Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/40—2,5-Pyrrolidine-diones
  • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
  • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
  • C07C275/14—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G71/00—Macromolecular compounds obtained by reactions forming a ureide or urethane link, otherwise, than from isocyanate radicals in the main chain of the macromolecule
  • C08G71/02—Polyureas

Definitions

• the subject of the invention is new new activated stable derivatives of carbamic acid, in particular new stable activated carbamates, their preparation process and their use for the preparation of urea.
• substituted ureas have experienced significant growth in recent years. These compounds are present in a certain number of active principles currently in development in the pharmaceutical industry such as HIV protease inhibitors, CCK-B receptor antagonists, or endothelin antagonists. 1
• oligoureas have been introduced as “scaffolds” for the creation of S-sheets 2 or else as mimes of the peptide skeleton 3 .
• the methods for forming substituted ureas are based on the reaction of amines with carbonylating agents 4 , with isocyanates 5 or carbamates 6 .
• Activated carbamates are generally prepared by reacting amines with carbonates 40 or chloroformates 3 * 65 , or else reacting isocyanates with alcohols 63 .
• One aspect of the invention is to provide new stable activated derivatives of carbamic acid, in particular new stable activated carbamates.
• One of the other aspects of the invention is to provide new isocyanates.
• One of the other aspects of the invention is to propose a new process for preparing cyclic or non-cyclic ureas.
• One of the other aspects of the invention is to propose new ureas, cyclic or not.
• the invention relates to the use of isocyanates obtained from amino acid derivatives for the preparation and optionally the isolation of stable activated derivatives of carbamic acid or of stable activated carbamates.
• the invention relates to the use of isocyanates, stable activated derivatives of carbamic acid, or stable activated carbamates defined above, for the preparation of substituted ureas, cyclic or not, in particular urea oligomers, cyclic or not, or for the preparation of peptides or pseudopeptides containing urea units, cyclic or not.
• amino acid derivative is meant amino acids (alpha-, beta-, gamma-, delta-amino, or other) whose primary or secondary amino function can be protected by a group chosen to give an amino function tertiary, urethane, amide, urea, nitro or phthalimide.
• amino acid derivative must be interpreted in the broad sense, as understood by a person skilled in the art, and denotes in particular a derivative of peptide, polypeptide, protein, pseudopeptide or oligourea.
• activated carbamate or “activated derivative of carbamic acid” is meant a carbamate or a derivative of carbamic acid capable of reacting with primary or secondary amines or alcohols in the presence or not of a base in an organic solvent and usually at room temperature.
• stable carbamate or “derivative of stable carbamic acid”, is meant a stable carbamate or a derivative of stable carbamic acid since it is isolable, purifiable and perhaps stored (preferably at 4 ° C.) for a period of at least 3 months without significant deterioration. The stability can be measured for example by the following test: HPLC or thin layer chromatography.
• isolation is meant the process of separation of the desired product from all of the impurities present in the reaction mixture (these may for example be an excess of one of the reagents used to carry out the reaction, symmetric urea, l amine obtained by rearranging the isocyanate in the presence of water) and recovering the product thus purified in a form allowing it to be stored (at
• urea oligomers designates a successive chain of units linked together by urea bonds (at least two) For example: NH 2 -CHR 1 -CHR ' 1 -NH-CO-NH-CHR 2 -CHR ' 2 -NH-CO-NH-CHR 3 -
• the subject of the invention is in particular a process for preparing stable activated derivatives of carbamic acid, from an amino acid derivative in which the amino group is protected, comprising: a) a step of transformation of the group -COOH of the amino acid derivative in group -CON 3 to obtain an acyl azide, b) a stage of transformation of the group -CON 3 of acyl azide in group -NCO to obtain an isocyanate, c) a stage of treatment of l isocyanate to obtain the above stable derivative of carbamic acid.
• step a) of transformation of the group -COOH into group -CON 3 is carried out by treatment, with the azide anion, of an activated derivative of the amino acid in which the amino group is protected.
• the azide anion may be used in the form of sodium azide.
• step a) of transformation of the group -COOH into the group -CON 3 can be carried out by treatment of the mixed anhydride (formed from the amino acid derivative) with sodium azide.
• step a) of transformation of the group -COOH into group -CON 3 is carried out by treatment, with hydrazine, of an activated derivative of the amino acid in which the amino group is protected, to obtain a hydrazide, which is then subjected to nitrosation.
• activated amino acid derivative is meant, for example, an acid ester, or an acid halide, such as an acid chloride.
• the carboxylic acid is first converted into an active derivative (ester, chloride, etc.) which the action of hydrazine transforms into hydrazide, which is then transformed into the desired acyl azide, by action of nitrous acid.
