Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
• • 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
• • 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 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.

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• 1992
  • 1992-05-21 FR FR9206177A patent/FR2691460B1/fr not_active Expired - Fee Related
• 1993
  • 1993-05-18 AU AU40758/93A patent/AU4075893A/en not_active Abandoned
  • 1993-05-18 CA CA002136211A patent/CA2136211A1/fr not_active Abandoned
  • 1993-05-18 SK SK1399-94A patent/SK139994A3/sk unknown
  • 1993-05-18 EP EP93910129A patent/EP0641334A1/fr not_active Withdrawn
  • 1993-05-18 ZA ZA933462A patent/ZA933462B/xx unknown
  • 1993-05-18 JP JP5519950A patent/JPH07506586A/ja active Pending
  • 1993-05-18 WO PCT/FR1993/000477 patent/WO1993023389A1/fr not_active Application Discontinuation
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• 1994
  • 1994-11-18 FI FI945439A patent/FI945439A/fi unknown
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