Classifications

• • 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
  • C07D243/10—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 condensed with carbocyclic rings or ring systems
  • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
  • C07D243/10—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 condensed with carbocyclic rings or ring systems
  • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
  • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
  • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
  • C07D243/24—Oxygen atoms
  • C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D267/02—Seven-membered rings
  • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D267/12—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
  • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D267/02—Seven-membered rings
  • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

• the present invention relates in particular to 2-alkoxy-3,4,5-trihydroxyalkylamide derivatives, their preparation, compositions containing them, and their use as a medicament.
• the invention relates to 2-alkoxy-3,4,5-trihydroxyalkylamide derivatives useful as anti-cancer agents.
• the problem to be solved by the present invention is to obtain new products with anticancer activity.
• some of these new products may also have advantageous properties in relation to their pharmacological activity, such as their pharmacokinetics, bioavailability, solubility, stability, toxicity, absorption or metabolism.
• R 1 is independently selected from the group consisting of (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 2 -C 12) alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyclo (C 1 -C 12) alkyl alkyl, cycloalkyl ( C2-C12) alkenyl, cycloalkyl (C2-C12) alkynyl, heterocyclyl (C1-C12) alkyl, heterocyclyl (C2-C12) alkenyl, heterocyclyl (C2-C12) alkynyl, aryl (C1-C12) alkyl, aryl (C2- C12) alkenyl, aryl (C2-C12) alkynyl, heteroaryl (C1-C12) alkyl, heteroaryl (C2-C12) alkenyl, heteroaryl (C1-C12) alkyl,
• R 2 is selected from the group consisting of (C 1 -C 6) alkyl, aryl (C 1 -C 6) alkyl, heteroaryl (C 1 -C 6) alkyl, aryl, heteroaryl, (C 1 -C 6) alkylthio (C 1 -C 6) alkyl , di (C1-C6) alkylamino (C1-C6) alkyl, aryloxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkyl;
• R 3 is selected from the group consisting of H, COO (R 5 ), CONH (R 5 ), CO (R 5 ), O (R 5 ), R 5 ;
• R 4 is independently selected from the group consisting of H, F, Cl, Br, N (Rs) 2 , NO 2 , CN, COO (R 5 ), CON (R 5 ) 2 , NHCO (R 5 ), NHCOO (R 5 ), OCONH (Rs), O (R 5 ), R 5 or two substituents R 4 , linked to 2 adjacent carbons of the phenyl, together form a ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more R 4 ;
• R 5 is independently selected from non-linking electron pairs, H, (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, halo (C1-C12) alkyl, aryl (C1- C12) alkyl, heteroaryl (C1-C12) alkyl, heteroarylaryl (C1-C12) alkyl, aryl, heteroaryl, cycloalkyl, wherein each R 5 is optionally substituted by at least one substituent selected from OH, halogen, (C1-C4) alkyl, (C 1 -C 4) alkoxy, aryl (C 1 -C 4) alkyl, aryl, heteroaryl (C 1 -C 4) alkyl, heteroaryl, -N (CH 3 ) 2 , -NH 2 , CONH 2 ,
• each of Rz is independently selected from the group consisting of H, COO (R 5 ), CONH (R 5 ), CON (R 5 ) 2 , CO (R 5 ), R 5 , wherein each
• R 5 is independently selected from (C1-C4) alkyl, halogen (C1-
• R 5 is optionally substituted with a substituent selected from OH, halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, aryl (C 1 -C 4) alkyl, aryl, heteroaryl (C 1 -C 4) alkyl, heteroaryl.
• R 1 is independently selected from the group consisting of (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 2 -C 12) alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl, aryl (C1-C12) alkyl, aryl (C2-C12) alkenyl, aryl (C2-C12) alkynyl, heteroaryl (C1-C12) alkyl, heteroaryl (C2-C12) alkenyl, heteroaryl (C2 C12) alkynyl.
• R 2 is selected from the group consisting of (C 1 -C 6) alkyl, aryl (C 1 -C 6) alkyl, heteroaryl (C 1 -C 6) alkyl , aryl, heteroaryl, (C 2 -C 12) alkenylaryl, (C 2 -C 12) alkenylheteroaryl, (C 1 -C 6) alkylthio (C 1 -C 6) alkyl, di (C 1 -C 6) alkylamino (C 1 -C 6) alkyl, aryloxy (C 1 -C 6) C6) alkyl.
