Conjugate of cytotoxic drug and prodrug form of said conjugate

The present invention relates to a specific conjugate of cytotoxic drugs and prodrug forms of said conjugate, for use in treating cancer and inflammatory diseases. The conjugate is represented by formula (I) wherein A represents a radical deriving from a cytotoxic drug, G is a self-immolative moiety, and m is 0 or 1, and pharmaceutically acceptable salts thereof.

CONJUGATE OF CYTOTOXIC DRUG AND PRODRUG FORM OF SAID CONJUGATE

The present invention relates to a specific conjugate of cytotoxic drugs and prodrug forms of said conjugate, for use in treating cancer and inflammatory diseases. The conjugate is represented by formula (I) wherein A represents a radical deriving from a cytotoxic drug, G is a self-immolative moiety, and m is 0 or 1, and pharmaceutically acceptable salts thereof.

IMINOSYDNONE DERIVATIVES FOR CONJUGATION AND RELEASE OF COMPOUNDS OF INTEREST

The present invention relates to the use of iminosydnone compounds in processes for the preparation of conjugates of two compounds of interest. The invention further relates to the use of said iminosydnone compounds in a process for releasing a compound of interest. The invention finally relates to novel iminosydnone compounds. 2. The process according to claim 1 , wherein F is selected from the group consisting of a carboxylic acid COOH group claim 1 , an activated ester and an alkyl group substituted by at least one of these groups.3. The process according to claim 1 , comprising a preliminary step of covalent bonding of the reactive group to C1.5. The process according to claim 4 , wherein the reactive group is an amino group or a thiol group.7. (canceled)8. A process for the preparation of a conjugate according to claim 19 , comprising the step of contacting a compound of formula (II) with the compound of interest C2 claim 19 , wherein C2 bears a reactive group which is able to react with R.910-. (canceled)14. The iminosydnone according to claim 13 , wherein F′ is a C═O group and R is an amino group claim 13 , forming a urea moiety with the F′ group claim 13 , and X is a halogen atom selected from chlorine and bromine.16. The process of preparation according to claim 15 , wherein the process comprises a preliminary step of covalent bonding of the strained alkyne moiety to the compound of interest C3.17. The process according to claim 15 ,wherein C1 is a nanoparticle or an antibody, C2 is a drug and C3 is a fluorophore.18. The process according to claim 16 ,wherein C1 is a nanoparticle or an antibody, C2 is a drug and C3 is a fluorophore. This application is a continuation of U.S. Ser. No. 15/319,387, filed Dec. 16, 2016, which is the U.S. national stage application of International Patent Application No. PCT/EP2015/063755, filed Jun. 18, 2015.The present invention relates to the use of iminosydnone compounds in processes for the preparation of conjugates of two ...

BIOCONJUGATES WITH A CONTROLLED DEGREE OF CONJUGATION, THEIR PROCESS OF PREPARATION, AND THE REAGENTS FOR THEIR PREPARATION

Disclosed is a process for preparation of heterogeneous monodisperse mixtures of protein conjugates with a defined degree of conjugation (1-8) obtained by using a tri-functional reagent allowing affinity concentration followed by subsequent simultaneous release-functionalization.

