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  • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
  • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
  • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
  • C07D211/76—Oxygen atoms attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/38—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D281/02—Seven-membered rings
  • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D281/02—Seven-membered rings
  • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates in particular to 2-alkoxy-3,4,5-trihydroxyalkylamides, their preparation, compositions containing them, and their use as a medicament.Furthermore, and according to a first aspect, the invention relates to 2- 3,4,5-alkoxy-trihydroxyalkylamides useful as anticancer agents.
• R2 is independently selected from the group consisting of:
• R9 is selected from the group consisting of H, COO (RIO), CONH (R10), CO (R10), O (R10), R10, wherein each R10 is independently selected from non-binder electron pair, H, -alkyl, -alkylene, -alkynyl, -alkyl halogen, -cycloalkyl, wherein each R10 is optionally substituted with at least one substituent selected from OH 1 halogen, - (C1-C4) alkyl, -O- (C1-C4) ) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl, -N (CHs) 2 , -NH 2 , -CONH 2 ,
• each of Rz is independently selected from the group consisting of H, COO (RIO), CONH (RIO) 1 CO (RIO), R10, wherein each R10 is independently selected from - (C1-C4) alkyl, - (C1- C4) halogenated alkyl, - (C1-C4) alkyl-aryl, - (C1-C4) alkyl-heteroaryl, wherein each R10 is optionally substituted with a substituent selected from OH, halogen, - (C1-C4) alkyl, - O- (C1-C4) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl;
• R'-i, R ' 2) and R' 3 are independently selected from H, R9 or together may form together with R9 an aliphatic or aromatic ring comprising from 5 to 7 members, and from 0 to 3 heteroatoms independently selected from O, S, N.
• R3 is selected from the group consisting of - (C1-C6) alkyl, - (C1-C6) alkyl-aryl, - (C1-C6) alkyl-heteroaryl, -aryl, -heteroaryl, -arylalkylene, - heteroarylalkylene .
• R2 is preferably selected from heterocycles of the following general formula (II):
• R9 is selected from the group consisting of H, COO (RIO), CONH (RIO), CO (RIO), O (R10), R10;
• X is selected from CH 2 , O, S, SO, SO 2 , NO, N (Ry) in which Ry is independently selected from the group consisting of R 9;
• Cy is (i) a bond or (ii) an aliphatic or aromatic ring comprising from 5 to 7 members, and from 0 to 3 heteroatoms independently selected from O, S, N;
• - 1 is 0 or 1
• each R8 is independently selected from the group consisting of H, F, Cl, Br, N (RIO) 2 , NO 2 , CN, COO (RIO), CONH (RIO), O (R10), R10 and m is values 0, 1, 2, 3, or 4;
• each R10 is independently selected from non-linking electron pair, H, -alkyl, -alkylene, -alkynyl, -alkyl halogen, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-aryl-heteroaryl, -aryl, - heteroaryl, -cycloalkyl, wherein each R10 is optionally substituted with at least one substituent selected from OH, halogen, - (C1 -C4) alkyl, -O- (C1 -C4) alkyl, - (C1 -C4) alkyl-aryl , aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl, -N (CH 3 ) 2 , -NH 2 , -CONH 2 ,
• each of Rz is independently selected from the group consisting of H, COO (RIO), CONH (RIO), CO (RIO), R10, wherein each R10 is independently selected from - (C1-C4) alkyl, - (C1- C4) halogenated alkyl, - (C1-C4) alkyl-aryl, - (C1-C4) alkyl-heteroaryl, wherein each R10 is optionally substituted with a substituent selected from OH, halogen, - (C1-C4) alkyl, - O- (C1-C4) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl;
• Rx is selected from H, alkyl, cycloalkyl, acyl, and wherein R6 is selected from H, OH, OCO-G, OCO-G-O-G-alkyl, with G selected from alkyl, allylene, aryl, heteroaryl;
• R1 is not:
• a preferred R 3 substituent is methyl.
