US 2009/0247472 A1 · TYPE 1, 4-NAPHTOQUINONE COMPOUNDS, COMPOSITIONS COMPRISING THEM AND USE OF THESE COMPOUNDS AS ANTI-CANCER AGENTS

Abstract

This invention relates to compounds with the formula (I) given below or one of their pharmaceutically acceptable salts, as a medicine; Formula (I) of pharmaceutical compositions comprising one or more compounds with Formula (I) as active constituent, use of compounds with Formula (I) for the preparation of compositions designed to prevent or treat at least one illness involving an abnormal cellular proliferation, pro-apoptotic compositions and/or anti-proliferative compositions comprising at least one compound with Formula (I)/and the use of compounds with formula (I) as pro-apoptotic and/or anti-proliferative agents.

An isolated compound of the following formula (I), or one of its pharmaceutically acceptable salts, by way of medication:

in which
A is —O—, —S—, —SO2—, —C(═S)—, —CO— or a chemical function such that Z′ and X′ are linked by a bioisosteric bond of the amine function,
R1 represents a hydrogen atom;
a halogen atom;
a hydroxyl function, possibly substituted;
a C1-18alkyl, C2-18alkene or C2-18alkyne radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
an C6-10aryl C1-6alkyl or C1-6alkyl C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a nitro function;
or an —X′-A′-Z′ function in which;
(i) X′ represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear, branched or cyclic, substituted or not, chiral or non-chiral, possibly interrupted by a heteroatom,
(ii) A′ is —O—, —S—, —NY′—, —SO2—, —C(═S)—, —CO— or a chemical function such that Z′ and X′ are linked by a bioisosteric bond of the amide function, where Y′ represents a hydrogen atom or a protective group, and
(iii) Z′ represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine or carboxyl function (ie not linked to X′) and any lateral chemical functions of Z′ being protected or not, where Z′ is linked to the X′ radical via an amide bond, a retro-inverso amide bond, an ester bond, or a sulphonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond, resulting from the coupling of X′ with a terminal aldehyde or alcohol function of Z′ resulting from the reduction of the terminal carboxyl function of the Z′ amino acid residue;
R2, R3, R4 and R5 represent independently of one another a hydrogen atom;
a halogen atom;
a hydroxyl function, possibly substituted, a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups, a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups, a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
or a nitro function;
or R2 and R3, R3 and R4 and/or R4 and R5 form together a ring or a heterocyclic compound, possibly substituted,
X represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear, branched or cyclic, substituted or not, chiral or non-chiral, possibly interrupted by a heteroatom, and
Z represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine or carboxyl function (ie not linked to X) and any lateral chemical functions of Z being protected or not, where Z is linked to the X radical via a retro-inverso amide bond, an ester bond, or a sulphonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond, resulting from the coupling of X with a terminal aldehyde or alcohol function of Z resulting from the reduction of the terminal carboxyl function of the Z amino acid residue;
or in which
A is —NY—;
and
(a)
R1 represents a hydrogen atom;
a halogen atom;
a hydroxyl function, possibly substituted;
a C1-18alkyl, C2-18alkene or C2-18alkyne radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a nitro function;
or an —X′-A′-Z′ function in which;
(i) X′ represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear, branched or cyclic, substituted or not, chiral or non-chiral, possibly interrupted by a heteroatom,
(ii) A′ is —O—, —S—, —NY′—, —SO2—, —C(═S)—, —CO— or a chemical function such that Z′ and X′ are linked by a bioisosteric bond of the amide function, where Y′ represents a hydrogen atom or a protective group, and
