Family of aryl, heteroaryl, O-aryl and O-heteroaryl carbasugars
Patents Granted (Contd.) FORM 25 (12)PATENT (19) ΑΡ ΤΖ GH ΖΜ SZ UG MW LS SD GM BW ΜΖ LR ΚΕ RW SL ΝΑ ZW (73) Appticant(s) TFCHEM, Pharma Parc II, Voie de I'lnnovation, Batlment C, F-27IOO Val de Reuil, France (72) Inventors LOPES Lenaig, France DELIENCOURT-GODEFROY Geraldine, France (74) Representative FISHER CORMACK & BOTHA, Malawi (54) Title Family of aryl, heteroaryl, O-aryl and O-heteroaryl carbasugars (57) Abstract The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium- dependent glucose co-transporter, such as SGLTI, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type- 11 diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti- inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin. (56) Documents Cited : WO 2009 076550 Α1 WO 2005 044256 Α1 US 2010 167989 Α1 WO 2008 070609 Α1 (11) Patent No : ΑΡ 3308 (21) Application No AP/P/2013/007322 (22) Filing Date : 29.05.2012 (24) (45) Date of Grant & Publication : 05/06/2015 (30) Priority Data (33) Country (31) Number (32) Date ΕΡ 11305645.1 26.05.2011 International Classification : C07C 43/225 (2006.01) C07C 43/23 (2006.01) C07C 43/247 (2006.01) C07C 43/253(2006.01) C07D 231/20(2006.01) C07D 333/16(2006.01) Α61Κ 31/085 (2006.01) Α61Κ 31/415(2006.01) Α61Κ 31/381 (2006.01) Α61Ρ 3/04 (2006.01) Α61Ρ 3/10 (2006.01) Α61Ρ 35/00 (2006.01) Α61Ρ 29/00 (2006.01) Α61Ρ 31/00 (2006.01) Α61Ρ 31/12 (2006.01) The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium-dependent glucose co-transporter, such as SGLT1, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti-inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin. A compound having the following formula (I):
or a pharmaceutically or cosmetically acceptable salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers in any proportion, in particular a mixture of enantiomers, and particularly a racemate mixture,
wherein:
- n, m and p represent, independently from one another, 0 or 1, - R represents a hydrogen or a fluorine atom or a CH3, CH2F, CH2OH, CH2OSiRaRbRc, CH2OR11, CH2OCOR11, CH2OCO2R11, CH2OCONR12R13, CH2OP(O)(OR14)2 or CH2OSO3R14 group, - R1 and R2 represent, independently from one another, a fluorine atom or an OH, OSiRdReRf, OR15, OCOR15, OCO2R15 or OCONR16R17 group, - R3 represents a hydrogen or fluorine atom or an OH, OSiRgRhRi, OR18, OCOR18, OCO2R18, OCONR19R20, NR19R20 or NR19COR18 group, - R4 represents a hydrogen atom when n = 1, and R4 represents a hydrogen atom, an halogen atom or an OH, OSiRjRkRl, OR21, OCOR21, OCO2R21, or OCONR22R23 group when n = 0, - X1 represents a hydrogen atom, an halogen atom, a CN, OH, SO2, SiRmRnRo, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24, CO2R24, NR25R26, NR25COR24, CONR25R26, SR24, SO2R24, CSR24 or OSO3R24 group, and - U, V and W represent, independently from one another, a phenyl, pyrazolyl, N-(C1-C6)alkyl-pyrazolyl, or thienyl ring, - R11, R15, R18, R21 and R24 representing, independently from one another, a (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, 5 to 7 ring-membered heterocycloalkyl, aryl, aryl-(C1-C6)-alkyl or (C1-C6)-alkyl-aryl group, this group being possibly substituted by one or more groups chosen among an halogen atom, OH, COOH and CHO, - R12, R13, R16, R17, R19, R20, R22, R23, R25 and R26 representing, independently from one another, a hydrogen atom or a (C1-C6)-alkyl or aryl-(C1-C6)-alkyl group, - R14 representing a hydrogen atom or a (C1-C6)-alkyl group, - Ra to Ro representing, independently from one another, a (C1-C6)-alkyl, aryl or aryl-(C1-C6)-alkyl group, and - Rp to Rs representing, independently from one another, a hydrogen atom or a (C1-C6)-alkyl group, aryl or aryl-(C1-C6)-alkyl group. The compound according to claim 1, characterized in that it responds to the following formula (Ia), (Ib) or (Ic):
with R, R1, R2, R3, R4, X1, U, V, W, n, m and p as defined in claim 1. The compound according to claim 1 or 2, characterized in that it responds to the following formula (I-1), (I-1a), (I-1b) or (I-1c):
or a pharmaceutically or cosmetically acceptable salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers in any proportion, in particular a mixture of enantiomers, and particularly a racemate mixture,
wherein:
- R, R1, R2, and R3 are as defined in claim 1, and - X1, X2, X3, X4 and X5 represent, independently from one another, a hydrogen atom, an halogen atom, a CN, OH, SO2, SiRmRnRo, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24, CO2R24, NR25R26, NR25COR24, CONR25R26, SR24, SO2R24, CSR24 or OSO3R24 group. The compound according to claim 1 or 2, characterized in that it responds to the following formula (I-2), (I-2a) or (I-2b):
or a pharmaceutically or cosmetically acceptable salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers in any proportion, in particular a mixture of enantiomers, and particularly a racemate mixture,
wherein:
- R, R1, R2, and R3 are as defined in claim 1, and - X1, X2, X3, X4, X5, X6, X7, X8 and X9 represent, independently from one another, a hydrogen atom, an halogen atom, a CN, OH, SO2, SiRmRnRo, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24, CO2R24, NR25R26 , NR25COR24, CONR25R26, SR24, SO2R24, CSR24 or OSO3R24 group. The compound according to claim 1 or 2, characterized in that it responds to the following formula (I-3), (I-3a) or (I-3b):