• R9 is selected from the group consisting of H, COO (RIO), CONH (RIO), CO (RIO), R10, in which each R10 is independently selected from - (C1-C4) alkyl, - (C1-C4) halogenated alkyl, - (C1-C4) alkyl-aryl, - (C1-C4) alkyl-heteroaryl, wherein each R10 is optionally substituted with a substituent selected from OH, halogen, - (C1-C4) alkyl, -O- (C1-C4) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl,
• each of Rz is independently selected from the group consisting of H, COO (RIO), CONH (RIO), CO (RIO), R10, wherein each R10 is independently selected from ⁇ (C1-C4) alkyl, ⁇ (C1- C4) halogenated alkyl, - (C1- C4) alkyl-aryl, - (C1-C4) alkyl-heteroaryl, wherein each R10 is optionally substituted with a substituent selected from OH, halogen, - (C1-C4) alkyl, -O- (C1-C4) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl;
• R 90 and R 91 are each -CH 2 -;
• q and r each independently take a value selected from 0, 1, 2, 3, and 4;
• Cy is (i) a bond or (ii) an aliphatic or aromatic ring comprising from 5 to 7 members, and from 0 to 3 heteroatoms independently selected from O, S, N;
• - 1 is 0 or 1
• a preferred R2 substituent may be selected from the group consisting of:
• R2 substituent is selected from the group consisting of
• R9 is selected from the group consisting of H, alkene, - (C1-C6) alkylphenyl, - (C1-C6) alkylphenyl halogen, - (C1-C6) alkyl-phenyl-O-alkyl, - (C1-C6) alkyl-pyridine, - (C1-C6) alkyl-pyridine halogen, - (C1 -C6) alkyl- naphthyl, - (C1-C6) alkyl-N (CH 3) 2, and R8 and m are as defined in claim 2.
• R2 is selected from the group consisting of:
• R9 is an alkene or phenyl substituted with 4 or 5 substituents independently selected from R8 as defined in claim 2.
• R2 substituents may be selected from the group consisting of:
• each of R8 is independently selected from the group consisting of H, F, Cl, Br, N (RIO) 2 , NO 2 , COO (RIO), CONH (RIO), O (R10), R10, wherein each R10 is independently selected from H, - (C1-C4) alkyl, - (C1-C4) halogenated alkyl, - (C1-C4) alkyl-aryl, - (C1-C4) alkyl-heteroaryl, wherein each R10 is optionally substituted by a substituent selected from halogen, - (C1-C4) alkyl, -O- (C1-C4) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl ,
• each of R9, Ry is independently selected from the group consisting of H, COO (RIO), CONH (RIO), CO (R10), R10, wherein each R10 is independently selected from - (C1-C4) alkyl, - (C1-C4) alkyl halogen, - (C1-C4) alkyl-aryl, - (C1-C4) alkyl-heteroaryl, wherein each R10 is optionally substituted by a substituent selected from OH, halogen, - (C1 -C4) alkyl, -O- (C1-C4) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl,
• each of Rz is independently selected from the group consisting of H, COO (RIO), CONH (RIO), CO (RIO), R10, wherein each R10 is independently selected from - (C1-C4) alkyl, - (C1-C4) halogenated alkyl, - (C1-C4) alkyl-aryl, - (C1-C4) alkyl-heteroaryl, wherein each R10 is optionally substituted with a substituent selected from OH 1 halogen, - (C1-C4) alkyl, -O- (C1-C4) alkyl, - (C1-C4) alkyl-aryl, aryl, - (C1-C4) alkyl-heteroaryl, -heteroaryl.
• R2 substituents may be advantageously substituted by amines, and these amines may be advantageously salified.
• the invention relates to the products exemplified in Tables 1 and 2.
• Advantageously produced products according to the present invention are:
• the products according to the present invention may exist in the form of bases, addition salts with acids, solvates, hydrates or prodrugs.
• the products in accordance with the invention will preferably have a polyhydroxylated chain whose absolute conformation is:
• the products according to the invention may be in non-chiral, or racemic form, or enriched in a stereoisomer, or enriched in an enantiomer; and may possibly be salified.
• a product according to the invention may be used for the manufacture of a medicament useful for treating a pathological state, in particular a cancer.
• the present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with an excipient pharmaceutically acceptable according to the chosen mode of administration.
• the pharmaceutical composition may be in solid, liquid or liposome form.
• solid compositions include powders, capsules, tablets.
• Oral forms may also include solid forms protected from the acidic environment of the stomach.
• the supports used for the solid forms consist in particular of mineral supports such as phosphates, carbonates or organic supports such as lactose, celluloses, starch or polymers.
• the liquid forms consist of solutions of suspensions or dispersions. They contain as dispersive carrier either water, or an organic solvent (ethanol, NMP or others) or mixtures of surfactants and solvents or complexing agents and solvents.
• the liquid forms will preferably be injectable and, therefore, will have an acceptable formulation for such use.
• Acceptable injection routes of administration include intravenous, intraperitoneal, intramuscular, and subcutaneous routes, with the intravenous route being preferred.
• the administered dose of the compounds of the invention will be adapted by the practitioner according to the route of administration of the patient and the state of the latter.
• the compounds of the present invention may be administered alone or in admixture with other anticancer agents.
• anticancer agents we can mention:
• Platinum derivatives such as cisplatin, carboplatin or oxaliplatin
• antibiotic agents such as bleomycin, mitomycin, dactinomycin
• antimicrotubule agents such as vinblastine, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel)
• Anthracyclines such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone
• topoisomerases of groups I and II such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex
• Fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine
• Cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine
• Adenosine analogues such as pentostatin, cytarabine or fludarabine phosphate
• Antivascular agents such as derivatives of combretastatin or eolchicine and their prodrugs.
• halogen refers to an element selected from F, Cl, Br, and I.
• alkyl refers to a linear or branched, saturated hydrocarbon substituent having from 1 to 12 carbon atoms.
• the substituents methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,
• alkylene refers to a linear or branched hydrocarbon substituent having one or more unsaturations, having 2 to 12 carbon atoms.
• the substituents ethylenyl, 1-methylethylenyl, prop-1-enyl, prop-2-enyl, Z-1-methylprop-1-enyl, E-1-methylprop-1-enyl, Z-1,2-dimethylpropyl 1-enyl, E-1, 2-dimethylprop-1-enyl, but-1,3-dienyl, 1-methylidenylprop-2-enyl, 2-methylbut-1,3-dienyl, E-2 methylbut-1,3-dienyl, 2-methyl-1-methylidenylprop-2-enyl, undec-1-enyl and undec-10-enyl are examples of alkylene substituents.
• alkynyl refers to a linear or branched hydrocarbon substituent having at least two unsaturations carried by a pair of vicinal carbon atoms having 2 to 12 carbon atoms.
• Ethynyl substituents; prop-1-ynyl; prop-2-ynyl; and but-1 -ynyl are examples of alkynyl substituents.
• aryl refers to a mono- or polycyclic aromatic substituent having from 6 to 14 carbon atoms. Phenyl, naphth-1-yl substituents; naphth-2-yl; anthracen-9-yl; 1,2,3,4-tetrahydronaphth-5-yl; and 1,2,3,4-tetrahydronaphth-6-yl are examples of aryl substituents.
• heteroaryl refers to a mono- or polycyclic heteroaromatic substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms.
• Pyrrol-1-yl substituents; pyrrol-2-yl; pyrrol-3-yl; furyl; thienyl; imidazolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; 1,2,4-triazolyl; oxadiazolyl; thiadiazolyl; tetrazolyl; pyridyl; pyrimidyl; pyrazinyl; 1,3,5-triazinyl; indolyl; benzo [b] furyl; benzo [b] thienyl; indazolyl; benzimidazolyl; azaindolyl; quinolyl; isoquinolyl; carbazolyl; and acridyl are examples of heteroaryl substituents.
• heteroatom refers here to at least one divalent atom, different from carbon. NOT; O; S; and are examples of heteroatoms.
• cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having from 3 to 12 carbon atoms. Cyclopropyl substituents; cyclobutyl; cyclopentyl; cyclopentenyl; cyclopentadienyl; cyclohexyl; cyclohexenyl; cycloheptyl; bicyclo [2.2.1] heptyl; cyclooctyl; bicyclo [2.2.2] octyl; adamantyl; and perhydronaphthyl are examples of cycloalkyl substituents.
• heterocyclyl refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms.
• the saturated or partially unsaturated cyclic hydrocarbon substituent will be monocyclic and will have 4 or 5 carbon atoms and 1 to 3 heteroatoms.
• Step 3 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2- dimethyl-1,3-dioxan-4-yl] -2-methoxy-N- (2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl) acetamide (5)
• Step 2 Preparation of (R) -N - [(S) -1- (Biphenyl-4-ylmethyl) -2-oxo-perhydroazepin-3-yl] -2 - [(4R, 5S, 6R) ) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxan-4-yl] -2-methoxy-acetamide (8); )
• Step 3 Preparation of N - [(S) -1- (Biphenyl-4-ylmethyl) -2-oxo-perhydroazepin-3-yl] - (E) - (2R, 3R, 4S 1 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Example 2)
• Step 1 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2- dimethyl-1,3-dioxan-4-yl] -2-methoxy-N- (2-oxo-1-phenylazetidin-3-yl) -acetamide (10)
• Step 2 N- (2-Oxo-1-phenyl-azetidin-3-yl) - (EM2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl -non-6-ènamide (Ex3)
• Step 1 Preparation of (R) -2 - [(4R, 5S> 6R) -6 - ((E) -3 I 3-Dimethyl-but-1-enyl) - 5-hydroxy-2,2 dimethyl-1 s 3-dioxan-4-yl] -2-methoxy-N- (2-oxo-pyrroliciin-3-yl) - acetamide (12)
• the product visibly solubilized in the aqueous phase is extracted twice with a mixture of 50 mL of CH 2 Cl 2 and 5 mL of MeOH.
• the 3 organic phases are combined, dried, filtered and then evaporated to dryness.
• Step 1 Preparation of 4 - ⁇ (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2 Methyl 2-dimethyl-1,3-dioxan-4-yl] -2-methoxyacetylamino ⁇ -5-oxopyrrolidine-2-carboxylate (14)
• Step 1 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2- dimethyl-1,3-dioxan-4-yl] -2-methoxy-N- (2-oxo-piperidin-3-yl) -acetamide 16
• Step 1 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2- dimethyl-1,3-dioxan-4-yl]] - 2-methoxy-N- (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl) -acetamide (Q8)
• Example D N- (5-Oxo-perhydro-1,4-thiazepin-6-yl) - (E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8, 8-dimethyl-non-6-enamide
• Step 1 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2- 1,3-dimethyl-dioxan-4-yl] -2-methoxy-N- (5-oxo-perhydro-1,4-thiazepin-6-yl) -acetamide (20)
• Step 2 Preparation of N- (5-Oxo-perhydro-1, 4-thiazepin-6-yl) - (E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2 -methoxy-8,8-dimethyl-non-6-enamide (Ex8)
• Step 1 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2- 1-Dimethyl-1,3-dioxan-4-yl] -2-methoxy-N - ((7S, 12bR) -6-oxo-1-yl] hexadecylbenzazepine; ⁇ -yO-acetamide ⁇ )
• Step 2 Preparation of N - ((7S ) 12bR) -6-oxo-1,2,3,4,6,7,8,12b-octahydro-pyrido [2,1-a] [2] benzazepine -7-yl) - (EH 2 R, 3 R, 4 S, 5 R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex9)
• Step 2 Preparation of (R) -2 - [(4R, 5S, 6R) -6- (Benzyloxyimino-methyl) -5-hydroxy-2,2-dimethyl-1,3-dioxan-4-yl] N - [(S) -1- (Biphenyl-4-ylmethyl) -2-oxo-perhydro-azepin-3-yl] -2-methoxy-acetamide (25)
• Step 3 Preparation of N - [(S) -1- (biphenyl-4-ylmethyl) -2-oxo-perhydroazepin-3-yl] - (2R, 3R, 4S, 5R) -6- ( benzyloxyimino-3,4,5-trihydroxy-2-methoxyhexylamide (Ex10)
• Step 1 Preparation of tert-butyl (5-oxo-perhydro-1,4-thiazepin-6-yl) carbamate (26)
• Step 4 Preparation of (R) -N- (4-Benzyl-5-oxo-perhydro-1,4-thiazepin-6-yl) -2 - [(4R, 5S, 6R) -6 - (( E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4-yl] -2-methoxyacetamide (29)
• Example 12 N- (4- (3,4-difluorobenzyl) -5-oxo-perhydro-1,4-thiazepin-6-yl) - (EH 2 R, 3 R, 4 S, 5 R) -3.4.5 -Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide
• Step 1 Preparation of tert-butyl [4- (3,4-difluoro-benzyl) -5-oxo-perhydro-1,4-thiazepin-6-yl] carbamate (30)
• Step 3 Preparation of (R) -N- (4- (3,4-Difluorobenzyl) -5-oxo-perhydro-1,4-thiazepin-6-yl) -2 - [(4R, 5S, 6R) ) -6 - ((E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4-yl] -2-methoxyacetamide (32) )
• Step 4 Preparation of N- (4- (3,4-difluorobenzyl) -5-oxo-perhydro-1, 4-thiazepin-6-ylHE) - (2R, 3R, 4S, 5R) -3 4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex12)
• Step 1 Preparation of tert-butyl [4- (3,5-difluoro-benzyl) -5-oxo-perhydro-1,4-thiazepin-6-yl] carbamate (33)
• Step 3 Preparation of (R) -N- (4- (3,5-Difluorobenzyl) -5-oxo-perhydro-1,4-thiazepin-6-yl) -2 - [(4R, 5S, 6R) ) -6 - ((E) -3) 3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1, 3-dioxinan-4-yl] -2-methoxy-acetamide (35 ) 34 35
• Step 4 Preparation of N- (4- (3,5-difluoro-benzyl) -5-oxo-perhydro-1,4-thiazepin-6-yl) - (E) - (2R, 3R, 4S, 5R) -3,4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex13)
• Step 1 Preparation of [4- (2,6-Dichloro-pyridin-4-ylmethyl) -5-oxo-perhydro-1,4-thiazepin-6-yl] -carbamate
• Step 3 Preparation of (R) -N- (4- (2,6-Dichloro-pyridin-4-ylmethyl) -5-oxo-p ⁇ rhydro-1, 4-thiazepin-6-yl) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-dimethyl-1-butyl-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4-yl] -2-methoxyacetamide (38)
• Step 4 Preparation of N- (4- (2,6-Dichloro-pyridin-4-ylmethyl) -5-oxo-perhydro-1,4-thiazepin-6-yl) - (E) - (2R, 3R, 4S, 5R) -3,4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex14)
• Step 1 Preparation of tert-butyl [4- (4-butoxybenzyl) -5-oxo-perhydro-1,4-thiazepin-6-yl] carbamate (39)
• Step 3 Preparation of (R) -N- (4- (4-Butoxy-benzyl) -5-oxo-perhydro-1, 4-thiazepin- ⁇ -yO-a-1-R. N, N'-Dimethyl-but-1-enyl-5-hydroxy-1-dimethyl-1,3-dioxinan-4-yl] -2-methoxyacetamide (41)
• Step 1 Preparation of tert-butyl [4- (naphthalen-2-ylmethyl) -5-oxo-perhydro-1,4-thiazepin-6-yl] carbamate (42)
• Step 3 Preparation of (R) -N- (4- (naphthha-2-ylmethyl) -5-oxo-perhydro-1,4-thiazepin-6-yl) -2 - [(4R, 5S) 6R) -6 - ((E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4-yl] -2-methoxyacetamide (44)
• Step 1 Preparation of tert-butyl [4- (2-dimethylamino-ethyl) -5-oxo-perhydro-1,4-thiazepin-6-yl] carbamate (45)
• the medium is left stirring for 1.5 h, 20 ml of AcOEt and 20 ml of water are added to the reaction medium, after decantation, the organic phase is washed 3 times with 20 ml of water, 1 time with 20 ml of water, mL of HCI (1N) and finally 1 time with 20 mL of ammonia.
• Step 3 Preparation of (R) -N- (4- (2-Dimethylamino-ethyl) -5-oxo-perhydro-1, 4-thiazepin-6-yl) -2 - [(4R, 5S J 6R ) -6 - ((E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4-yl] -2-methoxyacetamide (47); )
• Step 4 Preparation of N- (4- (2-dimethylamino-ethyl) -5-oxo-perhydro-1, 4-thiazepin-6-yl) - (EH 2 R, 3 R, 4 S, 5 R) -3.4 5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex17)
• Step 1 Preparation of 6 - ⁇ (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2 Benzyl 2-dimethyl-1,3-dioxinan-4-yl] -2-methoxy-acetylamino ⁇ -5-oxo-perhydro-1,4-diazepine-1-carboxylate (49)
• Step 1 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2- 1,3-dimethyl-dioxinan-4-yl] -2-methoxy-N- (4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) acetamide (51.)
