccatin III or of 10-deacetyl baccatin III of general formula:
Figure imgf000005_0001
dans laquelle Ar est défini comme précédemment, G représente un groupement protecteur de la fonction hydroxy tel qu'un radical trichloro-2,2,2 éthoxycarbonyle ou trialkylsilyle, dialkylarylsilyle, alkyldiarylsilyle ou triarylsilyle dans lequel chaque partie alkyle contient 1 à 4 atomes de carbone et chaque partie aryle repré¬ sente de préférence un radical phényle et G2 représente un radical acétyle ou un groupement protecteur de la fonction hydroxy tel qu'un radical trichloro-2,2,2 éthoxycarbonyle, pour donner un produit de formule générale :
Figure imgf000005_0001
in which Ar is defined as above, G represents a protective group for the hydroxy function such as a 2,2,2-trichloroethoxycarbonyl or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radical in which each alkyl part contains 1 to 4 carbon atoms and each aryl part preferably represents a phenyl radical and G2 represents an acetyl radical or a protecting group for the hydroxy function such as a 2,2,2,2-trichloroethoxycarbonyl radical, to give a product of general formula:
Figure imgf000005_0002
Figure imgf000005_0002
5COC6H5 dans laquelle Ar, R, G et G2 sont définis comme précédemment, suivie du rempla¬ cement des groupements G^ et éventuellement G2 par des atomes d'hydrogène pour donner le produit de formule générale (lu) .5COC 6 H 5 in which Ar, R, G and G2 are defined as above, followed by the replacement of the groups G ^ and optionally G2 with hydrogen atoms to give the product of general formula (lu).
Le dérivé de la baccatine DI ou de la dêsacétyl-10 baccatine III de formule générale (V) peut être obtenu par action d'un acide minéral ou organique, dans des conditions qui sont sans effet sur les groupements protecteurs G et G2, sur un produit de formule générale :The derivative of baccatin DI or of desacetyl-10 baccatin III of general formula (V) can be obtained by the action of a mineral or organic acid, under conditions which have no effect on the protective groups G and G2, on a product of general formula:
Figure imgf000006_0001
dans laquelle Ar, Gj et G2 sont définis comme précédemment, Boc représente le radical tert-butoxycarbonyle et R2 et R3, identiques ou différents, représentent un atome d'hydrogène ou un radical alcoyle contenant 1 à 4 atomes de carbone, éven¬ tuellement substitué par un ou deux radicaux aryles (phényle) ou aryle (phényle) ou bien R2 et R3 forment ensemble avec l'atome de carbone auquel ils sont liés un cycle ayant de 4 à 7 chaînons. Le produit de formule (Vu) peut être obtenu par action d'un dérivé de l'oxa- zolidine de formule générale :
Figure imgf000006_0001
in which Ar, Gj and G2 are defined as above, Boc represents the tert-butoxycarbonyl radical and R2 and R3, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by one or two aryl (phenyl) or aryl (phenyl) radicals or else R2 and R3 form together with the carbon atom to which they are linked a ring having from 4 to 7 members. The product of formula (Vu) can be obtained by the action of an oxazolidine derivative of general formula:
Figure imgf000006_0002
dans laquelle Ar, 2, R3 et Boc sont définis comme précédemment, éventuellement sous forme d'anhydride sur un dérivé du taxane de formule générale :
Figure imgf000007_0001
Figure imgf000006_0002
in which Ar, 2, R3 and Boc are defined as above, optionally in the form of an anhydride on a taxane derivative of general formula:
Figure imgf000007_0001
