EP3687512A1 - Agents inhibiting tctp protein for the treatment of proliferative diseases, infectious diseases, allergies, inflammations and/or asthma - Google Patents

Agents inhibiting tctp protein for the treatment of proliferative diseases, infectious diseases, allergies, inflammations and/or asthma

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Publication number
EP3687512A1
EP3687512A1 EP18792980.7A EP18792980A EP3687512A1 EP 3687512 A1 EP3687512 A1 EP 3687512A1 EP 18792980 A EP18792980 A EP 18792980A EP 3687512 A1 EP3687512 A1 EP 3687512A1
Authority
EP
European Patent Office
Prior art keywords
group
atom
compound
acid
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18792980.7A
Other languages
German (de)
French (fr)
Inventor
Samir Messaoudi
Mouad Alami
Jean-Daniel Brion
Amélie CHABRIER
Adam Telerman
Robert Amson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Saclay
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Sud Paris 11
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Institut Gustave Roussy (IGR), Institut National de la Sante et de la Recherche Medicale INSERM, Universite Paris Sud Paris 11 filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP3687512A1 publication Critical patent/EP3687512A1/en
Withdrawn legal-status Critical Current

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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to TCTP protein inhibitor compounds for use in the treatment of proliferative diseases, infectious diseases, allergies, inflammation and / or asthma. STATE OF THE ART
  • Cancer is a leading cause of death in the world, with a growing number of new cases. According to the World Health Organization, as many as 15 million people die from cancer each year worldwide, almost one death every two seconds. Cancer has already claimed 84 million lives between 2005 and 2015 and if nothing is done, it will kill 19 million people a year in 2025.
  • Targeted therapies include several families of antitumor drugs: monoclonal antibodies, tyrosine kinase receptor inhibitors, and angiogenesis inhibitors. Despite all the interest of these targeted therapies, current treatments have shown limited results, due to the high biological diversity of cancers and the appearance of resistance phenomena.
  • Tumor reversion (1, 3) has recently emerged as a cellular process in its own right, leading to reprogramming of the cancer cell and the disappearance of its tumor. malignant phenotype. Forcing tumor cells to "revert” to become “pseudo” normal is a wise strategy. The mechanism of tumor reversion, through the identification of protein plays a major role, thus constitutes an extremely promising way for the development of new antitumor agents. As such, the TCTP (4) has been identified as one of the main players in tumor reversion. Indeed, it is overexpressed in many cancer cells and has anti-apoptotic activity using the p53 / MDM2 and / or Bcl-xL / Mcl-1 dependent pathways. The loss of the malignant phenotype in the tumor reversion therefore probably involves the restoration of normal apoptotic activity following at least partial inactivation of the action of TCTP in the cell.
  • TCTP is also involved in the mechanisms of infection of several parasites, including Plasmodium falciparum responsible for malaria, and its inhibition can prevent or treat the infections induced by these parasites (6, 7).
  • the TCTP may be inhibited by Sertraline (WO 2004/080445).
  • Sertraline WO 2004/080445
  • sertraline The applicant has discovered a new family of sertraline-derived compounds with a high affinity for TCTP. These compounds also possess good cytotoxicity on various human cancer cell lines.
  • X represents an oxygen atom, a sulfur atom, a nitrogen atom or a CH radical
  • the X-Y and Y bond are absent if X represents an oxygen or sulfur atom, the X-Y and Y bond are present if X represents a nitrogen atom or a CH radical,
  • Y represents
  • R is hydrogen, C 1-6 alkyl, aryl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, or acyl group,
  • X represents a radical CH, in which R 1 and R 2 represent, independently of each other, a hydrogen atom or a Ci-alkyl group; at C 6 , aryl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl or acyl, or R 1 and R 2 together with the atom of nitrogen which carries them a 5- or 6-membered heterocycle,
  • (Het) Ar is an aromatic ring selected from the group consisting of aryl and heteroaryl groups,
  • said aromatic ring may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1-6 alkyl group, a group -SR 10 , a group CF 3 , formyl group, OR 11 group, (C 2 -C 6 ) alkenyl group,
  • R 7 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group or a sugar residue
  • R 8 and R 9 representing, independently of each other, a hydrogen atom, a C 1-6 alkyl group, an aryl group, a heteroaryl group, a (C 2 -C 6 ) alkenyl group , a (C 2 -C 6 ) alkynyl group, a sugar residue, an amino acid residue, a peptide residue or R 8 and R 9 form together with the nitrogen atom which carries them a 5-membered heterocyclic ring; or 6 links,
  • R 10 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group, a sugar residue, a peptide residue comprising at least one cysteine or -SR 10 represents a cysteine residue with R 11 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group or a benzyl group,
  • R 3 , R 4 , R 5 and R 6 represent, independently of each other, a hydrogen atom, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 or a group -CF 3 , with R 12 and R 13 independently of one another a hydrogen atom, a C 1-6 alkyl group, an aryl group, a heteroaryl group, a (C 2 -C 6 ) alkenyl group, a (C 2 -C 6 ) alkynyl group or an acyl group, or R 12 and R 13 form together with the nitrogen atom which carries them a 5- or 6-membered heterocycle,
  • R 14 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group, a sugar residue, an amino acid residue or a peptide residue,
  • the compound of formula (I) according to the invention is not 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine or its hydrochloride salt.
  • the compound of formula (I) is not 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine or a pharmaceutically acceptable salt thereof.
  • Figure 1 Western blot showing expression on p53, from left to right, DMSO (control), sertaline at 1 ° C (comparative) and compound AC014 at 1 ° C (invention) with witness the expression of each of these three compounds on GAPDH.
  • Figure 2. Diagram representing the average weight of tumors extracted from mice treated for 12 days by injection of DMSO (left column), sertraline (central column) or compound AC070 (right column).
  • C 1 -C 6 alkyl is meant, in the sense of the present invention, a saturated monovalent hydrocarbon chain, linear or branched, having 1 to 6, preferably 1 to 4, carbon atoms.
  • aryl means an aromatic hydrocarbon group, preferably comprising from 6 to 10 carbon atoms, and comprising one or more contiguous rings, for example a phenyl or naphthyl group.
  • aryl is an aromatic hydrocarbon group, preferably comprising from 6 to 10 carbon atoms, and comprising one or more contiguous rings, for example a phenyl or naphthyl group.
  • it is phenyl.
  • heteroaryl means an aromatic group comprising one or more, especially 1 or 2, conjugated hydrocarbon rings, in which one or more carbon atoms, advantageously 1 to 4 and even more advantageously 1 or 2, are each replaced by a heteroatom such as, for example, a sulfur, nitrogen or oxygen atom.
  • heteroaryl groups are furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl, indyl, benzofuranyl or benzothiophenyl.
  • the heteroaryl group is chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, a benzofuran and a benzothiophene.
  • aromatic ring means an aryl group or a heteroaryl group as defined above.
  • (C 2 -C 6 ) alkenyl group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one double bond and having 2 to 6 carbon atoms.
  • (C 2 -C 6 ) alkynyl group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one triple bond and having 2 to 6 carbon atoms.
  • acyl is meant, in the sense of the present invention, a C 1 -C 6 alkyl or aryl group as defined above, linked to the rest of the molecule via a carbonyl (CO) group. . It may be in particular an acetyl or benzoyl group.
  • the term “5- or 6-membered heterocycle” means a 5- or 6-membered ring, saturated or non-saturated, but not aromatic, and containing one or more, advantageously 1 to 4, even more advantageously. 1 or 2, heteroatoms, such as, for example, sulfur, nitrogen or oxygen atoms. It may especially be pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group. Advantageously, it is a pyrrolydinyl or morpholinyl group.
  • halogen atom means the fluorine, chlorine, bromine and iodine atoms.
  • sucrose means a monosaccharide or a polysaccharide.
  • aldose an aldose. This may include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, or talose, in a form D or L. It is in particular glucose.
  • polysaccharide is meant, in the sense of the present invention, a sequence of at least two monosaccharide units as defined above. It may be in particular a disaccharide (sequence of two monosaccharide units), such as lactose.
  • sugar residue in the sense of the present invention, a sugar molecule as defined above, free of oxygen atom on its anomeric position, is bonded to the rest of the molecule by the carbon intermediate in the anomeric position.
  • amino acid is intended to mean a carboxylic acid which also has an amino functional group.
  • ⁇ -amino acids for example Alanine (Ala), Arginine (Arg), Asparagine (Asn), Aspartic acid (Asp), Cysteine (Cys), Glutamine (Gin), Glutamic acid (Glu) , Glycine (Gly), Histidine (His), Isoleucine (Ile), Leucine (Leu), Lysine (Lys), Methionine (Met), Phenylalanine (Phe), Proline (Pro), Serine (Ser), Threonine (Thr) , Tryptophan (Trp), Tyrosine (Tyr) and Valine (Val)) in D or L form, as well as unnatural amino acids (e.g., ⁇ -alanine, allylglycine, tert-leucine, acid).
  • unnatural amino acids e.g., ⁇ -alanine, allylglycine,
  • amino acid residue is intended to mean an amino acid as defined above bonded to the rest of the molecule by its amine function (NH 2 ), its carboxylic acid function (COOH) or any other functionality present on the amino acid such as a thiol (SH) function (e.g., in the case of a cysteine).
  • cyste residue is intended to mean a cysteine amino acid bound to the rest of the molecule by its sulfur atom.
  • peptide is meant, in the sense of the present invention, a sequence of amino acids (at least two) linked together by peptide bonds (amide bonds).
  • peptide residue is intended to mean a peptide as defined above bonded to the rest of the molecule by its amine function (NH 2 ), its acid function (COOH) or any other functionality. present on the amino acid such as a thiol function (SH) (eg in the case of a cysteine).
  • peptide residue containing at least one cysteine means a peptide as defined above containing at least one amino acid of the cysteine type and linked to the rest of the molecule by the thiol function. (SH) of cysteine.
  • amino acid residue containing at least one cysteine means a peptide as defined above containing at least one amino acid of the cysteine type and linked to the rest of the molecule by the thiol function. (SH) of cysteine.
  • amino acid function in its free form means, within the meaning of the present invention, an -OH group.
  • alcohol function in its protected form means an alcohol (OH) function in which the hydrogen atom has been replaced by an O-protective group.
  • O-protecting group is intended to mean any substituent which protects the hydroxyl or carboxyl group, ie a reactive oxygen atom, against undesirable reactions such as O-groups. protector described in "Greene's Protective Groups In Organic Synthesis", 4th Edition, 2007, John Wiley & Sons, Hoboken, New Jersey.
  • a hydroxyl group protected by an O-protecting group may be, for example, an ether, an ester, a carbonate, an acetal and the like.
  • the O-protecting groups comprise a (C 1 -C 6) alkyl group optionally substituted by one or more (in particular 1 to 3) halogen atoms (such as chlorine atoms), such as methyl, ethyl, tert-butyl and 2,2,2-trichloroethyl; an aryl (C1 -C6) alkyl group, the aryl ring being optionally substituted by one or more methoxy groups, such as benzyl (Bn) and p-methoxybenzyl (PMB); a trityl group of the formula -CA 2 Al 3 Ar 3 , such as triphenylmethyl (also called trityl-Tr), (4-methoxyphenyl) diphenylmethyl (also called methoxytrityl-NMT) and bis (4-methoxyphenyl) phenylmethyl (also called dimethoxytrityl - DMT); a substituted methyl group of formula CH 2
  • Ar 1 , Ar 2 and Ar 3 representing, independently of each other, an aryl, such as phenyl, optionally substituted by one or more methoxy groups
  • RGP 2 represents a (C 1 -C 6 ) alkyl group (such as methyl or ethyl) optionally substituted with aryl (such as phenyl), (C 1 -C 6 ) alkoxy (such as methoxy) or trialkylsilyl (such as SiMe 3 );
  • RGP 3 , RGP 4 and RGP 5 representing, independently of each other, a (C 1 -C 6 ) alkyl or aryl group (such as phenyl);
  • RGP 6 and RGP 7 represent, independently of one another, a (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, aryl, aryl- (C 6 -C 6 ) alkyl or 9-fluorenylmethyl group.
  • amine function in its free form is meant an -NH 2 group or an NH group which is not substituted by an N-protecting group.
  • amine function in its protected form means an amine (NH) function in which the hydrogen atom has been replaced by an N-protective group.
  • N-protecting group is intended to mean any substituent which protects the NH 2 group against undesirable reactions such as the N-protecting groups described in "Greene's Protective Groups In Organic Synthesis", 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey.
  • An amine function protected by an N-protecting group may be, for example, a carbamate, an amide, a sulfonamide, an N-alkyl derivative, an amino acetal derivative, an N-benzyl derivative, an imine derivative, an enamine derivative or a derivative. N-hetero.
  • the N-protecting groups comprise a formyl group; an aryl group, such as phenyl, optionally substituted with one or more methoxy groups, such as p-methoxyphenyl (PMP); an aryl (C1-C6) alkyl group, such as benzyl, the aryl ring being optionally substituted with one or more methoxy groups, such as benzyl (Bn), p-methoxybenzyl (PMB) and 3,4-dimethoxybenzyl ( DMPM); a group -CO-RGP 8 such as acetyl (Ac), pivaloyl (Piv or Pv), benzoyl (Bz) and p-methoxybenzylcarbonyl (Moz); a group -CO 2 -RGP 8 such as tbutyloxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc),
  • RGP 8 representing a (CrC 6 ) alkyl group optionally substituted with one or more halogen flavors such as F or Cl; a (C 2 -C 6 ) alkenyl group such as an allyl group; an aryl group, such as phenyl, optionally substituted by one or more groups selected from OMe (methoxy) and NO 2 (nitro); an aryl (C 1 -C 6 ) alkyl group, such as benzyl, the aryl ring being optionally substituted by one or more methoxy groups; or a 9-fluorenylmethyl group.
  • the groups - NR 1 R 2 and (Het) Ar are in cis conformation
  • the two groups - NR 1 R 2 and (Het) Ar are situated on the same side of the ring 1, 2,3,4-tetrahydronaphthyl of the compound according to formula (I).
  • Y represents a group -NR 1 R 2 and the groups -NR 1 R 2 and (Het) Ar are in cis-conformation
  • the compound of formula (I) according to the invention has the following formula:
  • the term "pharmaceutically acceptable” is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical.
  • pharmaceutically acceptable salt of a compound means a salt which is pharmaceutically acceptable, as defined herein, and which has the desired pharmacological activity of the parent compound.
  • the pharmaceutically acceptable salts comprise in particular:
  • pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with pharmaceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, acid glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-acid, toluenesulfonic acid, trimethylacetic acid, trifluoroace
  • the pharmaceutically acceptable salt is a hydrochloride.
  • proliferative disease is meant a disease in which cells proliferate in an uncontrolled manner.
  • infectious disease is meant any infection, and in particular infections due to parasites, also called parasitic infections.
  • An example of such an infection is malaria.
  • overexpressed TCTP level is meant that the level of expression of TCTP in the cell, particularly a cancer cell, is higher than the level of TCTP expression in a healthy cell, particularly a non-intact cell. cancerous.
  • Management of a disease is the prevention and / or treatment of the disease and / or its manifestations.
  • the compounds according to the invention have an affinity with the TCTP protein. They can therefore be used in the treatment of proliferative diseases, especially in the treatment of cancer, as antitumor agents. They can also be used in the treatment of infectious diseases, including parasitic infectious diseases such as malaria.
  • the compounds according to the invention can be used in the treatment or prevention of any disease or infection which requires, for its management, to inhibit the TCTP.
  • the compounds according to the invention have a strong affinity, since of the order of one micromolar, vis-à-vis the TCTP protein.
  • MTD maximum tolerated dose
  • the concentrations to be used in animals or humans with the compounds according to the invention can be reduced by compared to the concentrations required for sertraline.
  • the effective doses required are then decreased, leading to a greater difference with the maximum tolerated doses.
  • the use of the compounds according to the invention is therefore possible in humans and animals.
  • this improvement in the affinity of the compounds according to the invention also makes it possible to reduce undesirable side effects.
  • the affinity of the compounds according to the invention with respect to the TCTP protein is between 1 ⁇ M and 200 ⁇ M, advantageously between 1 ⁇ M and 195 ⁇ M, preferably between 1 nM and 200 ⁇ M, advantageously between 1 nM. and 195 ⁇ , or even between 1 nM and 150 ⁇ .
  • the compounds according to the invention are also capable of inducing the overexpression of p53 (1, 5).
  • the p53 protein is a transcription factor protein that regulates certain important cellular functions such as mitosis or programmed death. It also plays a major role in tumor reversion. Its activation may involve either cancer tumor reversion or apoptosis.
  • the induction of overexpression of p53 by the compounds according to the invention thus indicates that the compounds according to the invention can be used as antitumor agents and that they seem to act in particular through a tumor reversion mechanism.
  • the compounds according to the invention thus have an innovative therapeutic class of antitumor agents by acting in particular by a tumor reversion mechanism.
  • the compounds according to the invention are therefore particularly suitable for the treatment of cancer, in particular of cancer in which the TCTP is over-expressed.
  • the compound 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalene-1-ylamine or a pharmaceutically acceptable salt, especially its hydrochloride salt, is excluded from the formula (I). This includes any diastereoisomer or enantiomer of this compound, alone or in admixture. In particular, sertraline is excluded.
  • X represents an oxygen atom or a sulfur atom, Y being absent.
  • X represents an oxygen atom
  • X represents a sulfur atom.
  • X represents a nitrogen atom or a CH radical, Y being present.
  • X represents a nitrogen atom and Y is present.
  • Y then represents a group R.
  • R represents a hydrogen atom, an alkyl group at C 6, or an acyl group.
  • R represents a hydrogen atom
  • X represents a radical CH and Y is present.
  • Y represents a hydrogen atom.
  • Y represents a group -NR 1 R 2 .
  • R 1 or R 2 is an acyl group, it is chosen from benzoyl and acetyl.
  • -NR 1 R 2 represents a pyrrolydine or a morpholine.
  • Y represents a group -NR 1 R 2
  • R 1 and / or R 2 represent, independently of one another, a hydrogen atom or an acyl group.
  • R 1 represents an acyl group, preferably an acetyl group, and advantageously R 2 represents a hydrogen atom.
  • (Het) Ar when (Het) Ar is an aryl, it is advantageously chosen from a phenyl and a naphthyl.
  • the aryl group thus defined may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group with R 7 , R 8 , R 9 and R 10 as previously described, the aryl group being in particular not substituted by more than a halogen atom.
  • the aryl group may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the aryl group not being substituted by more than one halogen atom.
  • (Het) Ar is phenyl, it is unsubstituted or substituted in the meta or para position by any one of the groups previously described.
  • the halogen atom is chosen from a fluorine, chlorine, bromine or iodine atom. In particular, it is selected from a chlorine, bromine and iodine atom.
  • (Het) Ar when (Het) Ar is a heteroaryl, it is chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, benzofuran and benzothiophene.
  • the heteroaryl group thus defined may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group, with R 7 , R 8 , R 9 and R 10 as described above, the heteroaryl group being in particular not substituted by more than a halogen atom.
  • the aryl group may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than one halogen atom. In particular, heteroaryl is not substituted.
  • the aromatic ring Het (Ar) is substituted by one or more groups chosen from a halogen atom, a group - COOR 7 , and a group -CONR 8 R 9 with R 7 , R 8 and R 9 as described above, the aromatic ring Het (Ar) not being substituted by more than one halogen atom.
  • the halogen atom is chosen from a fluorine atom, chlorine, bromine and iodine. In particular, it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
  • R 7 advantageously represents a methyl group, an ethyl group or an isopropyl group.
  • the aromatic ring when the aromatic ring is substituted with a -CONR 8 R 9 group and when R 8 and / or R 9 represent a sugar residue, the sugar is advantageously selected from glucose, mannose, arabinose or galactose.
  • R 8 and R 9 form together with the atom nitrogen which carries them a 5- or 6-membered heterocycle, -NR 8 R 9 advantageously represents a pyrrolydine or a morpholine.
  • the aromatic ring when the aromatic ring is substituted with a -SR 10 group and when R 10 represents a sugar residue, the sugar is advantageously selected from glucose, mannose , arabinose or galactose.
  • the groups R 3 , R 4 , R 5 and R 6 represent a hydrogen atom.
  • R 3 , R 4 , R 5 and R 6 represent, independently of each other, an atom of hydrogen, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 , a group -CF 3 .
  • R 14 represents a methyl group.
  • R 14 represents a sugar residue
  • the sugar is chosen from glucose, mannose, arabinose or galactose.
  • Preferred compounds of formula (I) according to the invention are compounds corresponding to the following formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Het (Ar) are as previously defined for the compounds of formula (I),
  • proliferative diseases including cancer, infectious diseases, allergies, inflammation and / or asthma.
  • R 1 and / or R 2 represent, independently of one another, a hydrogen atom or an acyl group.
  • R 1 or R 2 is an acyl group, it is chosen from benzoyl and acetyl.
  • R 1 represents an acyl group, preferably an acetyl group, and advantageously R 2 represents a hydrogen atom.
  • R 2 represents a hydrogen atom.
  • (Het) Ar is an aryl, it is advantageously chosen from a phenyl or a naphthyl.
  • the aryl group thus defined may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted by more than a halogen atom.
  • the aryl group may be substituted by one or more groups selected from a halogen atom, a group - COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted with more than one halogen atom.
  • (Het) Ar is phenyl, it is unsubstituted or substituted in the meta or para position by any of the groups previously described.
  • the halogen atom is advantageously chosen from a fluorine, chlorine, bromine and iodine atom.
  • a chlorine, bromine and iodine atom preferably it is selected from a bromine atom and iodine, preferably it is selected from a bromine atom and iodine.
  • (Het) Ar when (Het) Ar is a heteroaryl, it is advantageously chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, a benzofuran and a benzothiophene.
  • the heteroaryl group thus defined may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than a halogen atom.
  • the heteroaryl group may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than one halogen atom. In particular, heteroaryl is not substituted.
  • the aromatic ring Het (Ar) is substituted by one or more groups selected from a hydrogen atom. halogen, a group - COOR 7 , and a group -CONR 8 R 9 with R 7 , R 8 and R 9 as described above, the aromatic ring Het (Ar) not being substituted by more than one atom 'halogen.
  • the halogen atom is advantageously chosen from an atom of fluorine, chlorine, bromine and iodine. In particular, it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
  • R 7 advantageously represents a methyl group, an ethyl group or an isopropyl group.
  • the Sugar is advantageously chosen from glucose, mannose, arabinose or galactose.
  • -NR 8 R 9 advantageously represents a pyrrolydine or a morpholine.
  • the sugar is advantageously chosen from glucose , mannose, arabinose or galactose.
  • the groups R 3 , R 4 , R 5 and R 6 represent a hydrogen atom.
  • R 3 , R 4 , R 5 and R 6 represent, independently of one another, a hydrogen atom, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 , a group -CF 3 .
  • R 14 represents a methyl group.
  • R 14 represents a sugar residue
  • the sugar is chosen from glucose, mannose, arabinose or galactose.
  • Het (Ar) represents a naphthalene or a phenyl substituted by a bromine atom, an iodine atom or a -COOiPr group.
  • compounds of formula (I) that are advantageous according to the invention are compounds of formula (III) below:
  • X ' represents CH 2 , O, S or NR
  • R, R 3 , R 4 , R 5 , R 6 and Het (Ar) are as defined above for the compounds of formula (I),
  • proliferative diseases including cancer, infectious diseases, allergies, inflammation and / or asthma.
  • X ' represents an oxygen atom or a sulfur atom.
  • X ' represents an oxygen atom.
  • X ' represents a sulfur atom.
  • X ' represents NR or CH 2 .
  • X ' represents NR.
  • R represents a hydrogen atom, an alkyl group at C 6, or an acyl group.
  • R represents a hydrogen atom and X 'represents NH.
  • X ' represents CH 2 .
  • (Het) Ar when (Het) Ar is an aryl, it is advantageously chosen from a phenyl or a naphthyl.
  • the aryl group thus defined may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group, with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted by more of a halogen atom.
  • the aryl group may be substituted by one or more groups selected from a halogen atom, a group - COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted with more than one halogen atom.
  • (Het) Ar is phenyl, it is unsubstituted or substituted in the meta or para position by any of the groups previously described.
  • the halogen atom is advantageously chosen from a fluorine, chlorine, bromine and iodine atom.
  • it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
  • (Het) Ar when (Het) Ar is a heteroaryl, it is advantageously chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, a benzofuran and a benzothiophene.
  • the heteroaryl group thus defined may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group, with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more of a halogen atom.
  • the heteroaryl group may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than one halogen atom. In particular, heteroaryl is not substituted.
  • the aromatic ring Het (Ar) is substituted by one or more groups. chosen from a halogen atom, a group -COOR 7 , and a group -CONR 8 R 9 with R 7 , R 8 and R 9 as described above, the aromatic ring Het (Ar) not being substituted by more of a halogen atom.
  • the halogen atom is advantageously chosen from an atom fluorine, chlorine, bromine and iodine.
  • it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
  • R 7 advantageously represents a methyl group, an ethyl group or an isopropyl group.
  • the groups R 3 , R 4 , R 5 and R 6 represent a hydrogen atom.
  • R 3 , R 4 , R 5 and R 6 represent, independently from each other, a hydrogen atom, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 , a group - CF 3 .
  • R 14 represents a methyl group.
  • R 14 represents a sugar residue
  • the sugar is chosen from glucose, mannose, arabinose or galactose.
  • the compounds of the present invention for their use in the treatment of proliferative diseases, in particular cancer, infectious diseases, in particular parasitic infectious diseases, allergies, inflammation and / or asthma, are preferably chosen from:
  • the compounds of the present invention for their use in the treatment of proliferative diseases, in particular cancer, infectious diseases, in particular parasitic infectious diseases, allergies, inflammation and / or asthma, are preferably chosen from:
  • the subject of the invention is the compounds according to the invention which can be used in the treatment of any disease which requires, for its management, the inhibition of TCTP.
  • the disease is a proliferative disease such as cancer, psoriasis, preferably cancer.
  • the disease is an infectious disease, particularly a parasitic infectious disease such as malaria (8).
  • the disease is an allergy, inflammation or asthma (9 - 14).
  • the subject of the invention is the compounds according to the invention which can be used in the treatment of proliferative diseases, in particular cancer and psoriasis, more particularly cancer, the treatment of infectious diseases, in particular malaria, and / or the treatment of allergies, inflammation and / or asthma. More particularly, the subject of the invention is the compounds according to the invention for their use in the treatment of cancer or malaria.
  • the subject of the invention is the compounds according to the invention which can be used in the treatment of cancer by inhibition of the TCTP protein, in particular in the treatment of cancer by tumor reversion.
  • the compounds according to the invention exhibit improved inhibition of the TCTP protein compared with sertraline and induce overexpression of the p53 protein.
  • the inhibition of the TCTP protein and the overexpression of the p53 protein are two features of the tumor reversion mechanism.
  • the subject of the invention is the compounds according to the invention for their use in the treatment of cancer, in particular a cancer in which the TCTP protein is overexpressed.
  • cancers non-limiting mention may be made of leukemias, lymphomas, sarcomas, liver cancer, pancreatic cancer, lung cancer, stomach cancer, esophageal cancer, kidney cancer, pleural cancer, thyroid cancer, skin cancer, cervical cancer, breast cancer, ovarian cancer, colon cancer, testicular cancer, prostate cancer, brain cancer, rectal cancer, or bone cancer.
  • the subject of the invention is the compounds according to the invention for their use in the treatment of cancer when the cancer is an acute myeloid leukemia, a breast cancer, a sarcoma, a colon cancer, a lung cancer, an melanoma or brain cancer.
  • the compounds for their use according to the invention are administered in combination with another active principle, in particular an anticancer compound, cytotoxic or otherwise.
  • the active ingredients that can be combined with the compounds for their use according to the present invention can be chosen from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel ,
  • the compounds for their use according to the invention are administered in combination with cytarabine.
  • a pharmaceutical composition comprising:
  • the active ingredient (s) may be as mentioned above.
  • the active ingredient may be cytarabine.
  • the compounds for their use according to the invention are administered during or possibly before and after radiotherapy.
  • the compounds according to the present invention may be administered by any of the usual routes, in particular orally, sublingually, parenterally subcutaneously, intramuscularly, intravenously, transdermally, locally, cutaneously, mucosally or rectally.
  • the compounds according to the present invention can be used at doses of between 0.01 mg and 1000 mg per day, given in a single dose once a day or preferably administered in several doses throughout the day, for example two times a day in equal doses.
  • the dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the practitioner can realize himself.
  • the present invention also relates to a method for inhibiting TCTP comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic, with at least one other active ingredient as defined above. above.
  • the present invention relates in particular to a method of treating proliferative diseases, in particular in the treatment of cancer, comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic, with minus another active ingredient as defined above.
  • the present invention relates in particular to a method of treating infectious diseases, especially parasitic infectious diseases such as malaria, comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic with at least one other active ingredient as defined above.
  • the present invention particularly relates to a method of treating allergies, inflammation and / or asthma, comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic, with at least one other active ingredient as defined above.
  • the present invention also relates to the use of a compound of the present invention for the preparation of a medicament for the treatment of proliferative diseases and infectious diseases, in particular in the treatment of cancer.
  • the present invention relates in particular to the use of a compound of the present invention for the preparation of a medicament for the treatment of proliferative diseases, in particular in the treatment of cancer.
  • the present invention relates in particular to the use of a compound of the present invention for the preparation of a medicament for the treatment of parasitic infectious diseases, particularly in the treatment of malaria.
  • the present invention particularly relates to the use of a compound of the present invention for the preparation of a medicament for the treatment of allergies, inflammation and / or asthma.
  • the patient in need of treatment is a mammal, especially a human.
  • the subject of the invention is also the novel compounds chosen from:
  • novel compounds are chosen from:
  • compositions according to the invention are provided.
  • the invention also relates to a pharmaceutical composition for its use in the treatment of proliferative diseases, infectious diseases, allergies, inflammation and / or asthma comprising a compound of formula (I), (II) or (III) according to the invention, according to any of the embodiments described above, and a pharmaceutically acceptable excipient.
  • compositions according to the invention may be intended for enteral (for example oral) or parenteral (for example intravenous) administration, preferably orally or intravenously.
  • the active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals, preferably mammals, including humans.
  • the pharmaceutical composition may be in solid or liquid form (solution or suspension).
  • a solid composition may be in the form of tablets, capsules, powders, granules and the like.
  • the active ingredient may be mixed with one or more pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. similar, before being compressed.
  • the tablets may further be coated, especially with sucrose or other suitable materials, or they may be treated in such a way that they have prolonged or delayed activity.
  • the active ingredient may be mixed or granulated with dispersants, wetting agents or suspending agents and with flavor correctors or sweeteners.
  • the active ingredient can be introduced into soft or hard capsules in the form of a powder or granules as mentioned above or in the form of a liquid composition as mentioned below.
  • a liquid composition may contain the active ingredient with a sweetener, flavor enhancer or a suitable colorant in a solvent such as water.
  • the liquid composition can also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It may be for example a syrup or an elixir.
  • the composition may be in the form of an aqueous suspension or a solution which may contain suspending agents and / or wetting agents.
  • the composition is advantageously sterile. It can be in the form of an isotonic solution (especially with respect to blood).
  • the compounds according to the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg per day, administered in a single dose once a day or in several doses during the day, for example twice per day. day in equal doses.
  • the dose administered daily is advantageously between 5 mg and 500 mg, and more preferably between 10 mg and 200 mg. However, it may be necessary to use doses outside these ranges, which can be appreciated by those skilled in the art.
  • the compounds according to the invention are obtained according to short synthesis methods and compatible with industrial requirements.
  • the synthesis route implements the key reaction between a tosylhydrazone of formula A and a boronic acid of formula B or an aryl iodide of formula C:
  • the compounds according to the invention may be prepared by a process comprising a step of coupling the compound of formula A, in which X, Y, R 3 , R 4 , R 5 and R 6 are as defined above, with the compound of formula B (Het) ArB (OH) 2 or the compound of formula C (Het) Ar-1, wherein (Het) Ar is as defined above.
  • the compounds according to the invention may be prepared by a process comprising the following successive steps:
  • the compounds of formula (I), (II) or (III) are thus obtained according to this process.
  • Those skilled in the art will know which groups of (Het) Ar, X, Y, R 3 , R 4 , R 5 and R 6 as defined above are compatible with the coupling and which groups will have to be protected beforehand and according to which method.
  • the compounds of formula (I) may then undergo several transformations through processes known to those skilled in the art to access other compounds of formula (I) variously functionalized.
  • the starting materials of formulas A ', B and C may be commercially available or prepared according to methods known to those skilled in the art.
  • the coupling of the compound of formula A with the compound of formula B (Het) ArB (OH) 2 takes place in the presence of a base.
  • Said base may be potassium carbonate, cesium carbonate, sodium carbonate, sodium, potassium e-butoxide, sodium methoxide or potassium methoxide.
  • the coupling of the compound of formula A with the compound of formula C (Het) Ar-1 takes place in the presence of a Pd / L catalytic system and a base.
  • the catalyst system may be in the form of a palladium complex and a ligand or precatalyst.
  • the Pd / L catalytic system can be Pd (OAc) 2 / XP os, Pd (OAc) 2 / DPPE, Pd 2 (dba) 3 / XP os.
  • the base may be potassium carbonate, cesium carbonate, sodium carbonate, sodium ⁇ -butoxide, potassium tert-butoxide, or triethylamine.
  • the coupling of the compound of formula A with the compound of formula C (Het) Ar-1 takes place in a solvent, such as dioxane, THF or toluene.
  • HRF histamine releasing factor
  • silica 60F Merck The silica used for the chromatographic column purifications corresponds to gel 60 (0.015-0.040 mm) from Merck The melting points (mp) were made on a Buchi B-450 apparatus and did not High resolution masses (HRMS) were made on a Brucker MicroTOF spectrometer, using methanol as a solvent, as well as ESI and APCI as ionization sources Calculated values and found values (m / z) are reported in Daltons Unless otherwise stated, the reagents used are commercial products that have been used without further purification in advance, and the same applies to organic solvents. during the syntheses described in this document.
  • aqueous phase is extracted three times using DCM.
  • the combined organic phases are then washed with a saturated aqueous solution of NaCl and then dried. on MgS0 4 , and finally filtered.
  • the solvent is then removed under reduced pressure using a rotary evaporator.
  • the products obtained are finally purified by chromatographic columns of silica or alumina.
  • the first step consists in dissolving the appropriate carboxylic acid (1.0 mmol), HOBt (1.2 mmol) in dimethylformamide (DMF) (10 mL). The whole is stirred for 15 minutes at room temperature under an argon atmosphere. The 8-aminoquinoline (1.2 mmol) is then added and the reaction medium is stirred at room temperature overnight. Then, the crude reaction product obtained is extracted 3 times with saturated aqueous NH 4 Cl solution. The combined organic phases are washed with a saturated aqueous solution of NaCl and then with water, before being dried with MgSO 4 and filtered. Once the solvent is evaporated by rotary evaporator, the products obtained are purified by chromatographic column of silica before being engaged in the next step.
  • DMF dimethylformamide
  • the compound is prepared according to the general procedure No. 3, followed by a hydrogenation reaction using 10% by weight of palladium on carbon (0.58 mmol, 0.15 equiv) dissolved in methanol (40.0 ml).
  • the medium is hydrogenated for 19 hours under atmospheric pressure of hydrogen (hydrogenation assembly made to measure in the laboratory).
  • hydrogenation assembly made to measure in the laboratory.
  • the crude reaction product is filtered through a celite block and the solvent is then evaporated under reduced pressure on a rotary evaporator.
  • a solution of the corresponding cis-benzoic acid (0.09 mmol, 1 equiv.) (Obtained by general procedure No. 1, followed by a hydrolysis reaction) is prepared in N, N-dimethylformamide (DMF). anhydrous (1 mL). The HOBi (0.1 18 mmol, 1.3 equiv.) And the EDC.HCl (0.120 mmol, 1.3 equiv) are then added to this solution. The whole is stirred for 30 minutes at room temperature.
  • the interaction of the synthesized molecules with the TCTP protein was evaluated by surface plasmon resonance (SPR) technique using the T200 biocore apparatus.
  • SPR surface plasmon resonance
  • a polarized monochromatic light beam illuminates a glass interface located between two media with different refractive index, since the angle of incidence is greater than the limit angle, all the light is reflected, it is this that we call a phenomenon of total internal reflection. There is no refraction but an electromagnetic component of the light, the evanescent wave propagates over a distance equivalent to its own wavelength, perpendicular to the interface.
  • a continuous measurement of the variations in the angle of refraction is performed using a micro-refractometer producing a sensorgram which makes it possible to follow in real time the binding of the molecules injected into the microfluidic cell.
  • the resonance signal is expressed in resonance unit (RU) and accounts for what is present at a given moment in the microfluidic cell.
  • the TCTP protein is bound on a chip composed of a layer of dextran placed on a gold leaf, itself placed on a glass plate. This layer is sandwiched between a microfluidic cell and a prism. The synthesized compounds are passed into the microfluidic cell and their interaction is evaluated through the received SPR signal (Table 1).
  • the cytotoxic activity of the compounds prepared was evaluated on the human cancer line HCT1 16 (colorectal carcinoma).
  • the selected line was incubated at 37 ° C in the presence of one of the compounds prepared, added in the culture medium at different concentrations.
  • the inhibitory concentration inducing the death of 50% of the cells was determined after 72 hours of incubation for each compound (Table 1).
  • Compounds AC014, AC096, AC087, AC069, AC085, AC056, AC034 and AC041 showed excellent affinities with respect to the TCTP protein and also have a profile of antiproliferative activity identical to that of sertraline.
  • Compound AC014 is capable of inducing overexpression of p53 (FIG. 1).
  • Western Blot analyzes show that the compound ACO14 induces at 10 ⁇ the expression of the p53 protein. This induction is more pronounced when compared to that induced by sertraline.
  • anti TCTP antibodies were generated against the TCTP human whole protein. These Polyclonal antibodies were purified by affinity column coupled to TCTP protein (Agro-Bio).
  • Mouse anti-P53 1 C12 antibody (Cell Signaling Technology) was used at a dilution of 1/1000.
  • the viability and proliferation of human HCT1 16 cells is measured using the "CelITiter Glo®” test (Promega) which makes it possible to measure the number of living cells by luminescence.
  • the compounds Sertraline and AC070 were tested at 10 concentrations and the results are expressed as GI50, TGI, LC50 and IC50 relative to the control cells (DMSO).
  • the CelITiter-GIo® test is a homogeneous method for determining the number of viable cells in culture based on quantification of ⁇ present, indicator of metabolically active cells.
  • the homogeneous test procedure involves the addition of a single reagent (the CelITiter-GIo® reagent) directly to cells grown in serum-enriched media.
  • the compound AC070 and sertraline were tested in vivo on C57BL / 6 mice.
  • ITR-1 Induced Tumor Reversion-1 tumor cells were removed from sarcomas developed by p53 / - knockout mice. Then, one million of these cells were injected (SC) into each C57BL / 6 mouse for the purpose of developing tumors.
  • SC sarcomas developed by p53 / - knockout mice.
  • SC injected
  • the compounds to be analyzed (sertraline and the compound AC070) were injected into the C57BL / 6 mice (30 mg / kg once a day by the IP route). This study was performed in double blind. After 12 days, the mice were sacrificed and their tumors were weighed and analyzed.
  • the results of these analyzes are retranscribed in diagrammatic form ( Figure 2).
  • the first column of the diagram corresponds to an injection of dimethylsulfoxide (DMSO) without presence of active ingredient and serves as a reference for the study.
  • DMSO dimethylsulfoxide
  • the value of p or "significance" has been calculated by software according to the Tukey method, and is significant if it is less than 0.05, which corresponds to a margin of error of 5%.

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Abstract

The present invention concerns the compounds of the following formula (I): (I) in which: - X represents an oxygen atom, a sulfur atom, a nitrogen atom or a CH radical, - The X--Y bond and Y are absent if X represents an oxygen or sulfur atom, the X--Y bond and Y are present if X represents a nitrogen atom or a CH radical, - When it is present, Y represents - an R group if X represents a nitrogen atom, - a hydrogen atom or an –NR1R2 group if X represents a CH radical, - (Het)Ar is an aromatic ring chosen from the group constituted by the aryl and heteroaryl groups, -R3, R4, R5, R6 represent, independently of one another, a hydrogen atom, a halogen atom, an –NR12R13 group, an –SR14 group, an –OR14 group or a -CF3 group, - When Y represents an –NR1R2 group, the –NR1R2 and (Het)Ar groups are in cis configuration, or a pharmaceutically acceptable salt of same, for the use thereof in the treatment of proliferative diseases, infectious diseases, allergies, an inflammation and/or asthma.

Description

AGENTS INHIBANT LA PROTEINE TCTP POUR LE TRAITEMENT DE MALADIES PROLIFERATIVES, DE MALADIES INFECTIEUSES, D'ALLERGIES,  TCTP PROTEIN-INHIBITING AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES, INFECTIOUS DISEASES, ALLERGIES,
D'INFLAMMATIONS ET/OU DE L'ASTHME  INFLAMMATION AND / OR ASTHMA
DOMAINE DE L'INVENTION FIELD OF THE INVENTION
L'invention concerne des composés inhibiteurs de la protéine TCTP pour leur utilisation dans le traitement de maladies prolifératives, de maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme. ETAT DE LA TECHNIQUE The invention relates to TCTP protein inhibitor compounds for use in the treatment of proliferative diseases, infectious diseases, allergies, inflammation and / or asthma. STATE OF THE ART
Le cancer est une cause de décès majeure dans le monde, avec un nombre de nouveaux cas qui ne cesse d'augmenter. Selon l'OMS, pas moins de 15 millions de décès sont dus au cancer dans le monde chaque année, soit presque 1 décès toutes les deux secondes. Le cancer a déjà fait 84 millions de victimes entre 2005 et 2015 et si rien n'est fait, il tuerait 19 millions de personnes par an en 2025. Cancer is a leading cause of death in the world, with a growing number of new cases. According to the World Health Organization, as many as 15 million people die from cancer each year worldwide, almost one death every two seconds. Cancer has already claimed 84 million lives between 2005 and 2015 and if nothing is done, it will kill 19 million people a year in 2025.
Parmi les thérapies utilisées, la chimiothérapie antitumorale dite conventionnelle, impliquant des agents cytotoxiques, seule ou associée à la chirurgie ou la radiothérapie, occupe une place majeure. Toutefois, les traitements sont fréquemment accompagnés d'effets indésirables, par manque de sélectivité vis-à-vis des cellules tumorales. De plus, la multi-résistance, le principal mécanisme par lequel de nombreux cancers échappent aux traitements, est un facteur important de l'échec de nombreuses chimiothérapies. Par conséquent, celle-ci se doit d'évoluer sans cesse afin de lever ces principales barrières. Les progrès récents accomplis dans le traitement des cancers sont liés à l'arrivée des « thérapies ciblées » visant spécifiquement certains mécanismes impliqués dans la régulation et la croissance cellulaire. Cette approche plus rationnelle a modifié de façon importante la prise en charge des patients. Les principes actifs utilisés sont généralement mieux tolérés et n'entraînent pas les effets secondaires propres aux chimiothérapies conventionnelles (alopécie, nausées, vomissements). Cependant, ils peuvent être à l'origine de toxicités telles qu'une hausse de la pression artérielle, des maux de tête, de protéinurie, de réactions allergiques ou d'atteintes digestives.  Among the therapies used, so-called conventional antitumor chemotherapy, involving cytotoxic agents, alone or associated with surgery or radiotherapy, occupies a major place. However, the treatments are frequently accompanied by undesirable effects due to a lack of selectivity with respect to the tumor cells. In addition, multi-resistance, the main mechanism by which many cancers escape treatment, is an important factor in the failure of many chemotherapies. Therefore, it must evolve constantly in order to remove these main barriers. Recent advances in the treatment of cancers are linked to the arrival of "targeted therapies" specifically targeting certain mechanisms involved in cell regulation and growth. This more rational approach has significantly changed the management of patients. The active ingredients used are generally better tolerated and do not cause the side effects of conventional chemotherapy (alopecia, nausea, vomiting). However, they can cause toxicities such as increased blood pressure, headaches, proteinuria, allergic reactions or digestive disorders.