• R 2 is preferably methyl.
• a first group is characterized in that R 3 is H.
• a second group is characterized in that R 3 is methyl.
• a third group is characterized in that R 3 is (C 1 -C 6) alkyl, (C 1 -C 6) alkenyl, benzyl or (3,5-difluoro) benzyl.
• Another subgroup is characterized in that ma is 0 or R 4 is phenyl.
• the invention relates to the products exemplified in Table 1.
• the invention relates to processes for the preparation of the products of general formula (I) or (I 1 ).
• the products of general formula (I ') are precursors, possibly active, of the products of general formula (I).
• the products of general formula (I) are obtained from the products of general formula (I 1 ) by described methods or by one or more conventional reactions for the skilled person such as, for example, a cyclopropanation, an oxidation or a separation chiral.
• the products of general formula (I) or (I 1 ) can be obtained by hydrolysis of a product of general formula (II):
• R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and m are as previously defined.
• R 1 , R 2 are as previously defined.
• R 1 , R 2 are as previously defined.
• the products of general formula (V) can be obtained by hydrolysis of a product of general formula (IV): wherein R 1, R 2 are as previously defined.
• R 2 is as defined above.
• the products of general formula (I 1 ), (II) and (III) as defined above are an object of the present invention.
• the products of general formula (VI) for which R 2 is methyl or ethyl are an object of the present invention.
• the products of general formula (VII) for which R 2 is methyl or ethyl are an object of the present invention.
• the products according to the present invention may exist in the form of bases, addition salts with acids, solvates, hydrates or prodrugs.
• 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.
• the products for which the carbon bound to the exocyclic amine is of (S) configuration are preferred.
• a product according to the invention may be used for the manufacture of a medicament useful for preventing or treating a pathological state, in particular a cancer.
• the products of the present invention can also be used for the manufacture of a medicament useful for preventing or treating a pathological condition in which neovascularization or angiogenesis is inappropriate, that is to say in cancers in general and in specific cancers such as Kaposi's sarcoma or infantile hemangioma, but also in rheumatoid arthritis, osteoarthritis and / or its associated pains, inflammatory bowel diseases such as ulcerative colitis or disease Crohn's, eye pathologies such as age-related macular degeneration, diabetic retinopathies, chronic inflammation, psoriasis.
• a pathological condition in which neovascularization or angiogenesis is inappropriate that is to say in cancers in general and in specific cancers such as Kaposi's sarcoma or infantile hemangioma, but also in rheumatoid arthritis, osteoarthritis and / or its associated pains, inflammatory bowel diseases such as ulcerative colitis or disease Crohn's
• Angiogenesis is a process of generating new capillaries from preexisting vessels.
• the present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with a pharmaceutically acceptable excipient 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.
• 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
• methotrexate and folinic acid • various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin as well as estrogenic and androgenic hormones
• Antivascular agents such as derivatives of combretastatin, for example CA4P, chalcones or colchicine, for example ZD6126, and their prodrugs.
• Biotherapeutic agents such as antibodies such as rituximab, bevacizumab, cetuximab, trastuzumab or alemtuzumab.
• Proteasome inhibitors such as bortesomib.
• 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.
• alkenyl refers to a linear or branched hydrocarbon substituent having one or more unsaturations having from 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-methylidenyl- prop-2-enyl, Z-2-methylbut-1,3-dienyl, E-2-methylbut-1,3-dienyl, 2-methyl-1-methylidenylprop-2-enyl, undec-1-enyl and undec Examples of alkylene substituents are 10-enyl.
• 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 hydrocarbon substituent cyclic saturated or partially unsaturated will be monocyclic and will have 4 or 5 carbon atoms and 1 to 3 heteroatoms.