• an active derivative ester, chloride, etc.
• the transformation of the -COOH group into the -NCO group can be carried out by the method using non-symmetrically disubstituted dimethylhydrazine (“UDMH”), according to the synthetic scheme indicated below for illustrative purposes:
• UDMH non-symmetrically disubstituted dimethylhydrazine
• a subject of the invention is also the compounds corresponding to formula (I)
• n is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - "i" is an integer varying from 2 to n + 1,
• - GP is a protective group chosen from:
• R trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , benzyl, allyl,
• urea RNHCO
• R H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• Rj, R and R may each represent independently of each other: hydrogen, halogen, the side chain of an amino acid chosen from natural or non-natural amino acids, an unsubstituted (C1-C20) alkyl group or substituted by one or more substituents among which:
• R representing an alkyl group of 1 to 20 carbon atoms, or an aryl group the ring structure of which contains 5 to 20 carbon atoms,
• Group X represents a group conferring on the compound of formula I an activated carbamate structure, which group X being derived from a compound chosen in particular from phenols, optionally substituted with at least one nitro or at least one halogen, or the derivatives of hydroxyamine, and more particularly chosen from the following compounds:
• R 1 , R ', R " can also be defined on the basis of intramolecular cyclizations which are the following: 1 / cyclization between R 1 and R "
• n> 2 the links a ,, a 1 + 1 , and b, belong to the aromatic cycle; the link b 1+! is in the orto position with respect to the link b,.,.
• n _> _ 3 the connections a ,, a, +2 , b, and b 1+ 1 belong to the aromatic cycle; the link b 1 + 2 is in the meta position relative to the link b,.,.
• R advantageously represents a hydrocarbon chain.
• the invention also relates to the compounds of formula (ILT)
• n is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - "i" is an integer varying from 2 to n + 1,
• R ,, R ,, R ' can represent each and independently of each other: hydrogen, the side chain of an amino acid chosen from natural amino acids or not, an alkyl group (C1-C20) unsubstituted or substituted by one or more substituents among which:
• R representing an alkyl group of 1 to 20 carbon atoms, or an aryl group the ring structure of which contains 5 to 20 carbon atoms, - the groups Y and Y ′ which can be or contain:
• p is an integer greater than or equal to 1, preferably from 1 to 50, and in particular from 1 to 10,
• - “k” is an integer varying from 1 to p
• - A is a group chosen from: * hydrogen
• ROCO oxycarbonyl
• Fmoc fluorényhnétoxycarbonyl
• R trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , benzyl, allyl,
• R CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• Z k , Z ' k , and Z " k may each represent, independently of one another, hydrogen, the side chain of an amino acid chosen from proteinogenic and nonproteinogenic amino acids an alkyl group (C1-C20) unsubstituted or substituted by one or more substituents among which: 1 / -COOR ,,
• R b representing an alkyl group of 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms.
• - “m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - “k” is an integer varying from 1 to m
• u is an integer greater than or equal to 1, preferably from 1 to 50, and in particular from 1 to 10,
• q is an integer greater than or equal to 1, preferably from 1 to 50, and in particular from 1 to 10,
• - "j" is an integer parameter greater than or equal to 2 defined as follows: j takes all integer values from 2 to u + 1,
• - or “r” is an integer parameter greater than or equal to 1 taking all the values from 1 to q, - "a ⁇ and a ' r J ", represented by a dotted line, are covalent bonds which can be single (s), or double (d),
• Z r j , Z ' r j are defined independently as above for R 1 , R, R' 1 ,
• Group X represents a group conferring on the compound of formula I an activated carbamate structure, which group X being derived from a compound chosen in particular from phenols, optionally substituted with at least one nitro or at least one halogen, or the derivatives of hydroxylamine, and more particularly chosen from the following compounds: - N-hydroxysuccirjimide
• R 1 , R ', R'' can also be defined on the basis of intramolecular cyclizations which are as follows: 1 / cyclization between R 1 and R' 1
• R 1 (or R 1 ) and R 1 + kc (or kc is a positive integer, preferably from 1 to 3)
• a subject of the invention is also the compounds of formula (131a)
• n is an integer greater than or equal to 1, preferably from 1 to 10, preferably from 1 to 4,
• - "i" is an integer varying from 2 to n + 1,
• - group Y can be or contain:
• p is an integer greater than or equal to 1, preferably from 1 to 50, and in particular from 1 to 10,
• - k is an integer varying from 1 to p
• - A is a group chosen from: * hydrogen
• ROCO oxycarbonyl
• Fmoc fluorenylmetoxycarbonyl
• R trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , benzyl, allyl,
• R CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• Z k , Z'k, and Z "k may each represent, independently of one another, hydrogen, the side chain protected or not of an amino acid chosen from the proteinogenic and nonproteinogenic amino acids, an alkyl group (C1-C20) unsubstituted or substituted by one or more substituents among which: 1 / -COORb 2 / -CONHR b 3 / -COOH
• F k and Fk ′ representing, independently of one another, hydrogen, the side chain protected or not of an amino acid chosen from proteinogenic amino acids and non-proteinogenic amino acids, a halogen, an alkyl group of 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms,
• - “m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - “k” is an integer varying from 1 to m
• GP group which can be: - a protective group chosen from:
• R trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2) C (CH 3 ) 3 , benzyl, allyl,
• the GP group can also be such that the “GP-N” entity forms a “NH 2 + ” entity,
• R 1 , R 1 and R may each represent, independently of each other: a hydrogen, a halogen, the side chain protected or not from an amino acid chosen from natural amino acids or not an alkyl group (C1 -C20) unsubstituted or substituted by one or more substituents among which: 1 / -COORa
• Ra representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl group having from 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms,
• Group X represents a group conferring on the compound of formula III bis a structure of activated derivative of carbamic acid, which group X being derived from a compound chosen in particular from phenols, optionally substituted with at least one nitro or at least one halogen, or hydroxylamine derivatives, and more particularly chosen from the following compounds:
• R 1 and R 1 can also be defined on the basis of intramolecular cyclizations which are the following:
• a subject of the invention is also the compounds of formula (I bis)
• n, i, GP, X, R 1 and R 1 have the meanings mentioned above, with regard to the formula (III bis).
• An advantageous group of compounds of formula (I bis) consists of those in which 1 ⁇ n ⁇ 4, X is as defined above with respect to the formula (Illbis) and is in particular derived from p-nitrophenol, N- hydroxysuccinimide, pentafluorophenol, hydroxy-1,2,3-benzotriazole or imidazole, GP is an oxycarbonyl or acyl group as defined above with regard to formula (III bis), and in particular those in which GP is advantageously Boc, Fmoc , and in particular the compounds corresponding to the following formulas:
• the compounds of formulas (131) and (III bis) are activated carbamates analogous to the compounds of formulas (I) and (I bis) for which the protective group is replaced for example by a chain of amino acids, a pseudopeptide, or an urea oligomer. They can be obtained from the corresponding isocyanates of formula (TV) defined below.
• the compounds of formulas (I) and (I bis) are activated carbamates derived from N-protected amino acids of formula (IX) defined below and which can be obtained from isocyanates of formula (II) defined below after.
• the invention also relates to the compounds of formula (IV)
• n is an integer greater than or equal to 1, preferably from 1 to 10, preferably from 1 to 4, - "i" is an integer varying from 2 to n + 1,
• the group Y can be or contain:
• p is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - “k” is an integer varying from 1 to p
• - or A is a group chosen from:
• RCO acyl
• RNHCO urea
• group A can form with the nitrogen atom N to which it is contiguous an entity "NH 2 + " - Z, Z'k, and Z '' k can represent each and independently: a hydrogen, the protected side chain or not of an amino acid chosen from proteinogenic and non-proteinogenic amino acids, an alkyl group (C1-C20), unsubstituted or substituted by one or more substituents among which:
• - “m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - “k” is an integer varying from 1 to m
• R CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• the GP group can also be such that the entity “GP-N” forms an entity “NH 2 + ”
• R ⁇ , Rj and R can each represent, independently of one another: a hydrogen a halogen the side chain protected or not of an amino acid chosen from natural amino acids or not an alkyl group (C1 -C20) unsubstituted or substituted with one or more substituents among which: 1 / -COORa
• R a representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• R 1 and R ′ can also be defined on the basis of intramolecular cyclizations which are the following:
• a subject of the invention is also the compounds of formula (H)
• n, i, GP, R 1 and R 1 have the meanings mentioned above with regard to the formula (IN).
• the isocyanates of formula (IV) can be used as precursors for the synthesis of the compounds of formula (III) and (HI bis) and can be obtained from the compounds of formula (X) defined below.
• the isocyanates of formula (II) are the precursors used in the synthesis of the compounds of formula (I) and (I bis) and can be obtained from N-protected amino acid derivatives of formula (IX) defined below .
• the invention also relates to compounds of formula (V)
• n is an integer greater than or equal to 1, going in particular from 1 to 4 and preferably from 1 to 2,
• - “d” is an integer ranging from 0 to 4, preferably equal to 0 or 1,
• - "i" is a number varying from 2 to n + 1,
• - group Y can be or contain:
• p is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - A is a group chosen from:
• ROCO oxycarbonyl
• Fmoc fluorenylmetoxycarbonyl
• R trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , benzyl, allyl,
• R CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• - Z k , Z ′ k , and Z ′′ k can each represent, independently of one another: a hydrogen, the side chain protected or not of an amino acid chosen from proteinogenic and non-proteinogenic amino acids, a alkyl group (C1-C20), unsubstituted or substituted by one or more substituents among which: 1 / -COORb 2 / -CONHRb 3 / -COOH 4 / -OH, ORb
• -CH 2 CONH 2 Rb representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• - "m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10, - "k” is an integer varying from 1 to m
• R 1 , R 1 and R may each represent, independently of one another: a hydrogen, a halogen, the side chain, protected or not, of an amino acid chosen from natural or non-natural amino acids, an alkyl group (C1-C20), unsubstituted or substituted by xm or more substituents among which:
• an OR group has an NH group 2 xm OH group
• R a representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• the group G can be or contain:
• v is xm whole number greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10 with preferably v> 3 and v> 5,
• - D can be: -NH 2 -NHCOR c -NHRc
• Rc CON (R d ) -OH -ORc Rc and Ra independently of one another representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• R e representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl group having from 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms.
• group X represents a group conferring on the compound of formula V an activated molecule structure capable of reacting with alcohols or amines to form derivatives of carbamic acids or ureas, and is in particular derived from a compound chosen from phenols, optionally substituted by nitro or halogen or hydroxylamine derivatives and more particularly chosen from: - N-hydroxysuccinimide
• R 1 and R 1 can also be defined on the basis of intramolecular cyclizations which are as follows:
• the compounds of formula (V) are activated carbamates analogous to the compounds of formula (I) and (I bis) for which the activated carbamate is introduced on the side chain of a protected amino acid or else of a peptide, of a pseudopeptide or an oligomer of urea.
• the invention also relates to compounds of formula (Vbis)
• n is an integer greater than or equal to 1, in particular from 1 to 4, and preferably from 1 to 2,
• - "d" is an integer from 0 to 4, preferably 0 or 1
• - "i" is an integer parameter greater than or equal to 2 defined as follows: i takes all integer values from 2 to n + 1,
• - group Y can be or contain: 1 / a pseudopeptide (peptide containing one or more pseudopeptide bonds)
• - "p" is xm whole number greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - “k” is an integer varying from 1 to p
• - A is a group chosen from:
• R trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , benzyl, allyl,
• R CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• Z k , Z ' k , and Z'' k may each represent, independently of one another: a hydrogen, the side chain, protected or not, of an amino acid chosen from proteinogenic and non-proteinogenic amino acids , an alkyl group (C1-C20), unsubstituted or substituted by one or more substituents among which: 1 / -COORb 2 / -CONHR b 3 / -COOH
• - "m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10, - "k” is an integer varying from 1 to m,
• R 1 , R 1 and R may each represent, independently of one another: a hydrogen, a halogen, the side chain, protected or not, of an amino acid chosen from natural or non-natural amino acids, an alkyl group (C1-C20) which is unsubstituted or substituted with one or more substituents among which:
• R a representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• - group G can be or contain
• v is xm whole number greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10 with preferably v> 3 and v> 5,
• - “k” is an integer varying from 1 to v, preferably from 1 to 50,
• - D can be -NH 2 -NHCOR -NHR c -NRcR -
• Rc and Rd independently of one another representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 atoms carbon,
• S - S k , S ' k , and S " k can each represent independently of one another: a hydrogen, the side chain protected or not of an amino acid chosen from proteinogenic and non-proteinogenic amino acids, a alkyl group (C1-C20) unsubstituted or substituted with one or more substituents among which: l / -COORe
• A N-hydroxysuccinimide
• the isocyanates of formula (Vbis) can be used as precursors for the synthesis of the compounds of formula (V) and can be obtained from the compounds (XI).
• the invention also relates to the compounds of formula (VII)
• n is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - "i" is an integer varying from 2 to n + 1,
• the group Y can be or contain:
• - "p" is x whole number greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10, - "k” is an integer varying from 1 to p,
• - or A is a group chosen from:
• ROCO oxycarbonyl
• Boc C (CH 3 ) 3
• Fmoc fluorenylmetoxycarbonyl
• benzyloxycarbonyl CH 2 PI1
• R alkyl (R), preferably R ⁇ trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , benzyl, allyl, * phenyl, in particular aryl,
• R CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• biotin * group A can form with the nitrogen atom N to which it is contiguous an entity
• - Z k , Z ', and Z " k may each represent, independently: a hydrogen, the side chain protected or not of an amino acid chosen from proteinogenic and non-proteinogenic amino acids, an alkyl group (C1-C20), unsubstituted or substituted by xm or more substituents including: 1 / -COOR b 2 / -CONHRb
• ⁇ k [*] - -CH (F k ) -; -CO-; -N (F k ) CO-; -CH (F k ) CO-; -CH (F k ) NHCO-;
• F k and F k ′ representing, independently of one another, hydrogen, the side chain protected or not of an amino acid chosen from proteinogenic amino acids and non-proteinogemic amino acids, a halogen, an alkyl group from 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms,
• - “m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - “k” is an integer varying from 1 to m
• R trityl, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , benzyl, allyl,
• R CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , C (CH 3 ) 3 , phenyl, benzyl, allyl,
• the GP group can also be such that the “GP-N” entity forms an “NH2 + ” entity
• the groups R 1 , R 1 and R may each represent, independently of each other: a hydrogen, a halogen, the side chain protected or not of an amino acid chosen from natural and non-natural amino acids, an alkyl group (C1-C20), unsubstituted or substituted by one or more substituents among which: 1 / -COORa 2 / -CONHR a 3 / -COOH
• Ra representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl group having from 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms,
• - group B can be either N-W or O
• - groups W and W can be or contain:
• R h representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• - "h” is xm whole number greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10, - "k” is an integer varying from 1 to h,
• - D can be: hydrogen, -COOH -COOR c -CONH2
• Rc Rc and Rd representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl group having 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms,
• S, S ' k , and S " k can each represent independently of one another: xm hydrogen, the side chain protected or not of an amino acid chosen from proteinogenic and non-proteinogenic amino acids, a group (C1-C20) alkyl, unsubstituted or substituted by xm or more substituents among which: l / -COORe
• - "v” is xm whole number greater than or equal to 1 preferably from 1 to 50, preferably from 1 to 10 with preferably v> 3 and v> 5, - "k” is an integer varying from 1 to v ,
• R 1 and R 1 can also be defined on the basis of intramolecular cyclizations which are the following: 1 / cyclization between R 1 and R ' + kc (or kc is a positive integer, preferably from 1 to 3)
• the compound of formula (VII) is different from the analogs of the peptide Tyr-Gly-Gly-Phe-Leu-OH, containing one or more derivatives as defined below mimicking the side chain of the amino acids present in the peptide and allowing the introduction of one or more urea bonds, that is to say that the compound of formula (VII) is different from the following compounds:
• R represents a hydroxybenzyl, a hydrogen atom, a benzyl group, or an isobutyl group, and provided that the compound of formula (VII) is different from:
• N corresponds to the nitrogen atom
• B represents O
• O corresponds to the oxygen atom
• the invention also relates to the compounds of formula (NI)
• the compounds of type (VI) are the reaction products of the compounds of type (I) and (I bis) or optionally (II) with derivatives containing a primary or secondary arnine or an alcohol.
• An advantageous group of compounds of formula (Vu) consists of those in which 1 ⁇ n ⁇ 4, and in particular the following compounds for which v, h, m and p are from 1 to 10 and preferably from 1 to 5 and more particularly the following compounds:
• n nt from 1 to v-1
• the invention also relates to the compounds of formula (VIE)
• the group Y in this new case can be or contain:
• alkyl group (C1-C20), unsubstituted or substituted by one or more substituents among which:
• p is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - Z k , Z ′ k , and Z ′′ k can each represent, independently of one another: a hydrogen, the side chain of an amino acid chosen from proteinogenic and non-proteinogenic amino acids, an alkyl group ( C1-C20), unsubstituted or substituted by one or more substituents among which: 1 / -COOR b 2 / -CONHR b
• R b representing an alkyl group of 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms,
• F k and F ' k representing, independently of one another, hydrogen, halogen, an alkyl group of 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 atoms of carbon,
• - “m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• V / a urea oligomer defined as follows
• - “u” is an integer greater than or equal to 1, preferably from 1 to 50, and preferably from 1 to 10
• - “q” is an integer greater than or equal to 1, preferably from 1 to 50, and preferably from 1 to 10,
• - "j" is an upper integer parameter ranging from 2 to u + 1,
• - "r" is an integer parameter greater than or equal to 1 taking all the values from 1 to q-1.
• B r j and b r j I are covalent bonds which can be single (s), double (d) or triple (t) provided that:
• IZ r , Z r j , Z ' r j have the meanings indicated in connection with R 1 , R 1 , R''as defined above.
• An advantageous group of compounds of formula (VIII) consists of those in which 1 ⁇ n ⁇ 4, and in particular the following compounds for which h, v, t, p, m, and q are included from 1 to 10 and preferably from 1 to 5, and more particularly the following compounds:
• R 1 and R 2 have the meanings indicated above and in which Z, Z, Z 2 Z 2 2 , Z 3 'and Z 3 2 have the meanings indicated in connection with Z r j .
• a subject of the invention is also the cyclic compounds of formula (VIE bis)
• the total number of atoms forming the ring is greater than six, and preferably greater than or equal to 7,
• n is an integer greater than or equal to 1, preferably from 1 to 10, preferably from 1 to 4, - "i" is an integer varying from 2 to n + 1,
• R 1 , R 1 and R n + can each represent, independently of one another: a hydrogen a halogen the side chain protected or not of an amino acid chosen from natural amino acids or not an alkyl group (C1-C20) unsubstituted or substituted with one or more substituents among which: 1 / -COOR a
• R a representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• R 1 and R 1 can also be defined on the basis of intramolecular cyclizations which are the following: 1 / cyclization between R 1 and R , + kc (or kc is a positive integer, preferably from 1 to 3)
• - group Y can be or contain:
• - “p” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10, - Z k , Z ' k , and Z " k may each represent, independently of one another: xm hydrogen, the side chain protected or not from an amino acid chosen from proteinogemic and non-proteinogenic amino acids, a alkyl group (C1-C20), unsubstituted or substituted by one or more substituents among which: 1 / -COOR b 2 / -CONHR b 3 / -COOH 4 / -OH, OR
• R- b representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• - “m” is an integer greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - group B can be either N-W or O
• - the group W can be or contain:
• R h representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• Cl an aryl group, the cyclic structure of which contains from 5 to 20 carbon atoms,
• - “h” is xm whole number greater than or equal to 1, preferably from 1 to 50, preferably from 1 to 10,
• - D may be: xm hydrogen, -COOH, -COOR c -CONH 2 .CH 2 COORc
• Rc and R representing an allyl, benzyl, t-butyl, fluorenylmethyl or alkyl group having from 1 to 20 carbon atoms, or an aryl group the ring structure of which contains from 5 to 20 carbon atoms,
• S - S k , S ', and S " can represent each and independently of each other: xm hydrogen, the side chain protected or not of an amino acid chosen from proteinogenic and non-proteinogemic amino acids, an alkyl group (C1-C20), unsubstituted or substituted by xm or more substituents among which:
• v is an integer greater than or equal to 1 preferably from 1 to 50, preferably from 1 to 10 with preferably v> 3 and v> 5,
• - “k” is an integer varying from 1 to v
• S k , S 'and S " k are defined independently as above, and more particularly the compounds corresponding to the formula (VIE bis) for which 1 ⁇ n ⁇ 4, h, v, p and m are from 1 to 10 and preferably from 1 to 5.
• Compounds of type (Nffl) and (VIE bis) are cyclic compounds obtained from compounds of type (JE) and (m bis) or (TV) and by intra-molecular reaction with an amine released after elimination of a protection temporary.
• the compounds of type (VEI) and (VIE bis) are cyclic compounds obtained from the compounds of type (JE) and (ffl bis) or (TV) and by intra-molecular reaction with an amine released after elimination of a protection temporary.
• the aryl group is advantageously chosen from :
• 10 / pyrollyl or the aryl group can be substituted with 1 to 6 substituents chosen in particular from: 1 / alkyl of 1 to 10 carbon atoms
• the preparation of the compounds of formula (I bis) (H), (LU bis), (IN), (V) or (Vbis) can be carried out from:
• step b) of transformation of the acyl azide (XE) or (Xffl) or (XIV) into the corresponding isocyanate ( ⁇ ) or (TV) or (Vbis) respectively, is carried out for example by heating a solution acyl azide in an appropriate solvent, in particular toluene or xylene, the formation of the isocyanate being able to be followed by observation of the gas evolution in the flask, the end of the gas evolution signifying the completion of the Curtius rearrangement
• step c) of treatment of the corresponding isocyanate (E) or (IN) or (Vbis) is carried out, when the isocyanate is found in solution, for example in hot toluene, with one of the derivatives of the following list:
• the mixed anhydride is formed by reaction of the acid (TX), (X) or (XI) with ethyl or isobutyl chloroformate in the presence of a tertiary amine such as ⁇ MM ( ⁇ -methylmorpholine), DIEA (di-isopropylethylamine), or also Et 3 ⁇ in THF (tetra.ahydrofuran) at a temperature of -15 ° C.
• a tertiary amine such as ⁇ MM ( ⁇ -methylmorpholine), DIEA (di-isopropylethylamine), or also Et 3 ⁇ in THF (tetra.ahydrofuran) at a temperature of -15 ° C.
• the solution of the acyl azide is heated in the appropriate solvent (in particular toluene or xylene), at a temperature of 65 ° C.