• Example 20 N- (5- (3,5-difluoro-benzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (EH 2 R, 3 R, m.p. 4S, 5R) -3,4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide
• Step 1 Preparation of tert-butyl (5-oxo-perhydro-1,4-thiazepin-6-yl) carbamate (52)
• Step 2 Preparation of tert-butyl [5- (3,5-difluoro-benzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] carbamate (53)
• Step 3 Preparation of 3-Amino-5- (3,5-difluoro-benzyl) -2,3-dihydro-5H-1,5-benzothiazepin-4-one hydrochloride (54)
• Step 4 Preparation of (R) -N- [5- (3,5-Difluoro-benzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4- yl] -2-methoxyacetamide (55)
• Step 5 Preparation of N- (5- (3,5-difluoro-benzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylHE) - (2R, 3R, 4S, 5R) -3,4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex20)
• Step 1 Preparation of tert-butyl (5-allyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) -carbamate (56)
• Step 3 Preparation of (R) -N- (5-Allyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) -2 - [(4R, 5S) 6R) -6 - ((E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4-yl] -2-methoxyacetamide (58)
• Step 4 Preparation of N- (5-allyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylHE) - (2R, 3R, 4S, 5R) -3 4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex21)
• Example 22a & b N- (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl) - (E) - (2R, 3R, 4S, 5R) -3.4 , 5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide
• Step 1 Preparation of (R) -2 - [(4R, 5S, 6R) -6 - ((E) -3,3-Dimethyl-but-1-enyl) -5-hydroxy-2,2- dimethyl-1,3-dioxinan-4-yl] -2-methoxy-N- (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl) acetamide (60a); b)
• Step 2 Preparation of N- (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylHE) - (2R, 3R, 4S, 5R) -3 ) 4, 5-Trihydroxy-2-methoxy-8,8-dimethyl-non-enamide (Ex22a & b)
• Step 1 Preparation of tert-butyl (S) - (I-Dec-9-enyl-2-oxo-perhydro-azepin-3-yl) carbamate (62)
• the anti-tumor activity of products 1 to 10 was determined by measuring the inhibition of cell proliferation of Hep-G2 cells.
• the cells are seeded in a cell culture medium at a concentration of 1000 cells per well, and incubated for 4 hours at 37 ° C. and 5% CO 2 .
• Medium used for the culture of Hep-G2 cells and HCT-116 Dubelcco modified Eagle's medium / Ham's F12 mixture (Gibco); NEAA (10%, non-essential amino acids, Gibco); sodium pyruvate (1%, Gibco); L-glutamine (1%, Gibco); Fetal calf serum (5%, PAA).
• test products dissolved in a DMSO / cell culture medium mixture are added at various concentrations and the resulting mixtures are incubated for 72 hours at 37 ° C. and 5% CO 2 .
• Intracellular ATP content was measured using the CelITiterGIo assay reagent (Promega).
• the antiproliferative activity of the products of the examples of Table 2 was determined by measuring the inhibition of cell proliferation of HCT116 cells.
• the cells are seeded in a cell culture medium at a concentration of 10,000 cells per well, in 0.17 ml of medium, and 20 ⁇ l of product to be tested, at different concentrations, and 10 ⁇ l of Thymidine [methyl-14C] (100 ⁇ l).
• ⁇ Ci / ml - specific activity 47.90 mCi / mmol, NEN Technologies reference NEC568 batch 3550-001) are added, and the cells are then incubated at 37 ° C. and 5% CO 2 .
• DMEM medium 2 mM L-glutamine, 200 IU / ml penicillin, 200 ⁇ g / ml streptomycin and 10% (V / V) fetal calf serum (Life Technologies).
• the IC50 values are calculated using equation 205 of the XLFit software (IDBS company, UK) using nonlinear regression analysis using the Marquardt algorithm (Donald W. MARQUARDT, J.Soc.industry.appI, Vol 11, No. 2, June, 1963).
• the products of Table 2 exhibit an IC50 on HCT116 cells generally less than 30 .mu.M and preferably less than 10 .mu.m.

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