• Step 1 Preparation of (3R, 4R, 5S) -4-hydroxy-5 - ((E) - (R) -1-hydroxy-4,4-dimethyl-pent-2-enyl) -3-methoxy-dihydro -furan-2-one (2)
• Step 2 Preparation of (S) -7-amino-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one hydrochloride (4)
• Step 3 Preparation of N - ((S) -8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl) - (E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex1)
• Step 1 Preparation of tert-butyl ((S) -9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl) carbamate )
• Step 2 Preparation of 7- (S) -amino-9-methyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one hydrochloride (6)
• Step 3 Preparation of N - ((S) -9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl) - (E) - ( 2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex2)
• Step 1 Preparation of 3- (S) -amino-1,3,4,5-tetrahydro-1,5-benzodiazepine hydrochloride
• Step 2 Preparation of N - ((S) -2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl) - (E) - (2R, 3R, 4S , 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex3)
• Step 1 Preparation of tert-butyl ((S) -1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H-1,5-benzodiazepin-3-yl) carbamate (9)
• Step 3 Preparation of N - ((S) -1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl) - (E) - (2R , 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex4)
• Step 1 Preparation of tert-butyl ((S) -1-methyl-4-oxo-2,3,4,5-tetrahydro-1 H-1,5-benzodiazepin-3-yl) carbamate (H)
• Step 3 Preparation of N - ((S) -1-methyl-4-oxo-2,3,4,5-tetrahydro-1H-1,5-bezodiazepin-3-yl) - (E) - (2R , 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex5)
• Step 2 Preparation of N- (2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl) - (E) - (2R, 3R, 4S, 5R) - 3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex6)
• Step 1 Preparation of [(3S) -1-Benzyl-4-oxo-2,3,4,5-tetrahydro-1H-1, 5-benzodiazepin-3-yl] tert-butyl carbamate (15)
• Step 3 Preparation of (2f I 3fi, 4S, 5fî, 6E) - ⁇ / - [(3S) -1-benzyl-4-oxo-2,3,4,5-tetrahydro-1 H-1, 5- benzodiazepin-3-yl] -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide (Ex7)
• Step 1 Preparation of tert-butyl [(3S) -1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1 H-1,5-benzodiazepin-3-yl] carbamate (17)
• Step 1 Preparation of tert -butyl [(3S) -5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] carbamate (19)
• Step 3 Preparation of - ⁇ / - [(3S) -5-ethyl-4-oxo-2,3,4 I 5- tetrahydro-1, 5-benzoxazepine (2f, 3f, 4S, 5fî, 6 £?) 3-yl] -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide (Ex9)
• Step 1 Preparation of Fe [(3S) -5-allyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] carbamate (21)
• Step 3 Preparation of (2H, 3H, 4S, 5H, 6E) -NH - [(3S) -5-allyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3 -yl] -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide (Ex10)
• Step 1 Preparation of tert-butyl [(3S) -4-oxo-5-propyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] carbamate (23)
• Step 3 Preparation of (2fi, 3fi, 4S, 5 /:, 6 £?) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl- ⁇ / - [(3S) -4-oxo 5-propyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] non-6-enamide (Ex11)
• Step 1 Preparation of tert-butyl [(3S) -5-isopropyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] carbamate (25)
• Step 2 Preparation of (3S) -3-amino-5-isopropyl-2,3-dihydro-1,5-benzoxazepin-4 (5 / -) - one hydrochloride (26)
• Step 3 Preparation of (2H, 3H, 4S, 5H, 6H) -3A5-trihydroxy-N - [(3S) -5-isopropyl-4-oxo-2,3,4,5-tetrahydro-1 5-benzoxazepin-3-yl] -2-methoxy-8,8-dimethylnon-6-enamide) (Ex12)
• Step 1 Preparation of tert -butyl [(3S) -5- (3,5-difluorobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] carbamate ( 27)
• Step 3 Preparation of (2fi, 3fi, 4S, 5 /:, 6 £?) - ⁇ / - [(3S) -5- (3,5-difluorobenzyl) -4-oxo-2, 3,4,5 1-tetrahydro-1,5-benzoxazepin-3-yl] -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide (Ex13)
• Step 1 Preparation of (4 ⁇ , 4 ⁇ , 7 ⁇ , 7 ⁇ -tert -7-methoxy-2,2-dimethyl-4-vinyltetrahydro-6H-furo [3,2- ⁇ ]] [1,3] dioxin-6-one (30)
• the homogeneous medium thus obtained is refluxed for 3 hours. Allowed to return to 20 0 C +/- 5 ° C, then poured 1000 ml of a solution of NaHCO 3 10% (effervescence, athermic) (pH 8.0-8.5). 185.5 g of Na 2 SaO 3 are then added until almost total discoloration (appearance of a mineral precipitate). After stirring at 20 0 C +/- 5 ° C for 30 minutes, the solid is filtered and rinsed with THF. The filtrate THF / H 2 O is partially concentrated on a rotary evaporator at a temperature below 35 ° C. The aqueous concentrate is saturated with NaCl and extracted with 1500 ml of CH 2 Cl 2 .