(iii) Z′ represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine or carboxyl function (ie not linked to X′) and any lateral chemical functions of Z′ being protected or not, where Z′ is linked to the X′ radical via an amide bond, a retro-inverso amide bond, an ester bond, or a sulphonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond, resulting from the coupling of X′ with a terminal aldehyde or alcohol function of Z′ resulting from the reduction of the terminal carboxyl function of the Z′ amino acid residue;
R3, R4 and R5 represent independently of one another a hydrogen atom;
a halogen atom;
a hydroxyl function, possibly substituted, a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups, a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10 aryl or hydroxyl groups;
a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
or a nitro function;
R2 represents, independently of R1, R2, R3, R4 and R5, a hydrogen atom;
a halogen atom;
a substituted hydroxyl function;
a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxyl groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
or a nitro function;
or R2 and R3, R3 and R4 and/or R4 and R5 form together a ring or a heterocyclic compound, possibly substituted,
X represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear, branched or cyclic, substituted or not, chiral or non-chiral, possibly interrupted by a heteroatom,
Y represents a hydrogen atom or a protective group, and
Z represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine function (ie not linked to X) and any lateral chemical functions of Z being protected or not, where Z is linked to the X radical via an amide bond;
(b)
R1 represents a hydrogen atom;
a halogen atom;
a hydroxyl function, possibly substituted;
a C1-18alkyl, C2-18alkene or C2-18alkyne radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a nitro function;
or an —X′-A′-Z′ function in which;
(i) X′ represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear, branched or cyclic, substituted or not, chiral or non-chiral, possibly interrupted by a heteroatom,
(ii) A′ is —O—, —S—, —NY′—, —SO2—, —C(═S)—, —CO— or a chemical function such that Z′ and X′ are linked by a bioisosteric bond of the amide function, where Y′ represents a hydrogen atom or a protective group, and
(iii) Z′ represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine or carboxyl function (ie not linked to X′) and any lateral chemical functions of Z being protected or not, where Z′ is linked to the X′ radical via an amide bond, a retro-inverso amide bond, an ester bond, or a sulphonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond, resulting from the coupling of X′ with a terminal aldehyde or alcohol function of Z′ resulting from the reduction of the terminal carboxyl function of the Z′ amino acid residue;
R3, R4 and R5 represent independently of one another a hydrogen atom;
a halogen atom;
a hydroxyl function, possibly substituted, a C6-10aryl, C1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups, a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups, a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
or a nitro function;
R2 represents a hydroxyl function;
or R3 and R4 and/or R4 and R5 form together a ring or a heterocyclic compound, possibly substituted,
X represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear or cyclic, not substituted, possibly interrupted by a heteroatom,
Y represents a hydrogen atom or a protective group, and
Z represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine function (ie not linked to X) and any lateral chemical functions of Z being protected or not, where Z is linked to the X radical via an amide bond;
or in which:
(c)
R1 represents a halogen atom;
a hydroxyl function, possibly substituted, a C1-18alkyl, C2-18alkene, or C2-18alkyne radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a nitro function;
or an —X′-A′-Z′ function in which;
(i) X′ represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear, branched or cyclic, substituted or not, chiral or non-chiral, possibly interrupted by a heteroatom,