• the treatment of the isocyanate is carried out, when it is found in solution, for example in hot tol
• the process for preparing the compounds of formula (NI) or (VU) comprises reacting compounds containing primary or secondary amines or alcohols with one of the products of formula (I bis), (II), (m bis), (IN), (V) or (Vbis) defined above, for example in a solvent such as DMF, H 2 O / acetone, THF, dichloromethane or acetonitrile with or without the addition of a base such as a tertiary amine (for example Et j ⁇ , DIEA,
• ⁇ MM ⁇ MM, coUidine, lutidine
• sodium carbonate ⁇ a 2 CO 3
• sodium hydrogen carbonate NaHCO 3
• the process for the preparation of the compounds of formula (Vffl bis) comprises the intramolecular cyclization of the products of formula (JE bis) or of the compounds of formula (VII), for example in a solvent such as DMF, H 2 O / acetone, THF, dichloromethane or acetonitrile with or without the addition of a base such as a tertiary amine (for example EtjN, DIEA, NMM, coUidine, lutidine) or such as sodium carbonate
• a solvent such as DMF, H 2 O / acetone, THF, dichloromethane or acetonitrile
• a base such as a tertiary amine (for example EtjN, DIEA, NMM, coUidine, lutidine) or such as sodium carbonate
• Figure 1 corresponds to the X-ray structure of carbamate (Ig) corresponding to the following formula:
• Example I the reaction of O-succinimidyl-2-fô / - butoxycarbonyl.aminoj-ethylcarbamate derivatives with primary aliphatic or aromatic amines, secondary amines, or derivatives of ⁇ - or ⁇ -amino acids, leads quickly to the urea derivatives or to the urea oligomers expected with good yields.
• Example ⁇ the O-succinimidyl-2 - [(9H-fluoren-9-ylmemoxy) carbonylamino] -ethylc, arbamate derivatives used repeatedly in the solid phase make it possible to obtain the urea pseudopeptides and the urea oligomers desired with good yields.
• the N-Boc-protected amino acids (IX) are first tr, ansformed into corresponding acyl azides (XII) by reaction of their mixed anhydride (prepared with EtOCOCl / ⁇ -methylmo ⁇ holine) with ⁇ a ⁇ 3 .
• the isocyanates (II), generated in situ by heating the acyl azide (XII) in toluene at 65 ° are immediately treated with N-hydroxysuccinimide (1 equiv.) In the presence of pyridine (1 equiv.) To give the carbamate (I) and (I bis).
• This reaction sequence from (IX) is generally complete in less than an hour (Scheme 1).
• Reagents (a) i-BuOCOCl, NMM, THF, -20 ° C; (b) NaN 3 , H 2 O; (c) Toluene, 65 ° C; (d) N-hyckoxysuccinimide, pyridine.
• O-succinimidyl carbamates (LL) and (Ibis) crystallize in most cases directly from the toluene solution at room temperature and are obtained simply by filtration in satisfactory yields. Recrystallization from toluene or another suitable solvent provides the pure samples for analysis. It is interesting to note that the mild conditions used are compatible with the use of functionalized side chains (Table 1).
• Carbamates (I), (I bis) and (Ig) are stable, crystalline solids which can be stored for months at 4 ° C without degradation.
• various amines and amino acids were treated with the carbamates (I) and (I bis). The results are shown in Table 2.
• the amino acid derivatives were purchased from Neosystem or Novabiochem. THF is distilled with Na / benzophenone under argon before use. The toluene is distilled over P 2 O 5 and stored on a 4 ⁇ molecular sieve. The aniline was passed through an alumina column before use. The Boc? Amino-acids were prepared according to literature procedures for approval of 10 Eistert Arndt-protected commercial amino acids. The reactions were carried out under argon pressure.
• HPLC analysis was performed on a Nucleosil C 18 column (5 m, 3.9 x 150 mm) using a linear gradient of A (0.1% CF3COOH in H2O) and B (MeCN) at a flow rate of 1.2 ml / min with detection UV at 214 nm.
• N-protected amino acid J (10 mmol) is dissolved in THF (30 ml) under Argon and cooled to -20 °. After addition of i-BuOCOCl (11 mmol) and NMM (11 mmol, 1.1 equiv.), The reaction mixture is stirred at -20 ° for 20 min. The resulting white suspension is warmed to -5 °, and is treated with a solution (5 ml) of NaN. (25 mmol). The mixture is then stirred for 5 min, diluted with EtOAc, washed with saturated NaCl, dried over MgSO 4 and concentrated under reduced pressure to give the acyl azide (XI) which is used without further purification.