ÔCOCgHg dans laquelle G et G2 sont définis comme précédemment, en opérant en présence d'un agent de condensation et d'un agent d'activation dans un solvant organique à une température comprise entre 0 et 90°C. Le dérivé de l'oxa-zolidine de formule générale (NUI) peut être obtenu par saponification en milieu basique de l'ester correspondant qui est lui-même obtenu par action d'un méthoxyalcène éventuellement substitué par un ou plusieurs radicaux aryles, d'un gem-diméthoxyalcane éventuellement substitué par tm ou plusieurs radi¬ caux aryles ou d'un gem-diméthoxycycloalcane contenant 4 à 7 atomes de carbone sur un dérivé de la phénylisosérine de formule générale :ÔCOCgHg in which G and G2 are defined as above, operating in the presence of a condensing agent and an activating agent in an organic solvent at a temperature between 0 and 90 ° C. The oxa-zolidine derivative of general formula (NUI) can be obtained by saponification in basic medium of the corresponding ester which is itself obtained by the action of a methoxyalkene optionally substituted by one or more aryl radicals, of a gem-dimethoxyalkane optionally substituted by tm or more aryl radi¬ or a gem-dimethoxycycloalkane containing 4 to 7 carbon atoms on a phenylisoserine derivative of general formula:
Figure imgf000007_0002
dans laquelle Ar et Boc sont définis comme précédemment et R4 représente un radi¬ cal alcoyle contenant 1 à 4 atomes de carbone éventuellement substitué par t radi¬ cal phényle. Le produit de formule générale (X) peut être obtenu par acylation d'un dérivé de la β-phénylisosérine de formule générale :
Figure imgf000007_0002
in which Ar and Boc are defined as above and R4 represents an alkyl radi¬ cal containing 1 to 4 carbon atoms optionally substituted by t radi¬ phenyl. The product of general formula (X) can be obtained by acylation of a β-phenylisoserine derivative of general formula:
Ar COOR4 Ar COOR 4
/ \ (Xi)/ \ (Xi)
H2Ν OH dans laquelle Ar et R4 sont définis comme précédemment.H 2 Ν OH in which Ar and R4 are defined as above.
Le dérivé de la β-phénylisosérine de formule générale (XI) peut être obtenu selon les méthodes connues et en particulier à partir de l'acide β-phénylglycidique dans les conditions décrites par J-N. Denis et coll., J. Org. Chem., 5L 46-50 (1986). Les dérivés de formule générale (DI) dans laquelle Rj représente un radical de formule générale (H) dans laquelle Rj, R2 et n sont définis comme précédemment peuvent être obtenus par action d'une aminé de formule générale :The β-phenylisoserine derivative of general formula (XI) can be obtained according to known methods and in particular from β-phenylglycidic acid under the conditions described by JN. Denis et al., J. Org. Chem., 5L 46-50 (1986). The derivatives of general formula (DI) in which Rj represents a radical of general formula (H) in which Rj, R2 and n are defined as above can be obtained by the action of an amine of general formula:
R KR K
N-(CH2)n-NH2 (XII)N- (CH 2 ) n-NH 2 (XII)
R /R /
dans laquelle Rj, R2 et n sont définis comme précédemment, sur un dérivé du taxane de formule générale :in which Rj, R2 and n are defined as above, on a taxane derivative of general formula:
Figure imgf000008_0001
Figure imgf000008_0001
OCOC6H5 dans laquelle Ar et R sont définis comme précédemment, suivie du remplacement du groupement protecteur en -7 (CI3CCH2OCO-) par un atome d'hydrogène en opérant à une température inférieure à 50°C.OCOC 6 H 5 in which Ar and R are defined as above, followed by the replacement of the protective group at -7 (CI3CCH2OCO-) by a hydrogen atom operating at a temperature below 50 ° C.
L'exemple suivant illustre l'invention.The following example illustrates the invention.
EXEMPLEEXAMPLE
A une solution de 2,5 g de tert-butoxycarbonylamino-3 hydroxy-2 phényl-3 propionate-(2R,3S) d'acétoxy-4 benzoyloxy-2α époxy-5β,20 trihydroxy-l,7β,10β oxo-9 taxène-11 yle-13α dans 500 cm3 de méthanol on ajoute 0,25 g de bromure de zinc anhydre. Le milieu réactionnel est chauffé sous agitation pendant 50 heures à une température voisine de 50°C puis refroidi à une température voisine de 20°C et maintenu sous agitation à cette température pendant 15 heures. Le milieu réactionnel est ensuite concentré à sec sous pression réduite (2,7 kPa) à 50°C. On obtient 2,5 g d'une meringue blanche que l'on purifie par chromatographie sur 60 g de silice (0,063-0,2 mm) contenus dans une colonne de 2,5 cm de diamètre [éluant : dichlo- rométhane-méthanol (98-2 en volumes)] en recueillant des fractions de 20 cm3. Les fractions 19 à 35 sont réunies et concentrées à sec sous pression réduite (2,7 kPa) à une température voisine de 40°C. On obtient ainsi 1,2 g d'une meringue blanche que l'on purifie à nouveau par une seconde chromatographie sur 60 g de silice (0,063-0,2 mm) contenus dans une colonne de 2,5 cm de diamètre [éluant : dichlorométhane-méthanol (99-1 en volumes)] en recueillant des fractions de 10 cm3. Les fractions 26 à 40 sont réunies et concentrées à sec sous pression réduite (2,7 kPa) à une température voisine de 40°C. On obtient ainsi 0,91 g de tert- butoxycarrκ>nylamino-3 hydroxy-2 phényl-3 propionate-(2R,3S) d'acétoxy-4 benzoyloxy-2α époxy-5β,20 trihydroxy-l,7α,10β oxo-9 taxène-11 yle-13α sous forme d'une meringue blanche dont les caractéristiques sont les suivantes :To a solution of 2.5 g of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy-l, 7β, 10β oxo-9 taxene-11 yle-13α in 500 cm3 of methanol 0.25 g of anhydrous zinc bromide is added. The reaction medium is heated with stirring for 50 hours to a temperature in the region of 50 ° C, then cooled to a temperature in the region of 20 ° C and kept stirring at this temperature for 15 hours. The reaction medium is then concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 2.5 g of a white meringue are obtained which is purified by chromatography on 60 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter [eluent: dichloromethane-methanol (98-2 by volume)] by collecting fractions of 20 cm3. Fractions 19 to 35 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1.2 g of a white meringue are thus obtained, which is again purified by a second chromatography on 60 g of silica. (0.063-0.2 mm) contained in a column 2.5 cm in diameter [eluent: dichloromethane-methanol (99-1 by volume)], collecting 10 cm 3 fractions. Fractions 26 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. This gives 0.91 g of tert-butoxycarrκ> 3-nylamino-3-hydroxy-3-phenyl-propionate- (2R, 3S) acetoxy-4-benzoyloxy-2α epoxy-5β, 20 trihydroxy-l, 7α, 10β oxo- 9 taxene-11 yle-13α in the form of a white meringue, the characteristics of which are as follows:
- pouvoir rotatoire : [α]20j) = -35° (c = 0,41 ; méthanol)- rotary power: [α] 20d) = -35 ° (c = 0.41; methanol)
- spectre de RMN (250 MHz ; CDCI3) δ (ppm) : 1,11 (s, 3H : -ÇH3 16 ou 17) ; 1,25 (s, 3H : -CH3 16 ou 17) ; 1,32 (s, 9H : -C(CH3)3) ; 1,73 (s, 3H : -CH3 19) ; 1,78 (s, 3H : -CH3 18) ; 2,15 à 2,45 (m, 4H : -CH2- 6 et -CH2- 14) ; 2,5 (s, 3H : -COCH3) ; 3,3 (m, 1H : -OH 2') ; 3,68 (ddd, 1H,- NMR spectrum (250 MHz; CDCI3) δ (ppm): 1.11 (s, 3H: -ÇH3 16 or 17); 1.25 (s, 3H: -CH 3 16 or 17); 1.32 (s, 9H: -C (CH 3 ) 3 ); 1.73 (s, 3H: -CH 3 19); 1.78 (s, 3H: -CH3 18); 2.15 to 2.45 (m, 4H: CH2 6 and -CH 2 - 14); 2.5 (s, 3H: -COCH3); 3.3 (m, 1H: -OH 2 '); 3.68 (ddd, 1H,
J = 12,6 et 4 Hz : -H 7) ; 3,94 (d, 1H, J = 7 Hz : -H 3) ; 4,13 (m, 1H : -OH. 10) ; 4,4 (ab, 2H, Ja = 9 Hz : -CU2" 20) ; 4,64 (m, 1H : -H 2') ; 4,72 (d, 1H, J = 12 Hz -OH 7) ; 4,92 (dd, 1H, J = 9 et 5 Hz : -H 5) ; 5,29 (dd, 1H, J = 10 et 2,5 Hz : -H 3')J = 12.6 and 4 Hz: -H 7); 3.94 (d, 1H, J = 7 Hz: -H 3); 4.13 (m, 1H: -OH. 10); 4.4 (ab, 2H, J a = 9 Hz: -CU2 "20); 4.64 (m, 1H: -H 2 '); 4.72 (d, 1H, J = 12 Hz -OH 7) ; 4.92 (dd, 1H, J = 9 and 5 Hz: -H 5); 5.29 (dd, 1H, J = 10 and 2.5 Hz: -H 3 ')
5,42 (d, 1H, J = 10 Hz : -NHCO-) ; 5,46 (s, 1H : -H 10) ; 5,75 (d, 1H, J = 7 Hz -H 2) ; 6,28 (t, 1H, J = 8,5 Hz : -fl 13) ; 7,2 à 7,5 (m, 5H : -C6H5 3') ; 7,52 [t, 2H,5.42 (d, 1H, J = 10 Hz: -NHCO-); 5.46 (s, 1H: -H 10); 5.75 (d, 1H, J = 7 Hz -H 2); 6.28 (t, 1H, J = 8.5 Hz: -fl 13); 7.2 to 7.5 (m, 5H: -C6H5 3 '); 7.52 [t, 2H,
J = 7,5 Hz : -OCOC6H5 (-H 3 et -H 5)] ; 7,63 [t, 1H, J = 7,5 Hz : -OCOCgHsJ = 7.5 Hz: -OCOC6H5 (-H 3 and -H 5)]; 7.63 [t, 1H, J = 7.5 Hz: -OCOCgHs
(-H 4)] ; 8,14 [d, 2H, J = 7,5 Hz : -OCOC6H5 (-H 2 et -H 6).(-H 4)]; 8.14 [d, 2H, J = 7.5 Hz: -OCOC 6 H 5 (-H 2 and -H 6).
Les nouveaux produits de formule générale (I) présentent des activités bio¬ logiques particulièrement intéressantes.The new products of general formula (I) present particularly interesting biological activities.
Les nouveaux produits de formule générale (I) manifestent une activité inhibitrice significative de la prolifération cellulaire anormale et possèdent des pro¬ priétés thérapeutiques permettant le traitement de malades ayant des conditions pathologiques associées à une prolifération cellulaire anormale. Les conditions pathologiques incluent la prolifération cellulaire anormale de cellules malignes ou non malignes de divers tissus et/ou organes comprenant, de manière non limitative, les tissus musculaires, osseux ou conjonctifs, la peau, le cerveau, les poumons, les organes sexuels, les systèmes lymphatiques ou rénaux, les cellules mammaires ou sanguines, le foie, l'appareil digestif, le pancréas et les glandes thyroïdes ou adré- nales. Ces conditions pathologiques peuvent inclure également le psoriasis, les tumeurs solides, les cancers de l'ovaire, du sein, du cerveau, de la prostate, du colon, de l'estomac, du rein ou des testicules, le sarcome de Kaposi, le cholangiocarcinome, le choriocarcinome, le neuroblastome, la tumeur de Wilms, la maladie de Hodgkin, les mélanomes, les myélomes multiples, les leucémies lymphocytaires chroniques, les lymphomes granulocytaires aigus ou chroniques. Les nouveaux produits selon l'invention sont particulièrement utiles pour le traitement du cancer de l'ovaire. Les produits selon l'invention peuvent être utilisés pour prévenir ou retarder l'apparition ou la réapparition des conditions pathologiques ou pour traiter ces conditions pathologiques.The new products of general formula (I) demonstrate a significant inhibitory activity against abnormal cell proliferation and have therapeutic properties allowing the treatment of patients with pathological conditions associated with abnormal cell proliferation. Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, lymphatic or renal systems, mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands. These pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas. The new products according to the invention are particularly useful for the treatment of ovarian cancer. The products according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.
Les produits selon l'invention peuvent être administrés à un malade selon différentes formes adaptées à la voie d'administration choisie qui, de préférence, est la voie parentérale. L'administration par voie parentérale comprend les administra- tions intraveineuse, intrapéritonéale, intramusculaire ou sous-cutanée. Plus particu¬ lièrement préférée est radministration intrapéritonéale ou intraveineuse.The products according to the invention can be administered to a patient in different forms adapted to the chosen route of administration which, preferably, is the parenteral route. Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.
La présente invention comprend également les compositions pharmaceu¬ tiques qui contiennent au moins un produit de formule générale (la) en une quantité suffisante adaptée à l'emploi en thérapeutique humaine ou vétérinaire. Les compo- sitions peuvent être préparées selon les méthodes habituelles en utilisant un ou plu¬ sieurs adjuvants, supports ou excipients pharmaceutiquement acceptables. Les sup¬ ports convenables incluent les diluants, les milieux aqueux stériles et divers solvants non toxiques. De préférence les compositions se présentent sous forme de solutions ou de suspensions aqueuses, de solutions injectables qui peuvent contenir des agents émusifîants, des colorants, des préservatifs ou des stabilisants.The present invention also comprises the pharmaceutical compositions which contain at least one product of general formula (Ia) in a sufficient quantity suitable for use in human or veterinary therapy. The compositions can be prepared according to the usual methods using one or more adjuvants, carriers or pharmaceutically acceptable excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents. Preferably the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifying agents, dyes, preservatives or stabilizers.
Le choix des adjuvants ou excipients peut être déterminé par la solubilité et les propriétés chimiques du produit, le mode particulier d'administration et les bonnes pratiques pharmaceutiques.The choice of adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices.
Pour l'administration parentérale, on utilise des solutions ou des suspensions stériles aqueuses ou non aqueuses. Pour la préparation de solutions ou de suspensions non aqueuses peuvent être utilisés des huiles végétales naturelles telle que l'huile d'olive, l'huile de sésame ou l'huile de paraffine ou les esters organiques injectables tel que l'oléate d'éthyle. Les solutions stériles aqueuses peuvent être constituées d'une solution d'un sel pharmaceutiquement acceptable en solution dans de l'eau. Les solutions aqueuses conviennent pour l'administration intraveineuse dans la mesure où le pH est convenablement ajusté et où l'isotonicité est réalisée, par exemple, par une quantité suffisante de chlorure de sodium ou de glucose. La stérélisation peut être réalisée par chauffage ou par tout autre moyen qui n'altère pas la composition.For parenteral administration, aqueous or non-aqueous sterile solutions or suspensions are used. For the preparation of non-aqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate . The sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water. The aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.
II est bien entendu que tous les produits entrant dans les compositions selon l'invention doivent être purs et non toxiques pour les quantités utilisées. Les compositions peuvent contenir au moins 0,01 % de produit thérapeuti- quement actif. La quantité de produit actif dans une composition est telle qu'une posologie convenable puisse être prescrite. De préférence, les compositions sont préparées de telle façon qu'une dose unitaire contienne de 0,01 à 1000 mg environ de produit actif pour l'administration par voie parentérale.It is understood that all the products entering into the compositions according to the invention must be pure and non-toxic for the quantities used. The compositions can contain at least 0.01% of therapeutically active product. The amount of active ingredient in a composition is such that a suitable dosage can be prescribed. Preferably, the compositions are prepared in such a way that a unit dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.
Le traitement thérapeutique peut être effectué concuremment avec d'autres traitements thérapeutiques incluant des médicaments antinéoplastiques, des anticorps monoclonaux, des thérapies immunologiques ou des radiothérapies ou des modificateurs des réponses biologiques. Les modificateurs des réponses incluent, de manière non limitative, les lymphokines et les cytokines telles que les interleukines, les interférons(α, β ou δ) et le TNF. D'autres agents chimiothérapeutiques utiles dans le traitement des désordres dus à la prolifération anormale des cellules incluent, de manière non limitative, les agents alkylants tels que les moutardes à l'azote comme la mechloretamine, le cyclophosphamide, le melphalan et le chlorambucil, des sulfo- nates d'alkyle comme le busulfan, les nitrosourées comme la carmustine, la lomu- sine, la sémustine et la streptozocine, les triazènes comme la dacarbazine, les antimé- tabolites comme les analogues de l'acide folique tel que le méthotrexate, les ana¬ logues de pyrimidine comme le fluorouracil et la cytarabine, des analogues de purines comme la mercaptopurine et la tWoguanine, des produits naturels tels que les alcaloïdes de vinca comme la vinblastine, la vincristine et la vendésine, des épipodo- phyllotoxines comme l'étoposide et le teniposide, des antibiotiques comme la dacti- nomycine, la daunorubicine, la doxorubicine, la bléomycine, la plicamycine et la mitomycine, des enzymes comme la L-asparaginase, des agents divers comme les complexes de coordination du platine tel que le cisplatine, les urées substituées tel que l'hydroxyurée, les dérivés de méthylhydrazine comme la procarbazine, les sup¬ presseurs adrénocoticoïques comme le mitotane et l'aminoglutéthymide, les hormones et les antagonistes comme les adrénocorticostéroïdes comme la predni- sone, les progestines comme le caproate d'hydroxyprogestérone, l'acétate de méthoxyprogestérone et l'acétate de megestrol, les oestrogènes comme le diéthylstil- bestrol et l'éthynylestradiol, les antioestrogène comme le tamoxifène, les androgènes comme le propionate de testostérone et la fluoxymesterone.Therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses. Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (α, β or δ) and TNF. Other chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogues such as fluorouracil and cytarabine, purine analogs such as mercaptopurine and tWoguanine, natural products such as vinca alkaloids such as vinblastine, vincristine and vendesin, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, d es enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocotic suppressants such as mitotane and l aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens such as diethylstil- bestrol and ethynylestradiol, antiestrogens like tamoxifen, androgens like testosterone propionate and fluoxymesterone.
Les doses utilisées pour mettre en oeuvre les méthodes selon l'invention sont celles qui permettent un traitement prophylactique ou un maximum de réponse thérapeutique. Les doses varient selon la forme d'administration, le produit particu- lier sélectionné et les caractéristiques propres du sujet à traiter. En général, les doses sont celles qui sont thérapeutiquement efficaces pour le traitement des désordres dus à une prolifération cellulaire anormale. Les produits selon l'invention peuvent être administrés aussi souvent que nécessaire pour obtenir l'effet thérapeutique désiré. Certains malades peuvent répondre rapidement à des doses relativement fortes ou faibles puis avoir besoin de doses d'entretien faibles ou nulles. Généralement, de faibles doses seront utilisées au début du traitement et, si nécessaire, des doses de plus en plus fortes seront administrées jusqu'à l'obtention d'un effet optimum. Pour d'autres malades il peut être nécessaire d'administrer des doses d'entretien 1 à 8 fois par jour, de préférence 1 à 4 fois, selon les besoins physiologiques du malade consi- déré. Il est aussi possible que pour certains malades il soit nécessaire de n'utiliser qu'une à deux administrations journalières.The doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response. The doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation. The products according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to relatively large or low doses and may require low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasing doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient considered. It is also possible that for some patients it is necessary to use only one or two daily administrations.
Chez l'homme, les doses sont généralement comprises entre 0,01 et 200 mg kg. Par voie intrapéritonéale, les doses seront en général comprises entre 0,1 et 100 mg kg et, de préférence entre 0,5 et 50 mg/kg et , encore plus spécifiquement entre 1 et 10 mg/kg. Par voie intraveineuse, les doses sont généralement comprises entre 0,1 et 50 mg/kg et, de préférence entre 0,1 et 5 mg/kg et, encore plus spécifi¬ quement entre 1 et 2 mg/kg. Il est entendu que, pour choisir le dosage le plus appro¬ prié, devront être pris en compte la voie d'administration, le poids du malade, son état de santé général, son âge et tous les facteurs qui peuvent influer sur l'efficacité du traitement.In humans, the doses are generally between 0.01 and 200 mg kg. Intraperitoneally, the doses will generally be between 0.1 and 100 mg kg and, preferably between 0.5 and 50 mg / kg and, even more specifically between 1 and 10 mg / kg. Intravenously, the doses are generally between 0.1 and 50 mg / kg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the efficacy must be taken into account. of treatment.
L'exemple suivant illustre une composition selon l'invention.The following example illustrates a composition according to the invention.
EXEMPLEEXAMPLE
On dissout 40 mg du produit obtenu à l'exemple 1 dans 1 cm3 d'Emulphor EL 620 et 1 cm3 d'éthanol puis la solution est diluée par addition de 18 cm3 de sérum physiologique.40 mg of the product obtained in Example 1 are dissolved in 1 cm 3 of Emulphor EL 620 and 1 cm 3 of ethanol then the solution is diluted by adding 18 cm 3 of physiological saline.
La composition est administrée par introduction dans une perfusion d'un soluté physiologique pendant 1 heure. The composition is administered by introduction into an infusion of a physiological solution for 1 hour.