CONJUGATE OF CYTOTOXIC DRUG AND PRODRUG FORM OF SAID CONJUGATE

The present invention relates to a specific conjugate of cytotoxic drugs and prodrug forms of said conjugate, for use in treating cancer and inflammatory diseases. The conjugate is represented by formula (I) wherein A represents a radical deriving from a cytotoxic drug, G is a self-immolative moiety, and m is 0 or 1, and pharmaceutically acceptable salts thereof 113-. (canceled)15. The conjugate according to claim 14 , wherein the cytotoxic drug is selected from anthracyclines claim 14 , doxorubicin claim 14 , dolastatins claim 14 , dolastatin 10 claim 14 , dolastatin 15 claim 14 , auristatin E claim 14 , auristatin EB (AEB) claim 14 , auristatin EFP (AEFP) claim 14 , monomethyl auristatin F (MMAF) claim 14 , monomethyl auristatin D (MMAD) claim 14 , monomethyl auristatin E (MMAE) claim 14 , 5-benzoylvaleric acid-AE ester (AEVB) or derivatives thereof claim 14 , camptothecin analogs claim 14 , and SN-38.16. The conjugate according to claim 14 , wherein the cytotoxic drug is selected from the group consisting of SN-38 claim 14 , doxorubicin claim 14 , MMAF claim 14 , MMAE claim 14 , MMAD and derivatives thereof.18. A prodrug comprising at least one molecule of the conjugate according to claim 14 , said molecule of the conjugate being linked via a covalent bond to a protein molecule or a fragment or a derivative thereof.19. The prodrug according to claim 18 , wherein the covalent bond is established with the thiol function of the cysteine in position 34 of albumin.21. The prodrug according to claim 20 , wherein Prt represents a radical deriving from albumin and n is 1.22. A pharmaceutical composition comprising an effective amount of at least one conjugate as defined according to or at least one prodrug thereof claim 14 , and a pharmaceutically acceptable carrier.23. A method for treating a cancer and/or an inflammatory disease claim 14 , comprising administering to a subject in need thereof an effective amount of a conjugate according to .24. A method for treating a ...

PROTEIN-DRUG CONJUGATES AND THEIR USE IN THE TREATMENT OF CANCERS

This invention pertains to protein-drug conjugates that may be used in the treatment of cancers and to pharmaceutical compositions containing the same. The protein-drug conjugate has the following formula (I), wherein: L is a cysteine-containing protein residue linked through one or more of the cysteine groups of the protein, R 1 is selected from the group consisting of arylene, arylene-heteroarylene, heteroarylene-arylene and heteroarylene, n is an integer from 0 to 5, p and q are independently 0 or 1, R 2 , R 3 and Z are spacers, u is 0 or 1 and T is a cleavable unit sensitive to hydrolases, k is 1 or 2 and D is a cytotoxic drug residue selected from dolastatin residues, which may be identical to or different from each other when k is 2, m is the mean payload-to-protein ratio (PPR) of the conjugate, which ranges from 0.1 to 16.

Method for producing pyrazoles, novel pyrazoles and applications thereof

A method for preparing a pyrazole of formula (I) in which R,R′ and R″ have different meanings, characterised in that it involves reacting a sydnone of formula (II) in which R and R′ have the meanings already indicated, with an alkyne of formula (III) in which R″ has the meaning already indicated, in the presence of copper, to obtain a pyrazole compound of formula (I) that is then isolated and salified if desired.

IMINOSYDNONE DERIVATIVES FOR CONJUGATION AND RELEASE OF COMPOUNDS OF INTEREST

The present invention relates to the use of iminosydnone compounds in processes for the preparation of conjugates of two compounds of interest. The invention further relates to the use of said iminosydnone compounds in a process for releasing a compound of interest. The invention finally relates to novel iminosydnone compounds. 114-. (canceled)16. Process according to claim 15 , wherein F is selected from the group consisting of a carboxylic acid COOH group claim 15 , an activated ester and an alkyl group substituted by at least one of these groups.17. Process according to claim 15 , comprising a preliminary step of covalent bonding of the reactive group to C1.19. Process according to claim 18 , wherein the reactive group is an amino group or a thiol group.22. Process for the preparation of a conjugate according to claim 21 , comprising the step of contacting a compound of formula (II) with the compound of interest C2 claim 21 , wherein C2 bears a reactive group which is able to react with R.24. Process of preparation according to claim 23 , wherein the process comprises a preliminary step of covalent bonding of a strained alkyne moiety to the compound of interest C3.28. Iminosydnone according to claim 27 , wherein F′ is a C═O group and R is an amino group claim 27 , forming a urea moiety with the F′ group claim 27 , and X is a halogen atom selected from chlorine and bromine. The present invention relates to the use of iminosydnone compounds in processes for the preparation of conjugates of two compounds of interest. The invention further relates to the use of said iminosydnone compounds in a process for releasing a third compound of interest. The invention finally relates to said new iminosydnone compounds.The present invention relates to the domain of click chemistry (bioorthogonal reaction) and of bioconjugation of compounds of interest. Five main approaches are currently available for metal-free coupling two different compounds of interest ( and ▪). These ...