Les traitements ciblés regroupent plusieurs familles de médicaments antitumoraux : les anticorps monoclonaux, les inhibiteurs de récepteurs à activité tyrosine kinase et les inhibiteurs de l'angiogenèse. Malgré tout l'intérêt de ces thérapies ciblées, les traitements actuels ont montré des résultats limités, en raison de la grande diversité biologique des cancers et l'apparition de phénomènes de résistance.  Targeted therapies include several families of antitumor drugs: monoclonal antibodies, tyrosine kinase receptor inhibitors, and angiogenesis inhibitors. Despite all the interest of these targeted therapies, current treatments have shown limited results, due to the high biological diversity of cancers and the appearance of resistance phenomena.
La réversion tumorale (1 , 3) a récemment émergé comme processus cellulaire à part entière, menant à une reprogrammation de la cellule cancéreuse et à la disparition de son phénotype malin. Forcer les cellules tumorales à se « réverter » pour qu'elles deviennent « pseudo » normales est une stratégie judicieuse. Le mécanisme de la réversion tumorale, par l'identification de protéine y jouant un rôle majeur, constitue ainsi une voie extrêmement prometteuse pour le développement de nouveaux agents antitumoraux. A ce titre, la TCTP (4) (translationnally Controlled Tumour protein), a été identifiée comme étant un des principaux acteurs de la réversion tumorale. En effet, elle est surexprimée dans de nombreuses cellules cancéreuses et elle possède une activité anti-apoptotique en utilisant les voies dépendant de p53/MDM2 et/ou Bcl-xL/Mcl-1 . La perte du phénotype malin dans la réversion tumorale passe donc probablement par le rétablissement d'une activité apoptotique normale suite à une inactivation au moins partielle de l'action de la TCTP dans la cellule. Tumor reversion (1, 3) has recently emerged as a cellular process in its own right, leading to reprogramming of the cancer cell and the disappearance of its tumor. malignant phenotype. Forcing tumor cells to "revert" to become "pseudo" normal is a wise strategy. The mechanism of tumor reversion, through the identification of protein plays a major role, thus constitutes an extremely promising way for the development of new antitumor agents. As such, the TCTP (4) has been identified as one of the main players in tumor reversion. Indeed, it is overexpressed in many cancer cells and has anti-apoptotic activity using the p53 / MDM2 and / or Bcl-xL / Mcl-1 dependent pathways. The loss of the malignant phenotype in the tumor reversion therefore probably involves the restoration of normal apoptotic activity following at least partial inactivation of the action of TCTP in the cell.
La TCTP est également impliquée dans les mécanismes d'infection de plusieurs parasites, dont Plasmodium falciparum responsable de la malaria, et son inhibition permet de prévenir ou traiter les infections induites par ces parasites (6, 7).  TCTP is also involved in the mechanisms of infection of several parasites, including Plasmodium falciparum responsible for malaria, and its inhibition can prevent or treat the infections induced by these parasites (6, 7).
La TCTP peut notamment être inhibée par la Sertraline (WO 2004/080445). Malgré l'action antitumorale de la Sertraline sur l'homme, son affinité vis-à-vis de la TCTP reste relativement faible (Kd = 198 μΜ). Par conséquent, la dose efficace nécessaire est proche de sa dose maximale tolérée (MTD = 400 mg/jour) et entraine des effets secondaires indésirables. Ce phénomène a été observé lors d'essais cliniques en phase l/ll sur des patients réfractaires ou en rechute atteints de leucémie myéloblastique aiguë (LMA). In particular, the TCTP may be inhibited by Sertraline (WO 2004/080445). Despite the antitumor action of sertraline on humans, its affinity for TCTP remains relatively low (Kd = 198 μΜ). Therefore, the required effective dose is close to its maximum tolerated dose (MTD = 400 mg / day) and causes undesirable side effects. This phenomenon has been observed in phase I / ll clinical trials in refractory or relapsed patients with acute myelogenous leukemia (AML).
sertraline La demanderesse a découvert une nouvelle famille de composés dérivés de la sertraline présentant une forte affinité vis-à-vis de la TCTP. Ces composés possèdent également une bonne cytotoxicité sur diverses lignées cellulaires cancéreuses humaines.  sertraline The applicant has discovered a new family of sertraline-derived compounds with a high affinity for TCTP. These compounds also possess good cytotoxicity on various human cancer cell lines.
EXPOSE DE L'INVENTION L'invention a pour objet les composés de formule (I) suivante : SUMMARY OF THE INVENTION The subject of the invention is the compounds of formula (I) below:
-Y  -Y
(Het)Ar Dans laquelle : (Het) Ar In which :
X représente un atome d'oxygène, un atome de soufre, un atome d'azote ou un radical CH,  X represents an oxygen atom, a sulfur atom, a nitrogen atom or a CH radical,
La liaison X— Y et Y sont absents si X représente un atome d'oxygène ou de soufre, la liaison X— Y et Y sont présents si X représente un atome d'azote ou un radical CH,  The X-Y and Y bond are absent if X represents an oxygen or sulfur atom, the X-Y and Y bond are present if X represents a nitrogen atom or a CH radical,
Lorsqu'il est présent, Y représente  When present, Y represents
o un groupe R si X représente un atome d'azote,  a group R if X represents a nitrogen atom,
dans lequel R représente un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2- C6)alcynyle ou un groupe acyle, wherein R is hydrogen, C 1-6 alkyl, aryl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, or acyl group,
o un atome d'hydrogène ou un groupe -NR1R2 si X représente un radical CH, dans lequel R1 et R2 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2-C6)alcynyle ou un groupe acyle, ou R1 et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, a hydrogen atom or a group -NR 1 R 2 if X represents a radical CH, in which R 1 and R 2 represent, independently of each other, a hydrogen atom or a Ci-alkyl group; at C 6 , aryl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl or acyl, or R 1 and R 2 together with the atom of nitrogen which carries them a 5- or 6-membered heterocycle,
(Het)Ar est un cycle aromatique choisi dans le groupe constitué par les groupes aryles et hétéroaryles,  (Het) Ar is an aromatic ring selected from the group consisting of aryl and heteroaryl groups,
ledit cycle aromatique pouvant être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, un groupe CF3, un groupe formyle, un groupe OR11, un groupe (C2-C6) alcényle, said aromatic ring may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1-6 alkyl group, a group -SR 10 , a group CF 3 , formyl group, OR 11 group, (C 2 -C 6 ) alkenyl group,
avec R7 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle ou un résidu de sucre, with R 7 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group or a sugar residue,
avec R8 et R9 représentant, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2-C6)alcynyle, un résidu de sucre, un résidu d'acide aminé, un résidu de peptide ou R8 et R9 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, with R 8 and R 9 representing, independently of each other, a hydrogen atom, a C 1-6 alkyl group, an aryl group, a heteroaryl group, a (C 2 -C 6 ) alkenyl group , a (C 2 -C 6 ) alkynyl group, a sugar residue, an amino acid residue, a peptide residue or R 8 and R 9 form together with the nitrogen atom which carries them a 5-membered heterocyclic ring; or 6 links,
avec R10 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un résidu de sucre, un résidu de peptide comprenant au moins une cystéine ou -SR10 représente un résidu de cystéine, avec R11 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle ou un groupe benzyle, with R 10 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group, a sugar residue, a peptide residue comprising at least one cysteine or -SR 10 represents a cysteine residue with R 11 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group or a benzyl group,
R3, R4, R5, R6 représentent, indépendamment les uns des autres, un atome d'hydrogène, un atome d'halogène, un groupe -NR12R13, un groupe -SR14, un groupe -OR14 ou un groupe -CF3, avec R12 et R13 représentant indépendamment l'un de l'autre un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2-C6)alcynyle ou un groupe acyle, ou R12 et R13 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, R 3 , R 4 , R 5 and R 6 represent, independently of each other, a hydrogen atom, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 or a group -CF 3 , with R 12 and R 13 independently of one another a hydrogen atom, a C 1-6 alkyl group, an aryl group, a heteroaryl group, a (C 2 -C 6 ) alkenyl group, a (C 2 -C 6 ) alkynyl group or an acyl group, or R 12 and R 13 form together with the nitrogen atom which carries them a 5- or 6-membered heterocycle,
avec R14 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un résidu de sucre, un résidu d'acide aminé ou un résidu de peptide, with R 14 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group, a sugar residue, an amino acid residue or a peptide residue,
Lorsque Y représente un groupe -NR1R2, les groupes - NR1R2 et (Het)Ar sont en conformation cis, When Y represents a group -NR 1 R 2 , the groups - NR 1 R 2 and (Het) Ar are in cis-conformation,
les fonctions alcool du résidu de sucre et les fonctions aminé du résidu d'acide aminé, du résidu de cystéine ou du résidu de peptide étant sous leur forme libre ou protégée,  the alcohol functions of the sugar residue and the amino functions of the amino acid residue, the cysteine residue or the peptide residue being in their free or protected form,
ainsi que leurs sels pharmaceutiquement acceptables, as well as their pharmaceutically acceptable salts,
à l'exception du composé de formule suivante : with the exception of the compound of the following formula:
pour leur utilisation dans le traitement de maladies prolifératives, de maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme. Plus particulièrement, le composé de formule (I) selon l'invention n'est pas la 4-(3,4- dichloro-phényl)-1 ,2,3,4-tétrahydronaphtalène-1 -ylamine ou son sel de chlorhydrate. De préférence, le composé de formule (I) n'est pas la 4-(3,4-dichloro-phényl)-1 , 2,3,4- tétrahydronaphtalène-1 -ylamine ou un de ses sels pharmaceutiquement acceptable. DESCRIPTION DES FIGURES for their use in the treatment of proliferative diseases, infectious diseases, allergies, inflammation and / or asthma. More particularly, the compound of formula (I) according to the invention is not 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine or its hydrochloride salt. Preferably, the compound of formula (I) is not 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine or a pharmaceutically acceptable salt thereof. DESCRIPTION OF THE FIGURES
Figure 1. Western Blot montrant l'expression sur p53, en allant de gauche à droite, du DMSO (témoin), de la sertaline à 1 C^g (comparatif) et du composé AC014 à 1 C^g (invention) avec pour témoin l'expression de chacun de ces trois composés sur GAPDH. Figure 2. Diagramme représentant le poids moyen des tumeurs extraites de souris traitées 12 jours par injection de DMSO (colonne de gauche), de sertraline (colonne centrale) ou du composé AC070 (colonne de droite). DEFINITIONS Figure 1. Western blot showing expression on p53, from left to right, DMSO (control), sertaline at 1 ° C (comparative) and compound AC014 at 1 ° C (invention) with witness the expression of each of these three compounds on GAPDH. Figure 2. Diagram representing the average weight of tumors extracted from mice treated for 12 days by injection of DMSO (left column), sertraline (central column) or compound AC070 (right column). DEFINITIONS
Par groupement « alkyle en Ci à C6», on entend, au sens de la présente invention, une chaîne hydrocarbonée monovalente saturée, linéaire ou ramifiée, comportant 1 à 6, de préférence 1 à 4, atomes de carbone. A titre d'exemple, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, sec-butyle, ie/f-butyle, pentyle ou encore hexyle. By "C 1 -C 6 alkyl" group is meant, in the sense of the present invention, a saturated monovalent hydrocarbon chain, linear or branched, having 1 to 6, preferably 1 to 4, carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, β-butyl, pentyl or hexyl groups.
Par « aryle », on entend, au sens de la présente invention, un groupement hydrocarboné aromatique, comportant de préférence de 6 à 10 atomes de carbone, et comprenant un ou plusieurs cycles accolés, comme par exemple un groupement phényle ou naphtyle. Avantageusement, il s'agit du phényle.  For the purposes of the present invention, the term "aryl" means an aromatic hydrocarbon group, preferably comprising from 6 to 10 carbon atoms, and comprising one or more contiguous rings, for example a phenyl or naphthyl group. Advantageously, it is phenyl.
Par « hétéroaryle », on entend, au sens de la présente invention, un groupe aromatique comprenant un ou plusieurs, notamment 1 ou 2, cycles hydrocarbonés accolés, dans lequel un ou plusieurs atomes de carbone, avantageusement 1 à 4 et encore plus avantageusement 1 ou 2, sont chacun remplacés par un hétéroatome tel que par exemple un atome de soufre, d'azote ou d'oxygène. Des exemples de groupes hétéroaryles sont les groupes furyle, thiényle, pyrrolyle, pyridyle, oxazolyle, isoxazolyle, thiazolyle, isothiazolyle, imidazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle, triazolyle, tétrazolyle, pyridazinyle, pyrimidinyle, pyrazinyle, triazinyle, quinolyle, isoquinolyle, quinoxalyle, indyle, benzofuranyle ou encore benzothiophényle. Avantageusement le groupe hétéroaryle est choisi parmi une pyridine, une pyrimidine, une pyrazine, une quinoléine, une isoquinoléine, un indole, un benzofurane et un benzothiophène.  For the purposes of the present invention, the term "heteroaryl" means an aromatic group comprising one or more, especially 1 or 2, conjugated hydrocarbon rings, in which one or more carbon atoms, advantageously 1 to 4 and even more advantageously 1 or 2, are each replaced by a heteroatom such as, for example, a sulfur, nitrogen or oxygen atom. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl, indyl, benzofuranyl or benzothiophenyl. Advantageously, the heteroaryl group is chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, a benzofuran and a benzothiophene.
Par « cycle aromatique », on entend, au sens de la présente invention, un groupe aryle ou un groupe hétéroaryle tel que défini précédemment. For the purposes of the present invention, the term "aromatic ring" means an aryl group or a heteroaryl group as defined above.
Par groupement « (C2-C6)alcényle », on entend, au sens de la présente invention, une chaîne hydrocarbonée, linéaire ou ramifiée, comportant au moins une double liaison et comportant 2 à 6 atomes de carbone. A titre d'exemple, on peut citer les groupes éthényle ou allyle. By "(C 2 -C 6 ) alkenyl" group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one double bond and having 2 to 6 carbon atoms. By way of example, mention may be made of ethenyl or allyl groups.
Par groupement « (C2-C6)alcynyle », on entend, au sens de la présente invention, une chaîne hydrocarbonée, linéaire ou ramifiée, comportant au moins une triple liaison et comportant 2 à 6 atomes de carbone. A titre d'exemple, on peut citer les groupes éthynyle ou propynyle. By "(C 2 -C 6 ) alkynyl" group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one triple bond and having 2 to 6 carbon atoms. By way of example, mention may be made of ethynyl or propynyl groups.
Par « acyle », on entend, au sens de la présente invention, un groupe alkyle en Ci à C6 ou aryle tel que défini ci-dessus, lié au reste de la molécule par l'intermédiaire d'un groupement carbonyle (CO). Il peut s'agir en particulier d'un groupement acétyle ou benzoyle. Par « hétérocycle à 5 ou 6 chaînons », on entend, au sens de la présente invention, un cycle à 5 ou 6 chaînons, saturé ou non, mais non aromatique, et contenant un ou plusieurs, avantageusement 1 à 4, encore plus avantageusement 1 ou 2, hétéroatomes, tels que par exemple des atomes de soufre, azote ou oxygène. Il peut s'agir notamment du groupe pyrrolidinyle, pipéridinyle, pipérazinyle ou morpholinyle. Avantageusement, il s'agit d'un groupe pyrrolydinyle ou morpholinyle. By "acyl" is meant, in the sense of the present invention, a C 1 -C 6 alkyl or aryl group as defined above, linked to the rest of the molecule via a carbonyl (CO) group. . It may be in particular an acetyl or benzoyl group. For the purposes of the present invention, the term "5- or 6-membered heterocycle" means a 5- or 6-membered ring, saturated or non-saturated, but not aromatic, and containing one or more, advantageously 1 to 4, even more advantageously. 1 or 2, heteroatoms, such as, for example, sulfur, nitrogen or oxygen atoms. It may especially be pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group. Advantageously, it is a pyrrolydinyl or morpholinyl group.
Par « atome d'halogène », on entend, au sens de la présente invention, les atomes de fluor, de chlore, de brome et d'iode.  For the purposes of the present invention, the term "halogen atom" means the fluorine, chlorine, bromine and iodine atoms.
Par « sucre », on entend au sens de la présente invention, un monosaccharide ou un polysaccharide.  For the purposes of the present invention, the term "sugar" means a monosaccharide or a polysaccharide.
Par « monosaccharide », on entend, au sens de la présente invention, un aldose. Il peut s'agir notamment de l'érythrose, du thréose, du ribose, de l'arabinose, du xylose, du lyxose, de l'allose, de l'altrose, du glucose, du mannose, du gulose, de l'idose, du galactose, ou du talose, sous une forme D ou L. Il s'agit en particulier du glucose.  By "monosaccharide" is meant, within the meaning of the present invention, an aldose. This may include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, or talose, in a form D or L. It is in particular glucose.
Par « polysaccharide », on entend, au sens de la présente invention, un enchaînement d'au moins deux motifs monosaccharide tel que défini ci-dessus. Il pourra s'agir en particulier d'un disaccharide (enchaînement de deux motifs monosaccharide), tel que le lactose. By "polysaccharide" is meant, in the sense of the present invention, a sequence of at least two monosaccharide units as defined above. It may be in particular a disaccharide (sequence of two monosaccharide units), such as lactose.
Par « résidu de sucre », on entend, au sens de la présente invention, qu'une molécule de sucre telle que définie ci-dessus, dépourvue d'atome d'oxygène sur sa position anomérique, est liée au reste de la molécule par l'intermédiaire du carbone en position anomérique.  By "sugar residue" is meant in the sense of the present invention, a sugar molecule as defined above, free of oxygen atom on its anomeric position, is bonded to the rest of the molecule by the carbon intermediate in the anomeric position.
Par « acide aminé », on entend, au sens de la présente invention, un acide carboxylique qui possède également un groupe fonctionnel aminé. En particulier on entend tous les acides α-aminés naturels (par exemple Alanine (Ala), Arginine (Arg), Asparagine (Asn), Acide aspartique (Asp), Cystéine (Cys), Glutamine (Gin), Acide glutamique (Glu), Glycine (Gly), Histidine (His), Isoleucine (Ile), Leucine (Leu), Lysine (Lys), Méthionine (Met), Phénylalanine (Phe), Proline (Pro), Sérine (Ser), Thréonine (Thr), Tryptophane (Trp), Tyrosine (Tyr) et Valine (Val)) sous la forme D ou L, ainsi que les acides aminés non naturels (par exemple la β-alanine, l'allylglycine, la tert-leucine, l'acide 3-amino-adipique, l'acide 2-aminobenzoïque, l'acide 3-aminobenzoïque, l'acide 4-aminobenzoïque, l'acide 2- aminobutanoïque, la 4-amino-1 -carboxyméthyl pipéridine, l'acide 1 -amino-1 - cyclobutanecarboxylique, l'acide 4-aminocyclohexaneacétique, l'acide 1 -amino-1 - cyclohexanecarboxyilique, l'acide (1 R,2R)-2-aminocyclohexanecarboxylique, l'acide (1 R,2S)-2-aminocyclohexanecarboxylique, l'acide (1 S,2/?)-2- aminocyclohexanecarboxylique, l'acide (1 S,2S)-2-aminocyclohexanecarboxylique, l'acide 3-aminocyclohexanecarboxylique, l'acide 4-aminocyclohexanecarboxylique, l'acide (1 R,2R)-2-aminocyclopentanecarboxylique, l'acide (IR,2S)-2- aminocyclopentanecarboxyilique l'acide 1 -amino-1 -cyclopentanecarboxylique, l'acide 1 - amino-1 -cyclopropanecarboxylique, l'acide 4-(2-aminoéthoxy)-benzoïque, l'acide 3- aminométhylbenzoïque, l'acide 4-aminométhylbenzoïque, l'acide 2-aminobutanoïque, l'acide 4-aminobutanoïque, l'acide 6-aminohexanoïque, l'acide 1 -aminoindane-1 - carboxylique, l'acide 4-aminométhyl-phénylacétique, l'acide 4-aminophénylacétique, l'acide 3-amino-2-naphtoïque, l'acide 4-aminophénylbutanoïque, l'acide 4-amino-5-(3- indolyl)-pentanoïque, l'acide (4/?,5S)-4-amino-5-méthylheptanoïque, l'acide (R)-4-amino- 5-méthylhexanoïque, l'acide (R)-4-amino-6-méthylthiohexanoïque, l'acide (S)-4-amino- pentanoïque, l'acide (R)-4-amino-5-phénylpentanoïque, l'acide 4- aminophénylpropionique, l'acide (R)-4-aminopimérique, l'acide (4/?,5R)-4-amino-5- hyroxyhexanoïque, l'acide (R)— 4-amino-5-hydroxypentanoïque, l'acide (R)-4-amino-5-(p- hydroxyphényl)-pentanoïque, l'acide 8-aminooctanoïque, l'acide (2S,4/?)-4-amino- pyrrolidine-2-carboxylique, l'acide (2S,4S)-4-amino-pyrrolidine-2-carboxylique, l'acide azétidine-2-carboxylique, l'acide (2S,4R)-4-benzyl-pyrrolidine-2-carboxylique, l'acide (S)- 4,8-diaminooctanoïque, l'acide ie/f-butylglycine, le γ-carboxyglutamate, la β- cyclohexylalanine, la citruline, l'acide 2,3-diamino propionique, l'acide hippurique, l'homocyclohexylalanine, la moleucine, l'homophénylalanine, la 4-hydroxyproline, l'acide indoline-2-carboxylique, l'acide isonipécotique, Γα-méthyl-alanine, l'acide nicopetique, la norleucine, la norvaline, l'acide octahydroindole-2-carboxylique, l'ornithine, la pénicillamine, la phénylglycine, l'acide 4-phényl-pyrrolidine-2-carboxylique, l'acide pipécolique, la propargylglycine, la 3-pyridinylalanine, la 4-pyridinylalanine, l'acide 1 - pyrrolidine-3-carboxylique, la sarcosine, les statines, l'acide tétrahydroisoquinoline-1 - carboxylique, l'acide 1 ,2,3,4-tétrahydroisoquinoline-3-carboxylique, l'acide tranexamique). Par « résidu d'acide aminé », on entend, au sens de la présente invention, un acide aminé tel que défini ci-dessus lié au reste de la molécule par sa fonction amine (N H2), sa fonction acide carboxylique (COOH) ou tout autre fonctionnalité présente sur l'acide aminé telle qu'une fonction thiol (SH) (par ex. dans le cas d'une cystéine). For the purposes of the present invention, the term "amino acid" is intended to mean a carboxylic acid which also has an amino functional group. In particular, it is meant all natural α-amino acids (for example Alanine (Ala), Arginine (Arg), Asparagine (Asn), Aspartic acid (Asp), Cysteine (Cys), Glutamine (Gin), Glutamic acid (Glu) , Glycine (Gly), Histidine (His), Isoleucine (Ile), Leucine (Leu), Lysine (Lys), Methionine (Met), Phenylalanine (Phe), Proline (Pro), Serine (Ser), Threonine (Thr) , Tryptophan (Trp), Tyrosine (Tyr) and Valine (Val)) in D or L form, as well as unnatural amino acids (e.g., β-alanine, allylglycine, tert-leucine, acid). 3-amino-adipic acid, 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 2-aminobutanoic acid, 4-amino-1-carboxymethyl piperidine, 1-amino acid Cyclobutanecarboxylic acid, 4-aminocyclohexaneacetic acid, 1-amino-1-cyclohexanecarboxylic acid, (1 R, 2R) -2-aminocyclohexanecarboxylic acid, (1 R, 2S) -2-aminocyclohexanecarboxylic acid (1S, 2H) -2-aminocyclohexanecarboxyl acid (1S, 2S) -2-aminocyclohexanecarboxylic acid, 3-aminocyclohexanecarboxylic acid, 4-aminocyclohexanecarboxylic acid, (1R, 2R) -2-aminocyclopentanecarboxylic acid, (IR, 2S) -2- aminocyclopentanecarboxylic acid 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1-cyclopropanecarboxylic acid, 4- (2-aminoethoxy) -benzoic acid, 3-aminomethylbenzoic acid, 4-aminomethylbenzoic acid, 2-aminobutanoic acid, 4-aminobutanoic acid, 6-aminohexanoic acid, 1-aminoindan-1-carboxylic acid, 4-aminomethylphenylacetic acid, 4-aminophenylacetic acid, 3-amino-2-naphthoic acid, 4-aminophenylbutanoic acid, 4-amino-5- (3-indolyl) -pentanoic acid, (4H, 5S) -4-amino-5- acid methylheptanoic acid, (R) -4-amino-5-methylhexanoic acid, (R) -4-amino-6-methylthiohexanoic acid, (S) -4-amino-pentanoic acid, (R) ) 4-amino-5-phenylpentanoic acid, 4-aminophenylpropionic acid, (R) -4-aminopimeric acid, (4 R, 5 R) -4-amino-5-hydroxyhexanoic acid, (R) -4-amino-5-hydroxypentanoic acid, (R) -4-amino-5- (p-hydroxyphenyl) -pentanoic acid, 8-aminooctanoic acid, (2S, 4H) -4-Amino-pyrrolidine-2-carboxylic acid, (2S, 4S) -4-amino-pyrrolidine-2-carboxylic acid, azetidine-2-carboxylic acid, (2S, 4R) -4-Benzyl-pyrrolidine-2-carboxylic acid, (S) -4,8-diaminooctanoic acid, β-butylglycine acid, γ-carboxyglutamate, β-cyclohexylalanine, citruline, 2,3-diaminopropionic acid, hippuric acid, homocyclohexylalanine, moleucine, homophenylalanine, 4-hydroxyproline, indoline-2-carboxylic acid, isonipecotic acid, Γα- methyl-alanine, nicotinic acid, norleucine, norvaline, octahydroindole-2-carboxylic acid, ornithine, penicillamine, phenylglycine, 4-phenyl-pyrrolidine-2-carboxylic acid, acid pipecolic, propargylglycine, 3-pyridinylalanine, 4-pyridinylalanine, 1-pyrrolidine-3-carboxylic acid, sarcosine, statins, tetrahydroisoquinoline-1-carboxylic acid, 1, 2,3 acid, 4-Tetrahydroisoquinoline-3-carboxylic acid, tra nexamique). For the purposes of the present invention, the term "amino acid residue" is intended to mean an amino acid as defined above bonded to the rest of the molecule by its amine function (NH 2 ), its carboxylic acid function (COOH) or any other functionality present on the amino acid such as a thiol (SH) function (e.g., in the case of a cysteine).
Par « résidu de cystéine » on entend, au sens de la présente invention, un acide aminé cystéine lié au reste de la molécule par son atome de soufre. For the purposes of the present invention, the term "cysteine residue" is intended to mean a cysteine amino acid bound to the rest of the molecule by its sulfur atom.
Par « peptide », on entend, au sens de la présente invention, un enchaînement d'acides aminés (au moins deux) liés entre eux par des liaisons peptidiques (liaisons amides). Par « résidu de peptide », on entend, au sens de la présente invention, un peptide tel que défini ci-dessus lié au reste de la molécule par sa fonction amine (NH2), sa fonction acide (COOH) ou tout autre fonctionnalité présente sur l'acide aminé telle qu'une fonction thiol (SH) (par ex. dans le cas d'une cystéine). By "peptide" is meant, in the sense of the present invention, a sequence of amino acids (at least two) linked together by peptide bonds (amide bonds). For the purposes of the present invention, the term "peptide residue" is intended to mean a peptide as defined above bonded to the rest of the molecule by its amine function (NH 2 ), its acid function (COOH) or any other functionality. present on the amino acid such as a thiol function (SH) (eg in the case of a cysteine).
Par « résidu de peptide contenant au moins une cystéine », on entend, au sens de la présente invention, un peptide tel que défini ci-dessus contenant au moins un acide aminé de type cystéine et lié au reste de la molécule par la fonction thiol (SH) de la cystéine. Par « fonction alcool sous sa forme libre » on entend, au sens de la présente invention, un groupement -OH. For the purposes of the present invention, the term "peptide residue containing at least one cysteine" means a peptide as defined above containing at least one amino acid of the cysteine type and linked to the rest of the molecule by the thiol function. (SH) of cysteine. By "alcohol function in its free form" means, within the meaning of the present invention, an -OH group.
Par « fonction alcool sous sa forme protégée », on entend, au sens de la présente invention, une fonction alcool (OH) dans laquelle l'atome d'hydrogène a été remplacé par un groupement O-protecteur.  For the purposes of the present invention, the term "alcohol function in its protected form" means an alcohol (OH) function in which the hydrogen atom has been replaced by an O-protective group.
Par « groupe O-protecteur », on entend, au sens de la présente invention, tout substituant qui protège le groupe hydroxyle ou carboxyle, c'est à dire un atome d'oxygène réactif, contre les réactions indésirables tels que les groupes O-protecteur décrits dans in "Greene's Protective Groups In Organic Synthesis", 4th édition, 2007, John Wiley & Sons, Hoboken, New Jersey. Un groupe hydroxyle protégé par un groupe O-protecteur peut être par exemple un éther, un ester, un carbonate, un acétal et similaire. En particulier, les groupes O-protecteurs comprennent un groupe (C1 -C6)alkyle éventuellement substitué par un ou plusieurs (notamment 1 à 3) atomes d'halogène (tels que des atomes de chlore), tel que les groupes méthyle, éthyle, tert-butyle et 2,2,2-trichloroéthyle ; un groupe aryl-(C1 -C6)alkyle, le noyau aryle étant éventuellement substitué par un ou plusieurs groupes méthoxy, tel que les groupes benzyle (Bn) et p-methoxybenzyle (PMB) ; un groupe trityle de formule -CA^Ai^Ar3, tel que les groupes triphénylméthyle (aussi appelé trityle - Tr), (4-méthoxyphényl)diphénylméthyle (aussi appelé méthoxytrityle - NMT) et bis- (4-méthoxyphényl)phénylméthyle (aussi appelé diméthoxytrityle - DMT) ; un groupe méthyle substitué de formule CH2ORGP2 ou CH2SRGP2 (en particulier CH2ORGP2), tel que les groupes méthoxyméthyle (MOM), benzyloxyméthyle, 2-méthoxyéthoxyméthyle (MEM), 2-(triméthylsilyl)éthoxyméthyle et méthylthiométhyle ; un groupe éthyle substitué de formule -CH2CH2ORGP2 ou -CH2CH2SRGP2 (en particulier -CH2CH2ORGP2), tel que le groupe éthoxyéthyle (EE) ; un groupe silyle de formule -SiRGP3RGP4RGP5, tel que les groupes triméthylsilyle (TMS), triéthylsilyle (TES), t-butyldiméthylsilyle (TBS ou TBDMS) et t-butyldiphénylsilyle (TBDPS) ; un groupe carbonylé de formule CO-RGP6, tel que les groupes acétyle (Ac), pivaloyle (Piv ou Pv) et benzoyle (Bz), ou de formule -C02-RGP7, tel que les groupes allyloxycarbonyle (Alloc) et 9-fluorénylméthyloxycarbonyle (Fmoc) ; ou un groupe tétrahydropyranyle (THP) ou tétrahydrofuranyle ; For the purposes of the present invention, the term "O-protecting group" is intended to mean any substituent which protects the hydroxyl or carboxyl group, ie a reactive oxygen atom, against undesirable reactions such as O-groups. protector described in "Greene's Protective Groups In Organic Synthesis", 4th Edition, 2007, John Wiley & Sons, Hoboken, New Jersey. A hydroxyl group protected by an O-protecting group may be, for example, an ether, an ester, a carbonate, an acetal and the like. In particular, the O-protecting groups comprise a (C 1 -C 6) alkyl group optionally substituted by one or more (in particular 1 to 3) halogen atoms (such as chlorine atoms), such as methyl, ethyl, tert-butyl and 2,2,2-trichloroethyl; an aryl (C1 -C6) alkyl group, the aryl ring being optionally substituted by one or more methoxy groups, such as benzyl (Bn) and p-methoxybenzyl (PMB); a trityl group of the formula -CA 2 Al 3 Ar 3 , such as triphenylmethyl (also called trityl-Tr), (4-methoxyphenyl) diphenylmethyl (also called methoxytrityl-NMT) and bis (4-methoxyphenyl) phenylmethyl (also called dimethoxytrityl - DMT); a substituted methyl group of formula CH 2 ORGP 2 or CH 2 SRGP 2 (in particular CH 2 ORGP 2 ), such as the methoxymethyl (MOM), benzyloxymethyl, 2-methoxyethoxymethyl (MEM), 2- (trimethylsilyl) ethoxymethyl and methylthiomethyl groups; ; a substituted ethyl group of formula -CH 2 CH 2 ORGP 2 or -CH 2 CH 2 SRGP 2 (in particular -CH 2 CH 2 ORGP 2 ), such as the ethoxyethyl group (EE); a silyl group of formula -SiRGP 3 RGP 4 RGP 5 , such as trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS or TBDMS) and t-butyldiphenylsilyl (TBDPS); a carbonyl group of formula CO-RGP 6 , such as the acetyl (Ac), pivaloyl (Piv or Pv) and benzoyl (Bz) groups, or of the formula -C0 2 -RGP 7 , such as the allyloxycarbonyl (Alloc) and 9-fluorenylmethyloxycarbonyl (Fmoc); or a tetrahydropyranyl (THP) or tetrahydrofuranyl group;
avec Ar1, Ar2 et Ar3 représentant, indépendamment les uns des autres, un aryle, tel que phényle, éventuellement substitué par un ou plusieurs groupes méthoxy ; RGP2 représentant un groupe (CrC6)alkyle (tel que méthyle or éthyle) éventuellement substitué par un groupe aryle (tel que phényle), (CrC6)alcoxy (tel que méthoxy) ou trialkylsilyle (tel que SiMe3) ; RGP3, RGP4 et RGP5 représentant, indépendamment les uns des autres, un groupe (CrC6)alkyle ou aryle (tel que phényle) ; et RGP6 et RGP7 représentant, indépendamment l'un de l'autre, un groupe (CrC6)alkyle, (C2-C6)alcényle, aryle, aryl-(d- C6)alkyle ou 9-fluorénylméthyle. with Ar 1 , Ar 2 and Ar 3 representing, independently of each other, an aryl, such as phenyl, optionally substituted by one or more methoxy groups; RGP 2 represents a (C 1 -C 6 ) alkyl group (such as methyl or ethyl) optionally substituted with aryl (such as phenyl), (C 1 -C 6 ) alkoxy (such as methoxy) or trialkylsilyl (such as SiMe 3 ); RGP 3 , RGP 4 and RGP 5 representing, independently of each other, a (C 1 -C 6 ) alkyl or aryl group (such as phenyl); and RGP 6 and RGP 7 represent, independently of one another, a (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, aryl, aryl- (C 6 -C 6 ) alkyl or 9-fluorenylmethyl group.
En particulier, il s'agit d'un groupe benzyle (Bn) ou acétyle (Ac). Par « fonction amine sous sa forme libre » on entend un groupement -NH2 ou un groupement NH qui n'est pas substitué par un groupement N-protecteur. In particular, it is a benzyl (Bn) or acetyl (Ac) group. By "amine function in its free form" is meant an -NH 2 group or an NH group which is not substituted by an N-protecting group.
Par « fonction amine sous sa forme protégée », on entend au sens de la présente invention, une fonction amine (NH) dans laquelle l'atome d'hydrogène a été remplacé par un groupement N-protecteur. For the purposes of the present invention, the term "amine function in its protected form" means an amine (NH) function in which the hydrogen atom has been replaced by an N-protective group.
Par « groupe N-protecteur », on entend, au sens de la présente invention, tout substituant qui protège le groupe NH2 contre les réactions indésirables tels que les groupes N- protecteur décrits dans in "Greene's Protective Groups In Organic Synthesis", 4th édition, 2007, John Wiley & Sons, Hoboken, New Jersey. Une fonction amine protégée par un groupe N-protecteur peut être par exemple un carbamate, un amide, un sulfonamide, un dérivé N-alkylé, un dérivé amino acétale, un dérivé N-benzylé, un dérivé imine, un dérivé énamine ou un dérivé N-hétéroatome. En particulier, les groupes N-protecteurs comprennent un groupe formyle ; un groupe aryle, tel que phényle, éventuellement substitué par un ou plusieurs groupes méthoxy, tel que le groupe p-méthoxyphényle (PMP); un groupe aryl-(C1 -C6)alkyle, tel que benzyle, le noyau aryle étant éventuellement substitué par un ou plusieurs groupes méthoxy, tel que les groupes benzyle (Bn), p- methoxybenzyle (PMB) et 3,4-diméthoxybenzyle (DMPM) ; un groupe -CO-RGP8 tel que les groupes acétyle (Ac), pivaloyle (Piv ou Pv), benzoyle (Bz) et p- méthoxybenzylcarbonyle (Moz) ; un groupe -C02-RGP8 tel que les groupes tbutyloxycarbonyle (Boc), trichloroéthoxycarbonyle (TROC), allyloxycarbonyle (Alloc), benzyloxycarbonyle (Cbz or Z) et 9-fluorénylméthyloxycarbonyle (Fmoc) ; un groupe - S02-RGP8 tel que les groupes phénylsulfonyle, tosyle (Ts ou Tos) et 2 nitrobenzènesulfonyle (aussi appelé nosyle - Nos or Ns) ; et similaire, For the purposes of the present invention, the term "N-protecting group" is intended to mean any substituent which protects the NH 2 group against undesirable reactions such as the N-protecting groups described in "Greene's Protective Groups In Organic Synthesis", 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey. An amine function protected by an N-protecting group may be, for example, a carbamate, an amide, a sulfonamide, an N-alkyl derivative, an amino acetal derivative, an N-benzyl derivative, an imine derivative, an enamine derivative or a derivative. N-hetero. In particular, the N-protecting groups comprise a formyl group; an aryl group, such as phenyl, optionally substituted with one or more methoxy groups, such as p-methoxyphenyl (PMP); an aryl (C1-C6) alkyl group, such as benzyl, the aryl ring being optionally substituted with one or more methoxy groups, such as benzyl (Bn), p-methoxybenzyl (PMB) and 3,4-dimethoxybenzyl ( DMPM); a group -CO-RGP 8 such as acetyl (Ac), pivaloyl (Piv or Pv), benzoyl (Bz) and p-methoxybenzylcarbonyl (Moz); a group -CO 2 -RGP 8 such as tbutyloxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz or Z) and 9-fluorenylmethyloxycarbonyl (Fmoc); a group - S0 2 -RGP 8 such as phenylsulfonyl, tosyl (Ts or Tos) and 2 nitrobenzenesulfonyl (also called nosyl - Nos or Ns); and similar,
avec RGP8 représentant un groupe (CrC6)alkyle éventuellement substitué par un ou plusieurs arômes d'halogènes tels que F ou Cl ; un groupe (C2-C6)alcényle tel qu'un groupe allyle ; un groupe aryle, tel que phényle, éventuellement substitué par un ou plusieurs groupes choisis parmi les groupes OMe (méthoxy) et N02 (nitro) ; un groupe aryl-(CrC6)alkyle, tel que benzyle, le noyau aryle étant éventuellement substitué par un ou plusieurs groupes méthoxy ; ou un groupe 9-fluorénylméthyle. with RGP 8 representing a (CrC 6 ) alkyl group optionally substituted with one or more halogen flavors such as F or Cl; a (C 2 -C 6 ) alkenyl group such as an allyl group; an aryl group, such as phenyl, optionally substituted by one or more groups selected from OMe (methoxy) and NO 2 (nitro); an aryl (C 1 -C 6 ) alkyl group, such as benzyl, the aryl ring being optionally substituted by one or more methoxy groups; or a 9-fluorenylmethyl group.
En particulier, il s'agit d'un groupe acétyle (Ac). In particular, it is an acetyl group (Ac).
Par « les groupes - NR1R2 et (Het)Ar sont en conformation cis », on entend, au sens de la présente invention, que les deux groupes - NR1R2 et (Het)Ar sont situés du même côté du cycle 1 ,2,3,4-tetrahydronaphtyle du composé selon la formule (I). Ainsi, lorsque Y représente un groupe -NR1R2 et que les groupes -NR1R2 et (Het)Ar sont en conformation cis, le composé de formule (I) selon l'invention a la formule suivante : By "the groups - NR 1 R 2 and (Het) Ar are in cis conformation" is meant, in the sense of the present invention, that the two groups - NR 1 R 2 and (Het) Ar are situated on the same side of the ring 1, 2,3,4-tetrahydronaphthyl of the compound according to formula (I). Thus, when Y represents a group -NR 1 R 2 and the groups -NR 1 R 2 and (Het) Ar are in cis-conformation, the compound of formula (I) according to the invention has the following formula:
Dans la présente invention, on entend désigner par « pharmaceutiquement acceptable » ce qui est utile dans la préparation d'une composition pharmaceutique qui est généralement sûr, non toxique et ni biologiquement ni autrement non souhaitable et qui est acceptable pour une utilisation vétérinaire de même que pharmaceutique humaine. On entend désigner par « sel pharmaceutiquement acceptable » d'un composé, un sel qui est pharmaceutiquement acceptable, comme défini ici, et qui possède l'activité pharmacologique souhaitée du composé parent.  In the present invention, the term "pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical. The term "pharmaceutically acceptable salt" of a compound means a salt which is pharmaceutically acceptable, as defined herein, and which has the desired pharmacological activity of the parent compound.
Les sels pharmaceutiquement acceptables comprennent notamment : The pharmaceutically acceptable salts comprise in particular:
(1 ) les sels d'addition d'acide pharmaceutiquement acceptable formés avec des acides inorganiques pharmaceutiquement acceptables tels que l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique, l'acide nitrique, l'acide phosphorique et similaires ; ou formés avec des acides organiques pharmaceutiquement acceptables tels que l'acide acétique, l'acide benzènesulfonique, l'acide benzoïque, l'acide camphresulfonique, l'acide citrique, l'acide éthane-sulfonique, l'acide fumarique, l'acide glucoheptonique, l'acide gluconique, l'acide glutamique, l'acide glycolique, l'acide hydroxynaphtoïque, l'acide 2-hydroxyéthanesulfonique, l'acide lactique, l'acide maléique, l'acide malique, l'acide mandélique, l'acide méthanesulfonique, l'acide muconique, l'acide 2-naphtalènesulfonique, l'acide propionique, l'acide salicylique, l'acide succinique, l'acide dibenzoyl-L-tartrique, l'acide tartrique, l'acide p-toluènesulfonique, l'acide triméthylacétique, l'acide trifluoroacétique et similaires, et  (1) pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with pharmaceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, acid glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-acid, toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like, and
(2) les sels d'addition de base pharmaceutiquement acceptable formés lorsqu'un proton acide présent dans le composé parent est soit remplacé par un ion métallique, par exemple un ion de métal alcalin, un ion de métal alcalino-terreux ou un ion d'aluminium ; soit coordonné avec une base organique pharmaceutiquement acceptable telle que la diéthanolamine, l'éthanolamine, N-méthylglucamine, la triéthanolamine, la trométhamine et similaires ; ou avec une base inorganique pharmaceutiquement acceptable telle que l'hydroxyde d'aluminium, l'hydroxyde de calcium, l'hydroxyde de potassium, le carbonate de sodium, l'hydroxyde de sodium et similaires.  (2) pharmaceutically acceptable base addition salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or a aluminum; is coordinated with a pharmaceutically acceptable organic base such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like; or with a pharmaceutically acceptable inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.
Avantageusement, le sel pharmaceutiquement acceptable est un chlorhydrate. Advantageously, the pharmaceutically acceptable salt is a hydrochloride.
Par « maladie proliférative », on entend une maladie dans laquelle les cellules prolifèrent de manière incontrôlée. Par « maladie infectieuse », on entend toute infection, et en particuliers les infections dues à des parasites, encore appelée infections parasitaires. Un exemple d'une telle infection est la malaria. By "proliferative disease" is meant a disease in which cells proliferate in an uncontrolled manner. By "infectious disease" is meant any infection, and in particular infections due to parasites, also called parasitic infections. An example of such an infection is malaria.
Par « un niveau de TCTP surexprimé » on entend que le niveau d'expression de TCTP dans la cellule, en particulier une cellule cancéreuse, est plus élevé que le niveau d'expression de la TCTP dans une cellule saine, en particulier une cellule non cancéreuse.  By "overexpressed TCTP level" is meant that the level of expression of TCTP in the cell, particularly a cancer cell, is higher than the level of TCTP expression in a healthy cell, particularly a non-intact cell. cancerous.