or a pharmaceutically or cosmetically acceptable salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers in any proportion, in particular a mixture of enantiomers, and particularly a racemate mixture,
wherein:
- R, R1, R2, and R3 are as defined in claim 1, - X1, X2, X3, X4, X5 and X6 represent, independently from one another, a hydrogen atom, an halogen atom, a CN, OH, SO2, SiRmRnRo, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24, CO2R24, NR25R26 , NR25COR24, CONR25R26, SR24, SO2R24, CSR24 or OSO3R24 group, and - X represents a hydrogen atom or a (C1-C6)-alkyl group. The compound according to claim 1 or 2, characterized in that it responds to the following formula (I-4), (I-4a) or (I-4b):
or a pharmaceutically or cosmetically acceptable salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers in any proportion, in particular a mixture of enantiomers, and particularly a racemate mixture,
wherein:
- R, R1, R2, R3 and R4 are as defined in claim 1, and - X1, X2, X3, X4, X5, X6, X7, X8 and X9 represent, independently from one another, a hydrogen atom, an halogen atom, a CN, OH, SO2, SiRmRnRo, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24, CO2R24, NR25R26 , NR25COR24, CONR25R26, SR24, SO2R24, CSR24 or OSO3R24 group. The compound according to claim 1 or 2, characterized in that:
- n = 0, - m = 1, - p = 1, - U and W are independently a phenyl optionally substituted with one or more substituents selected from the group consisting of an halogen atom, CN, OH, SO2, SiRmRnRo, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl (C3-C7)-cycloalkyl, OR24, COR24, OCOR24, COR24, NR25R26, NR25COR24, CONR25R26, SR24, SO2R24, CSR24 and OSO3R24, and - V is a thienyl optionally substituted with one or more substituents selected from the group consisting of an halogen atom, CN, OH, SO2, SiRmRnRo. (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24, CO2R24, NR25R26, NR25COR24, CONR25R26, SR24, SO2R24, CSR24 and OSO3R24. The compound according to any of claims 1 to 7, characterized in that R1, R2 and R3 are chosen, independently from one another, among an OH, -O-(C1-C6)-alkyl, -O-aryl, -O-(C1-C6)-alkyl-aryl and -OCO-(C1-C6)-alkyl group. The compound according to any of claims 1 to 8, characterized in that R represents a CH2OH, -CH2O-(C1-C6)-alkyl, -CH2O-aryl, -CH2O-(C1-C6)-alkyl-aryl or -CH2OCO-(C1-C6)-alkyl group. The compound according to any of claims 1 to 9, characterized in that R4 = H when n = 1 and R4 = H or OH when n = 0. The compound according to any one of claims 1 to 10, characterized in that U, V and W represent, independently from one another, a phenyl, pyrazolyl, N-(C1-C6)alkyl-pyrazolyl, or thienyl ring,
the said ring being optionally substituted with one or more substituents selected from the group consisting of an halogen atom, OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24 and CO2R24, and
X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are, independently from one another, selected from the group consisting of a hydrogen atom, a halogen atom, OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, OR24, COR24, OCOR24 and CO2R24. The compound according to any of claims 1 to 11, characterized in that it is chosen from the following compounds:
A compound according to any of claims 1 to 12, for use thereof as a drug. A compound according to any of claims 1 to 12, for use in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arteritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti-inflammatory drug. A cosmetic use of at least one compound according to any of claims 1 to 12, for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin, or as antioxidant. A pharmaceutical or cosmetic composition including at least one compound according to any of claims 1 to 12 and at least one pharmaceutically or cosmetically acceptable vehicle. A process for preparing a compound according to any one of claims 1 to 12 for which R4 = H comprising the fluorination of a compound of the following formula (II):
wherein R, R1, R2, R3, X1, U, V, W, n, m and p are as defined in claim 1. A process for preparing a compound according to any one of claims 1 to 12 for which n = 0 and R4 ≠ H comprising the coupling of a compound of the following formula (VIII):
wherein X1, U, V, W, m and p are as defined in claim 1 and A1 represents -Li or -Mg-Hal, Hal being a halogen atom,
and a compound of the following formula (XI)
wherein R, R1, R2, and R3 are as defined in claim 1,
to give a compound of formula (I) according to claim 1 for which n = 0 and R4 = OH, followed optionally by the substitution of the OH function to give a compound of formula (I) according to claim 1 for which n = 0 and R4 = halogen, OSiRjRkRl, OR21, OCOR21, OCO2R21, or OCONR22R23. A process for preparing a compound according to any one of claims 1 to 12 for which R4 = H comprising the following steps:
(a4) bromination of a compound of formula (I) with R4 = OH to give a compound of formula (I) with R4 = Br, and (b4) reduction of the compound of formula (I) with R4=Br obtained in previous step (a4) to give a compound of formula (I) with R4 = H. A process for preparing a compound according to any one of claims 1 to 12 for which R4 = H and n = 1 comprising a coupling reaction between a compound of the following formula (XVI):
wherein R, R1, R2, and R3 are as defined in claim 1 and R9 represents a leaving group, with a compound of the following formula (V):
wherein X1, U, V, W, m and p are as defined in claim 1.(84) Designated States: