US2003083497A1PendingUtilityA1
Taxoids, their preparation and pharmaceutical compositions containing them
Est. expiryDec 9, 2012(expired)· nominal 20-yr term from priority
C07D 305/14
51
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Claims
Abstract
New taxoids of general formula (I), their preparation, and pharmaceutical compounds containing them. In general formula (I), for example, Ar represents an aryl radical, R represents an alkoxyacetyl radical, R 1 represents a benzoyl radical or a radical of formula R 2 —O—CO— in which R 2 represents an optionally substituted alkyl radical, an alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical. The new products of general formula (I) have a remarkable antitumor activity.
Claims
exact text as granted — not AI-modified1 . A taxoid of the formula:
in which
R represents an alkoxyacetyl radical,
R 1 represents a benzoyl radical or a radical R 2 —O—CO in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical:
2 . The taxoid according to claim 1 , wherein:
R represents an alkoxyacetyl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO in which R 2 represents:
a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 10 carbon atoms,
these radicals being optionally substituted by one or more substituents, which are identical or different, chosen from halogen atoms and hydroxy radicals, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals (optionally substituted at position 4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals, cyano radicals, carboxy radicals and alkoxycarbonyl radicals whose alkyl portion contains 1 to 4 carbon atoms,
or a phenyl radical optionally substituted by one or more radicals, which are identical or different, chosen from alkyl radicals containing 1 to 4 carbon atoms and alkoxy radicals containing 1 to 4 carbon atoms,
or a saturated or unsaturated 5- or 6-membered nitrogen-containing heterocyclyl radical 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 one or more alkyl radicals containing 1 to 4 carbon atoms, and Ar represents a phenyl or α- or β-naphthyl radical optionally substituted by one or more atoms or radicals, chosen from halogen atoms (fluorine, chlorine, bromine, or iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it being 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 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- or β-naphthyl radicals or alternatively Ar represents a 5-membered aromatic heterocyclic radical containing one or more hetero atoms, which are identical or different, chosen from nitrogen, oxygen or sulphur atoms, optionally substituted by one or more substituents, which are identical or different, chosen from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy radicals containing 6 to 10 carbon atoms, amino radicals, alkylamino radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, acylamino radicals in which the acyl portion contains 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains 6 to 10 carbon atoms, cyano radicals, carboxy radicals, carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains 1 to 4 carbon atoms and alkoxycarbonyl radicals in which the alkoxy portion contains 1 to 4 carbon atoms.
3 . The taxoid according to claim 1 , wherein R 1 represents a benzoyl radical.
4 . The taxoid according to claim 1 , wherein R 1 represents a benzoyl radical and Ar represents a phenyl radical.
5 . A process for the preparation of a taxoid of claim 1 comprising esterifying a product of the formula:
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group, with a free acid of the formula:
or a derivative of the free acid capable of being converted into the free acid, in which Ar and R 1 are defined as in claim 1 , R 3 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or an optionally substituted aryl radical and R 4 represents a hydrogen atom, to give a product of the formula:
in which Ar, R and R 1 are defined as in claim 1 , R 3 , R 4 , and G 1 are defined as above, treating this product in acidic medium to give a product of the formula:
in which Ar, R 1 and G 1 , are defined as above, and then optionally replacing the protecting group G 1 by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product obtained.
6 . The process according to claim 5 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrogens at a temperature ranging from −10 to 90° C.
7 . The process according to claim 5 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
8 . The process according to claim 5 , wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
9 . The process according to claim 5 , wherein the acid treatment is carried out by means of an inorganic or organic acid in an organic solvent at a temperature ranging from −10 to 60° C.
10 . The process according to claim 9 , wherein the acid is chosen from hydrochloric, sulphuric, acetic, methanesulphonic, trifluoromethanesulphonic and p-toluenesulphonic acids, used alone or in the form of a mixture.
11 . The process according to claim 9 , wherein the solvent is chosen from alcohols, ethers, esters, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitrites.
12 . The process according to claim 5 , wherein the replacement by a hydrogen atom of the protecting group G 1 , when G 1 represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, is carried out by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate and n-butyl acetate in the presence of zinc optionally combined with copper, and, when G 1 represents an alkoxyacetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
13 . A process for the preparation of a taxoid according to claim 1 comprising esterifying a product of the formula:
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group, by means of a free acid of the formula:
or a derivative of the free acid capable of being converted into the free acid, in which Ar and R 1 are defined as in claim 1 , and R 3 and R 4 , which are identical or different, represent an alkyl radical containing 1 to 4 carbon atoms or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms or an aryl radical, or alternatively R 3 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R 4 represents a hydrogen atom, or alternatively R 3 and R 4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, to give, after treating in acidic medium, a product of the formula:
in which Ar is defined as in claim 1 , and G 1 is defined as above, and acylating the product by means of benzoyl chloride or a reactive derivative of the formula:
R 2 —O—CO—X
in which R 2 is defined as in claim 1 and X represents a halogen atom or a residue —O—R 2 or —O—CO—O—R 2 , in which R 2 is defined as in claim 1 , and then replacing the protecting group G 1 , if necessary, by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product obtained.