Par « prise en charge » d'une maladie on entend la prévention et/ou le traitement de la maladie et/ou de ses manifestations.  "Management" of a disease is the prevention and / or treatment of the disease and / or its manifestations.
Par « 4-(3, 4-dichloro-phényl)-1 ,2,3,4-tétrahydronaphtalène-1 -ylamine » on entend tous les énantiomères et diastéréoisomères de la molécule (incluant la sertraline), seuls ou en combinaison. By "4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine" is meant all enantiomers and diastereoisomers of the molecule (including sertraline), alone or in combination.
DESCRIPTION DETAILLEE DE L'INVENTION les composés de formule (I) suivante DETAILED DESCRIPTION OF THE INVENTION The compounds of the following formula (I)
telle que définie ci-dessus pour leur utilisation dans le traitement de maladies prolifératives, de maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme. as defined above for use in the treatment of proliferative diseases, infectious diseases, allergies, inflammation and / or asthma.
D'une manière surprenante, il a été découvert que les composés selon l'invention présentent une affinité avec la protéine TCTP. Ils peuvent donc être utilisés dans le traitement de maladies prolifératives, notamment dans le traitement du cancer, en tant qu'agents antitumoraux. Ils peuvent également être utilisés dans le traitement des maladies infectieuses, notamment des maladies infectieuses parasitaires telles que la malaria. Surprisingly, it has been discovered that the compounds according to the invention have an affinity with the TCTP protein. They can therefore be used in the treatment of proliferative diseases, especially in the treatment of cancer, as antitumor agents. They can also be used in the treatment of infectious diseases, including parasitic infectious diseases such as malaria.
D'une manière générale, les composés selon l'invention peuvent être utilisés dans le traitement ou la prévention de toute maladie ou infection qui nécessite, pour sa prise en charge, d'inhiber la TCTP.  In general, the compounds according to the invention can be used in the treatment or prevention of any disease or infection which requires, for its management, to inhibit the TCTP.
De plus, les composés selon l'invention présentent une affinité forte, puisque de l'ordre du micromolaire, vis-à-vis de la protéine TCTP. Ainsi, alors que pour la sertraline, la dose efficace nécessaire avoisine sa dose maximale tolérée (MTD), les concentrations à utiliser chez l'animal ou l'homme avec les composés selon l'invention peuvent être réduites par rapport aux concentrations nécessaires en sertraline. Les doses efficaces nécessaires sont alors diminuées, amenant à une plus grande différence avec les doses maximales tolérées. L'utilisation des composés selon l'invention est donc possible chez l'homme et l'animal. De plus, cette amélioration de l'affinité des composés selon l'invention permet aussi de réduire les effets secondaires indésirables. Avantageusement, l'affinité des composés selon l'invention vis-à-vis de la protéine TCTP est comprise entre 1 pM et 200 μΜ, avantageusement entre 1 pM et 195 μΜ, de préférence entre 1 nM et 200 μΜ, avantageusement entre 1 nM et 195 μΜ , voire entre 1 nM et 150 μΜ. In addition, the compounds according to the invention have a strong affinity, since of the order of one micromolar, vis-à-vis the TCTP protein. Thus, while for sertraline, the effective dose required is close to its maximum tolerated dose (MTD), the concentrations to be used in animals or humans with the compounds according to the invention can be reduced by compared to the concentrations required for sertraline. The effective doses required are then decreased, leading to a greater difference with the maximum tolerated doses. The use of the compounds according to the invention is therefore possible in humans and animals. In addition, this improvement in the affinity of the compounds according to the invention also makes it possible to reduce undesirable side effects. Advantageously, the affinity of the compounds according to the invention with respect to the TCTP protein is between 1 μM and 200 μM, advantageously between 1 μM and 195 μM, preferably between 1 nM and 200 μM, advantageously between 1 nM. and 195 μΜ, or even between 1 nM and 150 μΜ.
En lien avec leur affinité de l'ordre du micromolaire vis-à-vis de la protéine TCTP, les composés selon l'invention sont également capables d'induire la surexpression de p53 (1 , 5). La protéine p53 est une protéine facteur de transcription qui régule notamment certaines fonctions cellulaires importantes comme la mitose ou la mort programmée. Elle joue également un rôle majeur dans la réversion tumorale. Son activation peut impliquer soit la réversion tumorale des cellules cancéreuses soit leur apoptose. L'induction de la surexpression de p53 par les composés selon l'invention indique ainsi que les composés selon l'invention peuvent être utilisés en tant qu'agent antitumoraux et qu'ils semblent agir notamment à travers un mécanisme de réversion tumorale. In relation to their affinity of the micromolar order with respect to the TCTP protein, the compounds according to the invention are also capable of inducing the overexpression of p53 (1, 5). The p53 protein is a transcription factor protein that regulates certain important cellular functions such as mitosis or programmed death. It also plays a major role in tumor reversion. Its activation may involve either cancer tumor reversion or apoptosis. The induction of overexpression of p53 by the compounds according to the invention thus indicates that the compounds according to the invention can be used as antitumor agents and that they seem to act in particular through a tumor reversion mechanism.
Les composés selon l'invention présentent ainsi une classe thérapeutique innovante d'agents antitumoraux en agissant notamment par un mécanisme de réversion tumorale. Les composés selon l'invention sont donc particulièrement adaptés au traitement du cancer, en particulier du cancer dans lesquels la TCTP est sur-exprimée.  The compounds according to the invention thus have an innovative therapeutic class of antitumor agents by acting in particular by a tumor reversion mechanism. The compounds according to the invention are therefore particularly suitable for the treatment of cancer, in particular of cancer in which the TCTP is over-expressed.
Composés de formule (I) pour leur utilisation selon l'invention Compounds of formula (I) for their use according to the invention
les composés de formule (I) suivante :  the compounds of formula (I) below:
telle que définie ci-dessus pour leur utilisation dans le traitement de maladies prolifératives, de maladies infectieuses des allergies, d'une inflammation et/ou de l'asthme. as defined above for use in the treatment of proliferative diseases, infectious diseases of allergies, inflammation and / or asthma.
Le composé 4-(3,4-dichloro-phényl)-1 ,2,3,4-tétrahydronaphtalène-1 -ylamine ou un de ses sels pharmaceutiquement acceptable, notamment son sel de chlorhydrate, est exclu de la formule (I). Ceci inclut tout diastéréoisomère ou énantiomère de ce composé, seul ou en mélange. En particulier, la sertraline est exclue. Selon une premier mode de réalisation de l'invention, X représente un atome d'oxygène ou un atome de soufre, Y étant absent. The compound 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalene-1-ylamine or a pharmaceutically acceptable salt, especially its hydrochloride salt, is excluded from the formula (I). This includes any diastereoisomer or enantiomer of this compound, alone or in admixture. In particular, sertraline is excluded. According to a first embodiment of the invention, X represents an oxygen atom or a sulfur atom, Y being absent.
Dans une première variante du premier mode de réalisation, X représente un atome d'oxygène.  In a first variant of the first embodiment, X represents an oxygen atom.
Dans une seconde variante du premier mode de réalisation, X représente un atome de soufre. In a second variant of the first embodiment, X represents a sulfur atom.
Selon un second mode de réalisation de l'invention, X représente un atome d'azote ou un radical CH, Y étant présent. According to a second embodiment of the invention, X represents a nitrogen atom or a CH radical, Y being present.
Dans une première variante du second mode de réalisation, X représente un atome d'azote et Y est présent. Y représente alors un groupe R. En particulier R représente un atome d'hydrogène, un groupe alkyle en Ci à C6, ou un groupe acyle. In a first variant of the second embodiment, X represents a nitrogen atom and Y is present. Y then represents a group R. In particular, R represents a hydrogen atom, an alkyl group at C 6, or an acyl group.
En particulier, R représente un atome d'hydrogène. In particular, R represents a hydrogen atom.
Dans une seconde variante du second mode de réalisation, X représente un radical CH et Y est présent.  In a second variant of the second embodiment, X represents a radical CH and Y is present.
Avantageusement, Y représente un atome d'hydrogène.  Advantageously, Y represents a hydrogen atom.
Avantageusement, Y représente un groupe -NR1R2. Advantageously, Y represents a group -NR 1 R 2 .
Avantageusement, lorsque R1 ou R2 est un groupe acyle, il est choisi parmi un benzoyie et un acétyle. Advantageously, when R 1 or R 2 is an acyl group, it is chosen from benzoyl and acetyl.
Avantageusement, lorsque R1 et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, -NR1R2 représente une pyrrolydine ou une morpholine. En particulier, lorsque Y représente un groupe -NR1R2, R1 et/ou R2 représentent indépendamment l'un de l'autre, un atome d'hydrogène ou un groupe acyle. Advantageously, when R 1 and R 2 together with the nitrogen atom carrying them a 5- or 6-membered heterocycle, -NR 1 R 2 represents a pyrrolydine or a morpholine. In particular, when Y represents a group -NR 1 R 2 , R 1 and / or R 2 represent, independently of one another, a hydrogen atom or an acyl group.
De préférence, lorsque Y représente un groupe -NR1R2, R1 représente un groupe acyle, de préférence un groupe acétyle, et avantageusement R2 représente un atome d'hydrogène. Preferably, when Y represents a group -NR 1 R 2 , R 1 represents an acyl group, preferably an acetyl group, and advantageously R 2 represents a hydrogen atom.
Dans l'un quelconque de ces modes de réalisation, selon une variante de l'invention, lorsque (Het)Ar est un aryle, il est avantageusement choisi parmi un phényle et un naphtyle. Le groupe aryle ainsi défini peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, un groupe formyle, un groupe (C2- C6) alcényle avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe aryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, le groupe aryle peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe aryle n'étant pas substitué par plus d'un atome d'halogène. Avantageusement, lorsque (Het)Ar est un phényle, il est non substitué ou substitué en position méta ou para par l'un quelconque des groupes décrits précédemment. In any one of these embodiments, according to a variant of the invention, when (Het) Ar is an aryl, it is advantageously chosen from a phenyl and a naphthyl. The aryl group thus defined may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group with R 7 , R 8 , R 9 and R 10 as previously described, the aryl group being in particular not substituted by more than a halogen atom. In particular, the aryl group may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the aryl group not being substituted by more than one halogen atom. Advantageously, when (Het) Ar is phenyl, it is unsubstituted or substituted in the meta or para position by any one of the groups previously described.
Avantageusement, lorsque l'aryle est substitué par un atome d'halogène, l'atome d'halogène est choisi parmi un atome de fluor, de chlore, de brome ou d'iode. En particulier, il est choisi parmi un atome de chlore, de brome et d'iode. Advantageously, when the aryl is substituted with a halogen atom, the halogen atom is chosen from a fluorine, chlorine, bromine or iodine atom. In particular, it is selected from a chlorine, bromine and iodine atom.
Dans l'un quelconque de ces modes de réalisation, selon une variante de l'invention, lorsque (Het)Ar est un hétéroaryle, il est choisi parmi une pyridine, une pyrimidine, une pyrazine, une quinoléine, une isoquinoléine, un indole, un benzofurane et un benzothiophène. Le groupe hétéroaryle ainsi défini peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, un groupe CF3, un groupe formyle, un groupe (C2-C6) alcényle, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe hétéroaryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, le groupe aryle peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe hétéroaryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, l'hétéroaryle n'est pas substitué. In any of these embodiments, according to a variant of the invention, when (Het) Ar is a heteroaryl, it is chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, benzofuran and benzothiophene. The heteroaryl group thus defined may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group, with R 7 , R 8 , R 9 and R 10 as described above, the heteroaryl group being in particular not substituted by more than a halogen atom. In particular, the aryl group may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than one halogen atom. In particular, heteroaryl is not substituted.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention, avantageusement, selon une autre variante de l'invention, le cycle aromatique Het(Ar) est substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe - COOR7, et un groupe -CONR8R9 avec R7, R8 et R9 tels que décrits précédemment, le cycle aromatique Het(Ar) n'étant pas substitué par plus d'un atome d'halogène. In any of the embodiments and variants of the invention, advantageously, according to another variant of the invention, the aromatic ring Het (Ar) is substituted by one or more groups chosen from a halogen atom, a group - COOR 7 , and a group -CONR 8 R 9 with R 7 , R 8 and R 9 as described above, the aromatic ring Het (Ar) not being substituted by more than one halogen atom.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention, avantageusement, lorsque le cycle aromatique Het(Ar) est substitué par un atome d'halogène, l'atome d'halogène est choisi parmi un atome de fluor, de chlore, de brome et d'iode. En particulier, il est choisi parmi un atome de chlore, de brome et d'iode, de préférence il est choisi parmi un atome de brome et d'iode.  In any of the embodiments and variants of the invention, advantageously, when the aromatic ring Het (Ar) is substituted by a halogen atom, the halogen atom is chosen from a fluorine atom, chlorine, bromine and iodine. In particular, it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention, lorsque le cycle aromatique est substitué par un groupe -COOR7, R7 représente avantageusement un groupe méthyle, un groupe éthyle ou un groupe isopropyle. In any of the embodiments and variants of the invention, when the aromatic ring is substituted with a -COOR 7 group, R 7 advantageously represents a methyl group, an ethyl group or an isopropyl group.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention, lorsque le cycle aromatique est substitué par un groupe -CONR8R9 et lorsque R8 et/ou R9 représentent un résidu de sucre, le sucre est avantageusement choisi parmi le glucose, le mannose, l'arabinose ou le galactose. Lorsque R8 et R9 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, -NR8R9 représente avantageusement une pyrrolydine ou une morpholine. In any of the embodiments and variants of the invention, when the aromatic ring is substituted with a -CONR 8 R 9 group and when R 8 and / or R 9 represent a sugar residue, the sugar is advantageously selected from glucose, mannose, arabinose or galactose. When R 8 and R 9 form together with the atom nitrogen which carries them a 5- or 6-membered heterocycle, -NR 8 R 9 advantageously represents a pyrrolydine or a morpholine.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention, lorsque le cycle aromatique est substitué par un groupe -SR10 et lorsque R10 représente un résidu de sucre, le sucre est avantageusement choisi parmi le glucose, le mannose, l'arabinose ou le galactose. In any of the embodiments and variants of the invention, when the aromatic ring is substituted with a -SR 10 group and when R 10 represents a sugar residue, the sugar is advantageously selected from glucose, mannose , arabinose or galactose.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention, avantageusement, selon une variante de l'invention, les groupes R3, R4, R5, R6 représentent un atome d'hydrogène. In any of the embodiments and variants of the invention, advantageously, according to a variant of the invention, the groups R 3 , R 4 , R 5 and R 6 represent a hydrogen atom.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention, avantageusement, selon une autre variante de l'invention, R3, R4, R5, R6 représentent, indépendamment les uns des autres, un atome d'hydrogène, un atome d'halogène, un groupe -NR12R13, un groupe -SR14, un groupe -OR14, un groupe -CF3. In any of the embodiments and variants of the invention, advantageously, according to another variant of the invention, R 3 , R 4 , R 5 and R 6 represent, independently of each other, an atom of hydrogen, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 , a group -CF 3 .
Avantageusement R14 représente un groupe méthyle. Advantageously, R 14 represents a methyl group.
Avantageusement, lorsque R14 représente un résidu de sucre, le sucre est choisi parmi le glucose, le mannose, l'arabinose ou le galactose. Advantageously, when R 14 represents a sugar residue, the sugar is chosen from glucose, mannose, arabinose or galactose.
Composés de formule (II) pour leur utilisation selon l'invention Compounds of formula (II) for their use according to the invention
Des composés de formule (I) préférés selon l'invention sont des composés répondant à la formule (II) suivante : Preferred compounds of formula (I) according to the invention are compounds corresponding to the following formula (II):
Dans laquelle R1, R2, R3, R4, R5, R6 et Het(Ar) sont tels que définis précédemment pour les composés de formule (I), Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Het (Ar) are as previously defined for the compounds of formula (I),
pour leur utilisation dans le traitement de maladies prolifératives, notamment du cancer, de maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme. for use in the treatment of proliferative diseases, including cancer, infectious diseases, allergies, inflammation and / or asthma.
En particulier, R1 et/ou R2 représentent indépendamment l'un de l'autre, un atome d'hydrogène ou un groupe acyle. In particular, R 1 and / or R 2 represent, independently of one another, a hydrogen atom or an acyl group.
Avantageusement, lorsque R1 ou R2 est un groupe acyle, il est choisi parmi un benzoyie et un acétyle. Advantageously, when R 1 or R 2 is an acyl group, it is chosen from benzoyl and acetyl.
De préférence, R1 représente un groupe acyle, de préférence un groupe acétyle, et avantageusement R2 représente un atome d'hydrogène. Selon une variante de l'invention pour les composés de formule (II), lorsque (Het)Ar est un aryle, il est avantageusement choisi parmi un phényle ou un naphtyle. Le groupe aryle ainsi défini peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, un groupe formyle, un groupe (C2-C6) alcényle avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe aryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, le groupe aryle peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe - COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe aryle n'étant en particulier pas substitué par plus d'un atome d'halogène. Preferably, R 1 represents an acyl group, preferably an acetyl group, and advantageously R 2 represents a hydrogen atom. According to a variant of the invention for the compounds of formula (II), when (Het) Ar is an aryl, it is advantageously chosen from a phenyl or a naphthyl. The aryl group thus defined may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted by more than a halogen atom. In particular, the aryl group may be substituted by one or more groups selected from a halogen atom, a group - COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted with more than one halogen atom.
Avantageusement, lorsque (Het)Ar est un phényle, il est non substitué ou substitué en position méta ou para par l'un des quelconques groupes décrits précédemment.  Advantageously, when (Het) Ar is phenyl, it is unsubstituted or substituted in the meta or para position by any of the groups previously described.
Lorsque l'aryle est substitué par un atome d'halogène, l'atome d'halogène est avantageusement choisi parmi un atome de fluor, de chlore, de brome et d'iode. En particulier, il est choisi parmi un atome de chlore, de brome et d'iode, de préférence il est choisi parmi un atome de brome et d'iode, de préférence il est choisi parmi un atome de brome et d'iode. When the aryl is substituted by a halogen atom, the halogen atom is advantageously chosen from a fluorine, chlorine, bromine and iodine atom. In particular, it is selected from a chlorine, bromine and iodine atom, preferably it is selected from a bromine atom and iodine, preferably it is selected from a bromine atom and iodine.
Selon une variante de l'invention pour les composés de formule (II), lorsque (Het)Ar est un hétéroaryle, il est avantageusement choisi parmi une pyridine, une pyrimidine, une pyrazine, une quinoléine, une isoquinoléine, un indole, un benzofurane et un benzothiophène.  According to a variant of the invention for the compounds of formula (II), when (Het) Ar is a heteroaryl, it is advantageously chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, a benzofuran and a benzothiophene.
Le groupe hétéroaryle ainsi défini peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, un groupe formyle, un groupe (C2-C6) alcényle avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe hétéroaryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, le groupe hétéroaryle peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe hétéroaryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, l'hétéroaryle n'est pas substitué. The heteroaryl group thus defined may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than a halogen atom. In particular, the heteroaryl group may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than one halogen atom. In particular, heteroaryl is not substituted.
Dans l'une quelconque des variantes de l'invention pour les composés de formule (II), avantageusement, selon une autre variante de l'invention, le cycle aromatique Het(Ar) est substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe - COOR7, et un groupe -CONR8R9 avec R7, R8 et R9 tels que décrits précédemment, le cycle aromatique Het(Ar) n'étant pas substitué par plus d'un atome d'halogène. Dans l'une quelconque des variantes de l'invention pour les composés de formule (II), lorsque le cycle aromatique Het(Ar) est substitué par un atome d'halogène, l'atome d'halogène est avantageusement choisi parmi un atome de fluor, de chlore, de brome et d'iode. En particulier, il est choisi parmi un atome de chlore, de brome et d'iode, de préférence il est choisi parmi un atome de brome et d'iode. In any of the variants of the invention for the compounds of formula (II), advantageously, according to another variant of the invention, the aromatic ring Het (Ar) is substituted by one or more groups selected from a hydrogen atom. halogen, a group - COOR 7 , and a group -CONR 8 R 9 with R 7 , R 8 and R 9 as described above, the aromatic ring Het (Ar) not being substituted by more than one atom 'halogen. In any of the variants of the invention for the compounds of formula (II), when the aromatic ring Het (Ar) is substituted by a halogen atom, the halogen atom is advantageously chosen from an atom of fluorine, chlorine, bromine and iodine. In particular, it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
Dans l'une quelconque des variantes de l'invention pour les composés de formule (II), lorsque le cycle aromatique est substitué par un groupe -COOR7, R7 représente avantageusement un groupe méthyle, un groupe éthyle ou un groupe isopropyle. In any of the variants of the invention for the compounds of formula (II), when the aromatic ring is substituted with a -COOR 7 group, R 7 advantageously represents a methyl group, an ethyl group or an isopropyl group.
Dans l'une quelconque des variantes de l'invention pour les composés de formule (II), lorsque le cycle aromatique est substitué par un groupe -CONR8R9 et lorsque R8 et/ou R9 représentent un résidu de sucre, le sucre est avantageusement choisi parmi le glucose, le mannose, l'arabinose ou le galactose. Lorsque R8 et R9 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, -NR8R9 représente avantageusement une pyrrolydine ou une morpholine. In any of the variants of the invention for the compounds of formula (II), when the aromatic ring is substituted with a -CONR 8 R 9 group and when R 8 and / or R 9 represent a sugar residue, the Sugar is advantageously chosen from glucose, mannose, arabinose or galactose. When R 8 and R 9 form together with the nitrogen atom which carries them a 5- or 6-membered heterocycle, -NR 8 R 9 advantageously represents a pyrrolydine or a morpholine.
Dans l'une quelconque des variantes de l'invention pour les composés de formule (II), lorsque le cycle aromatique est substitué par un groupe -SR10 et lorsque R10 représente un résidu de sucre, le sucre est avantageusement choisi parmi le glucose, le mannose, l'arabinose ou le galactose. Dans l'une quelconque des variantes de l'invention pour les composés de formule (II), avantageusement, selon une variante de l'invention, les groupes R3, R4, R5, R6 représentent un atome d'hydrogène. In any of the variants of the invention for the compounds of formula (II), when the aromatic ring is substituted with a group -SR 10 and when R 10 represents a sugar residue, the sugar is advantageously chosen from glucose , mannose, arabinose or galactose. In any of the variants of the invention for the compounds of formula (II), advantageously, according to a variant of the invention, the groups R 3 , R 4 , R 5 and R 6 represent a hydrogen atom.
Dans l'une quelconque des variantes de l'invention pour les composés de formule (II), avantageusement, selon une autre variante de l'invention, R3, R4, R5, R6 représentent, indépendamment les uns des autres, un atome d'hydrogène, un atome d'halogène, un groupe -NR12R13, un groupe -SR14, un groupe -OR14, un groupe -CF3. In any of the variants of the invention for the compounds of formula (II), advantageously, according to another variant of the invention, R 3 , R 4 , R 5 and R 6 represent, independently of one another, a hydrogen atom, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 , a group -CF 3 .
Avantageusement R14 représente un groupe méthyle. Advantageously, R 14 represents a methyl group.
Avantageusement, lorsque R14 représente un résidu de sucre, le sucre est choisi parmi le glucose, le mannose, l'arabinose ou le galactose. Advantageously, when R 14 represents a sugar residue, the sugar is chosen from glucose, mannose, arabinose or galactose.
En particulier, Het(Ar) représente un naphtalène ou un phényle substitué par un atome de brome, un atome d'iode ou un groupement -COOiPr. In particular, Het (Ar) represents a naphthalene or a phenyl substituted by a bromine atom, an iodine atom or a -COOiPr group.
Composés de formule (III) pour leur utilisation selon l'invention Compounds of formula (III) for their use according to the invention
Dans un autre mode de réalisation, des composés de formule (I) avantageux selon l'invention sont des composés de formule (III) suivante : In another embodiment, compounds of formula (I) that are advantageous according to the invention are compounds of formula (III) below:
Dans laquelle :  In which :
- X' représente CH2, O, S ou N-R, X 'represents CH 2 , O, S or NR,
- R, R3, R4, R5, R6 et Het(Ar) sont tels que définis précédemment pour les composés de formule (I), R, R 3 , R 4 , R 5 , R 6 and Het (Ar) are as defined above for the compounds of formula (I),
pour leur utilisation dans le traitement de maladies prolifératives, notamment du cancer, de maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme. for use in the treatment of proliferative diseases, including cancer, infectious diseases, allergies, inflammation and / or asthma.
Selon une premier mode de réalisation de l'invention pour les composés de formule (III), X' représente un atome d'oxygène ou un atome de soufre. According to a first embodiment of the invention for the compounds of formula (III), X 'represents an oxygen atom or a sulfur atom.
Dans une première variante de ce premier mode de réalisation, X' représente un atome d'oxygène.  In a first variant of this first embodiment, X 'represents an oxygen atom.
Dans une seconde variante de ce premier mode de réalisation, X' représente un atome de soufre.  In a second variant of this first embodiment, X 'represents a sulfur atom.
Selon un second mode de réalisation de l'invention pour les composés de formule (III), X' représente N-R ou CH2. According to a second embodiment of the invention for the compounds of formula (III), X 'represents NR or CH 2 .
Dans une première variante de ce second mode de réalisation, X' représente N-R. En particulier R représente un atome d'hydrogène, un groupe alkyle en Ci à C6, ou un groupe acyle. In a first variant of this second embodiment, X 'represents NR. In particular R represents a hydrogen atom, an alkyl group at C 6, or an acyl group.
En particulier, R représente un atome d'hydrogène et X' représente donc NH.  In particular, R represents a hydrogen atom and X 'represents NH.
Dans une seconde variante de ce second mode de réalisation, X' représente CH2. In a second variant of this second embodiment, X 'represents CH 2 .
Selon une variante de l'invention pour les composés de formule (III), lorsque (Het)Ar est un aryle, il est avantageusement choisi parmi un phényle ou un naphtyle. Le groupe aryle ainsi défini peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, un groupe formyle, un groupe (C2-C6) alcényle, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe aryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, le groupe aryle peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe - COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe aryle n'étant en particulier pas substitué par plus d'un atome d'halogène. Avantageusement, lorsque (Het)Ar est un phényle, il est non substitué ou substitué en position méta ou para par l'un des quelconques groupes décrits précédemment. According to a variant of the invention for the compounds of formula (III), when (Het) Ar is an aryl, it is advantageously chosen from a phenyl or a naphthyl. The aryl group thus defined may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group, with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted by more of a halogen atom. In particular, the aryl group may be substituted by one or more groups selected from a halogen atom, a group - COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as described above, the aryl group being in particular not substituted with more than one halogen atom. Advantageously, when (Het) Ar is phenyl, it is unsubstituted or substituted in the meta or para position by any of the groups previously described.
Lorsque l'aryle est substitué par un atome d'halogène, l'atome d'halogène est avantageusement choisi parmi un atome de fluor, de chlore, de brome et d'iode. En particulier, il est choisi parmi un atome de chlore, de brome et d'iode, de préférence il est choisi parmi un atome de brome et d'iode. When the aryl is substituted by a halogen atom, the halogen atom is advantageously chosen from a fluorine, chlorine, bromine and iodine atom. In particular, it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
Selon une variante de l'invention pour les composés de formule (III), lorsque (Het)Ar est un hétéroaryle, il est avantageusement choisi parmi une pyridine, une pyrimidine, une pyrazine, une quinoléine, une isoquinoléine, un indole, un benzofurane et un benzothiophène. Le groupe hétéroaryle ainsi défini peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, un groupe formyle, un groupe (C2-C6) alcényle, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe hétéroaryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, le groupe hétéroaryle peut être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, et un groupe CF3, avec R7, R8, R9 et R10 tels que décrits précédemment, le groupe hétéroaryle n'étant en particulier pas substitué par plus d'un atome d'halogène. En particulier, l'hétéroaryle n'est pas substitué. According to a variant of the invention for the compounds of formula (III), when (Het) Ar is a heteroaryl, it is advantageously chosen from a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, an indole, a benzofuran and a benzothiophene. The heteroaryl group thus defined may be substituted with one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a CF 3 group, a formyl group, a (C 2 -C 6 ) alkenyl group, with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more of a halogen atom. In particular, the heteroaryl group may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1 -C 6 alkyl group, a group -SR 10 , and a group CF 3 , with R 7 , R 8 , R 9 and R 10 as previously described, the heteroaryl group being in particular not substituted by more than one halogen atom. In particular, heteroaryl is not substituted.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention pour les composés de formule (III), avantageusement, selon une autre variante de l'invention, le cycle aromatique Het(Ar) est substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, et un groupe -CONR8R9 avec R7, R8 et R9 tels que décrits précédemment, le cycle aromatique Het(Ar) n'étant pas substitué par plus d'un atome d'halogène. In any of the embodiments and variants of the invention for the compounds of formula (III), advantageously, according to another variant of the invention, the aromatic ring Het (Ar) is substituted by one or more groups. chosen from a halogen atom, a group -COOR 7 , and a group -CONR 8 R 9 with R 7 , R 8 and R 9 as described above, the aromatic ring Het (Ar) not being substituted by more of a halogen atom.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention pour les composés de formule (III), lorsque le cycle aromatique est substitué par un atome d'halogène, l'atome d'halogène est avantageusement choisi parmi un atome de fluor, de chlore, de brome et d'iode. En particulier, il est choisi parmi un atome de chlore, de brome et d'iode, de préférence il est choisi parmi un atome de brome et d'iode.  In any of the embodiments and variants of the invention for the compounds of formula (III), when the aromatic ring is substituted by a halogen atom, the halogen atom is advantageously chosen from an atom fluorine, chlorine, bromine and iodine. In particular, it is chosen from a chlorine, bromine and iodine atom, preferably it is chosen from a bromine and iodine atom.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention pour les composés de formule (III), lorsque le cycle aromatique Het(Ar) est substitué par un groupe -COOR7, R7 représente avantageusement un groupe méthyle, un groupe éthyle ou un groupe isopropyle. In any of the embodiments and variants of the invention for the compounds of formula (III), when the aromatic ring Het (Ar) is substituted with a -COOR 7 group, R 7 advantageously represents a methyl group, an ethyl group or an isopropyl group.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention pour les composés de formule (III), lorsque le cycle aromatique Het(Ar) est substitué par un groupe -CONR8R9 et lorsque R8 et/ou R9 représentent un résidu de sucre, le sucre est avantageusement choisi parmi le glucose, le mannose, l'arabinose ou le galactose. Lorsque R8 et R9 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, -NR8R9 représente en particulier une pyrrolydine ou une morpholine. In any of the embodiments and variants of the invention for the compounds of formula (III), when the aromatic ring Het (Ar) is substituted with a group -CONR 8 R 9 and when R 8 and / or R 9 represent a sugar residue, the sugar is advantageously chosen from glucose, mannose, arabinose or galactose. When R 8 and R 9 form together with the nitrogen atom which carries them a 5- or 6-membered heterocycle, -NR 8 R 9 represents in particular a pyrrolydine or a morpholine.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention pour les composés de formule (III), lorsque le cycle aromatique Het(Ar) est substitué par un groupe -SR10 et lorsque R10 représente un résidu de sucre, le sucre est avantageusement choisi parmi le glucose, le mannose, l'arabinose ou le galactose. In any of the embodiments and variants of the invention for the compounds of formula (III), when the aromatic ring Het (Ar) is substituted with a group -SR 10 and when R 10 represents a sugar residue the sugar is advantageously chosen from glucose, mannose, arabinose or galactose.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention pour les composés de formule (III), avantageusement, selon une variante de l'invention, les groupes R3, R4, R5, R6 représentent un atome d'hydrogène. In any of the embodiments and variants of the invention for the compounds of formula (III), advantageously, according to a variant of the invention, the groups R 3 , R 4 , R 5 and R 6 represent a hydrogen atom.
Dans l'un quelconque des modes de réalisation et des variantes de l'invention pour les composés de formule (III), avantageusement, selon une autre variante de l'invention, R3, R4, R5, R6 représentent, indépendamment les uns des autres, un atome d'hydrogène, un atome d'halogène, un groupe -NR12R13, un groupe -SR14, un groupe -OR14, un groupe - CF3. Avantageusement R14 représente un groupe méthyle. In any of the embodiments and variants of the invention for the compounds of formula (III), advantageously, according to another variant of the invention, R 3 , R 4 , R 5 and R 6 represent, independently from each other, a hydrogen atom, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 , a group - CF 3 . Advantageously, R 14 represents a methyl group.
Avantageusement, lorsque R14 représente un résidu de sucre, le sucre est choisi parmi le glucose, le mannose, l'arabinose ou le galactose. Advantageously, when R 14 represents a sugar residue, the sugar is chosen from glucose, mannose, arabinose or galactose.
Les composés de la présente invention pour leur utilisation dans le traitement de maladies prolifératives, notamment du cancer, de maladies infectieuses, notamment de maladies infectieuses parasitaires, des allergies, d'une inflammation et/ou de l'asthme sont de préférence choisis parmi :  The compounds of the present invention for their use in the treatment of proliferative diseases, in particular cancer, infectious diseases, in particular parasitic infectious diseases, allergies, inflammation and / or asthma, are preferably chosen from:
urs sels pharmaceutiquement acceptables, tels que les chlorhydrates. Les composés de la présente invention pour leur utilisation dans le traitement de maladies prolifératives, notamment du cancer, de maladies infectieuses, notamment de maladies infectieuses parasitaires, des allergies, d'une inflammation et/ou de l'asthme sont de préférence choisis parmi : pharmaceutically acceptable salts, such as hydrochlorides. The compounds of the present invention for their use in the treatment of proliferative diseases, in particular cancer, infectious diseases, in particular parasitic infectious diseases, allergies, inflammation and / or asthma, are preferably chosen from:
et leurs sels pharmaceutiquement acceptables, tels que les chlorhydrates. and their pharmaceutically acceptable salts, such as hydrochlorides.
Utilisations selon la présente invention Uses according to the present invention
L'invention a pour objet les composés selon l'invention qui peuvent être utilisés dans le traitement de toute maladie qui nécessite pour sa prise en charge d'inhiber la TCTP.  The subject of the invention is the compounds according to the invention which can be used in the treatment of any disease which requires, for its management, the inhibition of TCTP.
Dans une première variante, la maladie est une maladie proliférative telle que le cancer, le psoriasis, de préférence le cancer. Dans une deuxième variante, la maladie est une maladie infectieuse, en particulier une maladie infectieuse parasitaire telle que la malaria (8). In a first variant, the disease is a proliferative disease such as cancer, psoriasis, preferably cancer. In a second variant, the disease is an infectious disease, particularly a parasitic infectious disease such as malaria (8).
Dans une troisième variante, la maladie est une allergie, une inflammation ou l'asthme (9 - 14).  In a third variant, the disease is an allergy, inflammation or asthma (9 - 14).
En particulier, l'invention a pour objet les composés selon l'invention qui peuvent être utilisés dans le traitement des maladies prolifératives, en particulier le cancer et le psoriasis, plus particulièrement le cancer, le traitement des maladies infectieuses, en particulier la malaria, et/ou le traitement des allergies, d'une inflammation et/ou de l'asthme. Plus particulièrement, l'invention a pour objet les composés selon l'invention pour leur utilisation dans le traitement d'un cancer ou de la malaria. In particular, the subject of the invention is the compounds according to the invention which can be used in the treatment of proliferative diseases, in particular cancer and psoriasis, more particularly cancer, the treatment of infectious diseases, in particular malaria, and / or the treatment of allergies, inflammation and / or asthma. More particularly, the subject of the invention is the compounds according to the invention for their use in the treatment of cancer or malaria.
Avantageusement, l'invention a pour objet les composés selon l'invention qui peuvent être utilisés dans le traitement du cancer par inhibition de la protéine TCTP, en particulier dans le traitement du cancer par réversion tumorale. Advantageously, the subject of the invention is the compounds according to the invention which can be used in the treatment of cancer by inhibition of the TCTP protein, in particular in the treatment of cancer by tumor reversion.
En effet, les composés selon l'invention présentent une inhibition améliorée de la protéine TCTP par rapport à la sertraline et induisent une surexpression de la protéine p53. L'inhibition de la protéine TCTP et la surexpression de la protéine p53 sont notamment deux caractéristiques du mécanisme de réversion tumorale.  Indeed, the compounds according to the invention exhibit improved inhibition of the TCTP protein compared with sertraline and induce overexpression of the p53 protein. The inhibition of the TCTP protein and the overexpression of the p53 protein are two features of the tumor reversion mechanism.
En particulier, l'invention a pour objet les composés selon l'invention pour leur utilisation dans le traitement du cancer, en particulier un cancer dans lequel la protéine TCTP est surexprimée. Parmi les cancers, on peut citer de manière non limitative les leucémies, les lymphomes, les sarcomes, le cancer du foie, le cancer du pancréas, le cancer du poumon, le cancer de l'estomac, le cancer de l'œsophage, le cancer du rein, le cancer de la plèvre, le cancer de la tyroïde, le cancer de la peau, le cancer du col de l'utérus le cancer du sein, le cancer des ovaires, le cancer du côlon, le cancer des testicules, le cancer de la prostate, le cancer du cerveau, le cancer du rectum, ou le cancer des os. En particulier l'invention a pour objet les composés selon l'invention pour leur utilisation dans le traitement du cancer lorsque le cancer est une leucémie myéloïde aiguë, un cancer du sein, un sarcome, un cancer du côlon, un cancer du poumon, un mélanome ou un cancer du cerveau. In particular, the subject of the invention is the compounds according to the invention for their use in the treatment of cancer, in particular a cancer in which the TCTP protein is overexpressed. Among the cancers, non-limiting mention may be made of leukemias, lymphomas, sarcomas, liver cancer, pancreatic cancer, lung cancer, stomach cancer, esophageal cancer, kidney cancer, pleural cancer, thyroid cancer, skin cancer, cervical cancer, breast cancer, ovarian cancer, colon cancer, testicular cancer, prostate cancer, brain cancer, rectal cancer, or bone cancer. In particular, the subject of the invention is the compounds according to the invention for their use in the treatment of cancer when the cancer is an acute myeloid leukemia, a breast cancer, a sarcoma, a colon cancer, a lung cancer, an melanoma or brain cancer.
Selon un mode particulier de l'invention, les composés pour leur utilisation selon l'invention sont administrés en association avec un autre principe actif, notamment un composé anticancéreux, cytotoxique ou non. According to one particular embodiment of the invention, the compounds for their use according to the invention are administered in combination with another active principle, in particular an anticancer compound, cytotoxic or otherwise.
De manière non limitative, les principes actifs pouvant être associés aux composés pour leur utilisation selon la présente invention peuvent être choisis parmi la 6-mercaptopurine, la fludarabine, la cladribine, la pentostatine, la cytarabine, le 5-fluorouracile, la gemcitabine, le méthotrexate, le raltitrexed, l'irinotécan, le topotécan, l'étoposide, la daunorubicine, la doxorubicine, l'épirubicine, l'idarubicine, la pirarubicine, la mitoxantrone, la chlorméthine, la cyclophosphamide, l'ifosfamide, le melphalan, le chlorambucil, le busulfan, la carmustine, la fotémustine, la streptozocine, le carboplatine, le cisplatine, l'oxaliplatine, la procarbazine, la dacarbazine, la bléomycine, la vinblastine, la vincristine, la vindésine, la vinorelbine, le paclitaxel, le docétaxel, la L-asparaginase, la flutamide, la nilutamide, la bicalutamide, l'acétate de cyprotérone, la triptoréline, la leuproréline, la goséréline, la buséréline, le formestane, l'aminoglutéthimide, l'anastrazole, le létrozole, le tamoxifène, l'octréotide, le lanréotide, l'acide (Z)-3-[2,4-diméthyl-5-(2-oxo-1 ,2-dihydro- indol-3-ylidèneméthyl)-1 H-pyrrol-3-yl]-propionique, l'acide 4-((9-chloro-7-(2,6- difluorophényl)-5H-pyrimidol(5,4-d)(2)benzazépin-2-yl)amino)benzoïque, l'acide 5,6- diméthylxanthénone-4-acétique, l'acide 3-(4-(1 ,2-diphénylbut-1 -ényl)phényl)acrylique, l'imatinib, l'erlotinib, le sunitinib, le sorafénib, le lapatenib, le dasatinib, le trastuzumab, le cetuximab, et le rituximab. In a nonlimiting manner, the active ingredients that can be combined with the compounds for their use according to the present invention can be chosen from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel , docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide, lanreotide, (Z) -3- [2,4-dimethyl-5- (2-oxo-1,2-dihydroindol-3-ylidenemethyl) -1H-pyrrolic acid) -3-yl] -propionic acid, 4 - ((9-chloro-7- (2,6-difluorophenyl) -5H-pyrimidol (5,4-d) (2) benzazepin-2-yl) amine no) benzoic acid, 5,6-dimethylxanthenone-4-acetic acid, 3- (4- (1, 2-diphenylbut-1-enyl) phenyl) acrylic acid, imatinib, erlotinib, sunitinib , sorafenib, lapatenib, dasatinib, trastuzumab, cetuximab, and rituximab.
En particulier, les composés pour leur utilisation selon l'invention sont administrés en association avec la cytarabine. In particular, the compounds for their use according to the invention are administered in combination with cytarabine.
Une composition pharmaceutique comprenant : A pharmaceutical composition comprising:
(i) au moins un composé de la présente invention,  (i) at least one compound of the present invention,
(ϋ) au moins un autre principe actif,  (ϋ) at least one other active ingredient,
en tant que produits de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps peut être utilisée pour le traitement du cancer. as combination products for simultaneous, separate or spread use over time can be used for the treatment of cancer.
Le ou les principes actifs peuvent être tels que cités ci-dessus. En particulier, le principe actif peut être la cytarabine.  The active ingredient (s) may be as mentioned above. In particular, the active ingredient may be cytarabine.
Selon un mode particulier de l'invention, les composés pour leur utilisation selon l'invention sont administrés pendant ou éventuellement avant et après une radiothérapie. Les composés selon la présente invention peuvent être administrés par toute voie usuelle, en particulier par voie orale, sublinguale, parentérale sous-cutanée, intramusculaire, intraveineuse, transdermique, locale, cutanée, mucosale ou rectale. According to a particular embodiment of the invention, the compounds for their use according to the invention are administered during or possibly before and after radiotherapy. The compounds according to the present invention may be administered by any of the usual routes, in particular orally, sublingually, parenterally subcutaneously, intramuscularly, intravenously, transdermally, locally, cutaneously, mucosally or rectally.
Les composés selon la présente invention peuvent être utilisés à des doses comprises entre 0,01 mg et 1000 mg par jour, données en une seule dose une fois par jour ou de préférence administrées en plusieurs doses tout au long de la journée, par exemple deux fois par jour en doses égales. La dose administrée par jour est avantageusement comprise entre 5 mg et 500 mg, encore plus avantageusement entre 10 mg et 200 mg. Il peut être nécessaire d'utiliser des doses sortant de ces gammes ce dont le praticien peut se rendre compte lui-même. La présente invention concerne également une méthode pour inhiber la TCTP comprenant l'administration à un patient en ayant besoin d'un composé de la présente invention, seul ou en association, avantageusement synergique, avec au moins un autre principe actif tel que défini ci-dessus. The compounds according to the present invention can be used at doses of between 0.01 mg and 1000 mg per day, given in a single dose once a day or preferably administered in several doses throughout the day, for example two times a day in equal doses. The dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the practitioner can realize himself. The present invention also relates to a method for inhibiting TCTP comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic, with at least one other active ingredient as defined above. above.
La présente invention concerne en particulier une méthode de traitement de maladies prolifératives, notamment dans le traitement du cancer, comprenant l'administration à un patient en ayant besoin d'un composé de la présente invention, seul ou en association, avantageusement synergique, avec au moins un autre principe actif tel que défini ci- dessus. The present invention relates in particular to a method of treating proliferative diseases, in particular in the treatment of cancer, comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic, with minus another active ingredient as defined above.
La présente invention concerne en particulier une méthode de traitement de maladies infectieuses, notamment de maladies infectieuses parasitaires telles que la malaria, comprenant l'administration à un patient en ayant besoin d'un composé de la présente invention, seul ou en association, avantageusement synergique, avec au moins un autre principe actif tel que défini ci-dessus. The present invention relates in particular to a method of treating infectious diseases, especially parasitic infectious diseases such as malaria, comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic with at least one other active ingredient as defined above.