• the organic phase is dried over MgSO 4 , filtered and evaporated to dryness.
• the residue is taken up in 2000 ml of an H 2 O / acetone (75/25) mixture, the insolubles are filtered and rinsed with the H 2 O / acetone (75/25) mixture.
• the filtrates are concentrated on a rotary evaporator at 50 ° C. and 20 mbar and filtered again on a sintered glass (porosity No. 4).
• the aqueous phase is saturated with NaCl, is extracted 3 times with CH 2 Cl 2 (1000 mL, 500 mL, and 250 mL).
• Step 2 Preparation of (3H, 4H, 5S) -4-hydroxy-5 - [(1H) -1-hydroxyprop-2-en-1-yl] -3-methoxydihyd
• Step 3 Preparation of (3fi, 4fi, 5S) -5 - [(1 /: 2 £?) -3-cyclopentyl-1-hydroxyprop- 2-en-1-yl] -4-hydroxy-3-méthoxydihydrofuran -2 (3 / - /) - one (32)
• Step 4 Preparation of (2 R, 3 R, 4 S, 5 R, 6 E) -7-Cyclopentyl-3,4,5-trihydroxy-2-methoxy-N - [(3S) -5-methyl-4-oxo] 2,3,4,5-Tetrahydro-1,5-benzoxazepin-3-yl] hept-6-enamide (Ex14)
• Step 1 Preparation of O- (2-bromo-6-nitrophenyl) -N - (tert-butoxycarbonyl) -L-serine (34)
• Step 2 Preparation of N- (tert-butoxycarbonyl) -O- (3-nitrobiphenyl-2-yl) -L-serine (35)
• the dioxane is concentrated, and the aqueous phase is acidified to pH 2-3, extracted twice with 50 ml of AcOEt.
• the combined organic phases are dried over MgSO 4, filtered and evaporated to dryness.
• the crude is chromatographed on a silica cartridge (150 g, eluent CH 2 CVMeOH, gradient MeOH: 1 to 5%). 500 mg of expected product (Yellow Oil) is collected.
• Step 3 Preparation of O (3-aminobiphenyl-2-yl) -N - (tert-butoxycarbonyl) -L-serine (36)
• Step 4 Preparation of tert -butyl [(3S) -4-oxo-9-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] carbamate (37)
• Step 5 Preparation of (2f, 3f, 4S, 5 /:, 6 £?) -7-cyclopentyl-3,4,5-trihydroxy-2-methoxy- ⁇ / - [(3S) -4-oxo- 9-phenyl-2,3 ) 4,5-tetrahydro-1,5-benzoxazepin-3-yl] hept-6-enamide (Ex16)
• Step 2 Preparation of ⁇ - (tert-butoxycarbonyl) -O- (2-nitrobiphenyl-3-yl) -L-serine (41)
• Step 3 Preparation of 0 (2-Aminobiphenyl-3-yl) -N - (tert-butoxycarbonyl) -L-serine (42)
• Step 4 Preparation of tert-butyl [(3S) -4-oxo-6-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] carbamate (43)
• Step 5 Preparation of (2H, 3H, 4S, 5H, 6H) -7-cyclopentyl-3,4,5-trihydroxy-2-methoxy-N - [(3S) -4-oxo-6-phenyl) 2,3,4,5-Tetrahydro-1,5-benzoxazepin-3-yl] hept-6-enamide (Ex17)
• Step 2 Preparation of (2H, 3H, 4S, 5H, 6E) -7- (2-bromophenyl) -3,4,5-trihydroxy-2-methoxy-N - [(3S) -5-methyl-4 -oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl] hept-6-enamide (Ex18)
• Step 1 Preparation of (3H, 4H, 5S) -4-hydroxy-5 - [(1H, 2H) -1-hydroxy-3- (3-thienyl) prop-2-en-1-yl] 3-methoxydihydrofuran-2 (3 / -) - one (45)
• Step 2 Preparation of (2fi, 3fi> 4S, 5f, 6 £?) -3,4,5-trihydroxy-2-methoxy- ⁇ / - [(3S) -5-methyl-4-oxo-2,3 4,5-tetrahydro-1,5-benzoxazepin-3-yl] -7- (3-thienyl) hep
• Step 1 Preparation (4f, 4aS, 7f, 7a) -4- [(4f) -2,2-dimethyl-1,3-dioxolan-4-yl] -7-ethoxy-2,2-dimethyltetrahydro-6H- furo [3,2-c /] [1,3] dioxin-6-one
• Step 2 Preparation of (4f, 4aS, 7f, 7a) -4 - [(1f) -1,2-dihydroxyethyl] -7-ethoxy-2,2-dimethyltetrahydro-6H-furo [3,2 - ⁇ (] [1, 3] dioxin-6-one (49)
• Step 3 Preparation of (4f, 4aS, 7f, 7a) -7-ethoxy-2,2-dimethyl-4-vinyltetrahydro-6H-f
• Step 5 Preparation of (3f, 4a, 5S) -5 - [(1f, 2E) -3-cyclopentyl-1-hydroxyprop-2-en-1-yl] -3-ethoxy-4-hydroxydihydrofuran 2 (3H) -one (52)
• the antiproliferative activity of the products of the examples of Table 1 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% (WV) 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 1 have an IC50 on HCT116 cells generally less than 30 .mu.M and preferably less than 10 .mu.M.