• the toluene is then added under argon and the resulting solution is heated to 65 ° C with stirring. Once the evolution of gas has ceased (ca 10 min), N-hydroxysuccinimide (10 mmol) and pyridine (10 mmol) are added. The mixture is stirred for 5 min at 65 ° C and cooled to room temperature. In most cases, the desired product crystallizes from the toluene solution and is collected by filtration. Recrystallization from toluene makes it possible to obtain pure O-succinimidyl carbamate. Otherwise the solvent is evaporated in vacuo and the residue is purified by recrystallization from the appropriate solvent.
• O-succinimidyl carbamates (I) and (I bis) (1 mmol) and Hunig base (1 mmol) are added to a solution of the amine (1.3 mmol) in 5 ml DMF. After 10-30 min., The reaction mixture is diluted with saturated NaHCO 3 , and extracted with AcOEt.
• the N-Fmoc-protected amino acids / ⁇ (IX) comprising the side chains of the natural amino acids Ala, Val, Leu, Phe, Tyr, and Lys are converted into corresponding acyl azides (XII) by reaction of their mixed anhydride (formed with EtOCOCl / N-methyl morpholine ( ⁇ MM)) with an aqueous solution of ⁇ a ⁇ 3 (2.5 equiv).
• the intermediate isocyanates (II) obtained by Curtius rearrangement on (XII) (toluene, 65 ° C, 5 to 15 min) are immediately treated with N-hydroxysuccinimide (1 equiv) in the presence or not of pyridine (1 equiv) to give the carbamates (I) and (Ibis) as crystalline products (see yields in Table 1).
• this reaction sequence is generally complete in 1 hour.
• the carbamates (I) and (I bis) precipitate or recrystallize directly from the toluene solution and are simply collected by filtration. In the case of these protected Fmoc derivatives, the yields obtained (51-86%) are better than with the corresponding Boc derivatives.
• the peptide sequence chosen by way of example is that of the MART tumor antigen (27-35) of sequence:
• Solid phase synthesis of the peptide up to Gly 29 is carried out in Fmoc chemistry (Fluorenyl methoxycarbonyl) on a 100 mol scale starting with a Wang resin (p-benzyloxybenzyl alcohol) substituted by valine according to the methods solid phase peptide synthesis classics (References: Methods in Enzymology, Vol. 89, Solid Phase peptide Synthesis, Ed .: GB Fields, Académie Press, NY, USA).
• the desired raw product (VIIa) is obtained after lyophilization with a purity of 73% (by HPLC) (see table 2 below). After purification by HPLC and lyophilization, the product is obtained with a purity of 99.2%. The pure product is characterized by mass spectrometry (MALDI-MS) and by HPLC.
• Vlla uridopeptide
• Vllb oligoureas
• the amount of impurities present in the crude oil increases with the size of the oligomer.
• Analysis by MALDI-TOF-MS reveals that the major impurities isolated by HPLC on column C18 come either from deletions (products of lower masses which can result from incomplete couplings or else from incomplete deprotection of the Fmoc group in the last stages of the synthesis) , or more surprisingly by double insertion of monomers.
• a study of the stability of the carbamates (Ih) - (Im) in solutions of DMF containing 5% of diisopropyletnylamine (DIEA) revealed a notable degradation as well as a partial cleavage of the Fmoc group. Based on these results, milder reaction conditions were evaluated.
• the N-Boc or N-Fmoc-protected dipeptides (X) comprising the side chains of the natural amino acids Ala, Val, Leu, Phe, Tyr, and Lys, are converted into the corresponding acyl azides (XIII ) by reaction of their mixed anhydride (formed with EtOCOCl / N-methyl morpholine ( ⁇ MM)) with an aqueous solution of ⁇ a ⁇ 3 (2.5 equiv).
• the HPLC analyzes were carried out on a C 18 column (5 ⁇ m, 3.9 x 150 mm using a gradient of A (0.1% TFA in H 2 ⁇ ) and B (0.08% TFA in MeC ⁇ ) at a flow rate of 1.2 ml / min with UN detection at 214 nm.
• Diagram 2 Synthesis of ureas (VI) from carbamates (III) and (Illbis).
• the compound (VIII bis / 1) can for example be synthesized by intramolecular cyclization of the linear precursor below corresponding to the formula (VII / 1) (lmmol) by treatment with carbonyldiimidazole (1 mmol) in acetonitrile (200 ml ) and in the presence of an excess of DIEA (2.5 mmol) for 12 hours.
• the linear precursor (VEL / l) can be prepared according to scheme 1 below.
• the reaction of a first activated carbamate derived from an N-methylated beta amino acid on a monoprotected diamine leads to the production of a trisubstituted monourea.
• the deprotection of the Boc group and the reaction again of the O-succinimidyl carbamate previously used leads to the production of a di-urea.
• the successive deprotection of the protective groups Boc and Z gives the derivative (VII / 1).

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