SYDNONE DERIVATIVES FOR CONJUGATION OF COMPOUNDS OF INTEREST

The present invention relates to a process for the preparation of a first compound of interest C1 functionalized with a sydnone compound and to the corresponding functionalized C1 compound of interest. The present invention also relates to a process for the preparation of a conjugate of two compounds of interest C1 and C2 implying a sydnone compound and to the obtained conjugate. The present invention also relates to a process for preparing a compound of interest C2 comprising a strained alkyne moiety functionalized with a sydnone and to the corresponding functionalized compound of interest C2. It also relates to novel sydnone compounds substituted in position 4, which may be used in the above processes.

METHOD FOR PRODUCING PYRAZOLES, NOVEL PYRAZOLES AND APPLICATIONS THEREOF

A method for preparing a pyrazole of formula (I) in which R,R′ and R″ have different meanings, characterised in that it involves reacting a sydnone of formula (II) in which R and R′ have the meanings already indicated, with an alkyne of formula (III) in which R″ has the meaning already indicated, in the presence of copper, to obtain a pyrazole compound of formula (I) that is then isolated and salified if desired. 1. (canceled)2. (canceled)3. (canceled)4. (canceled)5. (canceled)6. (canceled)7. (canceled)8. (canceled)9. (canceled)10. (canceled)11. (canceled)13. A process as claimed in claim 12 , wherein R represents an unsubstituted or substituted aryl or heteroaryl radical.14. A process as claimed in claim 12 , wherein R′ represents a hydrogen atom.15. A process as claimed in claim 12 , wherein R″ represents a hydrogen atom; a halogen atom; a thio or -thioalkyl group; a hydroxyl or alkoxy group; an amino or -aminoalkyl group; an alkyl radical containing from 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with F claim 12 , Cl claim 12 , Br claim 12 , I claim 12 , CN claim 12 , OH claim 12 , —O-heterocycle which is substituted or unsubstituted claim 12 , NH claim 12 , —NH—(C-Calkyl) claim 12 , —N—(C-Calkyl) claim 12 , —NH—R′″ or —(C-Calkyl)-NH—R′″ where R′″ represents a sulfonated group claim 12 , SH; an aryl radical containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times with an alkyl or alkoxy radical containing 1 to 8 carbon atoms; a heterocycle; an amino acid; a polypeptide; a protein; a nucleic acid; a DNA molecule; a polysaccharide; a polymer; a nanoparticle; a dendrimer.16. A process as claimed in claim 15 , wherein R″ represents a heteroaryl radical or an aryl radical or an alkyl radical containing from 1 to 8 carbon atoms.17. A process as claimed in claim 12 , wherein the catalyst metal is used in the form of a copper salt complexed with a nitrogenous ligand.18. A process as claimed in claim 17 , ...

Protein-drug conjugates and their use in the treatment of cancers

This invention pertains to protein-drug conjugates that may be used in the treatment of cancers and to pharmaceutical compositions containing the same. The protein-drug conjugate has the following formula (I), wherein: L is a cysteine-containing protein residue linked through one or more of the cysteine groups of the protein, R 1 is selected from the group consisting of arylene, arylene-heteroarylene, heteroarylene-arylene and heteroarylene, n is an integer from 0 to 5, p and q are independently 0 or 1, R 2 , R 3 and Z are spacers, u is 0 or 1 and T is a cleavable unit sensitive to hydrolases, k is 1 or 2 and D is a cytotoxic drug residue selected from dolastatin residues, which may be identical to or different from each other when k is 2, m is the mean payload-to-protein ratio (PPR) of the conjugate, which ranges from 0.1 to 16.