La présente invention concerne en particulier une méthode de traitement des allergies, d'une inflammation et/ou de l'asthme, comprenant l'administration à un patient en ayant besoin d'un composé de la présente invention, seul ou en association, avantageusement synergique, avec au moins un autre principe actif tel que défini ci-dessus. The present invention particularly relates to a method of treating allergies, inflammation and / or asthma, comprising administering to a patient in need of a compound of the present invention, alone or in combination, advantageously synergistic, with at least one other active ingredient as defined above.
La présente invention concerne également l'utilisation d'un composé de la présente invention pour la préparation d'un médicament destiné au traitement de maladies prolifératives et de maladies infectieuses, en particulier dans le traitement du cancer. La présente invention concerne en particulier l'utilisation d'un composé de la présente invention pour la préparation d'un médicament destiné au traitement de maladies prolifératives, notamment dans le traitement du cancer. The present invention also relates to the use of a compound of the present invention for the preparation of a medicament for the treatment of proliferative diseases and infectious diseases, in particular in the treatment of cancer. The present invention relates in particular to the use of a compound of the present invention for the preparation of a medicament for the treatment of proliferative diseases, in particular in the treatment of cancer.
La présente invention concerne en particulier l'utilisation d'un composé de la présente invention pour la préparation d'un médicament destiné au traitement de maladies infectieuses parasitaires, notamment dans le traitement de la malaria. The present invention relates in particular to the use of a compound of the present invention for the preparation of a medicament for the treatment of parasitic infectious diseases, particularly in the treatment of malaria.
La présente invention concerne en particulier l'utilisation d'un composé de la présente invention pour la préparation d'un médicament destiné au traitement des allergies, d'une inflammation et/ou de l'asthme. The present invention particularly relates to the use of a compound of the present invention for the preparation of a medicament for the treatment of allergies, inflammation and / or asthma.
En particulier, le patient ayant besoin d'un traitement est un mammifère, notamment un humain.  In particular, the patient in need of treatment is a mammal, especially a human.
Composés nouveaux selon l'invention New compounds according to the invention
L'invention a également pour objet les composés nouveaux choisis parmi : The subject of the invention is also the novel compounds chosen from:
et eurs ses p armaceutquement accepta es. and they are readily accepted.
En particulier, les composés nouveaux sont choisis parmi :  In particular, the novel compounds are chosen from:
et leurs sels pharmaceutiquement acceptables. and their pharmaceutically acceptable salts.
Compositions pharmaceutiques selon l'invention Pharmaceutical compositions according to the invention
L'invention a également pour objet une composition pharmaceutique pour son utilisation dans le traitement de maladies prolifératives, de maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme comprenant un composé de formule (I), (II) ou (III) selon l'invention, selon l'un quelconque des modes de réalisations décrits ci-dessus, et un excipient pharmaceutiquement acceptable.  The invention also relates to a pharmaceutical composition for its use in the treatment of proliferative diseases, infectious diseases, allergies, inflammation and / or asthma comprising a compound of formula (I), (II) or (III) according to the invention, according to any of the embodiments described above, and a pharmaceutically acceptable excipient.
Les compositions pharmaceutiques selon l'invention peuvent être destinées à une administration par voie entérale (par exemple par voie orale) ou parentérale (par exemple intraveineuse), de préférence par voie orale ou intraveineuse. L'ingrédient actif peut être administré sous des formes unitaires pour l'administration, mélangé avec des supports pharmaceutiques classiques, à des animaux, de préférence des mammifères, incluant l'homme.  The pharmaceutical compositions according to the invention may be intended for enteral (for example oral) or parenteral (for example intravenous) administration, preferably orally or intravenously. The active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals, preferably mammals, including humans.
Pour l'administration orale, la composition pharmaceutique peut être sous une forme solide ou liquide (solution ou suspension). For oral administration, the pharmaceutical composition may be in solid or liquid form (solution or suspension).
Une composition solide peut se présenter sous la forme de comprimés, de gélules, de poudres, de granules et analogues. Dans les comprimés, l'ingrédient actif peut être mélangé avec un ou plusieurs véhicule(s) pharmaceutique(s) tel(s) que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique et similaires, avant d'être comprimé. Les comprimés peuvent en outre être enrobés, notamment avec du saccharose ou avec d'autres matériaux appropriés, ou ils peuvent être traités de telle manière qu'ils aient une activité prolongée ou retardée. Dans les poudres ou les granules, l'ingrédient actif peut être mélangé ou granulé avec des agents dispersants, des agents mouillants ou des agents de mise en suspension et avec des correcteurs de saveur ou des édulcorants. Dans les gélules, l'ingrédient actif peut être introduit dans des gélules molles ou dures sous la forme d'une poudre ou de granules comme mentionné précédemment ou sous la forme d'une composition liquide comme mentionné ci-après. Une composition liquide peut contenir l'ingrédient actif avec un édulcorant, un exhausteur de goût ou un colorant approprié dans un solvant tel que l'eau. La composition liquide peut également être obtenue en suspendant ou en dissolvant une poudre ou des granules, comme mentionné ci-dessus, dans un liquide tel que de l'eau, du jus, du lait, etc.. Il peut s'agir par exemple d'un sirop ou d'un élixir. A solid composition may be in the form of tablets, capsules, powders, granules and the like. In the tablets, the active ingredient may be mixed with one or more pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. similar, before being compressed. The tablets may further be coated, especially with sucrose or other suitable materials, or they may be treated in such a way that they have prolonged or delayed activity. In powders or granules, the active ingredient may be mixed or granulated with dispersants, wetting agents or suspending agents and with flavor correctors or sweeteners. In the capsules, the active ingredient can be introduced into soft or hard capsules in the form of a powder or granules as mentioned above or in the form of a liquid composition as mentioned below. A liquid composition may contain the active ingredient with a sweetener, flavor enhancer or a suitable colorant in a solvent such as water. The liquid composition can also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It may be for example a syrup or an elixir.
Pour l'administration parentérale, la composition peut se présenter sous la forme d'une suspension aqueuse ou d'une solution qui peut contenir des agents de suspension et / ou des agents mouillants. La composition est avantageusement stérile. Elle peut se présenter sous la forme d'une solution isotonique (en particulier par rapport au sang). Les composés selon l'invention peuvent être utilisés dans une composition pharmaceutique à une dose allant de 0,01 mg à 1000 mg par jour, administrés en une seule dose une fois par jour ou en plusieurs doses durant la journée, par exemple deux fois par jour à des doses égales. La dose administrée quotidiennement est avantageusement comprise entre 5 mg et 500 mg, et plus avantageusement entre 10 mg et 200 mg. Cependant, il peut être nécessaire d'utiliser des doses en dehors de ces plages, ce dont pourra se rendre compte l'homme du métier.  For parenteral administration, the composition may be in the form of an aqueous suspension or a solution which may contain suspending agents and / or wetting agents. The composition is advantageously sterile. It can be in the form of an isotonic solution (especially with respect to blood). The compounds according to the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg per day, administered in a single dose once a day or in several doses during the day, for example twice per day. day in equal doses. The dose administered daily is advantageously between 5 mg and 500 mg, and more preferably between 10 mg and 200 mg. However, it may be necessary to use doses outside these ranges, which can be appreciated by those skilled in the art.
Procédé de synthèse des composés selon la présente invention Process for synthesizing compounds according to the present invention
Les composés selon l'invention sont obtenus selon des procédés de synthèse courts et compatibles avec les exigences industrielles.  The compounds according to the invention are obtained according to short synthesis methods and compatible with industrial requirements.
A travers une stratégie de synthèse convergente, la voie de synthèse met en œuvre la réaction-clef entre une tosylhydrazone de formule A et un acide boronique de formule B ou un iodure d'aryle de formule C :  Through a convergent synthesis strategy, the synthesis route implements the key reaction between a tosylhydrazone of formula A and a boronic acid of formula B or an aryl iodide of formula C:
C 2. réduction (Pd/C, H2)  C 2. reduction (Pd / C, H2)
Avantageusement, les composés selon l'invention peuvent être préparés par un procédé comprenant une étape de couplage du composé de formule A, dans laquelle X, Y, R3, R4, R5 et R6 sont tels que définis précédemment, avec le composé de formule B (Het)ArB(OH)2 ou le composé de formule C (Het)Ar-l, dans laquelle (Het)Ar est tel que défini précédemment. Advantageously, the compounds according to the invention may be prepared by a process comprising a step of coupling the compound of formula A, in which X, Y, R 3 , R 4 , R 5 and R 6 are as defined above, with the compound of formula B (Het) ArB (OH) 2 or the compound of formula C (Het) Ar-1, wherein (Het) Ar is as defined above.
En particulier, les composés selon l'invention peuvent être préparés par un procédé comprenant les étapes successives suivantes : In particular, the compounds according to the invention may be prepared by a process comprising the following successive steps:
a) Réaction de la tosylhydrazine avec un composé de formule A'  a) Reaction of tosylhydrazine with a compound of formula A '
A'  AT'
dans laquelle X, Y, R3, R4, R5 et R6 sont tels que définis précédemment, pour conduire au composé tosylhydrazone de formule A, in which X, Y, R 3 , R 4 , R 5 and R 6 are as defined above, to yield the tosylhydrazone compound of formula A,
A  AT
b) Couplage du composé de formule A avec le composé de formule B (Het)ArB(OH)2 ou le composé de formule C (Het)Ar-l, dans laquelle (Het)Ar est tel que défini précédemment b) Coupling of the compound of formula A with the compound of formula B (Het) ArB (OH) 2 or the compound of formula C (Het) Ar-1, in which (Het) Ar is as defined previously
c) Eventuellement salification pour donner un sel pharmaceutique acceptable du composé selon l'invention  c) optionally salification to give an acceptable pharmaceutical salt of the compound according to the invention
d) Séparation du composé selon l'invention ou sons el pharmaceutiquement acceptable du milieu réactionnel résultant du couplage.  d) Separation of the compound according to the invention or the pharmaceutically acceptable salts of the reaction medium resulting from the coupling.
Les composés de formule (I), (II) ou (III) sont ainsi obtenus selon ce procédé. L'homme du métier saura quels groupements de (Het)Ar, X, Y, R3, R4, R5 et R6 tels que définis précédemment sont compatibles avec le couplage et quels groupements devront être préalablement protégés et selon quelle méthode. Les composés de formule (I) peuvent ensuite faire l'objet de plusieurs transformations à travers des procédés connus de l'homme du métier pour accéder à d'autres composés selon la formule (I) diversement fonctionnalisés. Les produits de départ de formules A', B, et C peuvent être disponibles dans le commerce ou préparés selon des méthodes connues de l'homme du métier. The compounds of formula (I), (II) or (III) are thus obtained according to this process. Those skilled in the art will know which groups of (Het) Ar, X, Y, R 3 , R 4 , R 5 and R 6 as defined above are compatible with the coupling and which groups will have to be protected beforehand and according to which method. The compounds of formula (I) may then undergo several transformations through processes known to those skilled in the art to access other compounds of formula (I) variously functionalized. The starting materials of formulas A ', B and C may be commercially available or prepared according to methods known to those skilled in the art.
En particulier, le couplage du composé de formule A avec le composé de formule B (Het)ArB(OH)2 a lieu en présence d'une base. Ladite base peut être du carbonate de potassium, du carbonate de césium, du carbonate de sodium, du ie/f-butoxyde de sodium, du ie/f-butoxyde de potassium, du méthylate de sodium ou du méthylate de potassium. In particular, the coupling of the compound of formula A with the compound of formula B (Het) ArB (OH) 2 takes place in the presence of a base. Said base may be potassium carbonate, cesium carbonate, sodium carbonate, sodium, potassium e-butoxide, sodium methoxide or potassium methoxide.
En particulier, le couplage du composé de formule A avec le composé de formule B (Het)ArB(OH)2 a lieu dans un solvant polaire, tel que le dioxane. In particular, the coupling of the compound of formula A with the compound of formula B (Het) ArB (OH) 2 takes place in a polar solvent, such as dioxane.
Avantageusement, le couplage du composé de formule A avec le composé de formule C (Het)Ar-l a lieu en présence d'un système catalytique Pd/L et d'une base. Le système catalytique peut être sous la forme d'un complexe de palladium et d'un ligand ou d'un précatalyseur. En particulier, le système catalytique Pd/L peut être Pd(OAc)2/XP os, Pd(OAc)2/DPPE, Pd2(dba)3/XP os. La base peut être du carbonate de potassium, du carbonate de césium, du carbonate de sodium, du ie/f-butoxyde de sodium, du tert- butoxyde de potassium, ou de la triéthylamine. Advantageously, the coupling of the compound of formula A with the compound of formula C (Het) Ar-1 takes place in the presence of a Pd / L catalytic system and a base. The catalyst system may be in the form of a palladium complex and a ligand or precatalyst. In particular, the Pd / L catalytic system can be Pd (OAc) 2 / XP os, Pd (OAc) 2 / DPPE, Pd 2 (dba) 3 / XP os. The base may be potassium carbonate, cesium carbonate, sodium carbonate, sodium β-butoxide, potassium tert-butoxide, or triethylamine.
En particulier, le couplage du composé de formule A avec le composé de formule C (Het)Ar-l a lieu dans un solvant, tel que le dioxane, le THF ou le toluène. In particular, the coupling of the compound of formula A with the compound of formula C (Het) Ar-1 takes place in a solvent, such as dioxane, THF or toluene.
REFERENCES BIBLIOGRAPHIQUES BIBLIOGRAPHIC REFERENCES
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Molecular identification of an IgE-dependent histamine-releasing factor. Science 269, 688-690.  Molecular identification of an IgE-dependent histamine-releasing factor. Science 269, 688-690.
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1 1 . Kashiwakura, J.C., Ando, T., Matsumoto, K., Kimura, M., Kitaura, J., Matho, M. H., Zajonc, D.M., Ozeki, T., Ra, C, MacDonald, S. M., et al. (2012). Histamine- releasing factor has a proinflammatory rôle in mouse models of asthma and allergy. J Clin Invest 122, 218-228.  1 1. Kashiwakura, J.C., Ando, T., Matsumoto, K., Kimura, M., Kitaura, J., Matho, M.H., Zajonc, D.M., Ozeki, T., Ra, C., MacDonald, S.M., et al. (2012). Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy. J Clin Invest 122, 218-228.
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Macdonald, S. M. (2012). Potential rôle of histamine releasing factor (HRF) as a therapeutic target for treating asthma and allergy. J Asthma Allergy 5, 51 -59. Macdonald, SM (2012). Potential role of histamine releasing factor (HRF) as a therapeutic target for asthma and allergy. J Asthma Allergy 5, 51-59.
EXEMPLES EXAMPLES
1. Synthèse - Procédure expérimentale et caractérisation des produits 1. Synthesis - Experimental procedure and product characterization
1.1 Général 1.1 General
Tous les produits décrits ont été analysés par des méthodes physiques conventionnelles telles que la RMN 1H, la RMN 13C, l'infrarouge (IR), la spectroscopie de masse (SM). Les spectres des RMN 1H et 13C ont été réalisés dans le chloroforme deutéré CDCI3, ou dans le méthanol deutéré MeOD, grâce à un spectromètre Bruker 300 (ou 400). Les déplacements chimiques des spectres RMN 1H sont reportés en ppm selon un standard interne (TMS) ou selon le chloroforme (7.26ppm). Les abréviations suivantes sont utilisées lors de la description des spectres RMN : (m) multiplet, s (singulet), d (doublet), t (triplet), dd (doublet dédoublé), td (triplet dédoublé), q (quadruplet), qui (quintuplet), sex (sextuplet). Les déplacements chimiques des spectres RMN 13C sont reportés en ppm selon le pic central du chloroforme (77.14ppm). Les spectres IR ont été réalisés à partir d'un spectrophotomètre Bruker Vector 22 et sont reportés en nombre d'ondes (cm"1). Les analyses de SM ont été enregistrées par un spectromètre Micromass. Les analyses CCM ont été réalisées sur des supports en silice 60F Merck. La silice utilisée pour les purifications par colonne chromatographique correspond au gel 60 (0.015-0.040 mm) de chez Merck. Les points de fusions (mp) ont été réalisés sur un appareil Buchi B-450 et n'ont pas été corrigés. Les masses hautes résolutions (HRMS) ont été faites sur un spectromètre Brucker MicroTOF, en utilisant le méthanol en tant que solvant, ainsi que l'ESI et l'APCI comme sources d'ionisation. Les valeurs calculées et les valeurs trouvées (m/z) sont reportées en Daltons. Sauf indications contraires, les réactifs utilisés sont des produits commerciaux qui ont été utilisés sans purification supplémentaire au préalable. Il en est de même pour les solvants organiques utilisés lors des synthèses décrites dans ce document. All the products described were analyzed by conventional physical methods such as 1 H NMR, 13 C NMR, infrared (IR), mass spectroscopy (MS). The 1 H and 13 C NMR spectra were carried out in deuterated chloroform CDCl 3 , or in deuterated methanol MeOD, using a Bruker 300 (or 400) spectrometer. The chemical shifts of the 1 H NMR spectra are reported in ppm according to an internal standard (TMS) or according to chloroform (7.26ppm). The following abbreviations are used when describing the NMR spectra: (m) multiplet, s (singlet), d (doublet), t (triplet), dd (doublet doubled), td (doubled triplet), q (quadruplet), who (quintuplet), sex (sextuplet). The chemical shifts of the 13 C NMR spectra are reported in ppm according to the central peak of chloroform (77.14 ppm). The IR spectra were made from a Bruker Vector 22 spectrophotometer and are plotted in wavenumber (cm -1 ) .The MS analyzes were recorded by a Micromass spectrometer. Silica 60F Merck The silica used for the chromatographic column purifications corresponds to gel 60 (0.015-0.040 mm) from Merck The melting points (mp) were made on a Buchi B-450 apparatus and did not High resolution masses (HRMS) were made on a Brucker MicroTOF spectrometer, using methanol as a solvent, as well as ESI and APCI as ionization sources Calculated values and found values (m / z) are reported in Daltons Unless otherwise stated, the reagents used are commercial products that have been used without further purification in advance, and the same applies to organic solvents. during the syntheses described in this document.
1.2 Procédure générale n°1  1.2 General procedure n ° 1
Introduire dans un tube réactionnel la /V-tosylhydrazone (1 .0 mmol), l'acide boronique approprié (1 .5 mmol), et le K2C03 (1 .5 mmol). Le dioxane sec (7 mL) est additionné, et l'ensemble est, dans un premier temps, agité à température ambiante pendant 10 minutes sous flux d'argon. Dans un deuxième temps, le tube est scellé, et le milieu réactionnel est agité à 1 10°C pendant 12 heures (ou jusqu'à la fin de la réaction qui est suivi par CCM). Lorsque la réaction est terminée, le brut réactionnel est refroidi à température ambiante, puis le solvant est évaporé sous vide. Du dichlorométhane (DCM) et une solution aqueuse saturée en NaHC03 sont ajoutés, puis les deux phases sont séparées. Par la suite, la phase aqueuse est extraite trois fois en utilisant du DCM. Les phases organiques combinées sont alors lavées avec une solution aqueuse saturée en NaCI, puis séchées sur MgS04, et enfin filtrées. Le solvant est ensuite éliminé sous pression réduite grâce à un évaporateur rotatif. Les produits obtenus sont finalement purifiés par colonnes chromatographiques de silice ou d'alumine. In a reaction tube, introduce the N-tosylhydrazone (1.0 mmol), the appropriate boronic acid (1.5 mmol), and the K 2 CO 3 (1.5 mmol). Dry dioxane (7 mL) is added, and the whole is, initially, stirred at room temperature for 10 minutes under argon flow. In a second step, the tube is sealed, and the reaction medium is stirred at 110 ° C. for 12 hours (or until the end of the reaction, which is followed by TLC). When the reaction is complete, the crude reaction product is cooled to room temperature and the solvent is then evaporated under vacuum. Dichloromethane (DCM) and a saturated aqueous solution of NaHCO 3 are added, and then the two phases are separated. Subsequently, the aqueous phase is extracted three times using DCM. The combined organic phases are then washed with a saturated aqueous solution of NaCl and then dried. on MgS0 4 , and finally filtered. The solvent is then removed under reduced pressure using a rotary evaporator. The products obtained are finally purified by chromatographic columns of silica or alumina.
1.3 Procédure générale n°2  1.3 General procedure n ° 2
Introduire dans un ballon à fond rond, le précatalyseur Xantphos-Pd-G3 (2 mol%), le thioglycoside (1 .0 mmol), ainsi que l'halogénure correspondant (1 .0 mmol). Après avoir purgé le milieu avec de l'argon, le tétrahydrofurane (THF) est ajouté (4 mL). Tout en agitant à température ambiante, la triéthylamine (NEt3) (1 .0 mmol) est additionnée au milieu réactionnel. L'ensemble est agité sous argon à température ambiante pendant 30 minutes. Une fois la réaction terminée, le solvant est évaporé sous pression réduite et le brut réactionnel est purifié par colonne chromatographique de silice afin de délivrer le produit attendu. In a round bottom flask, introduce the Xantphos-Pd-G3 precatalyst (2 mol%), the thioglycoside (1.0 mmol) and the corresponding halide (1.0 mmol). After purging the medium with argon, tetrahydrofuran (THF) is added (4 mL). While stirring at room temperature, triethylamine (NEt 3 ) (1.0 mmol) is added to the reaction medium. The whole is stirred under argon at room temperature for 30 minutes. Once the reaction is complete, the solvent is evaporated under reduced pressure and the crude reaction product is purified by silica chromatographic column in order to deliver the expected product.
1.4 Procédure générale n°3  1.4 General Procedure 3
Introduire dans un tube réactionnel la /V-tosylhydrazone (1 .0 mmol), le i-BuLi (2.2 mmol), le Pd2dba3 (10 mol%), le XPhos (20 mol%), ainsi que l'iodure d'aryle correspondant (1 .1 mmol). Le dioxane sec (5 mL) est additionné, puis le tube est scellé et l'ensemble est agité à 90°C pendant 8 heures. Une fois la réaction terminée, et refroidie à température ambiante, le dichlorométhane (DCM) est ajouté au milieu réactionnel. Ensuite, le brut est filtré sur un bloc de celite, puis le solvant est évaporé sous pression réduite. La dernière étape consiste en la purification sur une colonne chromatographique de silice. In a reaction tube, introduce the N-tosylhydrazone (1.0 mmol), the i-BuLi (2.2 mmol), the Pd 2 dba 3 (10 mol%), the XPhos (20 mol%) and the iodide. corresponding aryl (1 .1 mmol). Dry dioxane (5 mL) is added, then the tube is sealed and the whole is stirred at 90 ° C for 8 hours. Once the reaction is complete and cooled to room temperature, dichloromethane (DCM) is added to the reaction medium. Then, the crude is filtered on a celite block, then the solvent is evaporated under reduced pressure. The last step consists of the purification on a silica chromatographic column.
1.5 Procédure générale n°4  1.5 General Procedure 4
La première étape consiste à la dissolution de l'acide carboxylique approprié (1.0 mmol), d'HOBt (1 .2 mmol), dans du /V,/V-diméthylformamide (DMF) (10 mL). L'ensemble est agité pendant 15 minutes à température ambiante sous atmosphère d'argon. La 8- aminoquinoline (1 .2 mmol) est ensuite additionnée et le milieu réactionnel est agité à température ambiante durant une nuit. Ensuite, le brut réactionnel obtenu est extrait 3 fois avec une solution saturée aqueuse de NH4CI. Les phases organiques combinées sont lavées avec une solution saturée aqueuse de NaCI, puis avec de l'eau, avant d'être séchées par du MgS04 et filtrées. Une fois le solvant évaporé par évaporateur rotatif, les produits obtenus sont purifiés par colonne chromatographique de silice avant d'être engagés dans l'étape suivante. The first step consists in dissolving the appropriate carboxylic acid (1.0 mmol), HOBt (1.2 mmol) in dimethylformamide (DMF) (10 mL). The whole is stirred for 15 minutes at room temperature under an argon atmosphere. The 8-aminoquinoline (1.2 mmol) is then added and the reaction medium is stirred at room temperature overnight. Then, the crude reaction product obtained is extracted 3 times with saturated aqueous NH 4 Cl solution. The combined organic phases are washed with a saturated aqueous solution of NaCl and then with water, before being dried with MgSO 4 and filtered. Once the solvent is evaporated by rotary evaporator, the products obtained are purified by chromatographic column of silica before being engaged in the next step.
Dans un deuxième temps, introduire dans un tube sec le Cu(OAc)2 «H2O(20 mol%), l'Ag2C03 (2.0 mmol), le benzamide (1 .0 mmol) et le thiosucre (2.0 mmol). Le milieu est ensuite purger avec de l'argon pendant 10 minutes avant l'ajout de diméthylsulfoxyde (DMSO) (10 mL). Sceller le tube et laisser agiter l'ensemble à 1 10°C pendant 12 heures. Après la complétion de la réaction, le milieu est refroidi à température ambiante avant d'y introduire des morceaux de glace. Puis, le brut réactionnel est extrait trois fois avec de l'acétate d'éthyle (EtOAc). Enfin, les phases organiques sont séchées sur MgS04, filtrées, évaporées et purifiées par chromatographie sur colonne de silice. In a second step, introduce Cu (OAc) 2 " H 2 O (20 mol%), Ag 2 CO 3 (2.0 mmol), benzamide (1.0 mmol) and thiosugar (2.0) into a dry tube. mmol). The medium is then purged with argon for 10 minutes before addition of dimethylsulfoxide (DMSO) (10 mL). Seal the tube and let the mixture shake at 110 ° C for 12 hours. After the completion of the reaction, the medium is cooled to room temperature before introducing pieces of ice. Then, the crude reaction product is extracted three times with ethyl acetate (EtOAc). Finally, the organic phases are dried over MgSO 4 , filtered, evaporated and purified by chromatography on a silica column.
1.6 Procédure générale n°5  1.6 General Procedure No. 5
Introduire dans un tube sec le Co(acac)2 (10 mol%), l'Ag2C03 (0.53 mmol), l'acide carboxylique commercial correspondant (0.19 mmol) et le thiosucre (0.29 mmol). Le milieu est ensuite purgé avec de l'argon pendant 10 minutes avant l'ajout du trifluorotoluène (2 mL). Sceller le tube et laisser agiter l'ensemble à 150°C jusqu'à complétion de la réaction. Une fois le milieu refroidi à température ambiante, le brut réactionnel est filtré sur un petit bloc de celite et est rincé trois fois avec de l'acétate d'éthyle (EtOAc). Après évaporation du solvant sous pression réduite, le brut est alors purifié par chromatographie en utilisant une colonne de silice. Introduce into a dry tube Co (acac) 2 (10 mol%), Ag 2 CO 3 (0.53 mmol), the corresponding commercial carboxylic acid (0.19 mmol) and thiosugar (0.29 mmol). The medium is then purged with argon for 10 minutes before the addition of trifluorotoluene (2 mL). Seal the tube and allow the mixture to stir at 150 ° C until completion of the reaction. After the medium has cooled to room temperature, the crude reaction product is filtered through a small block of celite and rinsed three times with ethyl acetate (EtOAc). After evaporation of the solvent under reduced pressure, the crude is then purified by chromatography using a silica column.
1.7 Données caractéristiques des différents dérivés de type tetrahydronaphtalene 1.7 Characteristic data of the different derivatives of tetrahydronaphthalene type
1 -p enyl- 1,2,3, 4-tetra ydronap t ale 1 -p enyl-1,2,3,4-tetra ydronap t ale
Huile transparente obtenue selon la procédure générale n°1 (31.8 mg, 48% de rendement); CCM Rf = 0.50 (Cyclohexane, Si02); IR (film, cm"1) 2924, 2853, 1672, 1599, 1491 , 1448, 1 158, 1079, 1033, 1003; 1H RMN (300MHz, CDCI3) δ (ppm) 7.32 - 7.25 (m, 2H), 7.23 - 7.17 (m, 1 H), 7.16 - 7.1 1 (m, 3H), 7.09 (d, J = 3.3 Hz, 1 H), 7.03 (ddd, J = 8.7, 6.1 , 2.7 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 4.13 (t, J = 6.6 Hz, 1 H), 2.98 - 2.80 (m, 2H), 2.24 - 2.1 1 (m, 1 H), 1.90 (qdd, J = 10.0, 5.0, 2.0 Hz, 2H), 1 .81 - 1 .66 (m, 1 H); 13C RMN (75 MHz, CDCIs) δ (ppm) 147.7 (Cq), 139.5 (Cq), 137.7 (Cq), 130.3 (CH), 129.1 (CH), 129.0 (2 x CH), 128.4 (2 x CH), 126.1 (CH), 126.0 (CH), 125.8 (CH), 45.8 (CH), 33.4 (CH2), 29.9 (CH2), 21.1 (CH2). Transparent oil obtained according to General Procedure No. 1 (31.8 mg, 48% yield); TLC R f = 0.50 (Cyclohexane, SiO 2 ); IR (film, cm "1) 2924, 2853, 1672, 1599, 1491, 1448, 1158, 1079, 1033, 1003; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.32 - 7.25 (m, 2H) , 7.23 - 7.17 (m, 1H), 7.16 - 7.1 1 (m, 3H), 7.09 (d, J = 3.3 Hz, 1H), 7.03 (ddd, J = 8.7, 6.1, 2.7 Hz, 1H) , 6.85 (d, J = 8.0 Hz, 1H), 4.13 (t, J = 6.6 Hz, 1H), 2.98 - 2.80 (m, 2H), 2.24 - 2.1 1 (m, 1H), 1.90 (qdd , J = 10.0, 5.0, 2.0 Hz, 2H), 1 .81 - 1 .66 (m, 1 H); 13 C NMR (75 MHz, CDCl) δ (ppm) 147.7 (C q), 139.5 (C q ), 137.7 (C q ), 130.3 (CH), 129.1 (CH), 129.0 (2 x CH), 128.4 (2 x CH), 126.1 (CH), 126.0 (CH), 125.8 (CH), 45.8 (CH), ), 33.4 (CH 2 ), 29.9 (CH 2 ), 21.1 (CH 2 ).
1 -(4-met oxyp enyl)-1 ,2, 3, 4-tetrahydronaphthalene [RA004] 1 - (4-met oxypenyl) -1,2,3,4-tetrahydronaphthalene [RA004]
Huile transparente jaunâtre obtenue selon la procédure générale n°1 (40.1 mg, 53% de rendement); CCM Rf = 0.92 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2925, 2854, 161 1 , 1583, 151 1 , 1463, 1448, 1302, 1243, 1 177, 1 109, 1038; 1H RMN (300MHz, CDCI3) δ (ppm) 7.16 - 7.08 (m, 2H), 7.06 - 6.98 (m, 3H), 6.88 - 6.79 (m, 3H), 4.07 (t, J = 6.5 Hz, 1 H), 3.79 (s, 3H), 2.97 - 2.77 (m, 2H), 2.21 - 2.07 (m, 1 H), 1.88 (tdd, J = 1 1.6, 4.8, 1 .9 Hz, 2H), 1 .78 - 1 .71 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 145.5 (Cq), 139.9 (Cq), 139.8 (Cq), 137.7 (Cq), 130.3 (CH), 129.8 (2 x CH), 129.1 (CH), 126.0 (CH), 125.7 (CH), 1 13.8 (2 x CH), 55.4 (CH3), 44.9 (CH), 33.5 (CH2), 29.9 (CH2), 21 .1 (CH2). 1 -(4-chlorophenyl)-1 ,2, 3, 4-tetra 05] Yellowish transparent oil obtained according to General Procedure No. 1 (40.1 mg, 53% yield); TLC R f = 0.92 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2925, 2854, 161 1, 1583, 151 1, 1463, 1448, 1302, 1243, 1177, 1109, 1038; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.16 - 7.08 (m, 2H), 7.06 - 6.98 (m, 3H), 6.88 - 6.79 (m, 3H), 4.07 (t, J = 6.5 Hz, 1H), 3.79 (s, 3H), 2.97 - 2.77 ( m, 2H), 2.21 - 2.07 (m, 1H), 1.88 (tdd, J = 1.6, 4.8, 1.19 Hz, 2H), 1.78-1.71 (m, 1H), 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 145.5 (C q ), 139.9 (C q ), 139.8 (C q ), 137.7 (C q ), 130.3 (CH), 129.8 (2 x CH), 129.1 ( CH), 126.0 (CH), 125.7 (CH), 13.8 (2 x CH), 55.4 (CH 3 ), 44.9 (CH), 33.5 (CH 2 ), 29.9 (CH 2 ), 21 .1 (CH 2) ). 1 - (4-chlorophenyl) -1,2,3,4-tetra 05]
Solide amorphe obtenu selon la procédure générale n°1 (40.2 mg, 52% de rendement); CCM Rf = 0.84 (Cyclohexane/EtOAc, 9:1 , Si02); IR (film, cm"1) 2926, 1672, 1595, 1489, 1452, 1400, 1092, 1014; 1H RMN (300MHz, CDCI3) δ (ppm) 7.29 - 7.21 (m, 2H), 7.13 (dd, J = 5.0, 1.0 Hz, 2H), 7.09 - 6.98 (m, 3H), 6.81 (d, J = 7.7 Hz, 1 H), 4.10 (t, J = 6.4 Hz, 1 H), 2.97 - 2.78 (m, 2H), 2.16 (qd, J = 9.8, 5.1 Hz, 1 H), 1 .93 - 1 .80 (m, 2H), 1.79 - 1 .70 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 146.2 (Cq), 138.9 (Cq), 137.7 (Cq), 131 .8 (Cq), 130.3 (2 x CH), 130.2 (CH), 129.2 (CH), 128.5 (2 x CH), 126.3 (CH), 125.9 (CH), 45.2 (CH), 33.4 (CH2), 29.8 (CH2), 21 .0 (CH2). Amorphous solid obtained according to General Procedure No. 1 (40.2 mg, 52% yield); TLC R f = 0.84 (Cyclohexane / EtOAc, 9: 1, SiO 2 ); IR (film, cm "1) 2926, 1672, 1595, 1489, 1452, 1400, 1092, 1014; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.29 - 7.21 (m, 2H), 7.13 (dd, J = 5.0, 1.0 Hz, 2H), 7.09 - 6.98 (m, 3H), 6.81 (d, J = 7.7 Hz, 1H), 4.10 (t, J = 6.4 Hz, 1H), 2.97 - 2.78 (m , 2H), 2.16 (qd, J = 9.8, 5.1 Hz, 1H), 1.93-180 (m, 2H), 1.79-170 (m, 1H), 13 C NMR (75 MHz , CDCl 3 ) δ (ppm) 146.2 (C q ), 138.9 (C q ), 137.7 (C q ), 131.8 (C q ), 130.3 (2 x CH), 130.2 (CH), 129.2 (CH) 128.5 (2 x CH), 126.3 (CH), 125.9 (CH), 45.2 (CH), 33.4 (CH 2 ), 29.8 (CH 2 ), 21.0 (CH 2 ).
1-(3,4, 5-trimethoxyphenyl)-1 ,2, 3, 4-tetrahydronaphthalene [AC013]  1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydronaphthalene [AC013]
Huile transparente jaunâtre obtenue selon la procédure générale n°1 (50.6 mg, 54% de rendement); CCM Rf = 0.50 (Cyclohexane/EtOAc, 8:2, Si02); IR (film, cm"1) 2927, 1588, 1508, 1449, 1418, 1329, 1232, 1 124, 101 1 ; 1H RMN (300MHz, CDCI3) δ (ppm) 7.13 (dd, J = 4.9, 1 .1 Hz, 2H), 7.10 - 7.02 (m, 1 H), 6.89 (d, J = 7.7 Hz, 1 H), 6.33 (s, 2H), 4.10 - 4.00 (m, 1 H), 3.85 (s, 3H), 3.79 (s, 6H), 3.02 - 2.80 (m, 2H), 2.25 - 2.1 1 (m, 1 H), 2.01 - 1 .86 (m, 2H), 1 .83 - 1 .73 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 153.1 (2 x Cq), 143.2 (Cq), 139.3 (Cq), 137.5 (Cq), 136.3 (Cq), 130.1 (CH), 129.0 (CH), 126.1 (CH), 125.7 (CH), 106.0 (2 x CH), 60.9 (CH), 56.2 (2 x CH3), 46.3 (CH3), 33.4 (CH2), 29.9 (CH2), 21 .5 (CH2); HRMS (APCI) (M + Na)+ m/z calculé pour Ci9H2203Na 321.1467, trouvé 321.1470. Yellowish transparent oil obtained according to General Procedure No. 1 (50.6 mg, 54% yield); TLC R f = 0.50 (Cyclohexane / EtOAc, 8: 2, SiO 2 ); IR (film, cm "1) 2927, 1588, 1508, 1449, 1418, 1329, 1232, 1124, 101 1; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.13 (dd, J = 4.9, 1 .1 Hz, 2H), 7.10 - 7.02 (m, 1H), 6.89 (d, J = 7.7Hz, 1H), 6.33 (s, 2H), 4.10-4.00 (m, 1H), 3.85 (s). , 3H), 3.79 (s, 6H), 3.02 - 2.80 (m, 2H), 2.25 - 2.1 1 (m, 1H), 2.01-1.86 (m, 2H), 1.83-173 ( m, 1 H); 13 C NMR (75 MHz, CDCl 3) δ (ppm) 153.1 (2 x C q), 143.2 (C q), 139.3 (C q), 137.5 (C q), 136.3 (C q ), 130.1 (CH), 129.0 (CH), 126.1 (CH), 125.7 (CH), 106.0 (2 x CH), 60.9 (CH), 56.2 (2 x CH 3 ), 46.3 (CH 3 ), 33.4 ( CH 2 ), 29.9 (CH 2 ), 21.5 (CH 2 ), HRMS (APCI) (M + Na) + m / z calculated for C 19 H 22 O 3 Na 321.1467, found 321.1470.
1 ,2,3,4-tetrahydro-1 ,2'-binaphthale 1, 2,3,4-tetrahydro-1, 2'-binaphthale
Solide blanc obtenu selon la procédure générale n°1 (39.0 mg, 47% de rendement); mp: 72.7 - 73.4 °C; CCM Rf = 0.85 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2927, 2854, 1589, 1507, 1491 , 1449, 1 127; 1H RMN (300MHz, CDCI3) δ (ppm) 7.85 - 7.72 (m, 3H), 7.54 (s, 1 H), 7.47 - 7.40 (m, 2H), 7.25 (d, J = 6.7 Hz, 1 H), 7.15 (q, J = 7.2 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H), 4.28 (t, J = 5.6 Hz, 1 H), 3.03 - 2.82 (m, 2H), 2.28 - 2.16 (m, 1 H), 2.05 - 1.89 (m, 2H), 1 .88 - 1.75 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 145.0 (Cq), 139.4 (Cq), 137.8 (Cq), 133.6 (Cq), 132.2 (Cq), 130.4 (CH), 129.2 (CH), 128.1 (CH), 127.7 (2 x CH), 127.5 (CH), 127.4 (CH), 126.1 (CH), 126.0 (CH), 125.8 (CH), 125.4 (CH), 46.0 (CH), 33.3(CH2), 30.0 (CH2), 21.3 (CH2). White solid obtained according to General Procedure No. 1 (39.0 mg, 47% yield); mp: 72.7 - 73.4 ° C; TLC R f = 0.85 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2927, 2854, 1589, 1507, 1491, 1449, 1127; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.85 - 7.72 (m, 3H), 7.54 (s, 1 H), 7.47 - 7.40 (m, 2H), 7.25 (d, J = 6.7 Hz, 1H), 7.15 (q, J = 7.2 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.28 (t, J = 5.6 Hz, 1H), 3.03 - 2.82 (m, 2H), 2.28 - 2.16 (m, 1H), 2.05 - 1.89 (m). , 2H), 1 .88 - 1.75 (m, 1 H); 13 C NMR (75 MHz, CDCl 3) δ (ppm) 145.0 (C q), 139.4 (C q), 137.8 (C q), 133.6 ( C q ), 132.2 (C q ), 130.4 (CH), 129.2 (CH), 128.1 (CH), 127.7 (2 x CH), 127.5 (CH), 127.4 (CH), 126.1 (CH), 126.0 (CH), 125.8 (CH), 125.4 (CH), 46.0 (CH), ), 33.3 (CH 2 ), 30.0 (CH 2 ), 21.3 (CH 2 ).
1 -(4-bromophenyl)- 1, 2, 3, 4-tetra 23] 1 - (4-bromophenyl) -1,2,3,4-tetra 23]
Huile transparente obtenue selon la procédure générale n°1 (30.0 mg, 33% de rendement); CCM Rf = 0.81 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 3017, 2929, 2856, 1486, 1449, 1403, 1073, 1010; 1H RMN (300MHz, CDCI3) δ (ppm) 7.42 (dt, J = 8.0, 2.4 Hz, 2H), 7.16 (dt, J = 5.1 , 2.5 Hz, 2H), 7.10 - 7.02 (m, 1 H), 6.99 (dt, J = 8.0, 3.0 Hz, 2H), 6.83 (d, J = 7.1 Hz, 1 H), 4.1 1 (t, J = 6.4 Hz, 1 H), 3.00 - 2.81 (m, 2H), 2.25 - 2.09 (m, 1 H), 1 .94 - 1 .72 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 146.7 (Cq), 138.8 (Cq), 137.7 (Cq), 131 .4 (2 x CH), 130.7 (2 x CH), 130.2 (CH), 129.2 (CH), 126.3 (CH), 125.9 (CH), 1 19.9 (Cq), 45.2 (CH), 33.3 (CH2), 29.8 (CH2), 20.9 (CH2). Transparent oil obtained according to General Procedure No. 1 (30.0 mg, 33% yield); TLC R f = 0.81 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 3017, 2929, 2856, 1486, 1449, 1403, 1073, 1010; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.42 (dt, J = 8.0, 2.4 Hz, 2H) , 7.16 (dt, J = 5.1, 2.5 Hz, 2H), 7.10-7.02 (m, 1H), 6.99 (dt, J = 8.0, 3.0 Hz, 2H), 6.83 (d, J = 7.1 Hz, 1H). ), 4.1 1 (t, J = 6.4 Hz, 1H), 3.00 - 2.81 (m, 2H), 2.25 - 2.09 (m, 1 H), 1 .94 - 1 .72 (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 146.7 (C q ), 138.8 (C q ), 137.7 (C q ), 131.4 (2 x CH), 130.7 (2 x CH), 130.2 (CH) , 129.2 (CH), 126.3 (CH), 125.9 (CH), 19.9 (C q ), 45.2 (CH), 33.3 (CH 2 ), 29.8 (CH 2 ), 20.9 (CH 2 ).
Isopropyl 4-(1 ,2,3,4-tetra ydronap t alen-l -yl)benzoate [AC034] Isopropyl 4- (1,2,3,4-tetra-ydronaphthalen-1-yl) benzoate [AC034]
Huile jaune pâle obtenue selon la procédure générale n°1 (40.0 mg, 47% de rendement); CCM Rf = 0.78 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2979, 2931 , 2856, 1713, 1610, 1451 , 1415, 1373, 1352, 1274, 1 178, 1098, 1019; 1H RMN (300MHz, CDCI3) δ (ppm) 7.97 (d, J = 8.1 Hz, 2H), 7.23 - 7.09 (m, 4H), 7.04 (dd, J = 1 1 .0, 5.7 Hz, 1 H), 6.80 (d, J = 7.6 Hz, 1 H), 5.26 (dt, J = 12.7, 6.4 Hz, 1 H), 4.20 (t, J = 6.6 Hz, 1 H), 2.97 - 2.76 (m, 2H), 2.18 (dd, J = 12.9, 6.3 Hz, 1 H), 1.92 - 1.76 (m, 3H), 1.37 (d, J = 6.2 Hz, 6H); 13C RMN (75 MHz, CDCI3) δ (ppm) 166.3 (Cq), 152.9 (Cq), 145.6 (Cq), 138.7 (Cq), 137.7 (Cq), 130.2 (CH), 129.7 (2 x CH), 129.2 (CH), 128.9 (2 x CH), 126.3 (CH), 125.9 (CH), 68.3 (CH), 45.8 (CH), 33.3 (CH2), 29.8 (CH2), 22.1 (2 x CH3), 21 .1 (CH2); HRMS (APCI) (M + H)+ m/z calculé pour C20H23O2 295.1693, trouvé 295.1700. Pale yellow oil obtained according to General Procedure No. 1 (40.0 mg, 47% yield); TLC R f = 0.78 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm -1 ) 2979, 2931, 2856, 1713, 1610, 1451, 1415, 1373, 1352, 1274, 1178, 1098, 1019; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm) 7.97 ( d, J = 8.1 Hz, 2H), 7.23 - 7.09 (m, 4H), 7.04 (dd, J = 1.10, 5.7 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 5.26 (dt, J = 12.7, 6.4 Hz, 1H), 4.20 (t, J = 6.6 Hz, 1H), 2.97 - 2.76 (m, 2H), 2.18 (dd, J = 12.9, 6.3 Hz, 1H). ), 1.92 - 1.76 (m, 3H), 1.37 (d, J = 6.2 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 166.3 (C q ), 152.9 (C q ), 145.6 (C q ), 138.7 (C q ), 137.7 (C q ), 130.2 (CH), 129.7 (2 x CH), 129.2 (CH), 128.9 (2 x CH), 126.3 (CH), 125.9 (CH) , 68.3 (CH), 45.8 (CH), 33.3 (CH 2 ), 29.8 (CH 2 ), 22.1 (2 x CH 3 ), 21 .1 (CH 2 ), HRMS (APCI) (M + H) + m Z calculated for C 20 H 23 O 2 295.1693, found 295.1700.