14 . The process according to claim 13 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from −10 to 90° C.
15 . The process according to claim 13 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
16 . The process according to claim 13 , wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
17 . The process according to claim 13 , wherein the acid treatment is carried out by means of an inorganic or organic acid in an organic solvent at a temperature ranging from 0 to 50° C.
18 . The process according to claim 17 , wherein the acid is chosen from hydrochloric, sulphuric and formic acids.
19 . The process according to claim 17 , wherein the solvent is chosen from alcohols containing 1 to 3 carbon atoms.
20 . The process according to claim 13 , wherein the acylation is carried out in an inert organic solvent in the presence of an inorganic or organic base.
21 . The process according to claim 20 , wherein the inert organic solvent is chosen from esters and halogenated aliphatic hydrocarbons.
22 . The process according to claim 16 , wherein the procedure is carried out at a temperature ranging from 0 to 50° C.
23 . The process according to claim 13 , wherein the replacement by a hydrogen atom of the protecting group G 1 , when it represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, is carried out by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate and n-butyl acetate in the presence of zinc optionally combined with copper, or, when it represents an alkoxy acetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
24 . A process for the preparation of a taxoid according to claim 1 , comprising esterifying a product of the formula:
in which G 1 represents a hydroxy-protecting group, by means of a free acid of the formula:
or a derivative of the free acid capable of being converted into the free acid, in which Ar and R 1 are defined as in claim 1 and G 3 represents a hydroxy-protecting group, or of an activated derivative of this acid, to give a product of the formula:
in which Ar, R 1 , G 1 and G 3 are defined as above, replacing the protecting groups G 3 and optionally G 1 by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product obtained.
25 . The process according to claim 24 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from −10 to 90° C.
26 . The process according to claim 24 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
27 . The process according to claim 24 , wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
28 . The process according to claim 24 , wherein the replacement of the protecting groups G 1 and G 3 by hydrogen atoms is carried out by treatment with zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate and n-butyl acetate in the presence of zinc, optionally combined with copper, when G 1 and G 3 represent a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, or by treatment in acidic medium selected from hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, propanol or isopropanol) or aqueous hydrofluoric acid at a temperature ranging from 0 to 40° C. when G 3 represents a silylated radical or an acetal residue, followed by the replacement of the protecting group G 1 by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, or, when G 1 represents an alkoxyacetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
29 . The process according to claim 24 , wherein when G 3 represents a radical —CH 2 —Ph, the replacement of the group by a hydrogen atom is carried out by hydrogenolysis, after replacing the protecting group G 1 .
30 . A taxoid of the formula:
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group.
31 . A pharmaceutical composition comprising at least one product according to claim 1 , in combination with one or more pharmaceutically acceptable, inert or physiologically active, products.
32 . A method for treating mammalian tumors comprising administering to a mammal an effective amount of at least one compound according to claim 1 .
33 . A method for treating a pathological condition in a host wherein said pathological condition is associated with abnormal cell proliferation said method comprising administering to said host an effective amount of at least one compound according to claim 1 .
34 . A method according to claim 33 , wherein the abnormal cells are malignant cells.
35 . A method according to claim 33 , wherein the abnormal cells are non-malignant.
36 . A method according to claim 34 , wherein said pathological condition comprises abnormal cellular proliferation of malignant or non-malignant cells or various tissues and/or organs including, muscle, bone or connective tissues, skin, brain, lungs, sex organs, lymphatic or renal systems, mammary or blood cells, liver, digestive tract, pancreas and thyroid or adrenal glands.
37 . A method according to claim 33 , wherein the pathological condition is psoriasis, solid tumors, cancer of the ovary, breast, brain, prostate, colon, stomach, kidney or testicles, Kaposi's sarcoma, cholangioma, chorioma, neuroblastoma, Wilms' tumor, Hodgkin's disease, melanomas, multiple myelomas, lymphatic leukemia, and acute or chronic granulocytic lymphomas.
38 . A method according to claim 33 , wherein the pathological condition is ovarian cancer.