PROCESS FOR THE PRODUCTION OF PYRAZOLES, NEW PYRAZOLES AND THEIR APPLICATIONS

Procédé de préparation d'un pyrazole de formule I dans laquelle R, R' et R" ont différentes significations, caractérisé en ce que l'on fait réagir une sydnone de formule II dans laquelle R et R' ont les significations déjà indiquées, avec un alcyne de formule III dans laquelle R" a la signification déjà indiquée, en présence d'un métal catalyseur, pour obtenir un composé pyrazole de formule I que l'on isole et salifie si désiré. Process for the preparation of a pyrazole of formula I wherein R, R 'and R "have different meanings, characterized in that a sydnone of formula II is reacted in which R and R' have the meanings already indicated, with an alkyne of formula III wherein R "has the meaning already indicated, in the presence of a catalyst metal, to obtain a pyrazole compound of formula I which is isolated and salified if desired.

PROCESS FOR THE PRODUCTION OF PYRAZOLES, NEW PYRAZOLES AND THEIR APPLICATIONS

Conjugate of cytotoxic drug and prodrug form of said conjugate

The present invention relates to a specific conjugate of cytotoxic drugs and prodrug forms of said conjugate, for use in treating cancer and inflammatory diseases. The conjugate is represented by formula (I) wherein A represents a radical deriving from a cytotoxic drug, G is a self-immolative moiety, and m is 0 or 1, and pharmaceutically acceptable salts thereof.

Iminosydnone derivatives for conjugation and release of compounds of interest

The present invention relates to the use of iminosydnone compounds in processes for the preparation of conjugates of two compounds of interest. The invention further relates to the use of said iminosydnone compounds in a process for releasing a compound of interest. The invention finally relates to novel iminosydnone compounds.

Iminosydnone derivatives for conjugation and release of compounds of interest

The present invention relates to the use of iminosydnone compounds in processes for the preparation of conjugates of two compounds of interest. The invention further relates to the use of said iminosydnone compounds in a process for releasing a third compound of interest. The invention finally relates to said new iminosydnone compounds.

Sydnone derivatives for conjugation of compounds of interest

The present invention relates to a process for the preparation of a first compound of interest C1 functionalized with a sydnone compound and to the corresponding functionalized C1 compound of interest. The present invention also relates to a process for the preparation of a conjugate of two compounds of interest C1 and C2 implying a sydnone compound and to the obtained conjugate. The present invention also relates to a process for preparing a compound of interest C2 comprising a strained alkyne moiety functionalized with a sydnone and to the corresponding functionalized compound of interest C2. It also relates to novel sydnone compounds substituted in position 4, which may be used in the above processes.

Sydnone derivatives for conjugation of compounds of interest

The present invention relates to a process for the preparation of a first compound of interest C1 functionalized with a sydnone compound and to the corresponding functionalized C1 compound of interest. The present invention also relates to a process for the preparation of a conjugate of two compounds of interest C1 and C2 implying a sydnone compound and to the obtained conjugate. The present invention also relates to a process for preparing a compound of interest C2 comprising a strained alkyne moiety functionalized with a sydnone and to the corresponding functionalized compound of interest C2. It also relates to novel sydnone compounds substituted in position 4, which may be used in the above processes.

Bioconjugates with a controlled degree of conjugation, their process of preparation, and the reagents for their preparation

The present invention relates to a process for preparation of heterogeneous monodisperse mixtures of protein conjugates with a defined degree of conjugation (1-8) obtained by using a tri-functional reagent allowing affinity concentration followed by subsequent simultaneous release-functionalization.

Bioconjugates with a controlled degree of conjugation, their process of preparation, and the reagents for their preparation

Disclosed is a process for preparation of heterogeneous monodisperse mixtures of protein conjugates with a defined degree of conjugation (1-8) obtained by using a tri-functional reagent allowing affinity concentration followed by subsequent simultaneous release-functionalization.

Conjugate of cytotoxic drug and prodrug form of said conjugate