1-(3, 5-dimethylphenyl)-1 ,2, 3, 4-tetrahydronaphthalene [AC035] 1- (3,5-Dimethylphenyl) -1,2,3,4-tetrahydronaphthalene [AC035]
Solide blanc obtenu selon la procédure générale n°1 (47.0 mg, 62% de rendement); mp: 57,6 - 58,6 °C; CCM Rf = 0.82 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2932, 2856, 2361 , 1706, 1602, 1437, 1 179, 1 120; 1H RMN (300MHz, CDCI3) δ (ppm) 7.19 - 7.13 (m, 2H), 7.07 (ddd, J = 8.6, 5.9, 3.0 Hz, 1 H), 6.89 (dd, J = 3.4, 2.7 Hz, 2H), 6.77 (s, 2H), 4.07 (t, J = 6.1 Hz, 1 H), 3.00 - 2.81 (m, 2H), 2.31 (d, J = 0.5 Hz, 6H), 2.24 - 2.12 (m, 1 H), 2.02 - 1.87 (m, 2H), 1 .86 - 1.74 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 147.6 (Cq), 139.8 (Cq), 137.8 (2 x Cq), 137.6 (Cq), 130.3 (CH), 129.0 (CH), 127.8 (CH), 126.8 (2 x CH), 125.9 (CH), 125.7 (CH), 45.8 (CH3), 33.5 (CH2), 30.0 (CH2), 21 .5 (CH3), 21 .4 5 (CH2). White solid obtained according to General Procedure No. 1 (47.0 mg, 62% yield); mp: 57.6-58.6 ° C; TLC R f = 0.82 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2932, 2856, 2361, 1706, 1602, 1437, 1179, 1120; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.19 - 7.13 (m, 2H), 7.07 ( ddd, J = 8.6, 5.9, 3.0 Hz, 1H), 6.89 (dd, J = 3.4, 2.7 Hz, 2H), 6.77 (s, 2H), 4.07 (t, J = 6.1 Hz, 1H), 3.00 - 2.81 (m, 2H), 2.31 (d, J = 0.5 Hz, 6H), 2.24 - 2.12 (m, 1H), 2.02 - 1.87 (m, 2H), 1.86 - 1.74 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 147.6 (C q ), 139.8 (C q ), 137.8 (2 x C q ), 137.6 (C q ), 130.3 (CH), 129.0 (CH), 127.8 (CH), 126.8 (2 x CH), 125.9 (CH), 125.7 (CH), 45.8 (CH 3 ), 33.5 (CH 2 ), 30.0 (CH 2 ), 21.5 (CH 3 ), 21. 4 (CH 2 ).
1-(3-vinylp enyl)-1,2, 3, 4-tetra ] 1- (3-vinylp enyl) -1,2,3,4-tetra]
Huile transparente obtenue selon la procédure générale n°1 (57.6 mg, 77% de rendement); CCM Rf = 0.79 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 3016, 2930, 2856, 1631 , 1600, 1578, 1491 , 1451 , 1403; 1H RMN (300MHz, CDCI3) δ (ppm) 7.30 (dd, J = 8.3, 2.4 Hz, 2H), 7.16 (dd, J = 8.5, 5.5 Hz, 3H), 7.09 - 6.97 (m, 2H), 6.87 (d, J = 7.6 Hz, 1 H), 6.71 (dd, J = 17.6, 10.8 Hz, 1 H), 5.74 (d, J = 17.6 Hz, 1 H), 5.24 (d, J = 10.9 Hz, 1 H), 4.14 (t, J = 6.0 Hz, 1 H), 2.99 - 2.85 (m, 2H), 2.20 (ddd, J = 1 1.8, 8.4, 5.6 Hz, 1 H), 2.02 - 1 .71 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 147.9 (Cq), 139.4 (Cq), 137.7 (Cq), 137.6 (Cq), 137.1 (CH), 130.3 (CH), 129.1 (CH), 128.6 (2 x CH), 127.0 (CH), 126.1 (CH), 125.8 (CH), 123.9 (CH), 1 13.8 (CH2), 45.8 (CH), 33.4 (CH2), 29.9 (CH2), 21 .3 (CH2). Transparent oil obtained according to General Procedure No. 1 (57.6 mg, 77% yield); TLC R f = 0.79 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm -1 ) 3016, 2930, 2856, 1631, 1600, 1578, 1491, 1451, 1403 1 H NMR (300 MHz, CDCl 3 ) δ (ppm) 7.30 (dd, J = 8.3, 2.4 Hz, 2H), 7.16 (dd, J = 8.5, 5.5 Hz, 3H), 7.09 - 6.97 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.71 (dd, J = 17.6, 10.8 Hz, 1H), 5.74 (d, J = 17.6Hz, 1H), 5.24 (d, J = 10.9Hz, 1H), 4.14 (t, J = 6.0Hz, 1H), 2.99 - 2.85 (m, 2H). ), 2.20 (ddd, J = 1.8, 8.4, 5.6 Hz, 1H), 2.02-1.71 (m, 3H), 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 147.9 (C q ) , 139.4 (C q ), 137.7 (C q ), 137.6 (C q ), 137.1 (CH), 130.3 (CH), 129.1 (CH), 128.6 (2 x CH), 127.0 (CH), 126.1 (CH) 125.8 (CH), 123.9 (CH), 13.8 (CH 2 ), 45.8 (CH), 33.4 (CH 2 ), 29.9 (CH 2 ), 21.3 (CH 2 ).
4-(1,2,3,4-tetrahydronaphthalen-1-yl)benzaldehyde [AC038] 4- (1,2,3,4-tetrahydronaphthalen-1-yl) benzaldehyde [AC038]
Huile opaque obtenue selon la procédure générale n°1 (25.0 mg, 33% de rendement); CCM Rf = 0.71 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2929, 2857, 1701 , 1605, 1574, 1491 , 1450, 1306, 121 1 , 1 168; 1H RMN (300MHz, CDCI3) δ (ppm) 9.99 (s, 1 H), 7.83 - 7.77 (m, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.18 - 7.13 (m, 2H), 7.05 (ddd, J = 8.6, 5.6, 3.4 Hz, 1 H), 6.79 (d, J = 7.9 Hz, 1 H), 4.23 (t, J = 6.4 Hz, 1 H), 2.98 - 2.82 (m, 2H), 2.27 - 2.14 (m, 1 H), 1.96 - 1 .76 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 192.13 (CH), 155.07 (Cq), 138.26 (Cq), 137.73 (Cq), 134.72 (Cq), 130.19 (CH), 129.99 (2 x CH), 129.63 (2 x CH), 129.34 (CH), 126.46 (CH), 125.99 (CH), 45.97 (CH), 33.19 (CH2), 29.77 (CH2), 20.93 (CH2); HRMS (APCI) (M + H)+ m/z calculé pour d7H170 237.1274, trouvé 237.1272. Opaque oil obtained according to General Procedure No. 1 (25.0 mg, 33% yield); TLC R f = 0.71 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2929, 2857, 1701, 1605, 1574, 1491, 1450, 1306, 121 1, 1168; 1 H NMR (300MHz, CDCl 3) δ (ppm) 9.99 (s, 1H) , 7.83 - 7.77 (m, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.18 - 7.13 (m, 2H), 7.05 (ddd, J = 8.6, 5.6, 3.4 Hz, 1H), 6.79 ( d, J = 7.9 Hz, 1H), 4.23 (t, J = 6.4 Hz, 1H), 2.98 - 2.82 (m, 2H), 2.27 - 2.14 (m, 1H), 1.96 - 1.76 (m). , 3H); 13 C NMR (75 MHz, CDCl 3) δ (ppm) 192.13 (CH), 155.07 (C q), 138.26 (C q), 137.73 (C q), 134.72 (C q), 130.19 (CH ), 129.99 (2 x CH), 129.63 (2 x CH), 129.34 (CH), 126.46 (CH), 125.99 (CH), 45.97 (CH), 33.19 (CH 2 ), 29.77 (CH 2 ), 20.93 (CH 2 ), CH 2 ); HRMS (APCI) (M + H) + m / z calcd for d 7 H 17 O 237.1274, found 237.1272.
1-(3-iodophenyl)-1,2, 3, 4-tetrahydronaphthalene [AC041 ] Huile transparente obtenue selon la procédure générale n°1 (48.6 mg, 44% de rendement); CCM Rf = 0.82 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 3058, 3016, 2931 , 2855, 1674, 1587, 1562, 1491 , 1470, 1451 , 1417; 1H RMN (300MHz, CDCI3) δ (ppm) 7.55 (dt, J = 6.8, 1 .9 Hz, 1 H), 7.50 (d, J = 1 .7 Hz, 1 H), 7.15 (dd, J = 4.8, 1 .0 Hz, 2H), 7.09 - 6.98 (m, 3H), 6.83 (d, J = 7.7 Hz, 1 H), 4.07 (t, J = 6.5 Hz, 1 H), 2.97 - 2.80 (m, 2H), 2.23 - 2.1 1 (m, 1 H), 1 .94 - 1.70 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 150.1 (Cq), 138.6 (Cq), 137.8 (CH), 137.7 (Cq), 135.2 (CH), 130.1 (2 x CH), 129.2 (CH), 128.3 (CH), 126.3 (CH), 125.9 (CH), 94.6 (CH), 45.4 (CH), 33.3 (CH2), 29.8 (CH2), 21 .0 (CH2); HRMS (ESI) (M + Na)+ m/z calculé pour d6H15INa 357.01 1 1 , trouvé 357.0121. 1- (3-iodophenyl) -1,2,3,4-tetrahydronaphthalene [AC041] Transparent oil obtained according to General Procedure No. 1 (48.6 mg, 44% yield); TLC R f = 0.82 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 3058, 3016, 2931, 2855, 1674, 1587, 1562, 1491, 1470, 1451, 1417; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.55 (dt, J = 6.8 , 1.9 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.15 (dd, J = 4.8, 1.0 Hz, 2H), 7.09-6.98 (m, 3H), 6.83 (d, J = 7.7 Hz, 1H), 4.07 (t, J = 6.5 Hz, 1H), 2.97 - 2.80 (m, 2H), 2.23 - 2.11 (m, 1H), 1.94 - 1.70 (m, 3H) 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 150.1 (C q ), 138.6 (C q ), 137.8 (CH), 137.7 (C q ), 135.2 (CH), 130.1 (2 x CH), 129.2 (CH), 128.3 (CH), 126.3 (CH), 125.9 (CH), 94.6 (CH), 45.4 (CH), 33.3 (CH 2 ), 29.8 (CH 2 ), 21. 0 (CH 2 ); HRMS (ESI) (M + Na) + m / z calcd for d 6 H 15 INa 357.0111, found 357.0121.
1 -(4-(benzyloxy)-3-chlorophenyl)-1,2, 3, 4-tetrahydronaphthalene [AC042] 1 - (4- (benzyloxy) -3-chlorophenyl) -1,2,3,4-tetrahydronaphthalene [AC042]
Solide jaune pâle obtenu selon la procédure générale n°1 (50.0 mg, 45% de rendement); mp: 89,9 - 91 ,5 °C; CCM Rf = 0.80 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2931 , 2857, 1603, 1497, 1452, 1381 , 1286, 1251 , 1061 , 1024; 1H RMN (300MHz, CDCI3) δ (ppm) 7.49 (dd, J = 8.0, 1 .6 Hz, 2H), 7.44 - 7.32 (m, 3H), 7.15 (d, J = 3.9 Hz, 3H), 7.06 (dt, J = 8.7, 4.2 Hz, 1 H), 6.90 (d, J = 1 .6 Hz, 2H), 6.85 (d, J = 7.7 Hz, 1 H), 5.14 (s, 2H), 4.06 (t, J = 6.3 Hz, 1 H), 2.98 - 2.79 (m, 2H), 2.21 - 2.04 (m, 1 H), 1 .94 - 1 .70 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 152.5 (Cq), 141 .3 (Cq), 139.0 (Cq), 137.6 (Cq), 136.9 (Cq), 130.6 (CH), 130.2 (CH), 129.2 (CH), 128.7 (2 x CH), 128.0 (CH), 128.0 (CH), 127.2 (2 x CH), 126.2 (CH), 125.9 (CH), 123.1 (Cq), 1 14.0 (CH), 71 .0 (CH2), 44.7 (CH), 33.3 (CH2), 29.8 (CH2), 20.9 (CH2); HRMS (ESI) (M + Na)+ m/z calculé pour C23H21CIONa 371 .1 179, trouvé 371.1 181. Pale yellow solid obtained according to General Procedure No. 1 (50.0 mg, 45% yield); mp 89.9-91.5 ° C; TLC R f = 0.80 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2931, 2857, 1603, 1497, 1452, 1381, 1286, 1251, 1061, 1024; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.49 (dd, J = 8.0, 1 .6 Hz, 2H), 7.44 - 7.32 (m, 3H), 7.15 (d, J = 3.9 Hz, 3H), 7.06 (dt, J = 8.7, 4.2 Hz, 1H), 6.90 (d, J = 1). .6 Hz, 2H), 6.85 (d, J = 7.7 Hz, 1H), 5.14 (s, 2H), 4.06 (t, J = 6.3 Hz, 1H), 2.98 - 2.79 (m, 2H), 2.21 2.04 (m, 1 H), 1.94-1.70 (m, 3H), 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 152.5 (C q ), 141.3 (C q ), 139.0 (C q ), 137.6 (C q ), 136.9 (C q ), 130.6 (CH), 130.2 (CH), 129.2 (CH), 128.7 (2 x CH), 128.0 (CH), 128.0 (CH), 127.2 (2 x CH), 126.2 (CH), 125.9 (CH), 123.1 (C q ), 1 14.0 (CH), 71.0 (CH 2 ), 44.7 (CH), 33.3 (CH 2 ), 29.8 ( CH 2 ), 20.9 (CH 2 ), HRMS (ESI) (M + Na) + m / z calculated for C 23 H 21 CIONa 371.117, found 371.1181.
1 -(3-met oxyp enyl)-1 ,2, 3, 4-tetrahydronaphthalene [AC046] 1 - (3-met oxypenyl) -1,2,3,4-tetrahydronaphthalene [AC046]
Huile transparente obtenue selon la procédure générale n°1 (60.8 mg, 80% de rendement); CCM Rf = 0.76 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2933, 2858, 2834, 2360, 2341 , 1610, 1582, 1489, 1452, 1281 , 1262, 1223; 1H RMN (300MHz, CDCI3) δ (ppm) 7.25 (dd, J = 9.5, 6.3 Hz, 1 H), 7.20 - 7.15 (m, 2H), 7.13 - 7.05 (m, 1 H), 6.92 (d, J = 7.9 Hz, 1 H), 6.80 (ddd, J = 8.2, 2.6, 0.9 Hz, 1 H), 6.75 (d, J = 7.6 Hz, 1 H), 6.73 - 6.70 (m, 1 H), 4.18 - 4.1 1 (m, 1 H), 3.81 (s, 3H), 3.04 - 2.81 (m, 2H), 2.26 - 2.14 (m, 1 H), 2.02 - 1 .89 (m, 2H), 1.87 - 1 .75 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 159.6 (Cq), 149.3 (Cq), 139.3 (Cq), 137.6 (Cq), 130.3 (CH), 129.3 (CH), 129.1 (CH), 126.0 (CH), 125.8 (CH), 121 .5 (CH), 1 15.1 (CH), 1 1 1 .1 (CH), 55.3 (CH), 45.8 (CH3), 33.2 (CH2), 29.9 (CH2), 21.1 (CH2); HRMS (APCI) (M + H)+ m/z calculé pour d7H190 239.1430, trouvé 239.1464. Transparent oil obtained according to General Procedure No. 1 (60.8 mg, 80% yield); TLC R f = 0.76 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2933, 2858, 2834, 2360, 2341, 1610, 1582, 1489, 1452, 1281, 1262, 1223; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.25 (dd, J = 9.5, 6.3 Hz, 1H), 7.20 - 7.15 (m, 2H), 7.13 - 7.05 (m, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.80 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.75 (d, J = 7.6Hz, 1H), 6.73 - 6.70 (m, 1H), 4.18 - 4.11 (m, 1H), 3.81 (s, 3H), 3.04 - 2.81 (m, 2H), 2.26 - 2.14 (m, 1H), 2.02-1.89 (m, 2H), 1.87-175 (m, 1H), 13 C NMR (75 MHz, CDCl 3) 3 ) δ (ppm) 159.6 (C q ), 149.3 (C q ), 139.3 (C q ), 137.6 (C q ), 130.3 (CH), 129.3 (CH), 129.1 (CH), 126.0 (CH), 125.8 (CH), 121.5 (CH), 1 15.1 (CH), 1 1 1 .1 (CH), 55.3 (CH), 45.8 (CH 3 ), 33.2 (CH 2 ), 29.9 (CH 2 ), 21.1 (CH 2 ) ; HRMS (APCI) (M + H) + m / z calcd for d 7 19 0 H 239.1430, found 239.1464.
N-(4-(4-met oxyp enyl)-1 ,2, 3, 4-tetra ydronap t alen-1-yl)acetamide [AC050] N- (4- (4-oxypenyl) -1,2,3,4-tetra-ydronapet-1-yl) acetamide [AC050]
Solide amorphe transparent obtenu selon la procédure générale n°1 (34.8 mg, 55% de rendement, d.e = 72%); mélange de diastéréoisomères [c/'s (mino): 14%, trans (majo): 86%]; CCM Rf = 0.06 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2932, 2857, 2835, 1635, 1542, 151 1 , 1445, 1243, 1 178, 1 1 12, 1036; 1H RMN (300MHz, CDCI3) δ (ppm) dia majoritaire (trans): 7.33 (d, J = 7.4 Hz, 1 H), 7.23 - 7.08 (m, 2H), 7.04 - 6.98 (m, 2H), 6.88 (d, J = 7.6 Hz, 1 H), 6.86 - 6.77 (m, 2H), 5.92 (d, J = 8.2 Hz, 1 H), 5.21 (dt, J = 8.2, 5.4 Hz, 1 H), 4.03 (t, J = 6.3 Hz, 1 H), 3.79 (s, 3H), 2.22 - 2.09 (m, 1 H), 2.04 (s, 3H), 2.00 - 1.81 (m, 3H) ; dia minoritaire (cis): 7.33 (d, J = 7.4 Hz, 1 H), 7.23 - 7.08 (m, 2H), 6.97 - 6.92 (m, 2H), 6.88 (d, J = 7.6 Hz, 1 H), 6.86 - 6.77 (m, 2H), 5.85 (d, J = 8.8 Hz, 1 H), 5.31 (dd, J = 12.7, 7.7 Hz, 1 H), 4.17 - 4.07 (m, 1 H), 3.78 (s, 3H), 2.22 - 2.09 (m, 1 H), 2.05 (s, 3H), 2.00 - 1 .81 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) dia majoritaire (trans): 169.4 (Cq),Transparent amorphous solid obtained by general procedure No. 1 (34.8 mg, 55% yield, = 72%); mixture of diastereoisomers [c / 's (mino): 14% trans (Majo): 86%]; TLC R f = 0.06 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2932, 2857, 2835, 1635, 1542, 151 1, 1445, 1243, 1178, 1 January 12, 1036; 1 H NMR (300MHz, CDCl 3) δ (ppm) majority dia ( trans): 7.33 (d, J = 7.4 Hz, 1H), 7.23 - 7.08 (m, 2H), 7.04 - 6.98 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.86 - 6.77 (m, 2H), 5.92 (d, J = 8.2 Hz, 1H), 5.21 (dt, J = 8.2, 5.4 Hz, 1H), 4.03 (t, J = 6.3 Hz, 1H), 3.79 (s, , 3H), 2.22 - 2.09 (m, 1H), 2.04 (s, 3H), 2.00 - 1.81 (m, 3H), minority dia (cis): 7.33 (d, J = 7.4 Hz, 1H), 7.23 - 7.08 (m, 2H), 6.97 - 6.92 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.86 - 6.77 (m, 2H), 5.85 (d, J = 8.8 Hz, 1H); ), 5.31 (dd, J = 12.7, 7.7 Hz, 1H), 4.17 - 4.07 (m, 1H), 3.78 (s, 3H), 2.22 - 2.09 (m, 1H), 2.05 (s, 3H) , 2.00 - 1.81 (m, 3H) 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) most (trans) dia: 169.4 (C q ),
158.1 (Cq), 140.3 (Cq), 138.6 (Cq), 137.2 (Cq), 130.3 (CH), 129.7 (2 x CH), 128.9 (CH), 127.6 (CH), 126.8 (CH), 1 13.9 (2 x CH), 55.4 (CH3), 47.8 (CH), 44.6 (CH), 29.7 (CH2), 27.6 (CH2), 23.7 (CH3) ; dia minoritaire (cis): 169.4 (Cq), 158.1 (Cq), 140.3 (Cq), 138.6 (Cq),158.1 (C q ), 140.3 (C q ), 138.6 (C q ), 137.2 (C q ), 130.3 (CH), 129.7 (2 x CH), 128.9 (CH), 127.6 (CH), 126.8 (CH) , 13.9 (2 x CH), 55.4 (CH 3 ), 47.8 (CH), 44.6 (CH), 29.7 (CH 2 ), 27.6 (CH 2 ), 23.7 (CH 3 ); dia minority (cis): 169.4 (C q ), 158.1 (C q ), 140.3 (C q ), 138.6 (C q ),
137.2 (Cq), 130.3 (CH), 129.7 (2 x CH), 128.9 (CH), 128.0 (CH), 127.5 (CH), 1 13.9 (2 x CH), 55.4 (CH3), 48.0 (CH), 44.7 (CH), 30.6 (CH2), 28.5 (CH2), 23.7 (CH3); HRMS (ESI)137.2 (C q ), 130.3 (CH), 129.7 (2 x CH), 128.9 (CH), 128.0 (CH), 127.5 (CH), 1 13.9 (2 x CH), 55.4 (CH 3 ), 48.0 (CH). ), 44.7 (CH), 30.6 (CH 2 ), 28.5 (CH 2 ), 23.7 (CH 3 ); HRMS (ESI)
(M + Na)+ m/z calculé pour Ci9H21N02Na 318.1470, trouvé 318.1466. (M + Na) + m / z calcd for C 19 H 21 N O 2 Na 318.1470, found 318.1466.
N-(4-(3, 4, 5-trimethoxyphenyl)-1 ,2, 3, 4-tetrahydronaphthalen- 1 -yl)acetamide [AC051 ]  N- (4- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-yl) acetamide [AC051]
Solide amorphe transparent obtenu selon la procédure générale n°1 (26.3 mg, 28% de rendement, d.e = 80%); brut réactionnel initialement composé d'un mélange de diastéréoisomères [c/'s (mino): 47%, trans (majo): 53%, d.e: 6%] enrichi par recristallisation avec un mélange cyclohexane/diisopropanol [c/'s (initialement mino): 90%, trans (initialement majo): 10%, d.e: 80%] ; CCM Rf = 0.12 (Cyclohexane/EtOAc, 6:4, Si02); IR (film, cm"1) 3277, 2937, 1648, 1539, 1421 , 1330, 1235, 1 126; 1H RMN (300MHz, CDCI3) δ (ppm) dia majoritaire (cis): 7.35 (d, J = 6.7 Hz, 1 H), 7.25 - 7.1 1 (m, 2H), 6.93 (d, J = 7.3 Hz, 1 H), 6.31 (s, 2H), 5.78 - 5.73 (m, 1 H), 5.22 (ddd, J = 5.3, 4.7, 2.7 Hz, 1 H), 4.01 - 3.95 (m, 1 H), 3.85 (s, 3H), 3.80 (s, 6H), 2.20 - 2.10 (m, 2H), 2.06 (s, 3H), 2.05 - 1 .96 (m, 1 H), 1 .94 - 1 .85 (m, 1 H) ; dia minoritaire (trans): 7.35 (d, J = 6.7 Hz, 1 H), 7.25 - 7.1 1 (m, 2H), 6.93 (d, J = 7.3 Hz, 1 H), 6.26 (s, 2H), 5.85 - 5.81 (m, 1 H), 5.18 (ddd, J = 5.2, 2.6, 1.2 Hz, 1 H), 4.01 - 3.95 (m, 1 H), 3.84 (s, 3H), 3.77 (s, 6H), 2.20 - 2.10 (m, 1 H), 2.06 (s, 3H), 2.05 - 1 .96 (m, 2H), 1 .94 - 1 .85 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) dia majoritaire (cis): 169.4 (Cq), 153.3 (2 x Cq), 142.0 (Cq), 139.9 (Cq), 137.1 (Cq), 136.8(Cq), 130.1 (CH), 129.0 (CH), 127.7 (CH), 127.0 (CH), 106.3 (2 x CH), 61.0 (CH), 56.4 (2 x CH3), 47.7 (CH), 46.0 (CH3), 29.5 (CH2), 28.1 (CH2), 23.7 (CH3) ; dia minoritaire (trans): 169.4 (Cq), 153.3 (2 x Cq), 142.0 (Cq), 139.9 (Cq), 137.1 (Cq), 136.8(C), 130.3 (CH), 129.0 (CH), 127.5 (CH), 127.0 (CH), 105.9 (2 x CH), 61 .0 (CH), 56.2 (2 x CH3), 48.1 (CH), 46.2 (CH3), 29.5 (CH2), 28.1 (CH2), 23.7 (CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C2i H25N04Na 378.1681 , trouvé 378.1675. Transparent amorphous solid obtained by general procedure No. 1 (26.3 mg, 28% yield, = 80%); reaction crude initially composed of a mixture of diastereoisomers [c / ' s (mino): 47%, trans (majo): 53%, of: 6%] enriched by recrystallization with a cyclohexane / diisopropanol mixture [c / ' s ( initially mino): 90%, trans (initially majo): 10%, of: 80%]; TLC R f = 0.12 (Cyclohexane / EtOAc, 6: 4, SiO 2 ); IR (film, cm "1) 3277, 2937, 1648, 1539, 1421, 1330, 1235, 1126; 1 H NMR (300MHz, CDCl 3) δ (ppm) majority dia (cis): 7.35 (d, J = 6.7 Hz, 1H), 7.25 - 7.1 1 (m, 2H), 6.93 (d, J = 7.3 Hz, 1H), 6.31 (s, 2H), 5.78 - 5.73 (m, 1H), 5.22 (ddd , J = 5.3, 4.7, 2.7 Hz, 1H), 4.01 - 3.95 (m, 1H), 3.85 (s, 3H), 3.80 (s, 6H), 2.20 - 2.10 (m, 2H), 2.06 (s, 3H), 2.05 - 1.96 (m, 1H). ), 1.94-185 (m, 1H); dia minority (trans): 7.35 (d, J = 6.7 Hz, 1H), 7.25 - 7.1 1 (m, 2H), 6.93 (d, J = 7.3 Hz, 1H), 6.26 (s, 2H), 5.85 - 5.81 (m, 1H), 5.18 (ddd, J = 5.2, 2.6, 1.2 Hz, 1H), 4.01-3.95 (m, 1H), 3.84 (s, 3H), 3.77 (s, 6H), 2.20 - 2.10 (m, 1H), 2.06 (s, 3H), 2.05-1.96 (m, 2H), 1.94-185 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) predominant dia (cis): 169.4 (C q ), 153.3 (2 x C q ), 142.0 (C q ), 139.9 (C q ), 137.1 (C q) ), 136.8 (C q ), 130.1 (CH), 129.0 (CH), 127.7 (CH), 127.0 (CH), 106.3 (2 x CH), 61.0 (CH), 56.4 (2 x CH 3 ), 47.7 ( CH), 46.0 (CH 3 ), 29.5 (CH 2 ), 28.1 (CH 2 ), 23.7 (CH 3 ); Minority (trans) dia: 169.4 (C q ), 153.3 (2 x C q ), 142.0 (C q ), 139.9 (C q ), 137.1 (C q ), 136.8 (C), 130.3 (CH), 129.0 ( CH), 127.5 (CH), 127.0 (CH), 105.9 (2 x CH), 61.0 (CH), 56.2 (2 x CH 3 ), 48.1 (CH), 46.2 (CH 3 ), 29.5 (CH 2) ), 28.1 (CH 2 ), 23.7 (CH 3 ); HRMS (ESI) (M + Na) + m / z calcd for C 2 H 25 N0 4 Na 378.1681, found 378.1675.
Cis - isopropyl 4-(4-aceta 1 -yl)benzoate [AC056-cis]  Cis - isopropyl 4- (4-acetyl-1-yl) benzoate [AC056-cis]
Solide blanc obtenu selon la procédure générale n°1 (15.0 mg, 18% de rendement); Purifié par HPLC en utilisant une colonne de type Xbridge Ci8 (4.6 x 150mm, δμηι) et un mélange H20/MeOH (30:70) en tant que solvant; mp: 146.8 - 148.4 °C; CCM Rf = 0.50 (EtOAc, Si02); IR (film, cm"1) 2959, 2923, 2852, 1701 , 1649, 1605, 1450; 1H RMN (300MHz, CDCI3) δ (ppm) 7.95 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 7.9 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.1 1 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 7.6 Hz, 1 H), 5.75 (d, J = 8.1 Hz, 1 H), 5.27 (ddd, J = 18.6, 12.6, 7.2 Hz, 2H), 4.18 (d, J = 6.2 Hz, 1 H), 2.30 - 2.15 (m, 2H), 2.06 (s, 3H), 1 .95 - 1.83 (m, 1 H), 1 .79 - 1.70 (m, 1 H), 1 .64 (s, 1 H), 1 .35 (d, J = 6.2 Hz, 6H); 13C RMN (75MHz, CDCI3) δ (ppm) 169.6 (Cq), 166.1 (Cq), 151 .7 (Cq), 139.3 (Cq), 137.6 (Cq), 130.3 (CH), 129.9 (2 x CH), 129.3 (Cq), 128.8 (2 x CH), 128.1 (CH), 127.7 (CH), 127.1 (CH), 68.4 (CH), 48.0 (CH), 45.7 (CH), 30.5 (CH2), 28.5 (CH2), 23.7 (CH3), 22.1 (2 x CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C22H25N03Na 374.1727, trouvé 374.1740. 4-(naphthalen-2-yl)chroman [AC0 White solid obtained according to General Procedure No. 1 (15.0 mg, 18% yield); Purified by HPLC using an Xbridge Ci 8 type column (4.6 x 150mm, δμηι) and an H 2 O / MeOH (30:70) mixture as a solvent; mp 146.8 - 148.4 ° C; TLC R f = 0.50 (EtOAc, Si0 2 ); IR (film, cm -1 ) 2959, 2923, 2852, 1701, 1649, 1605, 1450; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm) 7.95 (d, J = 8.2 Hz, 2H), 7.35 (d , J = 7.9 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.1 1 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 7.6 Hz, 1H), 5.75 (d, J = 8.1 Hz, 1H), 5.27 (ddd, J = 18.6, 12.6, 7.2 Hz, 2H), 4.18 (d, J = 6.2 Hz, 1H), 2.30 - 2.15 (m, 2H), 2.06 (s, 3H), 1.95 - 1.83 (m, 1H), 1.79 - 1.70 (m, 1H), 1.64 (s, 1H), 1.35 (d, J = 6.2). Hz, 6H); 13 C NMR (75MHz, CDCl 3) δ (ppm) 169.6 (C q), 166.1 (C q), 151 .7 (C q), 139.3 (C q), 137.6 (C q), 130.3 (CH), 129.9 (2 x CH), 129.3 (C q ), 128.8 (2 x CH), 128.1 (CH), 127.7 (CH), 127.1 (CH), 68.4 (CH), 48.0 (CH), 45.7 (CH), 30.5 (CH 2 ), 28.5 (CH 2 ), 23.7 (CH 3 ), 22.1 (2 x CH 3 ), HRMS (ESI) (M + Na) + m / z calculated for C 22 H 25 N0 3 Na 374.1727, found 374.1740 4- (naphthalen-2-yl) chroman [AC0
Solide beige obtenu selon la procédure générale n°1 (22.3 mg, 27% de rendement); mp: 84,8 - 85,6 °C;CCM Rf = 0.74 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 3054, 2950, 2878, 1604, 1581 , 1487, 1452, 1308, 1269, 1248, 1222; 1H RMN (300MHz, CDCI3) δ (ppm) 7.90 - 7.76 (m, 3H), 7.60 (s, 1 H), 7.54 - 7.45 (m, 2H), 7.33 (dd, J = 8.5, 1 .7 Hz, 1 H), 7.21 (tdd, J = 7.0, 1.8, 0.6 Hz, 1 H), 6.97 (dd, J = 8.1 , 0.8 Hz, 1 H), 6.87 (tdd, J = 8.7, 7.8, 1 .2 Hz, 2H), 4.38 (t, J = 6.5 Hz, 1 H), 4.31 - 4.21 (m, 2H), 2.46 - 2.33 (m, 1 H), 2.24 (dtd, J = 18.1 , 6.7, 4.1 Hz, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 155.34 (Cq), 143.07 (Cq), 133.48 (Cq), 132.41 (Cq), 130.86 (CH), 128.41 (CH), 128.06 (CH), 127.80 (CH), 127.72 (CH), 127.67 (CH), 126.78 (CH), 126.25 (CH), 125.75 (CH), 124.58 (Cq), 120.51 (CH), 1 16.96 (CH), 64.09 (CH2), 41.37 (CH), 31.63 (CH2); HRMS (APCI) (M + H)+ m/z calculé pour Ci9H170 261.1274, trouvé 261 ,1273. Beige solid obtained according to General Procedure No. 1 (22.3 mg, 27% yield); mp: 84.8-85.6 ° C TLC R f = 0.74 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 3054, 2950, 2878, 1604, 1581, 1487, 1452, 1308, 1269, 1248, 1222; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.90 - 7.76 (m, 3H ), 7.60 (s, 1H), 7.54 - 7.45 (m, 2H), 7.33 (dd, J = 8.5, 1.7 Hz, 1H), 7.21 (tdd, J = 7.0, 1.8, 0.6Hz, 1H), 6.97 (dd, J = 8.1, 0.8Hz, 1H), 6.87 (tdd, J = 8.7, 7.8, 1.2 Hz). , 2H), 4.38 (t, J = 6.5 Hz, 1H), 4.31 - 4.21 (m, 2H), 2.46 - 2.33 (m, 1H), 2.24 (dtd, J = 18.1, 6.7, 4.1 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 155.34 (C q ), 143.07 (C q ), 133.48 (C q ), 132.41 (C q ), 130.86 (CH), 128.41 (CH), 128.06 ( CH), 127.80 (CH), 127.72 (CH), 127.67 (CH), 126.78 (CH), 126.25 (CH), 125.75 (CH), 124.58 (C q ), 120.51 (CH), 1 16.96 (CH), 64.09 (CH 2 ), 41.37 (CH), 31.63 (CH 2 ); HRMS (APCI) (M + H) + m / z calcd for C 19 H 17 O 261.1274, found 261, 1273.
N-(1, 2, 3, 4-tetrahydro-l 1,2'-binaphthalen]-4-yl)acetamide [AC070] N- (1,2,3,4-tetrahydro-1, 2'-binaphthalen-4-yl) acetamide [AC070]
Solide transparent obtenu selon la procédure générale n°1 (39.0 mg, 48% de rendement, d.e = 74%) mélange de diastéréoisomères [c/'s (mino): 13%, trans (majo): 87%]; CCM Rf = 0.56 (EtOAc, Si02); IR (film, cm"1) 3268, 3055, 2930, 2855, 1634, 1540, 1450, 1371 ; 1H RMN (300MHz, CDCI3) δ (ppm) 7.79 (td, J = 9.7, 5.3 Hz, 3H), 7.53 (s, 1 H), 7.49 - 7.43 (m, 2H), 7.39 (d, J = 7.4 Hz, 1 H), 7.26 (d, J = 1.9 Hz, 1 H), 7.23 (d, J = 7.0 Hz, 1 H), 7.14 (dd, J = 10.7, 4.3 Hz, 1 H), 6.91 (d, J = 7.7 Hz, 1 H), 5.88 (d, J = 7.8 Hz, 1 H), 5.29 - 5.19 (m, 1 H), 4.24 (t, J = 6.1 Hz, 1 H), 2.19 (dd, J = 1 1 .7, 6.1 Hz, 1 H), 2.07 (s, 3H), 2.03 (dd, J = 6.8, 4.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 169.4 (Cq), 143.9 (Cq), 139.9 (Cq), 137.3 (Cq), 133.5 (Cq), 132.3 (Cq), 130.5 (CH), 129.1 (CH), 127.8 (2 x CH), 127.7 (CH), 127.6 (CH), 127.0 (2 x CH), 126.3 (CH), 125.7 (CH), 47.9 (CH), 45.6 (CH), 29.4 (CH2), 27.8 (CH2), 23.8 (CH3); HRMS (APCI) (M + H)+ m/z calculé pour C22H22NO 316.1696, trouvé 316,1699. Transparent solid obtained according to General Procedure 1 (39.0 mg, 48% yield, de = 74%) mixture of diastereomers [c / 's (mino): 13% trans (Majo): 87%]; TLC R f = 0.56 (EtOAc, Si0 2 ); IR (film, cm "1) 3268, 3055, 2930, 2855, 1634, 1540, 1450, 1371; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.79 (td, J = 9.7, 5.3 Hz, 3H) , 7.53 (s, 1H), 7.49-7.43 (m, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.14 (dd, J = 10.7, 4.3Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 5.88 (d, J = 7.8Hz, 1H), 5.29- 5.19 (m, 1H), 4.24 (t, J = 6.1Hz, 1H), 2.19 (dd, J = 1.17, 6.1Hz, 1H), 2.07 (s, 3H), 2.03 (dd, J = 6.8, 4.2 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 169.4 (C q ), 143.9 (C q ), 139.9 (C q ), 137.3 (C q ), 133.5 ( C q ), 132.3 (C q ), 130.5 (CH), 129.1 (CH), 127.8 (2 x CH), 127.7 (CH), 127.6 (CH), 127.0 (2 x CH), 126.3 (CH), 125.7 (CH), 47.9 (CH), 45.6 (CH), 29.4 (CH 2 ), 27.8 (CH 2 ), 23.8 (CH 3 ), HRMS (APCI) (M + H) + m / z calculated for C 22 H 22 316.1696, found 316.1699.
C/'s - N-(1 ,2,3,4-tetra ydro-fl ,2 [AC070-cis] C / ' s - N- (1, 2,3,4-tetra ydro-fl, 2 [AC070-cis]
Solide blanc obtenu selon la procédure générale n°1 (10.0 mg, 3% de rendement); Purifié par HPLC en utilisant une colonne de type Xbridge Ci8 (4.6 x 150mm, δμηι) et un mélange H20/MeOH (25:75) en tant que solvant; mp: 175.3 - 176.2 °C; CCM Rf = 0.67 (EtOAc, Si02); IR (film, cm"1) 3268, 3055, 2930, 2855, 1634, 1540, 1450, 1371 ; 1H RMN (300MHz, CDCIs) δ (ppm) 7.79 (ddd, J = 14.5, 7.4, 5.7 Hz, 3H), 7.50 (s, 1 H), 7.48 - 7.43 (m, 2H), 7.39 (d, J = 7.4 Hz, 1 H), 7.26 - 7.17 (m, 2H), 7.12 (t, J = 7.2 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 5.73 (d, J = 9.0 Hz, 1 H), 5.40 (dd, J = 13.1 , 8.9 Hz, 1 H), 4.36 - 4.27 (m, 1 H), 2.33 - 2.22 (m, 2H), 2.10 (s, 3H), 2.02 (dd, J = 17.5, 8.3 Hz, 1 H), 1 .77 (dd, J = 18.9, 9.6 Hz, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 170.5 (Cq), 143.9 (Cq), 143.3 (Cq), 140.0 (Cq), 137.7 (Cq), 133.6 (Cq), 130.6 (CH), 128.4 (CH), 128.0 (CH), 127.8 (2 x CH), 127.6 (CH), 127.5 (CH), 127.1 (CH), 127.0 (CH), 126.2 (CH), 125.7 (CH), 48.2 (CH), 45.9 (CH), 30.5 (CH2), 28.8 (CH2), 23.8 (CH3); HRMS (APCI) (M + H)+ m/z calculé pour C22H22NO 316.1696, trouvé 316,1699. White solid obtained according to General Procedure No. 1 (10.0 mg, 3% yield); Purified by HPLC using an Xbridge Ci 8 column (4.6 x 150mm, δμηι) and a mixture of H 2 0 / MeOH (25:75) as the solvent; mp 175.3-176.2 ° C; TLC R f = 0.67 (EtOAc, SiO 2 ); IR (film, cm "1) 3268, 3055, 2930, 2855, 1634, 1540, 1450, 1371; 1 H NMR (300MHz, CDCl) δ (ppm) 7.79 (ddd, J = 14.5, 7.4, 5.7 Hz, 3H ), 7.50 (s, 1H), 7.48 - 7.43 (m, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 7.5Hz, 1H), 5.73 (d, J = 9.0Hz, 1H), 5.40 (dd, J = 13.1, 8.9Hz, 1H), 4.36 - 4.27 (m. , 1H), 2.33-2.22 (m, 2H), 2.10 (s, 3H), 2.02 (dd, J = 17.5, 8.3Hz, 1H), 1.77 (dd, J = 18.9, 9.6Hz, 1H). H) 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 170.5 (C q ), 143.9 (C q ), 143.3 (C q ), 140.0 (C q ), 137.7 (C q ), 133.6 (C q ), 130.6 (CH), 128.4 (CH), 128.0 (CH), 127.8 (2 x CH), 127.6 (CH), 127.5 (CH), 127.1 (CH), 127.0 (CH), 126.2 (CH), 125.7 (CH), 48.2 (CH), 45.9 (CH), 30.5 (CH 2 ), 28.8 (CH 2 ), 23.8 (CH), 3 ); HRMS (APCI) (M + H) + m / z calcd for C 21 H 22 NO 316.1696, found 316.1699.