39 . A method according to claim 32 , wherein the treatment is performed concurrently with at least one other therapeutic treatment.
40 . A method according to claim 39 , wherein the other therapeutic treatment comprises antineoplastic drugs, monoclonal antibodies, immunotherapies, radiotherapies, or biological response modifiers.
41 . A method according to claim 40 , wherein the response modifiers comprise lymphokines and cytokines, including interleukins, interferons (α, β, or δ) and TNF.
42 . A method according to claim 40 , wherein the antineoplastic drugs comprise alkylating agents, including nitrogen mustards selected from mechlorethamine, cyclophosphamide, melphalan and chlorambucil; alkyl sulphates selected from busulfan; nitrosoureas selected from carmustine, lomustine, semustine and streptozoci; triazenes selected from dacarbazine; antimetabolites selected from folic acid analogues including methotrexate; pyrimidine analogues selected from fluorouracil and cytarabine; and purine analogues selected from mercaptopurine and thioguanine; natural products including vinca alkaloids selected from vinblastine, vincristine and vindesine; epipodophyllotoxins selected from etoposide and teniposid;, antibiotics selected from dactinomycin, daunorubicin, doxorubincin, bleomycin, plicamycin and mitomycin; enzymes selected from L-asparaginase; various agents selected from coordination complexes of platinum including cisplatin; substituted ureas including hydroxyurea; methylhydrazine derivatives selected from procarbazine; adrenocortical suppressants selected from mitotane and aminoglutethymide; hormones and antagonists selected from adrenocorticosteroids selected from prednisone; progestins selected from hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate; oestrogens selected from diethylstilbestrol and ethynylestradiol; antiestrogens selected from tamoxifen; and androgens selected from testosterone propionate and fluoroxymesterone.
43 . A pharmaceutical composition according to claim 31 , wherein the composition is suitable for parenteral administration.
44 . A pharmaceutical composition according to claim 43 , wherein the composition is suitable for intravenous, intraperitoneal, intramuscular or subcutaneous administration.
45 . A pharmaceutical composition according to claim 31 , comprising pharmaceutically acceptable adjuvants, carriers or excipients.
46 . A pharmaceutical composition according to claim 45 , wherein the adjuvant, carrier or excipient is selected from a diluent, sterile aqueous media and non-toxic solvents.
47 . A pharmaceutical composition according to claim 31 , wherein the composition is an aqueous solution, an aqueous suspension, or an injectable solution.
48 . A pharmaceutical composition according to claim 47 , wherein the composition comprises at least one emulsifying agent, colorant, preservative or stabilizer.
49 . A pharmaceutical composition according to claim 43 , wherein the composition is an aqueous or non-aqueous solution or suspension.
50 . A taxoid of the formula:
in which
R represents an alkoxyacetyl radical,
R 1 represents a radical R 2 —O—CO— in which R 2 represents an alkyl radical, and
Ar represents an aryl radical.
51 . A taxoid according to claim 50 , wherein:
R represents an alkoxyacetyl radical, R 1 represents a radical R 2 —O—CO in which R 2 represents:
a straight or branched alkyl radical containing 1 to 8 carbon atoms optionally substituted by one or more substituents, which are identical or different, chosen from halogen atoms and hydroxy radicals; alkoxy radicals containing 1 to 4 carbon atoms; dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms; piperidino radicals; morpholino radicals; 1-piperazinyl radicals (optionally substituted at position 4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl portion contains 1 to 4 carbon atoms); cycloalkyl radicals containing 3 to 6 carbon atoms; cycloalkenyl radicals containing 4 to 6 carbon atoms; phenyl radicals; cyano radicals; carboxy radicals or alkoxycarbonyl radicals whose alkyl portion contains 1 to 4 carbon atoms,
Ar represents a phenyl or α- or β-naphthyl radical optionally substituted by one or more atoms or radicals, chosen from halogen atoms (fluorine, chlorine, bromine, or iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it being 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 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- or β-naphthyl radicals or alternatively Ar represents a 5-membered aromatic heterocyclic radical containing one or more hetero atoms, which are identical or different, chosen from nitrogen, oxygen or sulphur atoms, optionally substituted by one or more substituents, which are identical or different, chosen from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy radicals containing 6 to 10 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, acylamino radicals in which the acyl portion contains 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains 6 to 10 carbon atoms, cyano radicals, carboxy radicals, carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains 1 to 4 carbon atoms or alkoxycarbonyl radicals in which the alkoxy portion contains 1 to 4 carbon atoms.
52 . A taxoid according to claim 50 , wherein R represents an alkoxyacetyl radical, R 1 represents a radical R 2 —O—CO— in which R 2 represents a t-butyl radical and Ar represents an aryl radical.
53 . A taxoid according to claim 50 , wherein R 1 represents a radical R 2 —O—CO in which R 2 represents a t-butyl radical and Ar represents a phenyl radical.
54 . A process for the preparation of a taxoid according to claim 50 , comprising esterifying a product of the formula:
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group, with a free acid of the formula:
or a derivative of the free acid capable of being converted into the free acid, in which Ar and R 1 are defined as in claim 50 , R 3 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or an optionally substituted aryl radical and R 4 represents a hydrogen atom, to give a product of the formula:
in which Ar, R and R 1 are defined as in claim 50 , R 3 , R 4 and G 1 are defined as above, treating this product in acidic medium to give a product of the formula:
in which Ar, R 1 and G 1 are defined as above, and then optionally replacing the protecting group G 1 by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product obtained.
55 . The process according to claim 54 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from −10 to 90° C.
56 . The process according to claim 54 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
57 . The process according to claim 54; wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
58 . The process according to claim 54 , wherein the acid treatment is carried out by means of an inorganic or organic acid in an organic solvent at a temperature ranging from −10 to 60° C.
59 . The process according to claim 57 , wherein the acid is chosen from hydrochloric, sulphuric, acetic, methanesulphonic, trifluoromethanesulphonic and p-toluenesulphonic acids, used alone or in the form of a mixture.
60 . The process according to claim 57 , wherein the solvent is chosen from alcohols, ethers, esters, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles.
61 . The process according to claim 54 , wherein the replacement by a hydrogen atom of the protecting group G 1 , when it represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, is carried out by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, and, when it represents an alkoxyacetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
62 . A process for the preparation of a taxoid according to claim 50 , comprising esterifying a product of the formula:
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group, by means of a free acid of the formula:
or a derivative of the free acid capable of being converted into the free acid, in which Ar and R 1 are defined as in claim 50 and R 3 and R 4 , which are identical or different, represent an alkyl radical containing 1 to 4 carbon atoms or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms or an aryl radical, or alternatively R 3 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R 4 represents a hydrogen atom, or alternatively R 3 and R 4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, to give, after treating in acidic medium, a product of the formula:
in which Ar is defined as in claim 50 and G 1 is defined as above, and acylating the product by means of benzoyl chloride or a reactive derivative of the formula:
R 2 —O—CO—X
in which R 2 is defined as in claim 50 and X represents a halogen atom or a residue —O—R 2 or —O—CO—O—R 2 , and then replacing the protecting group G 1 , if necessary, by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product obtained.
63 . The process according to claim 62 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from −10 to 90° C.
64 . The process according to claim 62 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
65 . The process according to claim 62 , wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
66 . The process according to claim 62 , wherein the acid treatment is carried out by means of an inorganic or organic acid in an organic solvent at a temperature ranging from 0 to 50° C.
67 . The process according to claim 66 , wherein the acid is chosen from hydrochloric, sulphuric and formic acids.
68 . The process according to claim 66 , wherein the solvent is chosen from alcohols containing 1 to 3 carbon atoms.
69 . The process according to claim 62 , wherein the acylation is carried out in an inert organic solvent in the presence of an inorganic or organic base.
70 . The process according to claim 69 , wherein the inert organic solvent is chosen from esters and halogenated aliphatic hydrocarbons.
71 . The process according to claim 65 , wherein the procedure is carried out at a temperature ranging from 0 and 50° C.
72 . The process according to claim 62 , wherein the replacement by a hydrogen atom of the protecting group G 1 , when it represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, is carried out by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, or, when it represents an alkoxy acetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
73 . A process for the preparation of a taxoid according to claim 50 , comprising esterifying a product of the formula:
in which G 1 represents a hydroxy-protecting group, by means of a free acid of the formula:
or a derivative of the free acid capable of being converted into the free acid, in which Ar and R 1 are defined as in claim 50 and G 3 represents a hydroxy-protecting group, or of an activated derivative of this acid, to give a product of the formula:
in which Ar, R 1 , G 1 and G 3 are defined as above, replacing the protecting groups G 3 and optionally G 1 by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product obtained.
74 . The process according to claim 73 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from −10 to 90° C.
75 . The process according to claim 73 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
76 . The process according to claim 73 , wherein the esterification is carried out by means of a halide or an anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen-from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
77 . The process according to claim 73 , wherein the replacement of the protecting groups G 1 and G 3 by hydrogen atoms is carried out by treatment with zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, when G 1 and G 3 represent a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, or by treatment in acidic medium selected from for example hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, propanol or isopropanol) or aqueous hydrofluoric acid at a temperature ranging from 0 to 40° C. when G 3 represents a silylated radical or an acetal residue, followed by the replacement of the protecting group G 1 by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid selected from hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester selected from ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, or, when G 1 represents an alkoxyacetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
78 . The process according to claim 73 , wherein when G 3 represents a radical —CH 2 —Ph, the replacement of the group by a hydrogen atom is carried out by hydrogenolysis, after replacing the protecting group G 1 .
79 . A pharmaceutical composition comprising at least one product according to claim 50 in combination with one or more pharmaceutically acceptable, inert or physiologically active, products.
80 . A method for treating mammalian tumors comprising administering to a mammal an effective amount of at least one compound according to claim 50 .
81 . A method for treating a pathological condition in a host wherein said pathological condition is associated with abnormal cell proliferation said method comprising administering to said host an effective amount of at least one compound according to claim 50 .
82 . A method according to claim 81 , wherein the abnormal cells are malignant cells.
83 . A method according to claim 81 , wherein the abnormal cells are non-malignant.
84 . A method according to claim 82 , wherein said pathological condition comprises abnormal cellular proliferation of malignant or non-malignant cells of various tissues and/or organs including, muscle, bone or connective tissues, skin, brain, lungs, sex organs, lymphatic or renal systems, mammary or blood cells, liver, digestive tract, pancreas and thyroid or adrenal glands.
85 . A method according to claim 81 , wherein the pathological condition is psoriasis, solid tumors, cancer of the ovary, breast, brain, prostate, colon, stomach, kidney or testicles, Kaposi's sarcoma, cholangioma, chorioma, neuroblastoma, Wilms' tumor, Hodgkin's disease, melanomas, multiple myelomas, lymphatic leukaemia, and acute or chronic granulocytic lymphomas.
86 . A method according to claim 81 , wherein the pathological condition is ovarian cancer.
87 . A method according to any one of claim 80 , wherein the treatment is performed concurrently with at least one other therapeutic treatment.
88 . A method according to claim 87 , wherein the other therapeutic treatment comprises antineoplastic drugs, monoclonal antibodies, immunotherapies, radiotherapies,or biological response modifiers.
89 . A method according to claim 88 , wherein the response modifiers comprise lymphokines and cytokines, including interleukins, interfeons (α, β or δ) and TNF.
90 . A method according to claim 88 , wherein the antineoplastic drugs comprise alkylating agents like nitrogen mustards selected from mechlorethamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulphates selected from busulfan, nitrosoureas selected from carmustine, lomustine, semustine and streptozocin, triazenes selected from dacarbazine, antimetabolites selected from folic analogies like methotrexate, pyrimidine analogues selected from fluorouracil and cytarabine, purine analogues selected from mercaptopurine and thioguanine, natural products like vinca alkaloids selected from vinblastine, vincristine and vindesine, epipodophyllotoxins selected from etoposide and teniposide, antibiotics selected from dactinomycin, daunorubicin, doxorubincin, bleomycin, plicamycin and mitomycin, enzymes selected from L-asparaginase, various agents selected from coordination complexes of platinum like cisplatin, substituted ureas like hydroxyurea, methylhydrazine derivatives selected from procarbazine, adrenocortical suppressants selected from mitotane and aminoglutethymide, hormones and antagonists selected from adrenocorticosteroids selected from prednisone, progestins selected from hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens selected from diethylstilbestrol and ethynylestradiol, antiestrogens selected from tamoxifen, and androgens selected from testosterone propionate and fluoxymesterone.
91 . A pharmaceutical composition according to claim 79 , wherein the composition is suitable for parenteral administration.
92 . A pharmaceutical composition according to claim 91 , wherein the composition is suitable for intravenous, intraperitoneal, intramuscular or subcutaneous administration.
93 . A pharmaceutical composition according to claim 79 , comprising a pharmaceutically acceptable adjuvants, carriers or excipients.
94 . A pharmaceutical composition according to claim 93 , wherein the adjuvant, carrier or excipient is selected from a diluent, sterile aqueous media and non-toxic solvents.
95 . A pharmaceutical composition according to claim 79 , wherein the composition is an aqueous solution, an aqueous suspension, or an injectable solution.
96 . A pharmaceutical composition according to claim 95 , wherein the composition comprises at least one emulsifying agent, colorant, preservative or stabilizer.
97 . A pharmaceutical composition according to claim 91 , wherein the composition is an aqueous or non-aqueous solution or suspension.
98 . The taxoid of claim 1 , wherein the alkoxy portion of the alkoxyacetyl radical contains 1 to 8 carbon atoms.