• the compound of Example 1 has an IC 50 of 60 nM
• the compound of Example 2 has an IC 50 of 32 nM
• the compound of Example 3 has an IC 50 of 88 nM
• the compound of the example 4 at an IC 50 of 45 nM
• the compound of Example 5 has an IC 50 of 28 nM.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Rheumatology (AREA)
• Dermatology (AREA)
• Oncology (AREA)
• Urology & Nephrology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Ophthalmology & Optometry (AREA)
• Pain & Pain Management (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Immunology (AREA)
• Vascular Medicine (AREA)
• Physical Education & Sports Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Plural Heterocyclic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=37561171

Family Applications (1)

Country Status (24)

Families Citing this family (2)

Family Cites Families (17)

• 2006
  • 2006-05-24 FR FR0604736A patent/FR2901556A1/fr active Pending
• 2007
  • 2007-05-17 TW TW096117598A patent/TW200812981A/zh unknown
  • 2007-05-21 PE PE2007000625A patent/PE20080099A1/es not_active Application Discontinuation
  • 2007-05-23 AR ARP070102224A patent/AR061105A1/es unknown
  • 2007-05-23 EA EA200870567A patent/EA200870567A1/ru unknown
  • 2007-05-23 CA CA002649685A patent/CA2649685A1/fr not_active Abandoned
  • 2007-05-23 KR KR1020087028525A patent/KR20090010215A/ko not_active Application Discontinuation
  • 2007-05-23 EP EP07765944A patent/EP2029555A2/fr not_active Withdrawn
  • 2007-05-23 CN CN2007800189401A patent/CN101454296B/zh not_active Expired - Fee Related
  • 2007-05-23 MX MX2008015003A patent/MX2008015003A/es unknown
  • 2007-05-23 WO PCT/FR2007/000868 patent/WO2007135295A2/fr active Application Filing
  • 2007-05-23 JP JP2009511547A patent/JP2009537616A/ja not_active Withdrawn
  • 2007-05-23 BR BRPI0712264-0A patent/BRPI0712264A2/pt not_active IP Right Cessation
  • 2007-05-23 AU AU2007253198A patent/AU2007253198A1/en not_active Abandoned
  • 2007-05-24 DO DO2007000105A patent/DOP2007000105A/es unknown
  • 2007-05-24 UY UY30367A patent/UY30367A1/es not_active Application Discontinuation
• 2008
  • 2008-10-17 TN TNP2008000411A patent/TNSN08411A1/en unknown
  • 2008-10-21 CR CR10390A patent/CR10390A/es not_active Application Discontinuation
  • 2008-11-02 IL IL195053A patent/IL195053A0/en unknown
  • 2008-11-10 US US12/267,692 patent/US7994161B2/en not_active Expired - Fee Related
  • 2008-11-21 GT GT200800252A patent/GT200800252A/es unknown
  • 2008-11-21 EC EC2008008899A patent/ECSP088899A/es unknown
  • 2008-12-05 MA MA31444A patent/MA30496B1/fr unknown
  • 2008-12-16 NO NO20085267A patent/NO20085267L/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events