C/'s - N-(4-(1H-indol-5-yl)-1,2,3A aœtamide [AC081-cis] C / ' s - N- (4- (1H-indol-5-yl) -1,2,3A-acetamide [AC081-cis]
Solide blanc obtenu selon la procédure générale n°1 (17.0 mg, 22% de rendement); mp: White solid obtained according to General Procedure No. 1 (17.0 mg, 22% yield); mp:
109.3 - 110.8 °C; CCM Rf = 0.46 (EtOAc, Si02); IR (film, cm"1) 3413, 3282, 3054, 2924, 2853, 1650, 1511, 1451, 1373, 1344, 1264, 1096; 1H RMN (300MHz, CDCI3) δ (ppm) 8.23 (s, 1H), 7.38 - 7.28 (m, 3H), 7.20 (dd, J = 8.6, 5.5 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.90 (dd, J= 15.1, 8.2 Hz, 2H), 6.51 -6.44 (m, 1H), 5.77 (d, J = 8.9 Hz, 1H), 5.37 (dt, J = 8.4, 4.5 Hz, 1H), 4.23 (dd, J = 8.2, 4.8 Hz, 1H), 2.29-2.19 (m, 2H), 2.07 (s, 3H), 2.06- 1.95 (m, 1H), 1.72 (ddd, J= 18.6, 10.8,5.6 Hz, 1H); 13C RMN (75 MHz, CDCI3) δ (ppm) 169.6 (Cq), 141.2 (Cq), 138.1 (Cq), 137.5 (Cq), 134.7 (Cq), 130.7 (CH), 128.0 (Cq), 127.8 (CH),109.3 - 110.8 ° C; TLC R f = 0.46 (EtOAc, SiO 2 ); IR (film, cm "1) 3413, 3282, 3054, 2924, 2853, 1650, 1511, 1451, 1373, 1344, 1264, 1096; 1 H NMR (300MHz, CDCl 3) δ (ppm) 8.23 (s, 1H ), 7.38 - 7.28 (m, 3H), 7.20 (dd, J = 8.6, 5.5 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.90 (dd, J = 15.1, 8.2 Hz, 2H) , 6.51 -6.44 (m, 1H), 5.77 (d, J = 8.9 Hz, 1H), 5.37 (dt, J = 8.4, 4.5 Hz, 1H), 4.23 (dd, J = 8.2, 4.8 Hz, 1H), 2.29-2.19 (m, 2H), 2.07 (s, 3H), 2.06-1.95 (m, 1H), 1.72 (ddd, J = 18.6, 10.8.5.6 Hz, 1H); 13 C NMR (75 MHz, CDCl 3) ) δ (ppm) 169.6 (C q ), 141.2 (C q ), 138.1 (C q ), 137.5 (C q ), 134.7 (C q ), 130.7 (CH), 128.0 (C q ), 127.8 (CH) ,
127.4 (CH), 126.6 (CH), 124.6 (CH), 123.1 (CH), 120.8 (CH), 111.2 (CH), 102.6 (CH), 48.2 (CH), 45.7 (CH), 31.1 (CH2), 28.8 (CH2), 23.8 (CH3); HRMS (APCI) (M + Na)+ m/z calculé pour C20H20N2ONa 327.1473, trouvé 327.1473. 127.4 (CH), 126.6 (CH), 124.6 (CH), 123.1 (CH), 120.8 (CH), 111.2 (CH), 102.6 (CH), 48.2 (CH), 45.7 (CH), 31.1 (CH 2 ) 28.8 (CH 2 ), 23.8 (CH 3 ); HRMS (APCI) (M + Na) + m / z calcd for C 20 H 20 N 2 ONa 327.1473, found 327.1473.
5-(1,2,3,4-tetrahydronaphthalen-1- ] 5- (1,2,3,4-tetrahydronaphthalen-1-)
Solide beige obtenu selon la procédure générale n°1 (56.0 mg, 71% de rendement); mp: 117.4 - 119.3 °C; CCM Rf = 0.71 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1); 1H RMNBeige solid obtained by general procedure No. 1 (56.0 mg, 71% yield); mp 117.4-119.3 ° C; TLC R f = 0.71 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1); 1H NMR
(300MHz, CDCI3)5 (ppm) 8.03 (s, 1H), 7.39 (s, 1H), 7.32 (d, J= 8.4 Hz, 1H), 7.16 (dd, J =(300 MHz, CDCl 3 ) (ppm) 8.03 (s, 1H), 7.39 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.16 (dd, J =
11.4, 4.7 Hz, 3H), 7.07 - 6.91 (m, 3H), 6.51 (d, J = 2.1 Hz, 1H), 4.30-4.18 (m, 1H), 2.9311.4, 4.7 Hz, 3H), 7.07 - 6.91 (m, 3H), 6.51 (d, J = 2.1 Hz, 1H), 4.30-4.18 (m, 1H), 2.93
(qd, J= 16.4, 7.8 Hz, 2H), 2.32-2.17 (m, 1H), 2.05- 1.91 (m, 2H), 1.86 - 1.77 (m, 1H);(qd, J = 16.4, 7.8Hz, 2H), 2.32-2.17 (m, 1H), 2.05-1.90 (m, 2H), 1.86-1.77 (m, 1H);
13C RMN (75 MHz, CDCI3) δ (ppm) 140.6 (Cq), 139.2 (Cq), 137.7 (Cq), 134.5 (Cq), 130.5 (CH), 129.0 (CH), 128.0 (Cq), 125.8 (CH), 125.7 (CH), 124.4 (CH), 123.4 (CH), 120.9 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 140.6 (C q ), 139.2 (C q ), 137.7 (C q ), 134.5 (C q ), 130.5 (CH), 129.0 (CH), 128.0 ( C q ), 125.8 (CH), 125.7 (CH), 124.4 (CH), 123.4 (CH), 120.9
(CH), 110.9 (CH), 102.6 (CH), 45.9 (CH), 33.9 (CH2), 30.1 (CH2), 21.4 (CH2); HRMS(CH), 110.9 (CH), 102.6 (CH), 45.9 (CH), 33.9 (CH 2 ), 30.1 (CH 2 ), 21.4 (CH 2 ); HRMS
(APCI) (M + H)+ m/z calculé pour d8H18N 248.1434, trouvé 248.1436. (APCI) (M + H) + m / z calcd for d 8 H 18 N 248.1434, found 248.1436.
C/'s - [AC083-cis] Solide blanc obtenu selon la procédure générale n°1 (10.7 mg, 13% de rendement); mp: 203.3 - 204.5 °C; CCM Rf = 0.53 (EtOAc, Si02); IR (film, cm"1) 3268, 3050, 2924, 2853, 1648, 1540, 1501 , 1449, 1371 , 1261 , 1 102, 1036; 1H RMN (300MHz, CDCI3) δ (ppm) 8.87 (d, J = 2.8 Hz, 1 H), 8.04 (t, J = 8.2 Hz, 2H), 7.45 (d, J = 8.7 Hz, 1 H), 7.43 - 7.34 (m, 3H), 7.24 (d, J = 7.7 Hz, 1 H), 7.13 (t, J = 7.4 Hz, 1 H), 6.87 (d, J = 7.7 Hz, 1 H), 5.78 (d, J = 8.6 Hz, 1 H), 5.38 (dd, J = 13.3, 8.1 Hz, 1 H), 4.35 (t, J = 6.0 Hz, 1 H), 2.33 - 2.14 (m, 2H), 2.08 (s, 3H), 2.02 (dd, J = 12.1 , 9.1 Hz, 1 H), 1.77 (ddd, J = 12.4, 10.4, 5.1 Hz, 1 H); 13C RMN (75 MHz, CDCIs) δ (ppm) 169.6 (Cq), 150.2 (CH), 147.4 (Cq), 144.8 (Cq), 139.4 (Cq), 137.7 (Cq), 135.9 (CH), 130.8 (CH), 130.4 (CH), 129.8 (CH), 128.3 (Cq), 128.2 (CH), 127.7 (CH), 127.1 (2 x CH), 121 .4 (CH), 48.0 (CH), 45.6 (CH), 30.4 (CH2), 28.5 (CH2), 23.7 (CH3); HRMS (APCI) (M + H)+ m/z calculé pour C2iH2iN20 317.1648, trouvé 317.1648. C / ' s - [AC083-cis] White solid obtained according to General Procedure No. 1 (10.7 mg, 13% yield); mp 203.3- 204.5 ° C; TLC R f = 0.53 (EtOAc, SiO 2 ); IR (film, cm "1) 3268, 3050, 2924, 2853, 1648, 1540, 1501, 1449, 1371, 1261, 1102, 1036; 1 H NMR (300MHz, CDCl 3) δ (ppm) 8.87 (d, J = 2.8 Hz, 1H), 8.04 (t, J = 8.2 Hz, 2H), 7.45 (d, J = 8.7 Hz, 1H), 7.43 - 7.34 (m, 3H), 7.24 (d, J = 7.7). Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 8.6 Hz, 1H), 5.38 (dd, J). = 13.3, 8.1 Hz, 1H), 4.35 (t, J = 6.0 Hz, 1H), 2.33 - 2.14 (m, 2H), 2.08 (s, 3H), 2.02 (dd, J = 12.1, 9.1 Hz, 1H), 1.77 (ddd, J = 12.4, 10.4, 5.1 Hz, 1 H); 13 C NMR (75 MHz, CDCl) δ (ppm) 169.6 (C q), 150.2 (CH), 147.4 (C q) , 144.8 (C q ), 139.4 (C q ), 137.7 (C q ), 135.9 (CH), 130.8 (CH), 130.4 (CH), 129.8 (CH), 128.3 (C q ), 128.2 (CH), 127.7 (CH), 127.1 (2 x CH), 121.4 (CH), 48.0 (CH), 45.6 (CH), 30.4 (CH 2 ), 28.5 (CH 2 ), 23.7 (CH 3 ), HRMS (APCI ) (M + H) + m / z calcd for C 2 iH 2 iN 2 O 317.1648, found 317.1648.
6-( 1,2,3, 4-tetra ydronap t alen-1-yl)isoquinoline [AC084] 6- (1,2,3,4-tetra-ydronapet-1-yl) isoquinoline [AC084]
Huile transparente obtenue selon la procédure générale n°1 (36.6 mg, 52% de rendement); CCM Rf = 0.36 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2958, 2924, 2853, 1734, 1595, 1495, 1467, 1264; 1H RMN (300MHz, CDCI3) δ (ppm) 8.87 (d, J = 3.0 Hz, 1 H), 8.05 (dd, J = 10.9, 8.8 Hz, 2H), 7.55 - 7.45 (m, 2H), 7.37 (dd, J = 8.3, 4.2 Hz, 1 H), 7.21 - 7.12 (m, 2H), 7.08 - 7.00 (m, 1 H), 6.85 (d, J = 7.6 Hz, 1 H), 4.33 (t, J = 6.8 Hz, 1 H), 3.02 - 2.82 (m, 2H), 2.33 - 2.17 (m, 1 H), 2.03 - 1.89 (m, 2H), 1 .86 - 1.75 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 150.0 (CH), 147.4 (Cq), 146.0 (Cq), 138.9 (Cq), 137.8 (Cq), 135.9 (CH), 131 .1 (CH), 130.4 (CH), 129.5 (CH), 129.3 (CH), 128.3 (Cq), 127.2 (CH), 126.3 (CH), 125.9 (CH), 121 .2 (CH), 45.7 (CH), 33.2 (CH2), 29.9 (CH2), 21.1 (CH2); HRMS (ESI) (M + H)+ m/z calculé pour d9H18N 260.1434, trouvé 260.1432. Transparent oil obtained according to General Procedure No. 1 (36.6 mg, 52% yield); TLC R f = 0.36 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm -1 ) 2958, 2924, 2853, 1734, 1595, 1495, 1467, 1264; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm) 8.87 (d, J = 3.0 Hz, 1H), 8.05 (dd, J = 10.9, 8.8 Hz, 2H), 7.55 - 7.45 (m, 2H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.08 - 7.00 (m, 1H), 6.85 (d, J = 7.6 Hz, 1H), 4.33 (t, J = 6.8 Hz, 1H), 3.02 - 2.82 (m, 2H), 2.33 - 2.17 (m, 1H). ), 2.03 - 1.89 (m, 2H), 1.86 - 1.75 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 150.0 (CH), 147.4 (C q ), 146.0 ( C q ), 138.9 (C q ), 137.8 (C q ), 135.9 (CH), 131.1 (CH), 130.4 (CH), 129.5 (CH), 129.3 (CH), 128.3 (C q ), 127.2 (CH), 126.3 (CH), 125.9 (CH), 121.2 (CH), 45.7 (CH), 33.2 (CH 2 ), 29.9 (CH 2 ), 21.1 (CH 2 ), HRMS (ESI) (M. + H) + m / z calcd for d 9 H 18 N 260.1434, found 260.1432.
4-(naphthalen-2-yl)thiochroman [A 4- (naphthalen-2-yl) thiochroman [A]
Solide beige obtenu selon la procédure générale n°1 (134.0 mg, 49% de rendement); mp: 65.6 - 67.3 °C; CCM Rf = 0.84 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 3054, 2919, 2851 , 1600, 1506, 1474, 1434, 1264, 1 164, 1090; 1H RMN (300MHz, CDCI3) δ (ppm) 7.89 - 7.76 (m, 3H), 7.49 (t, J = 4.7 Hz, 3H), 7.37 - 7.27 (m, 2H), 7.22 - 7.14 (m, 1 H), 6.98 (q, J = 7.4 Hz, 2H), 4.43 (t, J = 5.1 Hz, 1 H), 2.98 (dd, J = 8.9, 4.2 Hz, 2H), 2.51 - 2.42 (m, 2H); 13C RMN (75MHz, CDCI3) δ (ppm) 142.7 (Cq), 135.4 (Cq), 133.7 (Cq), 133.5 (Cq), 132.3 (Cq), 131 .5 (CH), 128.3 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 127.1 (CH), 126.8 (CH), 126.6 (CH), 126.2 (CH), 125.8 (CH), 124.2 (CH), 44.5 (CH), 30.8 (CH2), 23.8 (CH2). 6-methoxy-1 ,2, 3, 4-tetrahydro-1 ,2'-binaphthalene [AC086] Beige solid obtained according to General Procedure No. 1 (134.0 mg, 49% yield); mp 65.6-67.3 ° C; TLC R f = 0.84 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm -1 ) 3054, 2919, 2851, 1600, 1506, 1474, 1434, 1264, 1164, 1090, 1 H NMR (300 MHz, CDCl 3 ) δ (ppm) 7.89 - 7.76 (m, 3H) , 7.49 (t, J = 4.7 Hz, 3H), 7.37 - 7.27 (m, 2H), 7.22 - 7.14 (m, 1H), 6.98 (q, J = 7.4 Hz, 2H), 4.43 (t, J = 5.1 Hz, 1H), 2.98 (dd, J = 8.9, 4.2 Hz, 2H), 2.51 - 2.42 (m, 2H); 13 C NMR (75MHz, CDCl 3) δ (ppm) 142.7 (C q), 135.4 (C q ), 133.7 (C q ), 133.5 (C q ), 132.3 (C q ), 131.5 (CH), 128.3 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 127.1 (CH), 126.8 (CH), 126.6 (CH), 126.2 (CH), 125.8 (CH), 124.2 (CH), 44.5 (CH), 30.8 (CH 2 ), 23.8 (CH 2 ). 6-methoxy-1,2,3,4-tetrahydro-1,2'-binaphthalene [AC086]
Solide beige obtenu selon la procédure générale n°1 (70.2 mg, 83% de rendement); mp: 66.6 - 68.3 °C; CCM Rf = 0.80 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 3055, 2929, 2856, 2833, 1608, 1500, 1464, 1253, 1 155, 1038; 1H RMN (300MHz, CDCI3) δ (ppm) 7.92 - 7.81 (m, 3H), 7.63 (s, 1 H), 7.52 (dd, J = 6.7, 2.9 Hz, 2H), 7.35 (dd, J = 8.5, 1 .7 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 6.82 (d, J = 2.6 Hz, 1 H), 6.71 (dd, J = 8.5, 2.7 Hz, 1 H), 4.31 (t, J = 6.0 Hz, 1 H), 3.87 (s, 3H), 3.10 - 2.89 (m, 2H), 2.37 - 2.22 (m, 1 H), 2.13 - 1 .96 (m, 2H), 1.93 - 1.80 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 157.8 (Cq), 145.2 (Cq), 138.9 (Cq), 133.5 (Cq), 132.2 (Cq), 131 .6 (Cq), 131 .4 (CH), 128.0 (CH), 127.7 (2 x CH), 127.3 (2 x CH), 126.0 (CH), 125.4 (CH), 1 13.4 (CH), 1 12.2 (CH), 55.3 (CH), 45.3 (CH3), 33.5 (CH2), 30.3 (CH2), 21.3 (CH2); HRMS (ESI) (M + H)+ m/z calculé pour C2i H210 289.1587, trouvé 289.1588. Beige solid obtained according to General Procedure No. 1 (70.2 mg, 83% yield); mp 66.6-68.3 ° C; TLC R f = 0.80 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 3055, 2929, 2856, 2833, 1608, 1500, 1464, 1253, 1155, 1038; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.92 - 7.81 (m, 3H) , 7.63 (s, 1H), 7.52 (dd, J = 6.7, 2.9 Hz, 2H), 7.35 (dd, J = 8.5, 1.7 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H). H), 6.82 (d, J = 2.6Hz, 1H), 6.71 (dd, J = 8.5, 2.7Hz, 1H), 4.31 (t, J = 6.0Hz, 1H), 3.87 (s, 3H); , 3.10 - 2.89 (m, 2H), 2.37-2.22 (m, 1H), 2.13-1.96 (m, 2H), 1.93-1.80 (m, 1H), 13 C NMR (75 MHz, CDCl 3) ) δ (ppm) 157.8 (C q), 145.2 (C q), 138.9 (C q), 133.5 (C q), 132.2 (C q), 131 .6 (C q), 131 .4 (CH), 128.0 (CH), 127.7 (2 x CH), 127.3 (2 x CH), 126.0 (CH), 125.4 (CH), 1 13.4 (CH), 1 12.2 (CH), 55.3 (CH), 45.3 (CH 3 ), 33.5 (CH 2 ), 30.3 (CH 2 ), 21.3 (CH 2 ), HRMS (ESI) (M + H) + m / z calculated for C 2 H 21 O 289.1587, found 289.1588.
N-(4-(3-iodophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide [AC087] N- (4- (3-iodophenyl) -1,2,3,4-tetrahydronaphthalen-1-yl) acetamide [AC087]
Solide amorphe obtenu selon la procédure générale n°1 (47.3 mg, 47% de rendement, d.e = 12%) mélange de diastéréoisomères (obtenu après trituration du produit purifié, en utilisant du MeOH de grade HPLC), lors de la trituration le dia majoritaire (trans) est devenu minoritaire (et inversement pour le dia c/'s) [c/'s (majo): 56%, trans (mino): 44%]; CCM Rf = 0.62 (EtOAc, Si02); IR (film, cm"1) 3273, 3057, 2928, 2855, 1632, 1540, 1371 , 1263, 1 107, 1066; 1H RMN (300MHz, CDCI3) δ (ppm) dia majoritaire (trans): 7.55 (d, J = 6.9 Hz, 1 H), 7.45 (s, 1 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.25 - 7.12 (m, 2H), 7.06 - 6.92 (m, 2H), 6.87 - 6.80 (m, 1 H), 5.87 - 5.79 (m, 1 H), 5.24 - 5.16 (m, 1 H), 4.1 1 - 3.96 (m, 1 H), 2.21 - 2.13 (m, 1 H), 2.06 (s, 3H), 1 .91 (dd, J = 18.5, 6.5 Hz, 2H), 1 .79 - 1 .67 (m, ) ; dia minoritaire (cis): 7.55 (d, J = 6.9 Hz, 1 H), 7.45 (s, 1 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.25 - 7.12 (m, 2H), 7.06 - 6.92 (m, 2H), 6.87 - 6.80 (m, 1 H), 5.77 - 5.67 (m, 1 H), 5.36 - 5.28 (m, 1 H), 4.1 1 - 3.96 (m, 1 H), 2.21 - 2.13 (m, 1 H), 2.06 (s, 3H), 1 .91 (dd, J = 18.5, 6.5 Hz, 2H), 1.79 - 1 .67 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) dia majoritaire (trans): 169.7 (Cq), 149.0 (Cq), 139.1 (Cq), 137.7 (CH), 137.5 (Cq), 135.6 (CH), 130.3 (2 x CH), 129.1 (CH), 128.1 (CH), 127.7 (CH), 127.2 (CH), 94.7 (Cq), 47.8 (CH), 45.2 (CH), 29.6 (CH2), 27.6 (CH2), 23.7 (CH3) ; dia minoritaire (cis): 169.7 (Cq), 149.0 (Cq), 139.1 (Cq), 137.7 (CH), 137.5 (Cq), 135.6 (CH), 130.2 (2 x CH), 129.1 (CH), 128.3 (CH), 127.9 (CH), 127.2 (CH), 94.7 (Cq), 48.0 (CH), 45.2 (CH), 30.5 (CH2), 28.5 (CH2), 23.7 (CH3); HRMS (ESI) (M + Na)+ m/z calculé pour Ci8H18INONa 414.0325, trouvé 414.0328. Amorphous solid obtained according to the general procedure No. 1 (47.3 mg, 47% yield, = 12%) mixture of diastereoisomers (obtained after trituration of the purified product, using HPLC-grade MeOH), during the trituration the dia Majority (trans) became a minority (and conversely for the dia c / ' s) [c / ' s (majo): 56%, trans (mino): 44%]; TLC R f = 0.62 (EtOAc, SiO 2 ); IR (film, cm "1) 3273, 3057, 2928, 2855, 1632, 1540, 1371, 1263, 1107, 1066; 1 H NMR (300MHz, CDCl 3) δ (ppm) majority dia (trans): 7.55 ( d, J = 6.9 Hz, 1H), 7.45 (s, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.06 - 6.92 (m, 2H), 6.87 - 6.80 (m, 1H), 5.87 - 5.79 (m, 1H), 5.24 - 5.16 (m, 1H), 4.11 - 3.96 (m, 1H), 2.21 - 2.13 (m, 1H) , 2.06 (s, 3H), 1.91 (dd, J = 18.5, 6.5 Hz, 2H), 1.79-167 (m,), minority dia (cis): 7.55 (d, J = 6.9 Hz); , 7.45 (s, 1 H), 7.34 (d, J = 7.5 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.06 - 6.92 (m, 2H), 6.87 - 6.80 (m, 1H), 5.77 - 5.67 (m, 1H), 5.36 - 5.28 (m, 1H), 4.11 - 3.96 (m, 1H), 2.21 - 2.13 (m, 1H), 2.06 (s, 3H); ), 1.91 (dd, J = 18.5, 6.5 Hz, 2H), 1.79-167 (m, 1H), 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) most (trans) dia: 169.7 (C q ), 149.0 (C q ), 139.1 (C q ), 137.7 (CH), 137.5 (C q ), 135.6 (CH), 130.3 (2 x CH), 129.1 (CH), 128.1 (CH) , 127.7 (CH), 127.2 (CH), 94.7 (C q ), 47.8 (CH), 45.2 (CH), 29.6 (CH 2 ) 27.6 (CH 2 ), 23.7 (CH 3 ); dia minority (cis): 169.7 (C q ), 149.0 (C q ), 139.1 (C q ), 137.7 (CH), 137.5 (C q ), 135.6 (CH), 130.2 (2 x CH), 129.1 (CH) ), 128.3 (CH), 127.9 (CH), 127.2 (CH), 94.7 (C q ), 48.0 (CH), 45.2 (CH), 30.5 (CH 2 ), 28.5 (CH 2 ), 23.7 (CH 3 ); HRMS (ESI) (M + Na) + m / z calcd for Ci 8 H 18 Inona 414.0325, found 414.0328.
N-(4-(4-bromop enyl)-1 ,2, 3, 4-tetra ydronap t alen- 1 -yl)acetamide [AC088] N- (4- (4-bromopenyl) -1,2,3,4-tetra ydronapetalen-1-yl) acetamide [AC088]
Solide amorphe obtenu selon la procédure générale n°1 (37.6 mg, 42% de rendement, d.e = 48%) mélange de diastéréoisomères (obtenu après trituration du produit purifié, en utilisant du MeOH de grade HPLC) [c/'s (mino): 26%, trans (majo): 74%]; CCM Rf = 0.44 (EtOAc, Si02); IR (film, cm"1) 3268, 3059, 2928, 2856, 1633, 1543, 1487, 1372, 1262; 1H RMN (300MHz, CDCI3) δ (ppm) dia majoritaire (trans): 7.48 - 7.29 (m, 3H), 7.24 - 7.18 (m, 1 H), 7.16 - 7.10 (m, 1 H), 7.02 - 6.88 (m, 2H), 6.87 - 6.79 (m, 1 H), 5.80 - 5.62 (m, 1 H), 5.19 (dd, J = 12.6, 8.1 Hz, 1 H), 4.09 (dd, J = 17.2, 8.5 Hz, 1 H), 2.16 (dd, J = 10.3, 7.6 Hz, 1 H), 2.09 - 2.02 (s, 3H), 2.00 - 1 .80 (m, 3H) ; dia minoritaire (cis): 7.48 - 7.29 (m, 3H), 7.24 - 7.18 (m, 1 H), 7.16 - 7.10 (m, 1 H), 7.02 - 6.88 (m, 2H), 6.87 - 6.79 (m, 1 H), 5.80 - 5.62 (m, 1 H), 5.35 - 5.27 (m, 1 H), 4.09 (dd, J = 17.2, 8.5 Hz, 1 H), 2.16 (dd, J = 10.3, 7.6 Hz, 1 H), 2.09 - 2.02 (s, 3H), 2.00 - 1 .80 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) dia majoritaire (trans): 164.6 (Cq), 145.6 (Cq), 139.3 (Cq), 137.3 (Cq), 131 .7 (2 x CH), 130.6 (2 x CH), 130.3 (CH), 129.1 (CH), 127.9 (CH), 127.2 (CH), 120.3 (Cq), 47.9 (CH), 44.9 (CH), 29.6 (CH2), 27.5 (CH2), 23.8 (CH3) ; dia minoritaire (cis): 164.6 (Cq), 145.6 (Cq), 139.3 (Cq), 137.3 (Cq), 131 .7 (2 x CH), 130.6 (2 x CH), 130.3 (CH), 128.2 (CH), 127.7 (CH), 127.2 (CH), 120.3 (Cq), 48.0 (CH), 45.1 (CH), 30.5 (CH2), 28.5 (CH2), 23.8 (CH3); HRMS (ESI) (M + Na)+ m/z calculé pour Ci8H18BrNONa 366.0464, trouvé 366.0478. Amorphous solid obtained according to general procedure No. 1 (37.6 mg, 42% yield, = 48%) mixture of diastereoisomers (obtained after trituration of the purified product, using HPLC-grade MeOH) [c / ' s (min. ): 26%, trans (majo): 74%]; TLC R f = 0.44 (EtOAc, SiO 2 ); IR (film, cm "1) 3268, 3059, 2928, 2856, 1633, 1543, 1487, 1372, 1262; 1 H NMR (300MHz, CDCl 3) δ (ppm) majority dia (trans): 7.48 - 7.29 (m , 3H), 7.24 - 7.18 (m, 1H), 7.16 - 7.10 (m, 1H), 7.02 - 6.88 (m, 2H), 6.87 - 6.79 (m, 1H), 5.80 - 5.62 (m, 1 H), 5.19 (dd, J = 12.6, 8.1 Hz, 1H), 4.09 (dd, J = 17.2, 8.5Hz, 1H), 2.16 (dd, J = 10.3, 7.6 Hz, 1H), 2.09 - 2.02 (s, 3H), 2.00 - 1.80 (m, 3H), minority dia (cis): 7.48 - 7.29 (m, 3H), 7.24 - 7.18 (m, 1H), 7.16 - 7.10 (m, 1H). H), 7.02 - 6.88 (m, 2H), 6.87 - 6.79 (m, 1H), 5.80 - 5.62 (m, 1H), 5.35 - 5.27 (m, 1H), 4.09 (dd, J = 17.2, 8.5 Hz, 1H), 2.16 (dd, J = 10.3, 7.6 Hz, 1H), 2.09 - 2.02 (s, 3H), 2.00-180 (m, 3H), 13 C NMR (75 MHz, CDCl 3) 3 ) δ (ppm) major dia (trans): 164.6 (C q ), 145.6 (C q ), 139.3 (C q ), 137.3 (C q ), 131.7 (2 x CH), 130.6 (2 x CH) ), 130.3 (CH), 129.1 (CH), 127.9 (CH), 127.2 (CH), 120.3 (C q ), 47.9 (CH), 44.9 (CH), 29.6 (CH 2 ), 27.5 (CH 2 ), 23.8 (CH 3 ); minority dia (cis): 164.6 (C q ), 145.6 (C q ), 139.3 (C q ), 137.3 (C q ), 131.7 (2 x CH), 130.6 (2 x CH), 130.3 (CH), 128.2 (CH), 127.7 (CH), 127.2 (CH), 120.3 (C q ), 48.0 (CH), 45.1 (CH), 30.5 (CH 2 ), 28.5 (CH 2 ), 23.8 (CH 3 ); HRMS (ESI) (M + Na) + m / z calcd for Ci 8 H 18 BrNONa 366.0464, found 366.0478.
N-(4-(3-vinylphenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide [AC093] N- (4- (3-vinylphenyl) -1,2,3,4-tetrahydronaphthalen-1-yl) acetamide [AC093]
Solide blanc obtenu selon la procédure générale n°1 (31.6 mg, 42% de rendement, d.e = 52%) mélange de diastéréoisomères [c/'s (mino): 24%, trans (majo): 76%]; CCM Rf = 0.32 (Cyclohexane/EtOAc, 1 :1 , Si02); IR (film, cm"1) 3275, 3057, 2931 , 2856, 1647, 1553, 1487, 1450, 1372, 1265; 1H RMN (300MHz, CDCI3) δ (ppm) dia majoritaire: 7.32 (dd, J = 18.0, 6.1 Hz, 2H), 7.25 - 7.17 (m, 2H), 7.17 - 7.10 (m, 2H), 6.96 (d, J = 7.3 Hz, 1 H), 6.92 - 6.86 (m, 1 H), 6.68 (dt, J = 17.8, 8.9 Hz, 1 H), 5.93 - 5.82 (m, 1 H), 5.71 (dd, J = 17.6, 6.6 Hz, 1 H), 5.23 (dd, J = 1 1.2, 5.3 Hz, 2H), 4.08 (d, J = 7.8 Hz, 1 H), 2.21 - 2.1 1 (m, 1 H), 2.05 (s, 3H), 2.02 - 1 .90 (m, 3H) ; dia minoritaire: 7.32 (dd, J = 18.0, 6.1 Hz, 2H), 7.25 - 7.17 (m, 2H), 7.17 - 7.10 (m, 2H), 6.96 (d, J = 7.3 Hz, 1 H), 6.92 - 6.86 (m, 1 H), 6.68 (dt, J = 17.8, 8.9 Hz, 1 H), 5.93 - 5.82 (m, 1 H), 5.71 (dd, J = 17.6, 6.6 Hz, 1 H), 5.38 - 5.29 (m, 2H), 4.19 - 4.1 1 (m, 1 H), 2.21 - 2.1 1 (m, 1 H), 2.06 (s, 3H), 2.02 - 1 .90 (m, 3H); 13C RMN (75 MHz, CDCIs) δ (ppm) dia majoritaire: 169.4 (Cq), 146.7 (Cq), 139.8 (Cq), 137.9 (Cq), 137.2 (Cq), 137.0 (CH), 130.3 (CH), 129.0 (CH), 128.7 (CH), 128.4 (CH), 127.7 (CH), 127.0 (CH), 127.0 (CH), 124.2 (CH), 1 14.1 (CH2), 48.1 (CH), 45.6 (CH), 29.5 (CH2), 27.7 (CH2), 23.7 (CH3) ; dia minoritaire: 169.4 (Cq), 146.7 (Cq), 139.8 (Cq), 137.9 (Cq), 137.2 (Cq), 137.0 (CH), 130.4 (CH), 129.0 (CH), 128.7 (CH), 128.0 (CH), 127.6 (CH), 127.0 (CH), 126.9 (CH), 124.2 (CH), 1 14.1 (CH2), 47.8 (CH), 45.5 (CH), 30.6 (CH2), 28.7 (CH2), 23.7 (CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C20H21NONa 314.1515, trouvé 314,1518. White solid obtained according to General Procedure 1 (31.6 mg, 42% yield, de = 52%) mixture of diastereomers [c / 's (mino): 24% trans (Majo): 76%]; TLC R f = 0.32 (Cyclohexane / EtOAc, 1: 1, SiO 2 ); IR (film, cm "1) 3275, 3057, 2931, 2856, 1647, 1553, 1487, 1450, 1372, 1265; 1 H NMR (300MHz, CDCl 3) δ (ppm) majority dia: 7.32 (dd, J = 18.0, 6.1 Hz, 2H), 7.25 - 7.17 (m, 2H), 7.17 - 7.10 (m, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.92 - 6.86 (m, 1H), 6.68. (dt, J = 17.8, 8.9 Hz, 1H), 5.93 - 5.82 (m, 1H), 5.71 (dd, J = 17.6, 6.6Hz, 1H), 5.23 (dd, J = 1 1.2, 5.3 Hz). , 2H), 4.08 (d, J = 7.8 Hz, 1H), 2.21 - 2.1 1 (m, 1H), 2.05 (s, 3H), 2.02-1.90 (m, 3H), minority dia: 7.32 (dd, J = 18.0, 6.1 Hz, 2H), 7.25 - 7.17 (m, 2H), 7.17 - 7.10 (m, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.92 - 6.86 (m, 1H), 6.68 (dt, J = 17.8, 8.9 Hz, 1H), 5.93 - 5.82 (m, 1H), 5.71 (dd, J = 17.6, 6.6 Hz, 1H), 5.38 - 5.29 (m, 2H), 4.19 - 4.1 , 1H), 2.21 - 2.1 1 (m, 1H), 2.06 (s, 3H), 2.02-1.90 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ (ppm) predominant dia: 169.4 (C q ), 146.7 (C q ), 139.8 (C q ), 137.9 (C q ), 137.2 (C q ), 137.0 (CH) , 130.3 (CH), 129.0 (CH), 128.7 (CH), 128.4 (CH), 127.7 (CH), 127.0 (CH), 127.0 (CH), 124.2 (CH), 1 14.1 (CH 2 ), 48.1 (CH), CH), 45.6 (CH), 29.5 (CH 2 ), 27.7 (CH 2 ), 23.7 (CH 3 ); dia minority: 169.4 (C q ), 146.7 (C q ), 139.8 (C q ), 137.9 (C q ), 137.2 (C q ), 137.0 (CH), 130.4 (CH), 129.0 (CH), 128.7 ( CH), 128.0 (CH), 127.6 (CH), 127.0 (CH), 126.9 (CH), 124.2 (CH), 1 14.1 (CH 2 ), 47.8 (CH), 45.5 (CH), 30.6 (CH 2 ) , 28.7 (CH 2 ), 23.7 (CH 3 ); HRMS (ESI) (M + Na) + m / z calcd for C 20 H 21 NONa 314.1515, found 314.1518.
N-((4-(4-(benzyloxy)-3-chlorophenyl)- 1, 2, 3, 4-tetrahydronaphthalen- 1 -yl)acetamide  N - ((4- (4- (Benzyloxy) -3-chlorophenyl) -1,2,3,4-tetrahydronaphthalen-1-yl) acetamide
[AC094] [AC094]
Solide amorphe obtenu selon la procédure générale n°1 (49.1 mg, 48% de rendement, d.e = 54%) mélange de diastéréoisomères [c/'s (mino): 23%, trans (majo): 77%]; CCM Rf = 0.20 (Pentane/EtOAc, 1 :1 , Si02); IR (film, cm"1) 2958, 2923, 2853, 1736, 1654, 1501 , 1467, 1377, 1261 ; 1H RMN (300MHz, CDCI3) δ (ppm) dia majoritaire (trans): 7.50 - 7.44 (m, 2H), 7.37 (ddd, J = 15.2, 8.7, 1 .8 Hz, 4H), 7.24 - 7.09 (m, 3H), 6.95 - 6.79 (m, 3H), 6.02 - 5.89 (m, 1 H), 5.20 (dd, J = 9.6, 4.3 Hz, 1 H), 5.14 (s, 2H), 4.00 (t, J = 6.3 Hz, 1 H), 2.25 - 2.07 (m, 1 H), 2.04 (s, 3H), 1 .98 - 1.81 (m, 3H) ; dia minoritaire (cis): 7.50 - 7.44 (m, 2H), 7.37 (ddd, J = 15.2, 8.7, 1 .8 Hz, 4H), 7.24 - 7.09 (m, 3H), 6.95 - 6.79 (m, 3H), 5.84 - 5.77 (m, 1 H), 5.30 (dd, J = 8.4, 5.3 Hz, 1 H), 5.12 (s, 2H), 4.00 (t, J = 6.3 Hz, 1 H), 2.25 - 2.07 (m, 2H), 2.03 (s, 3H), 1.98 - 1 .81 (m, 1 H), 1.76 - 1 .65 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) dia majoritaire (trans): 169.5 (Cq), 152.8 (Cq), 140.2 (Cq), 139.5 (Cq), 137.2 (Cq), 136.7 (Cq), 130.4 (CH), 130.2 (CH), 129.0 (CH), 128.7 (2 x CH), 128.1 (2 x CH), 127.8 (CH), 127.2 (2 x CH), 127.1 (CH), 123.3 (Cq), 1 14.1 (CH), 71 .1 (CH2), 47.8 (CH), 44.4 (CH), 29.6 (CH2), 27.5 (CH2), 23.7 (CH3) ; dia minoritaire (cis): 169.6 (Cq), 152.8 (Cq), 140.2 (Cq), 139.5 (Cq), 137.5 (Cq), 136.7 (Cq), 130.6 (CH), 130.3 (CH), 129.0 (CH), 128.7 (2 x CH), 128.1 (2 x CH), 127.7 (CH), 127.2 (2 x CH), 127.1 (CH), 123.2 (Cq), 1 14.1 (CH), 71.1 (CH2), 47.9 (CH), 44.5 (CH), 30.4 (CH2), 28.4 (CH2), 23.7 (CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C25H24CIN02Na 428.1388, trouvé 428,1388. Amorphous solid obtained according to General Procedure 1 (49.1 mg, 48% yield, de = 54%) mixture of diastereomers [c / 's (mino): 23% trans (Majo): 77%]; TLC R f = 0.20 (Pentane / EtOAc, 1: 1, SiO 2 ); IR (film, cm "1) 2958, 2923, 2853, 1736, 1654, 1501, 1467, 1377, 1261; 1 H NMR (300MHz, CDCl 3) δ (ppm) majority dia (trans): 7.50 - 7.44 (m , 7.37 (ddd, J = 15.2, 8.7, 1.8 Hz, 4H), 7.24 - 7.09 (m, 3H), 6.95 - 6.79 (m, 3H), 6.02 - 5.89 (m, 1H), 5.20 (dd, J = 9.6, 4.3Hz, 1H), 5.14 (s, 2H), 4.00 (t, J = 6.3 Hz, 1H), 2.25 - 2.07 (m, 1H), 2.04 (s, 3H). ), 1.98 - 1.81 (m, 3H), minority dia (cis): 7.50 - 7.44 (m, 2H), 7.37 (ddd, J = 15.2, 8.7, 1.8 Hz, 4H), 7.24 - 7.09 ( m, 3H), 6.95-6.79 (m, 3H), 5.84-5.77 (m, 1H), 5.30 (dd, J = 8.4, 5.3Hz, 1H), 5.12 (s, 2H), 4.00 (t, J = 6.3 Hz, 1H), 2.25 - 2.07 (m, 2H), 2.03 (s, 3H), 1.98 - 1 .81 (m, 1 H), 1.76 - 1 .65 (m, 1 H); 13 NMR (75 MHz, CDCI 3 ) δ (ppm) most (trans) dia: 169.5 (C q ), 152.8 (C q ), 140.2 (C q ), 139.5 (C q ), 137.2 (C q ), 136.7 (C q ), 130.4 (CH), 130.2 (CH), 129.0 (CH), 128.7 (2 x CH), 128.1 (2 x CH), 127.8 (CH), 127.2 (2 x CH), 127.1 (CH) , 123.3 (C q ), 1 14.1 (CH), 71.1 (CH 2 ), 47.8 (CH), 44.4 (CH), 29.6 (CH 2 ), 27.5 (CH 2 ), 23.7 (CH 3 ); dia minority (cis): 169.6 (C q ), 152.8 (C q ), 140.2 (C q ), 139.5 (C q ), 137.5 (C q ), 136.7 (C q ), 130.6 (CH), 130.3 (CH) 129.0 (CH), 128.7 (2 x CH), 128.1 (2 x CH), 127.7 (CH), 127.2 (2 x CH), 127.1 (CH), 123.2 (C q ), 1 14.1 (CH), 71.1 (CH 2 ), 47.9 (CH), 44.5 (CH), 30.4 (CH 2 ), 28.4 (CH 2 ), 23.7 (CH 3 ); HRMS (ESI) (M + Na) + m / z calcd for C 25 H 24 CINO 2 Na 428.1388, found 428.1388.
1 -(3, 4-dichlorophenyl)-6-meth alene [AC095] Huile transparente obtenue selon la procédure générale n°1 (34.8 mg, 40% de rendement); CCM Rf = 0.76 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2932, 2859, 2834, 1609, 1576, 1501 , 1466, 1255, 1 124, 1041 ; 1H RMN (300MHz, CDCI3) δ (ppm) 7.33 (d, J = 8.3 Hz, 1 H), 7.18 (d, J = 2.0 Hz, 1 H), 6.92 (dd, J = 8.2, 2.0 Hz, 1 H), 6.76 - 6.61 (m, 3H), 4.03 (t, J = 6.3 Hz, 1 H), 3.79 (s, 3H), 2.92 - 2.75 (m, 2H), 2.22 - 2.08 (m, 1 H), 1 .88 - 1 .65 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 158.1 (Cq), 148.3 (Cq), 138.9 (Cq), 132.3 (Cq), 131 .1 (CH), 130.7 (CH), 130.3 (Cq), 130.3 (CH), 129.9 (Cq), 128.3 (CH), 1 13.6 (CH), 1 12.5 (CH), 55.3 (CH), 44.3 (CH3), 33.4 (CH2), 30.1 (CH2), 20.8 (CH2); HRMS (ESI) (M + H)+ m/z calculé pour Ci7H17CI20 307.0651 , trouvé 307.0508. 1- (3,4-dichlorophenyl) -6-methylene [AC095] Transparent oil obtained according to General Procedure No. 1 (34.8 mg, 40% yield); TLC R f = 0.76 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2932, 2859, 2834, 1609, 1576, 1501, 1466, 1255, 1124, 1041; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.33 (d, J = 8.3 Hz , 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.2, 2.0 Hz, 1H), 6.76 - 6.61 (m, 3H), 4.03 (t, J = 6.3 Hz , 1H), 3.79 (s, 3H), 2.92 - 2.75 (m, 2H), 2.22 - 2.08 (m, 1H), 1.88-165 (m, 3H), 13 C NMR (75 MHz , CDCl 3 ) δ (ppm) 158.1 (C q ), 148.3 (C q ), 138.9 (C q ), 132.3 (C q ), 131.1 (CH), 130.7 (CH), 130.3 (C q ), 130.3 (CH), 129.9 (C q ), 128.3 (CH), 13.6 (CH), 12.5 (CH), 55.3 (CH), 44.3 (CH 3 ), 33.4 (CH 2 ), 30.1 (CH 2 ) 20.8 (CH 2); HRMS (ESI) (m + H) + m / z calcd for Ci 7 H 17 CI 2 0 307.0651, found 307.0508.
1-(3, 4-dic lorop enyl)-1 ,2, 3, 4-tetra ydronap t alene [AC096] 1- (3,4-dicyclopentyl) -1,2,3,4-tetra ydronapetene [AC096]
Huile transparente obtenue selon la procédure générale n°1 (61.5 mg, 70% de rendement); CCM Rf = 0.89 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2932, 2858, 1588, 1560, 1491 , 1468, 1448, 1395, 1 130, 1030; 1H RMN (300MHz, CDCI3) δ (ppm) 7.35 (d, J = 8.2 Hz, 1 H), 7.20 (d, J = 1.9 Hz, 1 H), 7.16 (d, J = 4.2 Hz, 2H), 7.06 (dt, J = 8.4, 4.3 Hz, 1 H), 6.93 (dd, J = 8.2, 2.0 Hz, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 4.10 (t, J = 6.4 Hz, 1 H), 2.97 - 2.77 (m, 2H), 2.24 - 2.06 (m, 1 H), 1.94 - 1 .71 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 148.0 (Cq), 138.1 (Cq), 137.7 (Cq), 132.3 (Cq), 130.8 (CH), 130.3 (CH), 130.1 (CH), 130.0 (Cq), 129.4 (CH), 128.4 (CH), 126.5 (CH), 126.0 (CH), 45.0 (CH), 33.2 (CH2), 29.7 (CH2), 20.9 (CH2). Transparent oil obtained according to General Procedure No. 1 (61.5 mg, 70% yield); TLC R f = 0.89 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2932, 2858, 1588, 1560, 1491, 1468, 1448, 1395, 1130, 1030; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.35 (d, J = 8.2Hz , 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.16 (d, J = 4.2 Hz, 2H), 7.06 (dt, J = 8.4, 4.3 Hz, 1H), 6.93 (dd, J). = 8.2, 2.0 Hz, 1H), 6.81 (d, J = 7.6Hz, 1H), 4.10 (t, J = 6.4Hz, 1H), 2.97 - 2.77 (m, 2H), 2.24 - 2.06 (m , 1H), 1.94-1.71 (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 148.0 (C q ), 138.1 (C q ), 137.7 (C q ), 132.3 ( C q), 130.8 (CH), 130.3 (CH), 130.1 (CH), 130.0 (C q), 129.4 (CH), 128.4 (CH), 126.5 (CH), 126.0 (CH), 45.0 (CH), 33.2 (CH 2 ), 29.7 (CH 2 ), 20.9 (CH 2 ).
1 -(3-chlorophenyl)-6-methoxy-1,2, 3, 4-tetrahydronaphthalene [AC 101] 1 - (3-chlorophenyl) -6-methoxy-1,2,3,4-tetrahydronaphthalene [AC 101]
Huile transparente obtenue selon la procédure générale n°1 (47.9 mg, 60% de rendement); CCM Rf = 0.80 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2932, 2857, 2834, 1610, 1593, 1573, 1501 , 1466, 1428, 1256, 1039; 1H RMN (300MHz, CDCI3) δ (ppm) 7.24 - 7.14 (m, 2H), 7.09 (s, 1 H), 6.98 (d, J = 6.7 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.69 - 6.58 (m, 2H), 4.05 (t, J = 6.2 Hz, 1 H), 3.79 (s, 3H), 2.94 - 2.76 (m, 2H), 2.20 - 2.06 (m, 1 H), 1 .90 - 1 .71 (m, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 157.9 (Cq), 150.0 (Cq), 138.9 (Cq), 134.7 (Cq), 131 .2 (CH), 130.8 (Cq), 129.6 (CH), 128.9 (CH), 127.1 (CH), 126.2 (CH), 1 13.5 (CH), 1 12.4 (CH), 55.3 (CH3), 44.8 (CH3), 33.5 (CH2), 30.2 (CH2), 20.9 (CH2); HRMS (ESI) (M + H)+ m/z calculé pour Ci7H18CIO 273.1041 , trouvé 273.1046 Transparent oil obtained according to general procedure No. 1 (47.9 mg, 60% yield); TLC R f = 0.80 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2932, 2857, 2834, 1610, 1593, 1573, 1501, 1466, 1428, 1256, 1039; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.24 - 7.14 (m, 2H ), 7.09 (s, 1H), 6.98 (d, J = 6.7 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.69 - 6.58 (m, 2H), 4.05 (t, J); = 6.2 Hz, 1H), 3.79 (s, 3H), 2.94 - 2.76 (m, 2H), 2.20 - 2.06 (m, 1H), 1.90-1.71 (m, 3H), 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 157.9 (C q ), 150.0 (C q ), 138.9 (C q ), 134.7 (C q ), 131 .2 (CH), 130.8 (C q ), 129.6 ( CH), 128.9 (CH), 127.1 (CH), 126.2 (CH), 13.5 (CH), 12.4 (CH), 55.3 (CH 3 ), 44.8 (CH 3 ), 33.5 (CH 2 ), 30.2 ( CH 2 ), 20.9 (CH 2 ), HRMS (ESI) (M + H) + m / z calculated for C 17 H 18 CIO 273.1041, found 273.1046
(2R, 3R,4S, 5R, 6S)-2-(acetoxymethyl)-6-((3-(1 , 2, 3, 4-tetrahydronaphthalen- 1yl)phenyl)thio)t etrahydro-2H-pyran-3,4,5-triyl triacetate [AC116] (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6 - ((3- (1,2,3,4-tetrahydronaphthalenyl) phenyl) thio) etrahydro-2H-pyran-3, 4,5-triyl triacetate [AC116]
Solide blanc obtenu selon la procédure générale n°2 (169.9 mg, 90% de rendement, d.e = 0%) mélange de diastéréoisomères [dia 1 : 50%, dia 2: 50%]; CCM Rf = 0.53 (Cyclohexane/EtOAc, 6:4, Si02); IR (film, cm"1) 2929, 2854, 1756, 1590, 1366, 1248, 1213, 1091 , 1036; 1H RMN (300MHz, CDCI3) δ (ppm) dia 1: 7.30 (d, J = 7.5 Hz, 1 H), 7.20 (dd, J = 15.1 , 4.4 Hz, 2H), 7.13 (d, J = 4.0 Hz, 2H), 7.09 - 7.01 (m, 2H), 6.83 (dd, J = 7.2, 2.7 Hz, 1 H), 5.20 (td, J = 9.3, 2.7 Hz, 1 H), 5.1 1 - 4.89 (m, 2H), 4.67 (dd, J = 13.7, 10.1 Hz, 1 H), 4.22 - 4.06 (m, 2H), 4.06 - 3.93 (m, 1 H), 3.70 - 3.64 (m, 1 H), 2.86 (tt, J = 16.8, 8.3 Hz, 2H), 2.21 - 2.10 (m, 1 H), 2.08 - 1.96 (m, 12H), 1.92 - 1.81 (m, 2H), 1 .81 - 1 .71 (m, 1 H) ; dia 2: 7.30 (d, J = 7.5 Hz, 1 H), 7.20 (dd, J = 15.1 , 4.4 Hz, 2H), 7.13 (d, J = 4.0 Hz, 2H), 7.09 - 7.01 (m, 2H), 6.83 (dd, J = 7.2, 2.7 Hz, 1 H), 5.20 (td, J = 9.3, 2.7 Hz, 1 H), 5.1 1 - 4.89 (m, 2H), 4.67 {dd, J = 13.7, 10.1 Hz, 1 H), 4.22 - 4.06 (m, 2H), 4.06 - 3.93 (m, 1 H), 3.56 (dd, J = 9.8, 2.4 Hz, 1 H), 2.86 (tt, J = 16.8, 8.3 Hz, 2H), 2.21 - 2.10 (m, 1 H), 2.08 - 1 .96 (m, 12H), 1.92 - 1 .81 (m, 2H), 1 .81 - 1 .71 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) dia 1: 170.19 (2 x Cq), 169.37 (2 x Cq), 148.76 (Cq), 138.71 (Cq), 137.73 (Cq), 132.42 (CH), 131.54 (Cq), 130.17 (2 x CH), 129.1 1 (CH), 128.76 (2 x CH), 126.16 (CH), 125.76 (CH), 85.65 (CH), 75.72 (CH), 74.04 (CH), 69.83 (CH), 68.08 (CH), 62.05 (CH2), 45.38 (CH), 33.21 (CH2), 29.73 (CH2), 20.87 (CH2), 20.63 (4 x CH3) ; dia 2: 170.58 (2 x Cq), 169.23 (Cq), 169.14 (Cq), 148.63 (Cq), 138.71 (Cq), 137.59 (Cq), 132.95 (CH), 132.29 (Cq), 130.24 (CH), 129.75 (CH), 129.16 (CH), 128.90 (CH), 128.84 (CH), 126.23 (CH), 125.87 (CH), 86.25 (CH), 75.90 (CH), 74.07 (CH), 69.90 (CH), 68.24 (CH), 62.26 (CH2), 45.44 (CH), 33.21 (CH2), 29.73 (CH2), 20.87 (CH2), 20.76 (4 x CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C3oH3409SNa 593.1826, trouvé 593,1829. White solid obtained according to General Procedure No. 2 (169.9 mg, 90% yield, = 0%) mixture of diastereoisomers [dia 1: 50%, dia 2: 50%]; TLC R f = 0.53 (Cyclohexane / EtOAc, 6: 4, SiO 2 ); IR (film, cm "1) 2929, 2854, 1756, 1590, 1366, 1248, 1213, 1091, 1036; 1 H NMR (300MHz, CDCl 3) δ (ppm) dia 1: 7.30 (d, J = 7.5 Hz , 1H), 7.20 (dd, J = 15.1, 4.4 Hz, 2H), 7.13 (d, J = 4.0 Hz, 2H), 7.09 - 7.01 (m, 2H), 6.83 (dd, J = 7.2, 2.7 Hz , 1H), 5.20 (td, J = 9.3, 2.7 Hz, 1H), 5.11 - 4.89 (m, 2H), 4.67 (dd, J = 13.7, 10.1 Hz, 1H), 4.22 - 4.06 (m. , 2H), 4.06 - 3.93 (m, 1H), 3.70 - 3.64 (m, 1H), 2.86 (tt, J = 16.8, 8.3 Hz, 2H), 2.21 - 2.10 (m, 1H), 2.08 - 1.96 (m, 12H), 1.92 - 1.81 (m, 2H), 1.81-1.71 (m, 1H), dia 2: 7.30 (d, J = 7.5 Hz, 1H), 7.20 (dd, J = 15.1, 4.4 Hz, 2H), 7.13 (d, J = 4.0 Hz, 2H), 7.09-7.01 (m, 2H), 6.83 (dd, J = 7.2, 2.7 Hz, 1H), 5.20 (td, J = 9.3, 2.7 Hz, 1H), 5.11 - 4.89 (m, 2H), 4.67 (dd, J = 13.7, 10.1 Hz, 1H), 4.22 - 4.06 (m, 2H), 4.06 - 3.93 (m). , 1H), 3.56 (dd, J = 9.8, 2.4 Hz, 1H), 2.86 (tt, J = 16.8, 8.3Hz, 2H), 2.21 - 2.10 (m, 1H), 2.08-1.96 ( m, 12H), 1.92 - 1 .81 (m, 2H), 1 .81 - 1 .71 (m, 1 H); 13 C NMR (75 MHz, CDCl 3) (ppm) dia 1: 170.19 (2 x C q), 169.37 (2 x C q), 148.76 (C q), 138.71 (C q), 137.73 (C q), 132.42 (CH), 131.54 (C q) , 130.17 (2 x CH), 129.1 (CH), 128.76 (2 x CH), 126.16 (CH), 125.76 (CH), 85.65 (CH), 75.72 (CH), 74.04 (CH), 69.83 (CH) 68.08 (CH), 62.05 (CH 2 ), 45.38 (CH), 33.21 (CH 2 ), 29.73 (CH 2 ), 20.87 (CH 2 ), 20.63 (4 x CH 3 ); dia 2: 170.58 (2 x C q), 169.23 (C q), 169.14 (C q), 148.63 (C q), 138.71 (C q), 137.59 (C q), 132.95 (CH), 132.29 (C q ), 130.24 (CH), 129.75 (CH), 129.16 (CH), 128.90 (CH), 128.84 (CH), 126.23 (CH), 125.87 (CH), 86.25 (CH), 75.90 (CH), 74.07 (CH), ), 69.90 (CH), 68.24 (CH), 62.26 (CH 2 ), 45.44 (CH), 33.21 (CH 2 ), 29.73 (CH 2 ), 20.87 (CH 2 ), 20.76 (4 x CH 3 ); HRMS (ESI) (M + Na) + m / z calcd for C 3 H 3 40 9 SN? 593.1826, found 593.1829.
(2R, 3S, 4S, 5R, 6S)-2-( ydroxymet yl)-6-((3-(1 , 2, 3, 4-tetra ydronap t alen-1-yl)p enyl)t io) tetrahydro-2H-pyran-3, 4, 5-tri (2R, 3S, 4S, 5R, 6S) -2- (ydroxymethyl) -6 - ((3- (1,2,3,4-tetra-ydronapet-1-yl) p-enyl) tio) tetrahydro -2H-pyran-3, 4, 5-tri
Composé préparé selon la procédure générale n°2, suivi d'une réaction de deprotection utilisant le méthanolate de sodium [sodium (0.26 mmol, 1 .5 eq) dissous dans le méthanol (0.6 ml_)]. Puis, le milieu réactionnel est agité à température ambiante pendant 30 minutes, avant d'être acidifié par de la DOWEX® 50WX8-200 pendant 20 minutes. Le brut réactionnel est ensuite filtré et concentré sous vide afin d'offrir un solide marron clair (68.6 mg, 98% de rendement, d.e = 24%) mélange de diastéréoisomères [dia 1 : 60%, dia 2: 38%]; CCM Rf = 0.17 (EtOAc, Si02); IR (film, cm"1) 3357, 2926, 2854, 1589, 1451 , 1418, 1275, 1022; 1H RMN (300MHz, MeOD) δ (ppm) dia 1: 7.39 (t, J= 7.1 Hz, 1H), 7.32-7.20 (m, 2H), 7.15 - 7.07 (m, 2H), 7.06 - 6.98 (m, 2H), 6.80 (s, 1 H), 4.86 (s, 4H), 4.56 (dd, J = 12.1, 9.8 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 3.82-3.77 (m, 1H), 3.69-3.56 (m, 1H), 3.44- 3.31 (m, 2H), 3.30 - 3.16 (m, 2H), 2.87 (qd, J = 16.7, 7.8 Hz, 2H), 2.20 - 2.09 (m, 1H), 1.96 - 1.81 (m, 2H), 1.81 - 1.68 (m, 1 H) ; dia 2: 7.39 (t, J = 7.1 Hz, 1 H), 7.32 - 7.20 (m, 2H), 7.15 - 7.07 (m, 2H), 7.06 - 6.98 (m, 2H), 6.78 (s, 1H), 4.86 (s, 4H), 4.56 (dd, J = 12.1, 9.8 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 3.77-3.72 (m, 1H), 3.69-3.56 (m, 1H), 3.44- 3.31 (m, 2H), 3.30 - 3.16 (m, 2H), 2.87 (qd, J = 16.7, 7.8 Hz, 2H), 2.20 - 2.09 (m, 1H), 1.96 - 1.81 (m, 2H), 1.81 - 1.68 (m, 1H); 13C RMN (75 MHz, CDC ) δ (ppm) dia 1: 148.6 (Cq), 138.8 (Cq), 137.6 (Cq), 132.9 (Cq), 131.9 (CH), 130.2 (CH), 129.1 (2 x CH), 128.3 (CH), 126.2 (2 x CH), 125.8 (CH), 88.1 (CH), 79.4 (CH), 77.9 (CH), 72.4 (CH), 69.3 (CH), 61.7 (CH2), 45.4 (CH), 33.3 (CH2), 29.8 (CH2), 20.9 (CH2) ; dia 2: 148.7 (Cq), 138.8 (Cq), 137.7 (Cq), 133.3 (Cq), 131.9 (CH), 130.3 (CH), 129.1 (2 x CH), 128.3 (CH), 126.2 (2 x CH), 125.9 (CH), 88.6 (CH), 79.5 (CH), 77.9 (CH), 72.4 (CH), 69.2 (CH), 61.7 (CH2), 45.4 (CH), 33.3 (CH2), 29.8 (CH2), 20.9 (CH2); HRMS (ESI) (M + Na)+ m/z calculé pour C22H2605SNa 425.1393, trouvé 425.1399. Compound prepared according to general procedure No. 2, followed by a deprotection reaction using sodium methanolate [sodium (0.26 mmol, 1.5 eq) dissolved in methanol (0.6 ml)). Then, the reaction medium is stirred at room temperature for 30 minutes, before being acidified with DOWEX® 50WX8-200 for 20 minutes. The crude reaction product is then filtered and concentrated in vacuo to give a light brown solid (68.6 mg, 98% yield, = 24%) mixture of diastereoisomers [dia 1: 60%, dia 2: 38%]; TLC R f = 0.17 (EtOAc, SiO 2 ); IR (film, cm -1 ) 3357, 2926, 2854, 1589, 1451, 1418, 1275, 1022; 1 H NMR (300MHz, MeOD) δ (ppm) dia 1: 7.39 (t, J = 7.1 Hz, 1H), 7.32-7.20 (m, 2H), 7.15 - 7.07 (m, 2H), 7.06 - 6.98 (m , 2H), 6.80 (s, 1H), 4.86 (s, 4H), 4.56 (dd, J = 12.1, 9.8 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 3.82-3.77 (m. , 1H), 3.69-3.56 (m, 1H), 3.44- 3.31 (m, 2H), 3.30 - 3.16 (m, 2H), 2.87 (qd, J = 16.7, 7.8 Hz, 2H), 2.20 - 2.09 (m. , 1H), 1.96 - 1.81 (m, 2H), 1.81 - 1.68 (m, 1H); dia 2: 7.39 (t, J = 7.1 Hz, 1H), 7.32 - 7.20 (m, 2H), 7.15 - 7.07 (m, 2H), 7.06 - 6.98 (m, 2H), 6.78 (s, 1H), 4.86 (s, 4H), 4.56 (dd, J = 12.1, 9.8 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 3.77-3.72 (m, 1H), 3.69-3.56 (m, 1H). , 3.44- 3.31 (m, 2H), 3.30 - 3.16 (m, 2H), 2.87 (qd, J = 16.7, 7.8 Hz, 2H), 2.20 - 2.09 (m, 1H), 1.96 - 1.81 (m, 2H). 1.81 - 1.68 (m, 1H); 13 C NMR (75 MHz, CDC) δ (ppm) dia 1: 148.6 (C q ), 138.8 (C q ), 137.6 (C q ), 132.9 (C q ), 131.9 (CH), 130.2 (CH), 129.1 (2 x CH), 128.3 (CH), 126.2 (2 x CH), 125.8 (CH), 88.1 (CH), 79.4 (CH), 77.9 (CH), 72.4 (CH), 69.3 (CH), 61.7 (CH 2 ), 45.4 (CH), 33.3 (CH 2 ), 29.8 (CH 2 ), 20.9 (CH 2 ); dia 2: 148.7 (C q ), 138.8 (C q ), 137.7 (C q ), 133.3 (C q ), 131.9 (CH), 130.3 (CH), 129.1 (2 x CH), 128.3 (CH), 126.2 (2 x CH), 125.9 (CH), 88.6 (CH), 79.5 (CH), 77.9 (CH), 72.4 (CH), 69.2 (CH), 61.7 (CH 2 ), 45.4 (CH), 33.3 (CH), 2 ), 29.8 (CH 2 ), 20.9 (CH 2 ); HRMS (ESI) (M + Na) + m / z calcd for C 22 H 26 O 5 SN? 425.1393, found 425.1399.
4-(4-methoxyphenyl)chroman [AC 4- (4-methoxyphenyl) chroman [AC
Solide blanc obtenu selon la procédure générale n°1 (229.8 mg, 95% de rendement); mp: 90,3 - 90,7 °C; CCM Rf = 0.70 (Cyclohexane/EtOAc, 7:3, Si02); IR (film, cm"1) 2952, 2877, 2834, 1610, 1581, 1511, 1487, 1452, 1304, 1269, 1249; 1H RMN (300MHz, CDCI3) δ (ppm) 7.19 - 7.12 (m, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.92 - 6.79 (m, 5H), 4.19 (dt, J = 12.7, 5.8 Hz, 3H), 3.82 (s, 3H), 2.31 (ddd, J= 13.4, 10.6, 5.6 Hz, 1H), 2.09 (ddd, J= 10.9, 9.4, 4.9 Hz, 1H); 13C RMN (75 MHz, CDCI3) δ (ppm) 158.3 (Cq), 155.2 (Cq), 137.8 (Cq), 130.7 (CH), 129.7 (2 x CH), 127.9 (CH), 125.0 (Cq), 120.4 (CH), 116.8 (CH), 114.0 (2 x CH), 64.0 (CH2), 55.4 (CH), 40.3 (CH3), 31.9 (CH2); HRMS (ESI) (M + H)+ m/z calculé pour Ci6H1702241.1223, trouvé 241.1229. White solid obtained according to General Procedure No. 1 (229.8 mg, 95% yield); mp 90.3-90.7 ° C; TLC R f = 0.70 (Cyclohexane / EtOAc, 7: 3, SiO 2 ); IR (film, cm "1) 2952, 2877, 2834, 1610, 1581, 1511, 1487, 1452, 1304, 1269, 1249; 1 H NMR (300MHz, CDCl 3) δ (ppm) 7.19 - 7.12 (m, 1H ), 7.09 (d, J = 8.6 Hz, 2H), 6.92 - 6.79 (m, 5H), 4.19 (dt, J = 12.7, 5.8 Hz, 3H), 3.82 (s, 3H), 2.31 (ddd, J = 13.4, 10.6, 5.6 Hz, 1H), 2.09 (ddd, J = 10.9, 9.4, 4.9Hz, 1H); 13 C NMR (75 MHz, CDCl 3) δ (ppm) 158.3 (C q), 155.2 (C q ), 137.8 (C q ), 130.7 (CH), 129.7 (2 x CH), 127.9 (CH), 125.0 (C q ), 120.4 (CH), 116.8 (CH), 114.0 (2 x CH), 64.0 ( CH 2 ), 55.4 (CH), 40.3 (CH 3 ), 31.9 (CH 2 ), HRMS (ESI) (M + H) + m / z calculated for C 16 H 17 O 2 241.1223, found 241.1229.
C/'s - (2S, 3R, 4S, 5R, 6R)-2-((5-((4S)-4-acetamido-1 ,2, 3, 4-tetra ydronap t alen-1 -yl)-2-(qui nolin-8- ylcarbamoyl)-3-(((2R,3S R,5S,6S)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro- 2H-pyran-2-yl)thio) phenyl)thio)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [AC249-cis/ AC339-HPLC2] C 1 ' - (2S, 3R, 4S, 5R, 6R) -2 - ((5 - ((4S) -4-acetamido-1,2,3,4-tetra-ydronapet-1-yl) - 2- (which nolin-8-ylcarbamoyl) -3 - (((2R, 3SR, 5S, 6S) -3,4,5-triacetoxy-6- (acetoxymethyl) tetrahydro-2H-pyran-2-yl) thio phenyl) thio) -6- (acetoxymethyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate [AC249-cis / AC339-HPLC2]
Solide blanc obtenu selon la procédure générale n°4 (113.8 mg, 61% de rendement); mp: 153.8 - 155.4 °C; CCM Rf = 0.40 (EtOAc, Si02); IR (film, cm"1) 3334, 1755, 1649, 1524, 1367, 1212, 1036; 1H RMN (300MHz, CDCI3) δ (ppm) 9.82 (d, J= 5.5 Hz, 1H), 8.94-8.85 (m, 1H), 8.79 (t, J = 3.5 Hz, 1 H), 8.18 (d, J = 8.2 Hz, 1 H), 7.55 (d, J = 4.7 Hz, 2H), 7.52 - 7.47 (m, 1 H), 7.45 (d, J = 6.4 Hz, 2H), 7.39 (d, J = 7.4 Hz, 1 H), 7.33 - 7.26 (m, 1 H), 7.21 (dd, J= 14.4, 7.3 Hz, 1H), 6.92 (dd, J= 14.4, 7.4 Hz, 1H), 5.74 (d, J= 8.5 Hz, 1H), 5.38- 5.27 (m, 1H), 5.13-4.99 (m, 3H), 4.95 (d, J= 10.0 Hz, 1H), 4.89 (dd, J= 6.8, 2.4 Hz, 1H), 4.87 - 4.80 (m, 2H), 4.75 (t, J = 8.1 Hz, 1H), 4.26 - 4.18 (m, 1H), 4.16 - 4.04 (m, 2H), 3.99 (dd, J= 12.2, 1.7 Hz, 1H), 3.83 (dd, J= 12.0, 0.9 Hz, 1H), 3,67 - 3,57 (m, 1H), 3,50 (d, J = 9.4 Hz, 1H), 2.33 - 2.17 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.93 (s, 3H), 1.91 (s, 3H), 1.85 - 1.70 (m, 2H), 1.57 (s, 3H), 1.47 (s, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 170.6 (2 x Cq), 170.1 (3 x Cq), 169.5 (4 x Cq), 165.0 (Cq, splited 164.9), 149.1 (Cq, splited 148.9), 148.7 (CH), 143.8 (Cq, splited 143.6), 138.7 (Cq), 138.6 (Cq, splited 138.5), 138.0 (Cq, splited 137.8), 136.49 (CH, splited 136.38), 136.2 (CH), 134.4 (Cq, splited 134.3), 130.4 (Cq), 130.3 (CH, splited 130.2), 130.0 (Cq), 128.59 (CH, splited 128.4), 128.2 (Cq), 127.8 (CH), 127.5 (CH), 127.3 (CH), 122.4 (CH), 122.2 (CH, splited 122,1), 117.1 (CH), 86.9 (CH), 86.3 (CH), 76.0 (CH), 75.7 (CH), 74.1 (CH), 73.9 (CH), 69.8 (CH), 69.6 (CH), 68.3 (CH), 68.0 (CH), 61.9 (CH2), 61.54 (CH2), 47.8 (CH), 45.2 (CH, splited 45.1), 28.4 (CH2), 28.1 (CH2), 23.7 (CH3), 20.8 (3 x CH3), 20.7 (3 x CH3), 20.3 (CH3), 20.1 (CH3); HRMS (APCI) (M + H)+ m/z calculé pour C56H62N3O20S21160,3363, trouvé 1160,3368. White solid obtained according to General Procedure No. 4 (113.8 mg, 61% yield); mp: 153.8- 155.4 ° C; TLC R f = 0.40 (EtOAc, SiO 2 ); IR (film, cm "1) 3334, 1755, 1649, 1524, 1367, 1212, 1036; 1 H NMR (300MHz, CDCl 3) δ (ppm) 9.82 (d, J = 5.5 Hz, 1H), 8.94-8.85 (m, 1H), 8.79 (t, J = 3.5 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 4.7 Hz, 2H), 7.52-7.47 (m, 1H), 7.45 (d, J = 6.4 Hz, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.21 (dd, J = 14.4, 7.3 Hz, 1H), 6.92 (dd, J = 14.4, 7.4 Hz, 1H), 5.74 (d, J = 8.5 Hz, 1H), 5.38- 5.27 (m, 1H), 5.13-4.99 (m, 3H), 4.95 (d , J = 10.0 Hz, 1H), 4.89 (dd, J = 6.8, 2.4 Hz, 1H), 4.87-4.80 (m, 2H), 4.75 (t, J = 8.1 Hz, 1H), 4.26-4.18 (m, 1H), 4.16 - 4.04 (m, 2H), 3.99 (dd, J = 12.2, 1.7 Hz, 1H), 3.83 (dd, J = 12.0, 0.9 Hz, 1H), 3.67 - 3.57 (m, 1H), 3.50 (d, J = 9.4 Hz, 1H), 2.33 - 2.17 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 2.00 (s). , 3H), 1.99 (s, 3H), 1.93 (s, 3H), 1.91 (s, 3H), 1.85 - 1.70 (m, 2H), 1.57 (s, 3H), 1.47 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 170.6 (2 x C q ), 170.1 (3 x C q ), 169.5 (4 x C q ), 165.0 (C q , splited 164.9), 149.1 (C q , splited 148.9), 148.7 (CH), 143.8 (C q , splited 143.6), 138.7 (C q ), 138.6 (C q , splited 138.5), 138.0 (C q , splited 137.8), 136.49 (CH, splited 136.38), 136.2 (CH), 134.4 (C q , splited 134.3), 130.4 (C q ), 130.3 (CH, splited 130.2), 130.0 (C q ), 128.59 (CH, splited 128.4), 128.2 (C q ), 127.8 ( CH), 127.5 (CH), 127.3 (CH), 122.4 (CH), 122.2 (CH, splited 122.1), 117.1 (CH), 86.9 (CH), 86.3 (CH), 76.0 (CH), 75.7 (CH), CH), 74.1 (CH), 73.9 (CH), 69.8 (CH), 69.6 (CH), 68.3 (CH), 68.0 (CH), 61.9 (CH 2 ), 61.54 (CH 2 ), 47.8 (CH), 45.2 (CH, splited 45.1), 28.4 (CH 2 ), 28.1 (CH 2 ), 23.7 (CH 3 ), 20.8 (3 x CH 3 ), 20.7 (3 x CH 3 ), 20.3 (CH 3 ), 20.1 ( CH 3 ); HRMS (APCI) (M + H) + m / z calculated for C 5 H 62 N 3 O 20 S 2 1160.3363, found 1160.3368.
C/'s - (2S, 3R, 4S, 5R, 6R)-2-((3-((4S)-4-acetamido- 1,2,3, 4-tetra ydronap t alen- 1 - yl)phenyl)thio)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [AC268- CÏS/AC268-HPLC3] Solide blanc obtenu selon la procédure générale n°2 (18.0 mg, 23% de rendement); Purifié par HPLC en utilisant une colonne de type Xbridge Ci8 (4.6 x 150mm, δμηι) et un mélange H20/MeOH (40:60) en tant que solvant; mp: 232.9 - 234.3 °C; CCM Rf = 0.46 (EtOAc, Si02); IR (film, cm"1) 3371 , 2927, 1756, 1650, 1540, 1368, 1227, 1036; 1H RMN (300MHz, CDCIs) δ (ppm) 7.38 - 7.27 (m, 3H), 7.24 - 7.14 (m, 5H), 6.85 - 6.77 (m, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 5.27 - 5.20 (m, 1 H), 5.15 (t, J = 9.3 Hz, 1 H), 5.00 (t, J = 9.7 Hz, 1 H), 4.85 (t, J = 9.6 Hz, 1 H), 4.57 (d, J = 10.1 Hz, 1 H), 4.05 (t, J = 5.9 Hz, 1 H), 3.96 (dd, J = 12.3, 2.3 Hz, 1 H), 3.79 (dd, J = 12.4, 3.6 Hz, 1 H), 3.41 (dt, J = 10.1 , 3.0 Hz, 1 H), 2.24 - 2.09 (m, 3H), 2.05 (s, 9H), 2.02 (s, 3H), 1 .98 (s, 3H); 13C RMN (75 MHz, CDCI3) δ (ppm) 170.9 (Cq), 170.3 (Cq), 169.7 (Cq), 169.6 (Cq), 169.4 (Cq), 148.0 (Cq), 139.9 (Cq), 137.6 (Cq), 132.7 (CH), 132.3 (Cq), 131 .0 (CH), 130.1 (CH), 129.5 (CH), 129.3 (CH), 128.8 (CH), 127.5 (CH), 126.9 (CH), 85.9 (CH), 75.6 (CH), 74.0 (CH), 70.1 (CH), 68.0 (CH), 61.2 (CH2), 47.7 (CH), 45.5 (CH), 29.5 (CH2), 27.7 (CH2), 23.4 (CH3), 20.9 (2 x CH3), 20.7 (2 x CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C32H37NOioSNa 650,2036, trouvé 650,2042. C 1 ' - (2S, 3R, 4S, 5R, 6R) -2 - ((3 - ((4S) -4-acetamido-1,2,3,4-tetra-ydronapetalen-1-yl) phenyl thio) -6- (acetoxymethyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate [AC268-C15 / AC268-HPLC3] White solid obtained according to General Procedure No. 2 (18.0 mg, 23% yield); Purified by HPLC using an Xbridge Ci 8 type column (4.6 x 150mm, δμηι) and an H 2 0 / MeOH (40:60) mixture as the solvent; mp: 232.9-234.3 ° C; TLC R f = 0.46 (EtOAc, SiO 2 ); IR (film, cm "1) 3371, 2927, 1756, 1650, 1540, 1368, 1227, 1036; 1 H NMR (300MHz, CDCl) δ (ppm) 7.38 - 7.27 (m, 3H), 7.24 - 7.14 (m , 5H), 6.85 - 6.77 (m, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.27 - 5.20 (m, 1H), 5.15 (t, J = 9.3 Hz, 1H), 5.00 (t, J = 9.7 Hz, 1H), 4.85 (t, J = 9.6 Hz, 1H), 4.57 (d, J = 10.1 Hz, 1H), 4.05 (t, J = 5.9 Hz, 1H) ), 3.96 (dd, J = 12.3, 2.3 Hz, 1H), 3.79 (dd, J = 12.4, 3.6 Hz, 1H), 3.41 (dt, J = 10.1, 3.0 Hz, 1H), 2.24 - 2.09 (m, 3H), 2.05 (s, 9H), 2.02 (s, 3H), 1.98 (s, 3H), 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 170.9 (C q ), 170.3 (C q ), 169.7 (C q ), 169.6 (C q ), 169.4 (C q ), 148.0 (C q ), 139.9 (C q ), 137.6 (C q ), 132.7 (CH), 132.3 (C q), ), 131.0 (CH), 130.1 (CH), 129.5 (CH), 129.3 (CH), 128.8 (CH), 127.5 (CH), 126.9 (CH), 85.9 (CH), 75.6 (CH), 74.0 (CH), 70.1 (CH), 68.0 (CH), 61.2 (CH 2 ), 47.7 (CH), 45.5 (CH), 29.5 (CH 2 ), 27.7 (CH 2 ), 23.4 (CH 3 ), 20.9 ( 2 x CH 3 ), 20.7 (2 x CH 3 ), HRMS (ESI) (M + Na) + m / z calculated for C 32 H 37 N O 5 N at 650.2036, found 650.2042.
(2R)-2-acetamido-3-((3-((1R)-4-acetamido-1,2,3,4-tetrahydronaphthalen-1-yl)p  (2R) -2-acetamido-3 - ((3 - ((1R) -4-acetamido-1,2,3,4-tetrahydronaphthalen-1-yl) p
propanoic acid [AC300] propanoic acid [AC300]
Solide blanc obtenu selon la procédure générale n°2 (62.2 mg, 95% de rendement), mélange de diastéréoisomères, mais le d.e n'a pas pu être déterminé sur le spectre RMN proton 1H; CCM Rf = 0.03 (DCM/MeOH, 9:1 , Si02); IR (film, cm"1) 3376, 2932, 2278, 1630, 1545, 1404; 1H RMN (300MHz, MeOD) δ (ppm) 7.29 - 6.93 (m, 8H), 6.77 (d, J = 7.5 Hz, 1 H), 5.14 - 5.01 (m, 1 H), 4.44 - 4.32 (m, 1 H), 4.02 (t, J = 6.3 Hz, 1 H), 3.52 - 3.37 (m, 1 H), 3.29 - 3.25 (m, 1 H), 3.18 - 3.08 (m, 1 H), 2.1 1 - 2.00 (m, 1 H), 2.00 (s, 3H), 1.99 - 1 .93 (m, 1 H), 1 .88 (s, 3H); 13C RMN (75 MHz, MeOD) δ (ppm) 177.1 (Cq), 172.7 (Cq), 172.6 (Cq), 149.0 (Cq), 140.9 (Cq), 140.8 (Cq), 138.3 (Cq), 138.1 (Cq), 137.9 (Cq), 131 .6 (CH), 131 .1 (CH), 130.8 (CH), 129.9 (CH), 129.8 (CH), 129.1 (CH), 128.4 (CH), 127.9 (CH), 127.6 (CH), 56.0 (CH), 55.9 (CH), 48.9 (CH), 48.8 (CH), 46.6 (CH), 38.2 (CH2), 37.4 (CH2), 30.5 (CH2), 28.5 (CH2), 28.3 (CH2), 22.7 (2 x CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C23H26N204SNa 449,151 1 , trouvé 449,151 1 . White solid obtained according to General Procedure No. 2 (62.2 mg, 95% yield), mixture of diastereoisomers, but it could not be determined on the 1 H proton NMR spectrum; TLC R f = 0.03 (DCM / MeOH, 9: 1, SiO 2 ); IR (film, cm "1) 3376, 2932, 2278, 1630, 1545, 1404; 1 H NMR (300MHz, MeOD) δ (ppm) 7.29 - 6.93 (m, 8H), 6.77 (d, J = 7.5 Hz, 1H), 5.14 - 5.01 (m, 1H), 4.44 - 4.32 (m, 1H), 4.02 (t, J = 6.3 Hz, 1H), 3.52 - 3.37 (m, 1H), 3.29 - 3.25 (m, 1H), 3.18 - 3.08 (m, 1H), 2.1-1 - 2.00 (m, 1H), 2.00 (s, 3H), 1.99-193 (m, 1H), 1.88 (s, 3H) 13 C NMR (75 MHz, MeOD) δ (ppm) 177.1 (C q ), 172.7 (C q ), 172.6 (C q ), 149.0 (C q ), 140.9 (C q ), 140.8 (C q ), 138.3 (C q ), 138.1 (C q ), 137.9 (C q ), 131.6 (CH), 131.1 (CH), 130.8 (CH), 129.9 (CH), 129.8 (CH), ), 129.1 (CH), 128.4 (CH), 127.9 (CH), 127.6 (CH), 56.0 (CH), 55.9 (CH), 48.9 (CH), 48.8 (CH), 46.6 (CH), 38.2 (CH), 2 ), 37.4 (CH 2 ), 30.5 (CH 2 ), 28.5 (CH 2 ), 28.3 (CH 2 ), 22.7 (2 x CH 3 ), HRMS (ESI) (M + Na) + m / z calculated for C 23 H 26 N 2 O 4 SN? 449.151 1, found 449.151 1.
C/'s - (2S, 3R, 4S, 5R, 6R)-2-((4-((4S)-4-acetamido- 1,2,3, 4-tetra ydronap t alen- 1 - yl)benzoyl)oxy)-6-(acetoxymethyl)tetrahydro-2H-pyran-3, 4, 5-triyl triacetate [AC435] C 1 ' - (2S, 3R, 4S, 5R, 6R) -2 - ((4 - ((4S) -4-acetamido-1,2,3,4-tetra-ydronapetalen-1-yl) benzoyl ) oxy) -6- (acetoxymethyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate [AC435]
En utilisant le composé c/s-4-(4-acetamido-1 ,2,3,4-tetrahydronaphthalen-1 -yl)benzoic acid [VM055-cis] comme produit de départ, le composé final est préparé selon la procédure générale n°5 afin d'obtenir un solide blanc (68.5 mg, 55% de rendement); mp: 120.1 - 122.3 °C; CCM Rf = 0.45 (EtOAC, Si02); IR (film, cm"1) 3280, 2934, 1759, 1652, 1367, 1272, 1242, 1067, 1034 ; 1H RMN (300MHz, CDCI3) δ (ppm) 7.95 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1 H), 7.28 - 7.19 (m, 1 H), 7.13 (d, J = 8.1 Hz, 3H), 6.77 (d, J = 9.5 Hz, 1 H), 5.93 - 5.87 (m, 1 H), 5.75 (d, J = 8.1 Hz, 1 H), 5.37 - 5.27 (m, 2H), 5.22 - 5.13 (m, 1 H), 4.30 (dd, J = 12.7, 4.6 Hz, 1 H), 4.21 (t, J = 6.7 Hz, 1 H), 4.12 (dd, J = 8.8, 4.9 Hz, 1 H), 3.96 - 3.87 (m, 1 H), 2.30 - 2.10 (m, 2H), 2.06 (s, 6H), 2.04 (s, 3H), 2.03 (s, 3H), 1 .99 (d, J = 2.9 Hz, 3H), 1 .97 - 1 .83 (m,2 H), 1 .79 - 1.63 (m, 1 H); 13C RMN (75 MHz, CDCI3) δ (ppm) 170.73 (Cq), 170.20 (Cq), 169.55 (2 x Cq), 169.45 (Cq), 164.48 (Cq), 153.23 (Cq), 138.90 (Cq), 137.63 (Cq), 130.54 (2 x CH), 130.25 (CH), 129.13 (2 x CH), 128.24 (CH), 127.74 (CH), 127.27 (CH), 126.70 (Cq), 92.36 (CH), 72.85 (2 x CH), 70.30 (CH), 68.08 (CH), 61.64 (CH2), 47.88 (CH), 45.67 (CH), 30.28 (CH2), 28.31 (CH2), 23.69 (CH3), 20.81 (CH3), 20.71 (3 x CH3); HRMS (ESI) (M + Na)+ m/z calculé pour C33H37NOi2Na 662,2238, trouvé 662,2212. By using the compound c / s-4- (4-acetamido-1,2,3,4-tetrahydronaphthalen-1-yl) benzoic acid [VM055-cis] as starting material, the final compound is prepared according to the general procedure. # 5 to obtain a white solid (68.5 mg, 55% yield); mp: 120.1 - 122.3 ° C; TLC R f = 0.45 (EtOAc, SiO 2 ); IR (film, cm -1 ) 3280, 2934, 1759, 1652, 1367, 1272, 1242, 1067, 1034 1 H NMR (300 MHz, CDCl 3 ) δ (ppm) 7.95 (d, J = 8.1 Hz, 2H) , 7.35 (d, J = 7.7 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.13 (d, J = 8.1 Hz, 3H), 6.77 (d, J = 9.5 Hz, 1H), 5.93 - 5.87 (m, 1H), 5.75 (d, J = 8.1 Hz, 1H), 5.37 - 5.27 (m, 2H), 5.22 - 5.13 (m, 1H), 4.30 (dd, J = 12.7, 4.6 Hz, 1H), 4.21 (t, J = 6.7 Hz, 1H), 4.12 (dd, J = 8.8, 4.9 Hz, 1H), 3.96 - 3.87 (m, 1H), 2.30 - 2.10 (m, 2H), 2.06 (s, 6H), 2.04 (s, 3H), 2.03 (s, 3H), 1 .99 (d, J = 2.9 Hz, 3H), 1.97 - 1.83 (m, 2H). ), 1.79 - 1.63 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ (ppm) 170.73 (C q ), 170.20 (C q ), 169.55 (2 x C q ), 169.45 ( C q ), 164.48 (C q ), 153.23 (C q ), 138.90 (C q ), 137.63 (C q ), 130.54 (2 x CH), 130.25 (CH), 129.13 (2 x CH), 128.24 (CH); 127.74 (CH), 127.27 (CH), 126.70 (C q ), 92.36 (CH), 72.85 (2 x CH), 70.30 (CH), 68.08 (CH), 61.64 (CH 2 ), 47.88 (CH). , 45.67 (CH), 30.28 (CH 2 ), 28.31 (CH 2 ), 23.69 (CH 3 ), 20.81 (CH 3 ), 20.71 (3) x CH 3 ); HRMS (ESI) (M + Na) + m / z calcd for C 33 H 37 NO 2 Na 662.2238, found 662.2212.
C/'s - Et yl 4-((4S)-4-acetamido n-1-yl)benzoate [VM039-cis] C / ' s - and yl 4 - ((4S) -4-acetamido-n-1-yl) benzoate [VM039-cis]
Le composé est préparé selon la procédure générale n°3, suivi d'une réaction d'hydrogénation utilisant 10% massique de palladium sur charbon (0.58 mmol, 0.15 equiv.) dissous dans le méthanol (40.0 mL). Le milieu est hydrogéné pendant 19h sous pression atmosphérique d'hydrogène (montage d'hydrogénation réalisé sur mesure au laboratoire). Lorsque la réaction est terminée, le brut réactionnel est filtré sur un bloc de celite, puis le solvant est évaporé sous pression réduite à l'évaporateur rotatif. La purification par HPLC en utilisant une colonne de type Xbridge Ci8 (4.6 x 150mm, δμηι) et un mélange H20 + 0.1 % AF/ACN (gradient allant de 55% à 45% d'ACN en 15 minutes) en tant que solvant, a permis l'obtention d'un solide blanc (329.0 mg, 25 % de rendement); mp: 175.0 °C; CCM Rf = 0.57 (Toluène/Acétone, 7:3, Si02); IR (film, cm"1) 3280, 3060,The compound is prepared according to the general procedure No. 3, followed by a hydrogenation reaction using 10% by weight of palladium on carbon (0.58 mmol, 0.15 equiv) dissolved in methanol (40.0 ml). The medium is hydrogenated for 19 hours under atmospheric pressure of hydrogen (hydrogenation assembly made to measure in the laboratory). When the reaction is complete, the crude reaction product is filtered through a celite block and the solvent is then evaporated under reduced pressure on a rotary evaporator. Purification by HPLC using an Xbridge Ci 8 type column (4.6 x 150mm, δμηι) and a mixture of H 2 O + 0.1% AF / ACN (gradient ranging from 55% to 45% ACN in 15 minutes) as solvent, allowed to obtain a white solid (329.0 mg, 25% yield); mp 175.0 ° C; TLC R f = 0.57 (toluene / acetone, 7: 3, SiO 2 ); IR (film, cm -1 ) 3280, 3060,
2935, 2859, 1716, 1640, 1539, 1369, 1275, 1 104; 1H RMN (400MHz, CDCI3) δ (ppm) 7.97 (d, J = 10.8 Hz, 2H), 7.37 (d, J = 10.8 Hz, 1 H), 7.24 (t, J = 10.0 Hz, 1 H), 7.13 (d, J = 1 1.2 Hz, 3H), 6.82 (d, J = 10.0 Hz, 1 H), 5.78 (d, J = 1 1.6 Hz, 1 H), 5.39 - 5.31 (m, 1 H), 4.37 (q, J = 9.6 Hz, 2H), 4.24 - 4.20 (m, 1 H), 2.30 - 2.21 (m, 2H), 2.08 (s, 3H), 2.01 - 1.87 (m, 1 H), 1.85 - 1 .70 (m, 1 H), 1.39 (t, J = 9.6 Hz, 3H); 13C RMN (100 MHz, CDCI3) δ (ppm) 169.5 (Cq), 166.5 (Cq), 151 .7 (Cq), 139.1 (Cq), 137.5 (Cq), 130.2 (Cq), 129.7 (2 x CH), 128.7 (2 x CH), 128.0 (CH), 127.5 (CH), 127.0 (CH), 127.0 (CH), 60.9 (CH2), 47.8 (CH), 45.5 (CH), 30.3 (CH2), 28.3 (CH2), 23.5 (CH3), 14.3 (CH3); HRMS (ESI) (M + H)+ m/z calculé pour C21 H24NO3 338.1751 , trouvé 338.1756. 2935, 2859, 1716, 1640, 1539, 1369, 1275, 1140; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.97 (d, J = 10.8 Hz, 2H), 7.37 (d, J = 10.8 Hz, 1H), 7.24 (t, J = 10.0 Hz, 1H) , 7.13 (d, J = 1 1.2 Hz, 3H), 6.82 (d, J = 10.0 Hz, 1H), 5.78 (d, J = 1 1.6 Hz, 1H), 5.39 - 5.31 (m, 1H), 4.37 (q, J = 9.6 Hz). , 2H), 4.24 - 4.20 (m, 1H), 2.30 - 2.21 (m, 2H), 2.08 (s, 3H), 2.01 - 1.87 (m, 1H), 1.85 - 1.70 (m, 1H). ), 1.39 (t, J = 9.6 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ (ppm) 169.5 (C q ), 166.5 (C q ), 151.7 (C q ), 139.1 (C q ), 137.5 (C q ), 130.2 (C q) 129.7 (2 x CH), 128.7 (2 x CH), 128.0 (CH), 127.5 (CH), 127.0 (CH), 127.0 (CH), 60.9 (CH 2 ), 47.8 (CH), 45.5 (CH), ), 30.3 (CH 2 ), 28.3 (CH 2 ), 23.5 (CH 3 ), 14.3 (CH 3 ); HRMS (ESI) (M + H) + m / z calcd for C21H24NO3 338.1751, found 338.1756.
C/'s - 1 ,2,3,4-tetrahydro-[1 ,2'- loride [VM045-cis] C 1 ' - 1, 2,3,4-tetrahydro- [1, 2'-loride [VM045-cis]
Préparé selon la procédure générale n°1 , le composé (0.634 mmol, 1 .0 equiv.) est ensuite dissous dans du tétrahydrofurane (THF) anhydre (2 ml_, 0.317 M). Le milieu réactionnel est dégazé avec de l'argon, puis refroidi à 0°C. Dans un deuxième temps, la pyridine (0.757 mmol, 1 .2 equiv.) et le chlorure d'oxalyle (0.694 mmol, 1 .1 equiv.) sont ajoutés goutte à goutte au milieu réactionnel (apparition d'une suspension jaune). L'ensemble est agité à 0°C pendant 15 minutes, puis le propylène glycol (92 μί, 1 .26 mmol, 2 equiv.) est ajouté. Le propan-1 -ol (5.320 mmol, 8.0 equiv.) et l'HCI (4M dans le dioxane) (2.400 mmol, 3.8 equiv.) sont ajoutés à leur tour. Enfin, le milieu réactionnel est agité à température ambiante pendant une nuit. Une fois la complétion de la réaction atteinte, les solvants sont éliminés sous pression réduite et le brut est alors trituré avec du méthyl tert- butyl éther (MTBE) froid. Le solide obtenu est ensuite filtré, et rincé avec du MTBE froid. Ainsi, le solide blanc obtenu correspond au produit final attendu (145.0 mg, 74% de rendement); mp: 276 °C (décomposition); CCM Rf = 0.05 (DCM/MeOH, 95:5, Si02); IR (film, cm"1) 2900, 2613, 1610, 1574, 1508, 1457, 1 127; 1H RMN (400MHz, MeOD) δ (ppm) 8.65 (bs, ωι/2 = 31 Hz, 2H), 7.94 - 7.77 (m, 2H), 7.73 (d, J = 10.4 Hz, 1 H), 7.56 (s, 1 H), 7.54 - 7.42 (m, 2H), 7.33 (t, J = 9.6 Hz, 1 H), 7.28 - 7.18 (m, 2H), 6.87 (d, J = 10.4 Hz, 1 H), 4.64 (bs, ωι/2 = 15 Hz, 1 H), 4.37 (bs, ων2 = 15 Hz, 1 H), 2.42 - 2.14 (m, 2H), 2.04 - 1 .81 (m, 2H), pas de protons du NH2 observés; 13C RMN (15 MHz, MeOD) δ (ppm) 146.3 (Cq), 142.5 (Cq), 136.2 (Cq), 135.6 (Cq), 134.4 (Cq), 133.0 (CH), 131 .0 (CH), 130.7 (CH), 130.6 (CH), 130.2 (2 x CH), 129.6 (2 x CH), 129.3 (CH), 128.9 (CH), 128.3 (CH), 50.9 (CH), 47.0 (CH), 30.8 (CH2), 28.3 (CH2); HRMS (ESI) (M + H)+ m/z calculé pour C20H2iCIN 274.1590, trouvé 274.1601 . Prepared according to General Procedure No. 1, the compound (0.634 mmol, 1.0 equiv.) Is then dissolved in anhydrous tetrahydrofuran (THF) (2 mL, 0.317 M). The reaction medium is degassed with argon and then cooled to 0 ° C. In a second step, pyridine (0.757 mmol, 1.2 equiv.) And oxalyl chloride (0.694 mmol, 1 equiv.) Are added dropwise to the reaction medium (appearance of a yellow suspension). The mixture is stirred at 0 ° C. for 15 minutes and then propylene glycol (92 μl, 1.26 mmol, 2 equiv) is added. Propan-1-ol (5.320 mmol, 8.0 equiv.) And HCl (4M in dioxane) (2.400 mmol, 3.8 equiv.) Are added in turn. Finally, the reaction medium is stirred at room temperature overnight. After completion of the reaction, the solvents are removed under reduced pressure and the crude is then triturated with cold methyl tert-butyl ether (MTBE). The solid obtained is then filtered and rinsed with cold MTBE. Thus, the white solid obtained corresponds to the expected final product (145.0 mg, 74% yield); mp: 276 ° C (decomposition); TLC R f = 0.05 (DCM / MeOH, 95: 5, SiO 2 ); IR (film, cm "1) 2900, 2613, 1610, 1574, 1508, 1457, 1127; 1 H NMR (400MHz, MeOD) δ (ppm) 8.65 (bs, ωι / 2 = 31 Hz, 2H), 7.94 7.77 (m, 2H), 7.73 (d, J = 10.4 Hz, 1H), 7.56 (s, 1H), 7.54-7.42 (m, 2H), 7.33 (t, J = 9.6 Hz, 1H); , 7.28 - 7.18 (m, 2H), 6.87 (d, J = 10.4 Hz, 1H), 4.64 (bs, ωι / 2 = 15 Hz, 1H), 4.37 (bs, ω ν2 = 15 Hz, 1H) ), 2.42 - 2.14 (m, 2H), 2.04-1.81 (m, 2H), no observed NH 2 protons, 13 C NMR (15 MHz, MeOD) δ (ppm) 146.3 (C q ), 142.5 (C q ), 136.2 (C q ), 135.6 (C q ), 134.4 (C q ), 133.0 (CH), 131.0 (CH), 130.7 (CH), 130.6 (CH), 130.2 (2 x CH), 129.6 (2 x CH), 129.3 (CH), 128.9 (CH), 128.3 (CH), 50.9 (CH), 47.0 (CH), 30.8 (CH 2 ), 28.3 (CH 2 ), HRMS (ESI) (M + H) + m / z calcd for C 20 H 2 CIIN 274.1590, found 274.1601.
C/'s - 4-(4-acetamido-1 ,2,3,4-tetrahydronaphthalen-1 -yl)benzoic acid [VM055-cis] C / ' s - 4- (4-acetamido-1,2,3,4-tetrahydronaphthalen-1-yl) benzoic acid [VM055-cis]
Préparé selon la procédure générale n°1 , le composé subit ensuite une réaction d'hydrolyse en utilisant de l'hydroxyde de sodium (0.59 mmol, 2.0 equiv.) dissous dans l'éthanol (1 ml_). Le milieu réactionnel est alors agité à 50°C pendant 15 heures, avant d'être dilué avec de l'eau (20 mL), puis acidifié à pH = 1 avec de l'HCI (concentré à 37%). Le produit attendu précipite lors de la phase d'ajout d'HCI. L'ensemble est ensuite extrait deux fois avec de l'acétate d'éthyle (EtOAc). Les phases organiques combinées sont lavées avec de l'eau, puis une solution aqueuse saturée en NaCI, puis séchées avec MgS04, filtrées et évaporées, grâce à un évaporateur rotatif, sous pression réduite. Le produit attendu est récupéré sous forme d'un solide beige (80.2 mg, 87 % de rendement); mp: 282 °C (décomposition); CCM Rf = 0.01 (DCM/MeOH, 95:5, Si02); IR (film, cm"1) 3324, 2926, 1698, 1610, 1542, 1451 , 1376, 1241 , 1 179; 1H RMN (400MHz, MeOD) δ (ppm) 7.96 (d, J = 10.8 Hz, 2H), 7.31 (d, J = 10.4 Hz, 1 H), 7.25 - 7.18 (m, 3H), 7.12 (t, J = 9.6 Hz, 1 H), 6.80 (d, J = 10.4 Hz, 1 H), 5.24 (t, J = 8.4 Hz, 1 H), 4.29 (t, J = 8.8 Hz, 1 H), 2.33 - 2.27 (m, 1 H), 2.19 - 2.08 (m, 1 H), 2.05 (s, 3H), 1 .98 - 1 .88 (m, 1 H), 1 .82 - 1.76 (m, 1 H), pas de protons de C02H et de NH observés sur le spectre RMN 1H; 13C RMN (100 MHz, MeOD) δ (ppm) 172.7 (Cq), 169.8 (Cq), 153.7 (Cq), 140.4 (Cq), 138.8 (Cq), 131 .1 (Cq), 130.9 (2 x CH), 129.9 (2 x CH), 129.1 (CH), 128.4 (CH), 127.8 (CH), 128.9 (Cq), 46.7 (2 x CH), 31.5 (CH2), 29.2 (CH2), 22.7 (CH3); HRMS (ESI) (M + Na)+ m/z calculé pour Ci9H19N03Na 332.1257, trouvé 332.1256. Prepared according to General Procedure No. 1, the compound then undergoes a hydrolysis reaction using sodium hydroxide (0.59 mmol, 2.0 equiv) dissolved in ethanol (1 ml). The reaction medium is then stirred at 50 ° C. for 15 hours, before being diluted with water (20 ml) and then acidified to pH = 1 with HCl (37% concentrated). The expected product precipitates during the phase of adding HCI. The whole is then extracted twice with ethyl acetate (EtOAc). The combined organic phases are washed with water and then a saturated aqueous solution of NaCl, then dried with MgSO 4 , filtered and evaporated, using a rotary evaporator, under reduced pressure. The expected product is recovered in the form of a beige solid (80.2 mg, 87% yield); mp: 282 ° C (decomposition); TLC R f = 0.01 (DCM / MeOH, 95: 5, SiO 2 ); IR (film, cm "1) 3324, 2926, 1698, 1610, 1542, 1451, 1376, 1241, 1179; 1 H NMR (400MHz, MeOD) δ (ppm) 7.96 (d, J = 10.8 Hz, 2H) , 7.31 (d, J = 10.4 Hz, 1H), 7.25 - 7.18 (m, 3H), 7.12 (t, J = 9.6 Hz, 1H), 6.80 (d, J = 10.4 Hz, 1H), 5.24 (t, J = 8.4 Hz, 1H), 4.29 (t, J = 8.8 Hz, 1H), 2.33 - 2.27 (m, 1H), 2.19 - 2.08 (m, 1H), 2.05 (s, 3H). ), 1 .98 - 1 .88 (m, 1 H), 1 .82 - 1.76 (m, 1H), no proton C0 2 H and NH observed on the 1 H NMR spectrum, 13 C NMR ( 100 MHz, MeOD) δ (ppm) 172.7 (C q ), 169.8 (C q ), 153.7 (C q ), 140.4 (C q ), 138.8 (C q ), 131 .1 (C q ), 130.9 (2 x CH), 129.9 (2 x CH), 129.1 (CH), 128.4 (CH), 127.8 (CH), 128.9 (C q ), 46.7 (2 x CH), 31.5 (CH 2 ), 29.2 (CH 2 ) 22.7 (CH 3); HRMS (ESI) (m + Na) + m / z calcd for Ci 9 H 19 N0 3 Na 332.1257, found 332.1256.
Cis - (2R,3R S,5R,6R)-2-(4-aœtamido-1,2,3 -tetrahydronaphthaien-1-yi)benzam (acetoxy- methyl)tetra -cis]  Cis - (2R, 3R S, 5R, 6R) -2- (4-aetamido-1,2,3-tetrahydronaphthaien-1-yl) benzam (acetoxy-methyl) tetra-cis
Une solution de l'acide benzoïque cis (0.09 mmol, 1 .0 equiv.) correspondant (obtenu par la procédure générale n°1 , suivi d'une réaction d'hydrolyse) est préparée dans du N,N- diméthylformamide (DMF) anhydre (1 mL). L'HOBi (0.1 18 mmol, 1 .3 equiv.) et l'EDC.HCI (0.120 mmol, 1 .3 equiv.) sont alors ajoutés à cette solution. L'ensemble est agité 30 minutes à température ambiante. Dans un deuxième temps, le composé (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-aminotetrahydro-2/-/-pyran-3,4,5-triyl triacetate (0.1 18 mmol, 1 .3 equiv.) est ajouté en une seule fois au milieu réactionnel et le tout est agité à température ambiante pendant 15 heures. Une fois la réaction terminée, la réaction est diluée avec une solution aqueuse saturée en NH4CI, et extraite trois fois avec de l'acétate d'éthyle (EtOAc). Les phases organiques combinées sont lavées avec de l'eau, puis une solution aqueuse saturée en NaCI, puis séchées avec du MgS04, filtrées et évaporées, grâce à un évaporateur rotatif, sous pression réduite. Le produit attendu est récupéré sous forme d'un solide blanc (36 mg, 62 % de rendement); mp: 209 °C; CCM Rf = 0.45 (DCM/MeOH, 94:6, Si02); IR (film, cm"1) 3304, 2929, 1756, 1650, 1536, 1366, 1210, 1033; 1 H RMN (400MHz, MeOD) δ (ppm) 7.77 (d, J = 10.4 Hz, 2H), 7.67 (d, J = 10.8 Hz, 2H), 7.35 (d, J = 10.0 Hz, 1 H), 7.22 (t, J = 10.0 Hz, 1 H), 7.1 1 (d, J = 10.4 Hz, 3H), 6.78 (d, J = 10.0 Hz, 1 H), 6.08 (t, J = 8.0 Hz, 1 H), 5.99 - 5.88 (m, 1 H), 5.56 - 5.23 (m, 3H), 5.16 - 4.99 (m, 1 H), 4.35 - 4.25 (m, 1 H), 4.25 - 4.14 (m, 1 H), 4.10 (d, J = 16.0 Hz, 1 H), 3.89 (d, J = 13.6 Hz, 1 H), 2.30 - 2.10 (m, 2H), 2.16 (s, 3H), 2.06 (s, 6H), 2.04 (s, 6H), 1 .98 - 1 .80 (m, 2H), les proton de NHAc et de NHCO ne sont pas observés sur le spectre RMN 1 H; 13C RMN (100 MHz, MeOD) δ (ppm) 171 .4 (Cq), 170.6 (Cq), 169.8 (Cq), 169.6 (2 x Cq), 167.0 (Cq), 151 .3 (Cq), 138.9 (Cq), 137.5 (Cq), 130.9 (Cq), 130.1 (CH), 129.1 (2 x CH), 128.1 (CH), 127.6 (CH), 127.5 (2 x CH), 127.0 (CH), 78.9 (CH), 73.6 (CH), 72.6 (CH), 70.8 (CH), 68.3 (CH), 61 .7 (CH2), 47.7 (CH), 45.3 (CH), 30.2 (CH2), 28.2 (CH2), 23.5 (CH3), 20.7 (CH3), 20.6 (3 x CH3); HRMS (ESI) (M + H)+ m/z calculé pour C33H39N20i i 639.2548, trouvé 639.2535. (1 S, 4S)-N, N-Dimethyl- 1, 2, 3, 4-te n]-4-amine [VM-099] A solution of the corresponding cis-benzoic acid (0.09 mmol, 1 equiv.) (Obtained by general procedure No. 1, followed by a hydrolysis reaction) is prepared in N, N-dimethylformamide (DMF). anhydrous (1 mL). The HOBi (0.1 18 mmol, 1.3 equiv.) And the EDC.HCl (0.120 mmol, 1.3 equiv) are then added to this solution. The whole is stirred for 30 minutes at room temperature. In a second step, the compound (2R, 3R, 4S, 5R, 6R) -2- (acetoxymethyl) -6-aminotetrahydro-2H-pyran-3,4,5-triyl triacetate (0.1 18 mmol, 1 Equiv.) Is added all at once to the reaction medium and the whole is stirred at room temperature for 15 hours. Once the reaction is over, the The reaction is diluted with saturated aqueous NH 4 Cl solution and extracted three times with ethyl acetate (EtOAc). The combined organic phases are washed with water, then a saturated aqueous solution of NaCl, then dried with MgSO 4 , filtered and evaporated, using a rotary evaporator, under reduced pressure. The expected product is recovered as a white solid (36 mg, 62% yield); mp 209 ° C; TLC R f = 0.45 (DCM / MeOH, 94: 6, SiO 2 ); IR (film, cm "1) 3304, 2929, 1756, 1650, 1536, 1366, 1210, 1033; 1 H NMR (400MHz, MeOD) δ (ppm) 7.77 (d, J = 10.4 Hz, 2H), 7.67 ( d, J = 10.8 Hz, 2H), 7.35 (d, J = 10.0 Hz, 1H), 7.22 (t, J = 10.0 Hz, 1H), 7.1 1 (d, J = 10.4 Hz, 3H), 6.78 (d, J = 10.0 Hz, 1H), 6.08 (t, J = 8.0 Hz, 1H), 5.99 - 5.88 (m, 1H), 5.56 - 5.23 (m, 3H), 5.16 - 4.99 (m, 1H), 4.35-4.25 (m, 1H), 4.25-4.14 (m, 1H), 4.10 (d, J = 16.0Hz, 1H), 3.89 (d, J = 13.6Hz, 1H), 2.30 - 2.10 (m, 2H), 2.16 (s, 3H), 2.06 (s, 6H), 2.04 (s, 6H), 1.98-180 (m, 2H), the NHAc and NHCO protons are not observed on the 1 H NMR spectrum 13 C NMR (100 MHz, MeOD) δ (ppm) 171.4 (C q ), 170.6 (C q ), 169.8 (C q ), 169.6 (2 x C q ), 167.0 (C q), 151 .3 (C q), 138.9 (C q), 137.5 (C q), 130.9 (C q), 130.1 (CH), 129.1 (2 x CH), 128.1 (CH) 127.6 (CH), 127.5 (2 x CH), 127.0 (CH), 78.9 (CH), 73.6 (CH), 72.6 (CH), 70.8 (CH), 68.3 (CH), 61.7 (CH 2 ), , 47.7 (CH), 45.3 (CH), 30.2 (CH 2 ), 28.2 (CH 2 ), 23.5 (CH 3 ), .7 (CH 3 ), 20.6 (3 x CH 3 ); HRMS (ESI) (M + H) + m / z calcd for C 33 H 39 N 20 O 639.2548, found 639.2535. (1S, 4S) -N, N-Dimethyl-1,2,3,4-tetra] -4-amine [VM-099]
1 H RMN (400 MHz, CDCI3) δ 7.78 (d, J = 1 1 .2Hz, 3H), 7.66 (d, J = 9.2 Hz, 1 H), 7.61 (s, 1 H), 7.50-7.40 (m, 2H), 7.27-7.16 (m, 2H), 7.09 (t, J = 9.2 Hz, 1 H), 6.79 (d, J = 10 Hz, 1 H), 4.30 (m, 2H), 2.47 (s, 6H), 2.37-2.29 (m, 2H), 2.34-2.17 (m, 2H), 1 .98 (t, J = 12.8 Hz, 2H) ; 13C RMN (100 MHz, CDCI3) δ 145.4 [C], 142.8 [C], 135.0 [C], 133.8 [C], 131 .1 [CH], 129.2 [CH], 129.0 [CH], 128.6 [2xCH], 128.4 [CH], 128.2 [CH], 127.8 [CH], 127.4 [CH], 127.1 [CH], 126.5 [CH], 64.5 [CH], 47.5 [CH], 40.6 [2xCH3], 32.5 [CH2], 20.8 [CH2], un carbone quaternaire n'est pas visible ; H RMS (ES+) calculé pour C22H24N [M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 11.2 Hz, 3H), 7.66 (d, J = 9.2 Hz, 1H), 7.61 (s, 1H), 7.50-7.40 ( m, 2H), 7.27-7.16 (m, 2H), 7.09 (t, J = 9.2 Hz, 1H), 6.79 (d, J = 10Hz, 1H), 4.30 (m, 2H), 2.47 (s). , 6H), 2.37-2.29 (m, 2H), 2.34-2.17 (m, 2H), 1.98 (t, J = 12.8 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 145.4 [C], 142.8 [C], 135.0 [C], 133.8 [C], 131.1 [CH], 129.2 [CH], 129.0 [CH], 128.6 [ 2xCH], 128.4 [CH], 128.2 [CH], 127.8 [CH], 127.4 [CH], 127.1 [CH], 126.5 [CH], 64.5 [CH], 47.5 [CH], 40.6 [2xCH 3 ], 32.5 [CH 2 ], 20.8 [CH 2 ], a quaternary carbon is not visible; H MSY (ES +) calcd for C 22 H 24 N [M + H] +
302.1909, trouvé 302.1904. 2. Etude biologique 302.1909, found 302.1904. 2. Biological study
2.1 Interaction avec la TCTP  2.1 Interaction with the TCTP
L'interaction des molécules synthétisées avec la protéine TCTP a été évaluée par la technique de résonnance plasmonique de surface (SPR) en utilisant l'appareil biacore T200.  The interaction of the synthesized molecules with the TCTP protein was evaluated by surface plasmon resonance (SPR) technique using the T200 biocore apparatus.
Un faisceau de lumière monochromatique polarisée illumine une interface de verre située entre deux milieux dotés d'indice de réfraction différents, étant donné que l'angle d'incidence est supérieur à l'angle limite, toute la lumière est réfléchie, c'est ce que l'on nomme un phénomène de réflexion interne totale. Il n'y a alors pas de réfraction mais une composante électromagnétique de la lumière, l'onde évanescente se propage sur une distance équivalente à sa propre longueur d'onde, perpendiculairement à l'interface.  A polarized monochromatic light beam illuminates a glass interface located between two media with different refractive index, since the angle of incidence is greater than the limit angle, all the light is reflected, it is this that we call a phenomenon of total internal reflection. There is no refraction but an electromagnetic component of the light, the evanescent wave propagates over a distance equivalent to its own wavelength, perpendicular to the interface.
Au niveau de la feuille d'or localisée à l'interface entre les deux milieux on observe une résonance entre les plasmons de l'or et l'onde évanescente ce qui se traduit par une perte d'énergie lumineuse au niveau du faisceau réfléchi au niveau d'un angle précis que l'on nomme angle de résonnance. Cet angle est sensible à l'indice de réfraction du milieu dans lequel l'onde évanescente se propage. At the level of the gold leaf located at the interface between the two media, a resonance is observed between the gold plasmons and the evanescent wave, which results in a loss of light energy at the level of the beam reflected from the level of a precise angle called resonance angle. This angle is sensitive to the refractive index of the medium in which the evanescent wave propagates.
Une mesure en continu des variations de l'angle de réfraction est effectuée à l'aide d'un micro-réfractomètre produisant un sensorgramme qui permet de suivre en temps réel la fixation des molécules injectées dans la cellule microfluidique. Le signal de résonance est exprimé en unité de résonance (RU) et rend compte de ce qui est présent à un moment donné dans la cellule microfluidique.  A continuous measurement of the variations in the angle of refraction is performed using a micro-refractometer producing a sensorgram which makes it possible to follow in real time the binding of the molecules injected into the microfluidic cell. The resonance signal is expressed in resonance unit (RU) and accounts for what is present at a given moment in the microfluidic cell.
Ainsi, la protéine TCTP est liée sur une puce composée d'une couche de dextran posée sur une feuille d'or, elle-même posée sur une plaque de verre. Cette couche est prise en sandwich entre une cellule de microfluidique et un prisme. Les composés synthétisés sont passés dans la cellule microfluidique et leur interaction est évaluée à travers le signal SPR reçu (Tableau 1 ).  Thus, the TCTP protein is bound on a chip composed of a layer of dextran placed on a gold leaf, itself placed on a glass plate. This layer is sandwiched between a microfluidic cell and a prism. The synthesized compounds are passed into the microfluidic cell and their interaction is evaluated through the received SPR signal (Table 1).
2.2. Activité cytotoxique 2.2. Cytotoxic activity
L'activité cytotoxique des composés préparés a été évaluée sur la lignée cancéreuse humaine HCT1 16 (carcinome colorectal). La lignée sélectionnée a été incubée à 37°C en présence de l'un des composés préparé, ajouté dans le milieu de culture à différentes concentrations. La concentration inhibitrice induisant la mort de 50% des cellules (Cl50) a été déterminée après 72 heures d'incubation pour chaque composé (Tableau 1 ). Tableau 1 : The cytotoxic activity of the compounds prepared was evaluated on the human cancer line HCT1 16 (colorectal carcinoma). The selected line was incubated at 37 ° C in the presence of one of the compounds prepared, added in the culture medium at different concentrations. The inhibitory concentration inducing the death of 50% of the cells (Cl 50 ) was determined after 72 hours of incubation for each compound (Table 1). Table 1:
n.d : non déterminé n.d: not determined
Les composés AC014, AC096, AC087, AC069, AC085, AC056, AC034 et AC041 ont montré d'excellentes affinités vis-à-vis de la protéine TCTP et présentent également un profil d'activité antiproliférative identique à celui de la sertraline. Compounds AC014, AC096, AC087, AC069, AC085, AC056, AC034 and AC041 showed excellent affinities with respect to the TCTP protein and also have a profile of antiproliferative activity identical to that of sertraline.
2.3 .Surexpression de la protéine p53 2.3 .Surexpression of the p53 protein
Le composé AC014 est capable d'induire la surexpression de p53 (figure 1 ). Les analyses par Western Blot montrent que le composé AC014 induit à 10μΜ, l'expression de la protéine p53. Cette induction est plus prononcée si l'on compare à celle induite par la sertraline.  Compound AC014 is capable of inducing overexpression of p53 (FIG. 1). Western Blot analyzes show that the compound ACO14 induces at 10 μΜ the expression of the p53 protein. This induction is more pronounced when compared to that induced by sertraline.
Le Western blot a été réalisé selon le protocole décrit dans l'article suivant : The Western blot was carried out according to the protocol described in the following article:
Amson R, Pece S, Lespagnol A, Vyas R, Mazzarol G, Tosoni D, Colaluca I, Viale G, Rodrigues-Ferreira S, Wynendaele J, Chaloin O, Hoebeke J, Marine JC, Di Fiore PP, Telerman A. Nat Med. 201 1 Dec 1 1 ;18(1 ):91 -9. Amson R, Pece S, Lespagnol A, Vyas R, Mazzarol G, Tosoni D, Colaluca I, Viale G, Rodrigues-Ferreira S, Wynendaele J, Chaloin O, Hoebeke J, Marine JC, Di Fiore PP, Telerman A. Nat Med . 201 1 Dec 1 1; 18 (1): 91 -9.
Les anticorps suivants ont été utilisés dans l'analyse par Western blot: des anticorps anti TCTP ont été générés contre la protéine entière d'origine humaine de TCTP. Ces anticorps polyclonaux ont été purifiés par colonne d'affinité couplés à la protéine TCTP (Agro-Bio). The following antibodies were used in the Western blot assay: anti TCTP antibodies were generated against the TCTP human whole protein. These Polyclonal antibodies were purified by affinity column coupled to TCTP protein (Agro-Bio).
L'anticorps de souris anti-P53 1 C12 (Cell Signalling Technology) a été utilisé à une dilution de 1/1000.  Mouse anti-P53 1 C12 antibody (Cell Signaling Technology) was used at a dilution of 1/1000.
Les anticorps secondaires (anti-lapin et anti-souris) conjugués à l'HRP ont été utilisés à une dilution de 1/5000 pour visualiser les signaux par Western blots. Secondary antibodies (anti-rabbit and anti-mouse) conjugated to HRP were used at a dilution of 1/5000 to visualize the signals by Western blots.
2.4. Inhibition de la croissance cellulaire 2.4. Inhibition of cell growth
La viabilité et la prolifération de cellules humaines HCT1 16 est mesurée à l'aide du test « CelITiter Glo® » (Promega) qui permet de mesurer par luminescence le nombre de cellules vivantes. Les composés Sertraline et AC070 ont été testées à 10 concentrations et les résultats sont exprimés sous la forme de GI50, TGI, LC50 et IC50 par rapport aux cellules contrôles (DMSO). The viability and proliferation of human HCT1 16 cells is measured using the "CelITiter Glo®" test (Promega) which makes it possible to measure the number of living cells by luminescence. The compounds Sertraline and AC070 were tested at 10 concentrations and the results are expressed as GI50, TGI, LC50 and IC50 relative to the control cells (DMSO).
Le test CelITiter-GIo® est une méthode homogène de détermination du nombre de cellules viables en culture basée sur une quantification de ΓΑΤΡ présent, indicateur des cellules métaboliquement actives. La procédure de test homogène implique l'ajout d'un seul réactif (le réactif CelITiter-GIo®) directement sur les cellules cultivées dans un milieu enrichi en sérum. The CelITiter-GIo® test is a homogeneous method for determining the number of viable cells in culture based on quantification of ΓΑΤΡ present, indicator of metabolically active cells. The homogeneous test procedure involves the addition of a single reagent (the CelITiter-GIo® reagent) directly to cells grown in serum-enriched media.
Les résultats du test sont reportés dans les tableaux 2 et 3 suivants (tableau 2 : sertraline et tableau 3 : AC070) : The results of the test are reported in the following Tables 2 and 3 (Table 2: Sertraline and Table 3: AC070):
Tableau 2  Table 2
GI5oMédiane 1 2 3 Moyenne Ecart-typeGI 5 oMediane 1 2 3 Mean Standard deviation
8,886E-07 9,091 E-07 8,810E-07 8,783E-07 8,895E-07 1 .704E-08 8,886E-07 9,091 E-07 8,810E-07 8,783E-07 8,895E-07 1 .704E-08
TGI50 1 2 3 Moyenne Ecart-type médiane TGI 50 1 2 3 Mean median standard deviation
1 .442E-06 1 .480E-06 1 .439E-06 1 .406E-06 1 .442E-06 3,694E-08  1 .442E-06 1 .480E-06 1 .439E-06 1 .406E-06 1 .442E-06 3.694E-08
LC50 Médiane 1 2 3 Moyenne Ecart-typeLC50 Median 1 2 3 Mean Standard deviation
2,282E-06 2,344E-06 2,298E-06 2,196E-06 2,279E-06 7,569E-08 Tableau 3 2,282E-06 2,344E-06 2,298E-06 2,196E-06 2,279E-06 7,569E-08 Table 3
La sertraline présente une constante d'inhibition de la croissance cellulaire GI50 = 141 nM et une concentration létale LC50 = 355 nM tandis que le composé AC070 présente une GI50 = 889 nM et une LC50 = 2.2 μΜ. Le composé AC070 est donc légèrement moins actif que la sertraline sur la croissance cellulaire mais il est moins cytotoxique que la sertraline. Sertraline has an inhibition constant of GI50 cell growth = 141 nM and a LC50 lethal concentration = 355 nM while AC070 has a GI50 = 889 nM and an LC50 = 2.2 μΜ. AC070 is therefore slightly less active than sertraline on cell growth but is less cytotoxic than sertraline.
2.5. Test in vivo sur le modèle de souris chaque souris C57BL/6 2.5. In vivo test on mouse model each mouse C57BL / 6
Le composé AC070 et la sertraline ont été testés in vivo sur des souris C57BL/6. Dans un premier temps, des cellules tumorales ITR-1 (Induced Tumor Reversion-1 ) ont été prélevées de sarcomes développés par des souris ko p53 /- (« knock-out »). Puis, un million de ces cellules ont été injectées (SC) dans chaque souris C57BL/6 dans le but de développer des tumeurs. Une fois cette étape réalisée, les composés à analyser (la sertraline et le composé AC070), ont été injectés dans les souris C57BL/6 (30 mg/kg 1 x/j par voie IP). Cette étude a été effectuée en double aveugle. Au bout de douze jours, les souris ont été sacrifiées et leurs tumeurs ont été pesées et analysées. Les résultats de ces analyses sont retranscris sous forme de diagramme (figure 2). La première colonne du diagramme correspond à une injection de diméthylsulfoxyde (DMSO) sans présence de principe actif et sert de référence à l'étude. La valeur de p ou « signification » a été calculée par un logiciel selon la méthode de Tukey, et est significative si elle est inférieure à 0,05, ce qui correspond à une marge d'erreur de 5 %. The compound AC070 and sertraline were tested in vivo on C57BL / 6 mice. In a first step, ITR-1 (Induced Tumor Reversion-1) tumor cells were removed from sarcomas developed by p53 / - knockout mice. Then, one million of these cells were injected (SC) into each C57BL / 6 mouse for the purpose of developing tumors. Once this step was carried out, the compounds to be analyzed (sertraline and the compound AC070) were injected into the C57BL / 6 mice (30 mg / kg once a day by the IP route). This study was performed in double blind. After 12 days, the mice were sacrificed and their tumors were weighed and analyzed. The results of these analyzes are retranscribed in diagrammatic form (Figure 2). The first column of the diagram corresponds to an injection of dimethylsulfoxide (DMSO) without presence of active ingredient and serves as a reference for the study. The value of p or "significance" has been calculated by software according to the Tukey method, and is significant if it is less than 0.05, which corresponds to a margin of error of 5%.

Claims

REVENDICATIONS
(I) suivante : (I) following:
Dans laquelle : In which :
X représente un atome d'oxygène, un atome de soufre, un atome d'azote ou un radical CH,  X represents an oxygen atom, a sulfur atom, a nitrogen atom or a CH radical,
La liaison X— Y et Y sont absents si X représente un atome d'oxygène ou de soufre, la liaison X— Y et Y sont présents si X représente un atome d'azote ou un radical CH,  The X-Y and Y bond are absent if X represents an oxygen or sulfur atom, the X-Y and Y bond are present if X represents a nitrogen atom or a CH radical,
Lorsqu'il est présent, Y représente  When present, Y represents
o un groupe R si X représente un atome d'azote,  a group R if X represents a nitrogen atom,
dans lequel R représente un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2- C6)alcynyle ou un groupe acyle, wherein R is hydrogen, C 1-6 alkyl, aryl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, or acyl group,
o un atome d'hydrogène ou un groupe -NR1R2 si X représente un radical CH, dans lequel R1 et R2 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2-C6)alcynyle ou un groupe acyle, ou R1 et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, a hydrogen atom or a group -NR 1 R 2 if X represents a radical CH, in which R 1 and R 2 represent, independently of each other, a hydrogen atom or a Ci-alkyl group; at C 6 , aryl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl or acyl, or R 1 and R 2 together with the atom of nitrogen which carries them a 5- or 6-membered heterocycle,
(Het)Ar est un cycle aromatique choisi dans le groupe constitué par les groupes aryles et hétéroaryles,  (Het) Ar is an aromatic ring selected from the group consisting of aryl and heteroaryl groups,
ledit cycle aromatique pouvant être substitué par un ou plusieurs groupes choisis parmi un atome d'halogène, un groupe -COOR7, un groupe -CONR8R9, un groupe alkyle en Ci à C6, un groupe -SR10, un groupe CF3, un groupe formyle, un groupe OR11, un groupe (C2-C6) alcényle, said aromatic ring may be substituted by one or more groups selected from a halogen atom, a group -COOR 7 , a group -CONR 8 R 9 , a C 1-6 alkyl group, a group -SR 10 , a group CF 3 , formyl group, OR 11 group, (C 2 -C 6 ) alkenyl group,
avec R7 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle ou un résidu de sucre, with R 7 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group or a sugar residue,
avec R8 et R9 représentant, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2-C6)alcynyle, un résidu de sucre, un résidu d'acide aminé, un résidu de peptide ou R8 et R9 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, avec R10 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un résidu de sucre, un résidu de peptide comprenant au moins une cystéine ou -SR10 représente un résidu de cystéine, avec R11 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle ou un groupe benzyle, with R 8 and R 9 representing, independently of each other, a hydrogen atom, a C 1-6 alkyl group, an aryl group, a heteroaryl group, a (C 2 -C 6 ) alkenyl group , a (C 2 -C 6 ) alkynyl group, a sugar residue, an amino acid residue, a peptide residue or R 8 and R 9 form together with the nitrogen atom which carries them a 5-membered heterocyclic ring; or 6 links, with R 10 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group, a sugar residue, a peptide residue comprising at least one cysteine or -SR 10 represents a cysteine residue with R 11 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group or a benzyl group,
R3, R4, R5, R6 représentent, indépendamment les uns des autres, un atome d'hydrogène, un atome d'halogène, un groupe -NR12R13, un groupe -SR14, un groupe -OR14 ou un groupe -CF3, R 3 , R 4 , R 5 and R 6 represent, independently of each other, a hydrogen atom, a halogen atom, a group -NR 12 R 13 , a group -SR 14 , a group -OR 14 or a group -CF 3 ,
avec R12 et R13 représentant indépendamment l'un de l'autre un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un groupe (C2-C6)alcényle, un groupe (C2-C6)alcynyle ou un groupe acyle, ou R12 et R13 forment ensemble avec l'atome d'azote qui les porte un hétérocycle à 5 ou 6 chaînons, with R 12 and R 13 independently of one another a hydrogen atom, a C 1-6 alkyl group, an aryl group, a heteroaryl group, a (C 2 -C 6 ) alkenyl group, a (C 2 -C 6 ) alkynyl group or an acyl group, or R 12 and R 13 form together with the nitrogen atom which carries them a 5- or 6-membered heterocycle,
avec R14 représentant un atome d'hydrogène, un groupe alkyle en Ci à C6, un groupe aryle, un groupe hétéroaryle, un résidu de sucre, un résidu d'acide aminé ou un résidu de peptide, with R 14 representing a hydrogen atom, a C 1 -C 6 alkyl group, an aryl group, a heteroaryl group, a sugar residue, an amino acid residue or a peptide residue,
Lorsque Y représente un groupe -NR1R2, les groupes - NR1R2 et (Het)Ar sont en conformation cis, When Y represents a group -NR 1 R 2 , the groups - NR 1 R 2 and (Het) Ar are in cis-conformation,
les fonctions alcool du résidu de sucre et les fonctions aminé du résidu d'acide aminé, du résidu de cystéine ou du résidu de peptide étant sous leur forme libre ou protégée,  the alcohol functions of the sugar residue and the amino functions of the amino acid residue, the cysteine residue or the peptide residue being in their free or protected form,
ou un sel pharmaceutiquement acceptable de celui-ci, or a pharmaceutically acceptable salt thereof,
à l'exception du composé 4-(3,4-dichloro-phényl)-1 ,2,3,4-tétrahydronaphtalène-1 -ylamine ou un de ses sels pharmaceutiquement acceptable, with the exception of the compound 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine or a pharmaceutically acceptable salt thereof,
pour son utilisation dans le traitement de maladies prolifératives et des maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme. for use in the treatment of proliferative diseases and infectious diseases, allergies, inflammation and / or asthma.
2. Composé pour son utilisation selon la revendication 1 de formule (II) suivante : 2. Compound for its use according to claim 1 of formula (II) below:
(II) (II)
dans laquelle R1, R2, R3, R4, R5, R6 et Het(Ar) sont tels que définis à la revendication 1. wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Het (Ar) are as defined in claim 1.
3. Composé pour son utilisation selon la revendication 2, caractérisée en ce que R1 représente un groupe acyle, de préférence acétyle, et avantageusement R2 représente un atome d'hydrogène. utilisation selon la revendication 1 , de formule (III) suivante : 3. Compound for its use according to claim 2, characterized in that R 1 represents an acyl group, preferably acetyl, and advantageously R 2 represents a hydrogen atom. use according to claim 1, of formula (III) below:
III) III)
Dans laquelle :  In which :
X' représente CH2, O, S ou N-R, X 'represents CH 2 , O, S or NR,
R, R3, R4, R5, R6 et Het(Ar) sont tels que définis à la revendication 1 . R, R 3 , R 4 , R 5 , R 6 and Het (Ar) are as defined in claim 1.
5. Composé pour son utilisation selon l'une quelconque des revendications précédentes, caractérisé en ce que (Het)Ar est un cycle aromatique choisi dans le groupe constitué par les groupes phényles ou naphtyles, 5. Compound for its use according to any one of the preceding claims, characterized in that (Het) Ar is an aromatic ring selected from the group consisting of phenyl or naphthyl groups,
ledit cycle aromatique pouvant être substitué par un groupe -COOR7, un groupe - CONR8R9, un groupe -SR10, un groupe CF3, ou par au plus un atome d'halogène, R7, R8, R9 et R10 étant tels que définis à la revendication 1. said aromatic ring may be substituted with a group -COOR 7 , a group - CONR 8 R 9 , a group -SR 10 , a group CF 3 , or by at most one halogen atom, R 7 , R 8 , R 9 and R 10 being as defined in claim 1.
6. Composé pour son utilisation selon l'une quelconque des revendications précédentes, caractérisé en ce qu'il est choisi parmi : 6. Compound for use according to any one of the preceding claims, characterized in that it is chosen from:
et leurs sels pharmaceutiquement acceptables, tels que les chlorhydrates. and their pharmaceutically acceptable salts, such as hydrochlorides.
7. Composé pour son utilisation selon l'une quelconque des revendications précédentes, caractérisé en ce que ladite maladie proliférative est un cancer. 7. Compound for use according to any one of the preceding claims, characterized in that said proliferative disease is a cancer.
8. Composé pour son utilisation selon l'une quelconque des revendications précédentes pour son utilisation dans le traitement du cancer par réversion tumorale. A compound for use as claimed in any one of the preceding claims for use in treating cancer by tumor reversion.
9. Composé pour son utilisation selon l'une quelconque des revendications précédentes caractérisé en ce que la maladie proliférative est une leucémie myéloïde aigue, un cancer du sein ou un cancer du cerveau. 9. Compound for use according to any preceding claim characterized in that the proliferative disease is acute myeloid leukemia, breast cancer or brain cancer.
10. Composé pour son utilisation selon l'une quelconque des revendications précédentes caractérisé en ce qu'il est administré en association avec un autre principe actif, avantageusement un anticancéreux, avantageusement la cytarabine. 1 1 . Composé pour son utilisation selon l'une quelconque des revendications 1 à 7, caractérisé en ce que ladite maladie infectieuse est une maladie infectieuse parasitaire, notamment la malaria. 10. Compound for use according to any one of the preceding claims characterized in that it is administered in combination with another active ingredient, preferably an anticancer, preferably cytarabine. 1 1. Compound for its use according to any one of claims 1 to 7, characterized in that said infectious disease is an infectious parasitic disease, including malaria.
12. Composé choisi parmi : 12. Compound selected from:
et leurs sels pharmaceutiquement acceptables. and their pharmaceutically acceptable salts.
13. Composition pharmaceutique pour son utilisation dans le traitement de maladies prolifératives, de maladies infectieuses, des allergies, d'une inflammation et/ou de l'asthme comprenant un composé selon l'une quelconque des revendications 1 à 6 et un excipient pharmaceutiquement acceptable. A pharmaceutical composition for use in the treatment of proliferative diseases, infectious diseases, allergies, inflammation and / or asthma comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient .
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