99 . The taxoid of claim 50 , wherein the alkoxy portion of the alkoxyacetyl radical contains 1 to 8 carbon atoms.
100 . The taxoid of claim 50 , wherein R represents methoxyacetyl, R 2 represents a t-butyl radical, and Ar represents thienyl.
101 . The taxoid of claim 50 , wherein R represents methoxyacetyl, R 2 represents a t-butyl radical, and Ar represents phenyl.
102 . The taxoid of claim 50 , wherein R represents butoxyacetyl, R 2 represents a t-butyl radical, and Ar represents phenyl.
103 . The taxoid of claim 50 , wherein-R represents ethoxyacetyl, R 2 represents a t-butyl radical, and Ar represents phenyl.
104 . The taxoid of claim 50 , wherein R represents isopropoxyacetyl, R 2 represents a t-butyl radical, and Ar represents phenyl.
105 . A compound of the formula (XXII)
in which G 1 is an alkoxyacetyl radical or other hydroxy-protecting group.
106 . A method of preparing a compound of the formula (VI):
in which G 1 is an alkoxyacetyl radical or other hydroxy-protecting group, comprising reacting a compound of the formula (XXII)
with an alkali metal halide or an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate in an organic solvent and isolating the compound of formula (VI).
107 . The method according to claim 106 , wherein the compound of formula XXII is prepared by reacting a compound of the formula XX:
with trifluoro-methanesulfonic acid or a derivative thereof.
108 . The method of claim 107 , wherein the trifluoromethanesulphonic acid derivative is trifluoromethanesulfonic acid anhydride or N-phenyltrifluoromethanesulfonimide.
109 . A compound of the formula XXIII:
in which Ar represents an aryl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO— in which R 2 represents:
a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms,
these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals (optionally substituted at position 4 by alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals, cyano radicals, carboxy radicals or alkyloxycarbonyl radicals whose alkyl portion contains 1 to 4 carbon atoms,
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 or alkyloxy radicals containing 1 to 4 carbon atoms,
or a saturated or unsaturated 4- to 6-membered nitrogen-containing heterocyclyl radical 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 one or more alkyl radicals containing 1 to 4 carbon atoms; R 3 and R 4 , which are identical or different represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and their aryl portion preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R 3 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R 4 represents a hydrogen atom, or alternatively R 3 and R 4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, and G 1 represents an alkoxyacetyl radical or a hydroxy-protecting group.
110 . A compound according to claim 109 , wherein Ar represents a phenyl or α- or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcabamoyl, cyano, nitro and trifluoromethyl radicals, with the proviso 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 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- or β-naphthyl radicals or alternatively Ar represents a 5-membered aromatic heterocyclic radical containing one or more atoms, which are identical or different, chosen from nitrogen, oxygen or sulphur atoms, optionally substituted by one or more substituents, which are identical or different, chosen from halogen atoms, and alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy radicals containing 6 to 10 carbon atoms, amino radicals, alkylamino radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, acylamino radicals in which the acyl portion contains 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains 6 to 10 carbon atoms, cyano radicals, carboxy radicals, carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains 1 to 4 carbon atoms or alkoxycarbonyl radicals in which the alkoxy portion contains 1 to 4 carbon atoms.
111 . A compound according to claim 109 , wherein Ar represents a phenyl, 2- or 3-thienyl or 2- or 3-furyl radical optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.
112 . A compound according to claim 109 , wherein Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom or by an alkyl, alkoxy, dialkylamino, acylamino or alkoxycarbonylamino or 2- or 3-thienyl or 2- or 3-furyl radical.
113 . A compound according to claim 109 , wherein Ar represents a phenyl radical and R 1 represents a benzoyl or tert-butoxcarbonyl radical.
114 . A method of preparing a compound of the formula II:
in which Ar represents an aryl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO— in which R 2 represents:
a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms or hydroxy radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals (optionally substituted at position 4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals, cyano radicals, carboxy radicals or alkyloxycarbonyl radicals whose alkyl portion contains 1 to 4 carbon atoms,
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 or alkyloxy radicals containing 1 to 4 carbon atoms,
or a saturated or unsaturated 4- to 6-membered nitrogen-containing heterocyclyl radical 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 one or more alkyl radicals containing 1 to 4 carbon atoms; R 3 and R 4 , which are identical or different represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, or alternatively R 3 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R 4 represents a hydrogen atom, or alternatively R 3 and R 4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, and G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group, comprising reacting a compound of the formula (XXIII):
with an alkali metal halide or an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate in an organic solvent and isolating the compound of formula (II).