Claims

REVENDICATIONS
1 - Nouveaux dérivés du taxane de formule générale :1 - New taxane derivatives of general formula:
Figure imgf000013_0001
Figure imgf000013_0001
OCOC6H5 dans laquelle Ar représente un radical aryle, Ri représente un atome d'hydrogène ou un radical acétyle ou un radical de formule générale :OCOC 6 H 5 in which Ar represents an aryl radical, Ri represents a hydrogen atom or an acetyl radical or a radical of general formula:
O RK fN-(CH2)n-NH-C-O R K f N- (CH 2 ) n-NH-C-
//
R2 dans laquelle :R2 in which:
W\ et R2, identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle contenant 1 à 4 atomes de carbone en chaîne droite ou ramifiée, ou bien Rj et R2 forment ensemble avec l'atome d'azote auquel ils sont liés un heterocycle, saturé ou non saturé, à 5 ou 6 chaînons contenant éventuellement un second hétéroatome choisi parmi les atomes d'azote (éventuellement substitué par un radical alkyle contenant 1 à 4 atomes de carbone ou benzyle), d'oxygène et de soufre, n est égal à 2 ou 3, et R représenteW \ and R2, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, or else Rj and R2 form together with the nitrogen atom to which they are linked a 5 or 6-membered saturated or unsaturated heterocycle optionally containing a second heteroatom chosen from nitrogen atoms (optionally substituted by an alkyl radical containing 1 to 4 carbon or benzyl atoms), oxygen and sulfur, n is 2 or 3, and R represents
- un radical alcoyle droit ou ramifié contenant 1 à 8 atomes de carbone, alcényle contenant 3 à 8 atomes de carbone, alcynyle contenant 3 à 8 atomes de carbone, cycloalcoyle contenant 3 à 6 atomes de carbone, cycloalcényle contenant 4 à 6 atomes de carbone ou bicycloalcoyle contenant 7 à 10 atomes de carbone, ces radi- eaux étant éventuellement substitués par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux hydroxy, alcoyloxy contenant 1 à 4 atomes de carbone, dialcoylamino dont chaque partie alcoyle contient 1 à 4 atomes de carbone, pipéridino, morpholino, pipérazinyl-1 (éventuellement substitué en -4 par un radical alcoyle contenant 1 à 4 atomes de carbone ou par un radical phénylalcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone), cycloalcoyle contenant 3 à 6 atomes de carbone, cycloalcén le contenant 4 à 6 atomes de carbone, phényle, cyano, carboxy ou alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone,- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 3 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 with 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 atoms carbon, cycloalken containing it 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl in which the alkyl part contains 1 to 4 carbon atoms,
- ou un radical phényle éventuellement substitué par un ou plusieurs atomes ou radi- eaux choisis parmi les atomes d'halogène et les radicaux alcoyles contenant 1 à 4 atomes de carbone, alcoyloxy contenant 1 à 4 atomes de carbone,- or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms,
- ou un radical hétérocyclyle azoté saturé ou non saturé contenant 5 ou 6 chaînons et éventuellement substitué par un ou plusieurs radicaux alcoyles contenant 1 à 4 atomes de carbone, étant entendu que les radicaux cycloalcoyles, cycloalcényles ou bicycloalcoyles peu¬ vent être éventuellement substitués par un ou plusieurs radicaux alcoyles contenant 1 à 4 atomes de carbone.- or a saturated or unsaturated nitrogen heterocyclyl radical containing 5 or 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by a or more alkyl radicals containing 1 to 4 carbon atoms.
2 - Procédé de préparation d'un dérivé du taxane selon la revendication 1 caractérisé en ce que l'on chauffe un dérivé de formule générale :2 - Process for the preparation of a taxane derivative according to claim 1 characterized in that a derivative of general formula is heated:
Figure imgf000014_0001
dans laquelle Ar, R et Rj sont définis comme dans la revendication 1 à une tempéra¬ ture comprise entre 20°C et 97°C en présence d'une quantité catalytique d'un acide de Lewis.
Figure imgf000014_0001
wherein Ar, R and Rj are defined as in claim 1 at a temperature between 20 ° C and 97 ° C in the presence of a catalytic amount of a Lewis acid.
3 - Procédé selon la revendication 2 caractérisé en ce que l'on opère dans un alcool aliphatique contenant 1 à 4 atomes de carbone.3 - Process according to claim 2 characterized in that one operates in an aliphatic alcohol containing 1 to 4 carbon atoms.
4 - Procédé selon la revendication 2 caractérisé en ce que l'acide de Lewis est le bromure de zinc.4 - Process according to claim 2 characterized in that the Lewis acid is zinc bromide.
5 - Compositions pharmaceutique caractérisée en ce qu'elle contient une quantité suffisante d'au moins un dérivé selon la revendication 1 à l'état pur ou en association avec un ou plusieurs produits pharmaceutiquement acceptables qu'ils soient inertes ou physiologiquement actifs. 5 - Pharmaceutical compositions characterized in that it contains a sufficient amount of at least one derivative according to claim 1 in the pure state or in combination with one or more pharmaceutically acceptable products whether they are inert or physiologically active.
PCT/FR1993/000477 1992-05-21 1993-05-18 Novel taxane derivatives, their preparation and compositions containing same WO1993023389A1 (en)

Priority Applications (6)

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JP5519950A JPH07506586A (en) 1992-05-21 1993-05-18 Novel taxane derivatives, their production, and compositions containing them
EP93910129A EP0641334A1 (en) 1992-05-21 1993-05-18 Novel taxane derivatives, their preparation and compositions containing same
SK1399-94A SK139994A3 (en) 1992-05-21 1993-05-18 Taxane derivatives, their preparation and compositions containing same
NO944141A NO944141D0 (en) 1992-05-21 1994-10-31 New taxane derivatives, their preparation and drugs containing the derivatives
FI945439A FI945439A0 (en) 1992-05-21 1994-11-18 Novel taxane derivatives, their preparation and compositions containing them
KR1019940704156A KR950701629A (en) 1992-05-21 1994-11-19 Novel taxane derivatives, their preparation and compositions containing same

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FR92/06177 1992-05-21
FR9206177A FR2691460B1 (en) 1992-05-21 1992-05-21 NEW TAXANE DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM.

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US6596737B2 (en) 2000-02-02 2003-07-22 Fsu Research Foundation, Inc. C10 carbamoyloxy substituted taxanes
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US6660866B2 (en) 2000-02-02 2003-12-09 Psu Research Foundation, Inc. C10 carbonate substituted taxanes
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US20110178077A1 (en) * 2008-06-17 2011-07-21 Priscille Brodin Anti-infective compounds
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
CN105294610A (en) * 2015-07-16 2016-02-03 中国科学院上海药物研究所 Method for preparing 7-epi-taxane compounds
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same

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CN107021943B (en) * 2016-02-02 2020-12-29 中国科学院上海药物研究所 7-epi-baccatin III derivatives, and preparation method and application thereof

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6596737B2 (en) 2000-02-02 2003-07-22 Fsu Research Foundation, Inc. C10 carbamoyloxy substituted taxanes
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US6660866B2 (en) 2000-02-02 2003-12-09 Psu Research Foundation, Inc. C10 carbonate substituted taxanes
US6906088B2 (en) 2000-02-02 2005-06-14 Fsu Research Foundation, Inc. Taxanes having a C10 carbamoyloxy substituent
US7056946B2 (en) 2000-02-02 2006-06-06 Fsu Research Foundation, Inc. C10 carbonate taxane compositions
US7230013B2 (en) 2000-02-02 2007-06-12 Florida State University Research Foundation, Inc. C10 carbamoyloxy substituted taxane compositions
US7256213B2 (en) 2000-02-02 2007-08-14 Florida State University Research Foundation, Inc. Taxanes having a C10 carbonate substituent
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8003812B2 (en) 2004-02-13 2011-08-23 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes
US20110178077A1 (en) * 2008-06-17 2011-07-21 Priscille Brodin Anti-infective compounds
US8785452B2 (en) * 2008-06-17 2014-07-22 Institut National De La Sante Et De La Recherche Medicale Anti-infective compounds
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
US9308195B2 (en) 2012-10-01 2016-04-12 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
US9763880B2 (en) 2012-10-01 2017-09-19 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
CN105294610A (en) * 2015-07-16 2016-02-03 中国科学院上海药物研究所 Method for preparing 7-epi-taxane compounds

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KR950701629A (en) 1995-04-28
FR2691460A1 (en) 1993-11-26
EP0641334A1 (en) 1995-03-08
JPH07506586A (en) 1995-07-20
FI945439A (en) 1994-11-18
ZA933462B (en) 1993-12-14
CZ285294A3 (en) 1995-04-12
CA2136211A1 (en) 1993-11-25
TW227560B (en) 1994-08-01
MX9302915A (en) 1993-11-01
AU4075893A (en) 1993-12-13
SK139994A3 (en) 1995-07-11
FR2691460B1 (en) 1994-07-22
FI945439A0 (en) 1994-11-18

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