(ii) A′ is —O—, —S—, —NY′—, —SO2—, —C(═S)—, —CO— or a chemical function such that Z′ and X′ are linked by a bioisosteric bond of the amide function, where Y′ represents a hydrogen atom or a protective group, and
(iii) Z′ represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine or carboxyl function (ie not linked to X′) and any lateral chemical functions of Z being protected or not, where Z′ is linked to the X′ radical via an amide bond, a retro-inverso amide bond, an ester bond, or a sulphonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond, resulting from the coupling of X′ with a terminal aldehyde or alcohol function of Z′ resulting from the reduction of the terminal carboxyl function of the Z′ amino acid residue;
R2 represents a hydroxyl function;
R3, R4 and R5 represent independently of one another a hydrogen atom;
a halogen atom;
a hydroxyl function, possibly substituted, a C6-10aryl, C1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
a C6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups, a C6-10arylC1-6alkyl or C1-6alkylC6-10aryl radical, possibly substituted, in particular by one or more amino, carboxylic acid, carboxylic acid derivative, C1-18alkoxy, C6-10aryl or hydroxy groups;
or a nitro function;
or R3 and R4 and/or R4 and R5 form together a ring or a heterocyclic compound, possibly substituted,
X represents a divalent radical, in particular chosen from C1-18alkyls, C2-18alkenes or C2-18alkynes, linear, branched or cyclic, substituted or not, possibly interrupted by a heteroatom,
Y represents a hydrogen atom or a protective group, and
Z represents an amino acid residue, in particular D or L, natural or synthetic, in particular an α, β or γ amino acid residue, the terminal amine function (ie not linked to X) and any lateral chemical functions of Z being protected or not, where Z is linked to the X radical via an amide bond,
in particular, for the compounds described in parts (a), (b) and (c) above, and for the compounds of formula (I) above where A is —O—, —S—, —SO2—, —C(═S)—, —CO— or a chemical function such that Z′ and X′ are linked by a bioisosteric bond of the amide function, X and X′ are, independently of each other, possibly substituted by one or more chemical functions such as a lateral chain of a natural amino acid;
C1-6alkyl;
C2-6alkene;
C2-6alkyne;
C3-8cycloalkyl;
C1-6heteroalkyl;
C1-6haloalkyl;
C6-10aryl;
C3-10heteroaryl;
C5-20heterocyclic;
C1-6alkylC6-10aryl;
C1-6alkylC3-10heteroaryl;
C1-6alkoxy;
C6-10aryloxy;
C3-10heteroalkoxy;
C3-10heteroaryloxy;
C1-6heteroalkylthio;
C6-10arylthio;
C1-6heteroalkylthio;
C3-10heteroarylthio;
F;
Cl;
Br;
I;
—NO2;
—CN;
—CF3;
—CH2CF3;
—CHCl2, —CH2OH;
—CH2CH2OH;
—CH2NH2;
—CH2SO2CH3 or a -GRG1 function in which G is —O—, —S—, —NRG2—, —C(═O)—, —S(═O)—, —SO2—, —C(═O)O—, —C(═O)NRG2, —OC(═O)—, —NRG2C(═O)—, —OC(═O)0-, —OC(═O)NRG2—, —NRG2C(═O)O—, —NRG2C(═O)NRG2—, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NRG2)—, —C(═NRG2)O, —C(═NRG2)NRG3—, —OC(═NRG2)—NRG2C(═NRG3)—, —NRG2 SO2—, —NRG2SO2NRG2—, —NRG2C(═S)—, —SC(═S)NRG2—, —NRG2C(═S)S—, —NRG2C(═S)NRG2—, —SC(═NRG2)—, —C(═S)NRG2—, —OC(═S)NRG2—, NRG2C(═S)O—, —SC(═O)NRG2—, —NRG2C(═O)S—, —C(═O)S—, —SC(═O)—, —SC(═O)S—, —C(═S)O—, —OC(═S)—, —OC(═S)O— or —SO2NRG2—, where each occurrence of RG1, RG2 and RG3 is independently of the other occurrences of RG1 a hydrogen atom;
a halogen atom;
or a C1-18alkyl, C1-1 heteroalkyl, C2-14alkene or C2-18alkyne function, linear, branched or cyclic, possibly substituted;
or a C6-10aryl, C6-10heteroaryl, C5-10heterocyclic compound, C1-6alkylC6-10aryl or C1-6alkylC6-10heteroaryl group in which the aryl, heteroaryl or heterocyclic radical is possibly substituted;
or, when G represents —NRG2—, RG1 and RG2 conjointly with the nitrogen atom to which they are bonded form a heterocyclic compound or a heteroaryl, possibly substituted.

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Type 1, 4-naphtoquinone compounds, compositions comprising them and use of these compounds as anti-cancer agents

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Type 1, 4-naphtoquinone compounds, compositions comprising them and use of these compounds as anti-cancer agents

Life of this patent

Abstract

Claims12