115 . The method according to claim 114 , wherein the compound of formula XXIII is prepared by reacting a compound of the formula XXIV:
with trifluoro-methanesulfonic acid or a derivative thereof.
116 . The method of claim 115 , wherein the trifluoramethanesulfonic acid derivation is trifluoromethane sulfonic acid anhydrides or N-phenyltrifluoromethanesulfonimide.
117 . A method for the preparation of a taxoid of the formula
in which R represents an alkoxyacetyl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO— in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising reacting a compound of the formula XXII
in which G 1 is an alkoxyacetyl radical or other hydroxy-protecting group, with an alkali metal halide or an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate in an organic solvent to form a compound of the formula VI:
esterifying the product of formula VI:
with a free acid of the formula VII:
or a derivative of the free acid capable of being converted into the free acid, in which R 3 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or an optionally substituted aryl radical and R 4 represents a hydrogen atom, to give a product of the formula II:
treating this product in acidic medium to give a product of the formula III:
and then optionally replacing the protecting group G 1 by a hydrogen atom or alkoxyacetyl radicals and alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product (I) obtained.
118 . A process according to claim 117 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from −10 to 90° C.
119 . A process according to claim 117 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
120 . A process according to claim 117 , wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
121 . A process according to claim 117 , wherein the acid treatment is carried out by means of an inorganic or organic acid in an organic solvent at a temperature ranging from −10 to 60° C.
122 . A process according to claim 121 , wherein the acid is chosen from hydrochloric, sulphuric, acetic, methanesulphonic, trifluoromethanesulphonic and p-toluenesulphonic acids, used alone or in the form of a mixture.
123 . A process according to claim 121 , wherein the solvent is chosen form alcohols, ethers, esters, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles.
124 . A process according to claim 117 , wherein the replacement by a hydrogen atom of the protecting group G 1 , when it represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, is carried out by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, and, when it represents an alkoxyacetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
125 . A method for the preparation of a product of the formula I:
in which R represents an alkoxyacetyl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO— in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising reacting a compound of the formula XXII:
with an alkali metal halide or an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate in an organic solvent to form a compound of the formula VI:
esterifying a product of the formula VI:
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group, by means of free acid of the formula VII:
or a derivative of the free acid capable of being converted into the free acid, in which R 3 and R 4 , which are identical or different, represent an alkyl radical containing 1 to 4 carbon atoms or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms or an aryl radical, or alternatively R 3 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R 4 represents a hydrogen atom, or alternatively R 3 and R 4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, to give, after treating in acidic medium, a product of the formula IV:
and acylating the product by means of benzoyl chloride or a reactive derivative of the formula:
R 2 —O—CO—X
in which X represents a halogen atom or a residue —O—R 2 or —O—CO—O—R 2 , and then replacing the protecting group G 1 , if necessary, by a hydrogen atom or an alkoxyacetyl radical, alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product obtained.
126 . A process according to claim 125 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from −10 to 90° C.
127 . A process according to claim 125 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
128 . A process according to claim 125 , wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
129 . A process according to claim 125 , wherein the acid treatment is carried out by means of an inorganic or organic acid in an organic solvent at a temperature ranging from 0 to 50° C.
130 . A process according to claim 129 , wherein the acid is chosen from hydrochloric, sulphuric and formic acids.
131 . A process according to claim 129 , wherein the solvent is chosen from alcohols containing 1 to 3 carbon atoms.
132 . A process according to claim 129 , wherein the acylation is carried out in an inert organic solvent in the presence of an inorganic or organic base.
133 . A process according to claim 126 , wherein the inert organic solvent is chosen from esters and halogenated aliphatic hydrocarbons.
134 . A process according to claim 128 wherein the procedure is carried out at a temperature ranging from 0 to 50° C.
135 . A process according to claim 125 , wherein the replacement by a hydrogen atom of the protecting group G 1 , when it represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical, is carried out by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, or, when it represents an alkoxy acetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in ethanol at a temperature close to 20° C.
136 . A method for the preparation of a taxoid of the formula I:
in which R represents an alkoxyacetyl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO— in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising reacting a compound of the formula XXII:
in which G 1 represents a hydroxy-protecting group, with an alkali metal halide or an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate in an organic solvent to form a compound of the formula VI:
esterifying a product of the formula VI:
by means of a free acid of the formula XXVI:
or a derivative of the free acid capable of being converted into the free acid, in which G 3 represents a hydroxy-protecting group, or of an activated derivative of this acid, to give a product of the formula XXVII:
replacing the protecting groups G 3 and optionally G 1 by a hydrogen atom or an alkoxyacetyl radical, said alkoxyacetyl radical being obtained by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by a hydrogen atom, and isolating the product (I) obtained.
137 . A process according to claim 136 , wherein the esterification is carried out by means of the free acid, the procedure being carried out in the presence of a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitrites aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature of between −10 to 90° C.
138 . A process according to claim 136 , wherein the esterification by means of an anhydride derivative of the free acid is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 90° C.
139 . A process according to claim 136 , wherein the esterification is carried out by means of a halide or anhydride derivative of the free acid with an aliphatic or aromatic acid, optionally prepared in situ, the procedure being carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature ranging from 0 to 80° C.
140 . A process according to claim 136 , wherein the replacement of the protecting groups G 1 and G 3 by hydrogen atoms is carried out by treatment with zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, when G 1 and G 3 represent a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloro-methylpropoxy)carbonyl radical, or by treatment in acidic medium such as for example hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, propanol or isopropanol) or aqueous hydrofluoric acid at a temperature ranging from 0 to 40° C. when G 3 represents a silylated radical or an acetal residue, followed by the replacement of the protecting group G 1 by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature ranging from 30 to 60° C. or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc optionally combined with copper, or, when G 1 represents an alkoxyacetyl radical, by treatment in alkaline medium by means of ammonia in aqueous-alcoholic medium at a temperature close to 20° C. or by treatment using a zinc halide in methanol at a temperature close to 20° C.
141 . A process according to claim 136 , wherein when G 3 represents a radical —CH 2 —Ph, the replacement of the group by a hydrogen atom is carried out by hydrogenolysis after replacing the protecting group G 1 .
142 . A method for the preparation of a taxoid of the formula (I):
in which R represents an alkoxyacetyl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising esterifying a compound of the formula (XXIX):
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group and Ra represents a radical O—SO 2 —CF 3 or forms, together with the carbon atom of the a methyl group, a cyclopropyl ring, with a lactam of the formula (XXX):
wherein G 3 is a hydroxy-protecting group chosen from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilyloxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl, 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radicals, or CH 2 —Ph radicals in which Ph represents a phenyl radical optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms, and Ar and R 1 are defined as above, optionally transforming the O—SO 2 —CF 3 radical into a cyclopropyl ring; and
replacing G 3 by a hydrogen atom and optionally G 1 by a hydrogen atom, said method comprising the further step, if G 1 is replaced by a hydrogen atom, of converting said G 1 hydrogen atom to an alkoxyacetyl radical by action of an alkoxyacetic acid or derivative thereof on a compound obtained after replacement of G 1 by said hydrogen atom.
143 . A method for the preparation of a taxoid of the formula (I):
wherein R represents butoxyacetyl, ethoxyacetyl, and isopropoxyacetyl, R 1 represents a t-butoxycarbonyl radical, and Ar represents phenyl; comprising esterfying with an alkoxyacetic acid or derivative thereof, a compound of the formula (II):
wherein G 1 represents a hydrogen atom, and R 3 and R 4 , which are identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R 3 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R 4 represents a hydrogen atom, or alternatively R 3 and R 4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, and opening the oxazaldine ring portoin of the compound of formula (II) to obtain the compound of formula (I).
144 . The method of claim 143 , wherein the alkoxyacetic acid is selected from butoxyacetic acid, ethoxyacetic acid, and isoproxyacetic acid.
145 . A method for the preparation of a taxoid of the formula (I):
in which R represents an alkoxyacetyl radical, R 1 represents a benzoyl radical or a radical R 2 —O—CO in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising esterifying a compound of the formula (XXIX):
in which G 1 represents an alkoxyacetyl radical or other hydroxy-protecting group and Ra represents a radical O—SO 2 —CF 3 or forms, together with the carbon atom of the a methyl group, a cyclopropyl ring, with a free acid of the formula (VII):
in which R 3 and R 4 , which are identical or different represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R 3 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R 4 represents a hydrogen atom, or alternatively R 3 and R 4 form, together with the carbon atom to which they are attached, a 4- to 7-membered ring; and Ar and R 1 are defined as above;
optionally transforming the O—SO 2 —CF 3 radical into a cyclopropyl ring; and
removing, if G 1 is said other hydroxy-protecting group, said hydroxy-protecting group to obtain a hydrogen atom and converting said hydrogen atom to an alkoxyacetyl radical by action of an alkoxyacetic acid or derivative thereof on said compound obtained after replacement of said G 1 hydroxy-protecting group by a hydrogen atom.Join the waitlist — get patent alerts
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