| WO/1993/015220 | HOMOCYSTEINE ASSAY |
| JP2012523432 | How to treat edema associated with ischemia-reperfusion |
KINNE ROLF K-H (DE)
BOLAND WILHELM (DE)
BURSE ANTJE (DE)
CASTANEDA FRANCISCO (DE)
KINNE ROLF K-H (DE)
BOLAND WILHELM (DE)
BURSE ANTJE (DE)
| US4554349A | 1985-11-19 |
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Claims
1. Compounds having the general formula (I):
wherein
R * and R ** represent independently of each other hydrogen or -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC 4 H 9 , -CO-cyclo-C 4 H 7 , -COCH 2 CH(CH 3 ) 2 , -COCH(CH 3 )-C 2 H 5 , -COC(CHs) 3 , -COC 5 H 11 , -CO-CyClO-C 5 H 9 , -COCH 2 CH(CH 3 )-C 2 H 5 , -COC(CH 3 ) 2 -C 2 H 5 , -COCH 2 CH 2 CH(CH 3 ) 2 , -COCH 2 C(CH 3 ) 3 , -COC 6 H 13 , -COCH(CH 3 )-CH(CH 3 ) 2 , -COCH(CH 3 )-C 3 H 7 , -CO-CyCIo-C 6 H 11 ,
-COCH 2 CH(CHa)-C 3 H 7 , -COC(CH 3 ) 2 -C 3 H 7 , -COCH 2 CH 2 CH(CH 3 )-C 2 H 5 , -COCH 2 CH 2 C(CH 3 ) 3 , -COCH(CH 3 )-C(CH 3 ) 3 , -COCH(CH 3 )-CH 2 -CH(CH 3 ) 2 , -COCH(CH 3 )-C 4 H 9 , -COCH 2 CH 2 CH 2 CH(CH 3 ) 2 , -COCH 2 CH(C 2 Hs) 2 ,
-COCH 2 -CH(CH 3 )-CH(CH 3 ) 2 , -COCH(CH 3 )-CH(CH 3 )-C 2 H 5 ;
R 1 - R 5 represent independently of each other
-R S 1 _ R 7 t _ R 8 t _ R 9 _ _ R i o_ _ NHR i i t _NHR 12 , -NR 13 R 14 , -NR 15 R 16 ,
-OR 17 -OR 18 -COR 19 -COR 20 -CONH-R 21 -CONH-R 2 u2.
-COOR 23 , -COOR 24 , -OOC-R 25 , -OOC-R 26 , -NHCO-R 27 , -NHCO-R 28
-R 29 -R 30 -R 31 -R 32 -R 33.
R - R represent independently of each other _R* _ R 3 5I _ R * _ R ^ _ R j3*8 _CH 2 -R J9 , -C 2 H 4 -R 40 , -C 3 H 6 -R 41 , -C 4 H 8 -R 42 ,
,44
-C 5 H 10 -R 43 — CeHi 2 -R -C 7 Hi 4 -R 45 -CHR 46 R 47 , -CR 48 R 49 R 50 ,
-CHR 51 -CHR 52 R 53 , -CR^R^-CR^R^R 58 , -CHR 59 -CHR 60 -CHR 61 R 62 ,
-CR 63 R 64 -CR 65 R 66 -CR 67 R 68 R 69 ;
R 29 - R 80 represent independently of each other
-H, -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -0-CyCIo-C 3 H 5 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-cyclo-C 3 H 5 , -SCH(CH 3 ) 2 , -SC(CH 3 ) 3 , -NO 2 , -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC(CH 3 ) 3 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH(CH 3 ) 2 , -COOC(CH 3 ) 3 , -0OC-CH 3 , -0OC-C 2 H 5 , -0OC-C 3 H 7 , -OOC-cyclo-C 3 H 5 , -OOC-CH(CH 3 ) 2 , -OOC-C(CH 3 ) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-CyCIo-C 3 H 5 , -CONH[CH(CH 3 ) 2 ], -CONH[C(CH 3 J 3 ], -CON(CH 3 J 2 , -CON(C 2 Hs) 2 , -CON(C 3 H 7 ) 2 , -CON(cyclo-C 3 H 5 ) 2 ,
-CON[CH(CH 3 ) 2 ] 2 , -CON[C(CH 3 ) 3 ] 2 , -NHCOCH 3 , -NHCOC 2 H 5 ,
-NHCOC 3 H 7 , -NHCO-CyCIo-C 3 H 5 , -NHCO-CH(CH 3 ) 2 , -NHCO-C(CH 3 ) 3 , -NHCO-OCH 3 , -NHCO-OC 2 H 5 , -NHCO-OC 3 H 7 , -NHCO-O-CyCIo-C 3 H 5 , -NHCO-OCH(CH 3 ) 2 , -NHCO-OC(CH 3 ) 3 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 , -NH-cyclo-C 3 H 5 , -NHCH(CH 3 ) 2 , -NHC(CH 3 ) 3 , -N(CH 3 J 2 , -N(C 2 H 5 J 2 , -N(C 3 H 7 J 2 , -N(CyCIo-C 3 H 5 J 2 , -N[CH(CH 3 J 2 J 2 , -N[C(CH 3 J 3 J 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-CyCb-C 3 H 5 , -SOCH(CH 3 ) 2 , -SOC(CH 3 ) 3l -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -CyCIo-C 3 H 5 , -SO 2 CH(CH 3 ) 2 , -SO 2 C(CHa) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 , -SO 3 -CyCIo-C 3 H 5 , -SO 3 CH(CH 3 ) 2 , -SO 3 C(CH 3 ) 3 , -OCF 3 , -OC 2 F 5 , -0-COOCH 3 , -0-COOC 2 H 5 , -0-COOC 3 H 7 , -0-COO-CyCIo-C 3 H 5 , -O-COOCH(CH 3 ) 2 , -O-COOC(CH 3 ) 3 , -NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 Hs, -NH-CO-NHC 3 H 7 , -NH-CO-NH-CyCIo-C 3 H 5 ,
-NH-CO-NH[CH(CH 3 J 2 ], -NH-CO-NH[C(CH 3 J 3 ], -NH-CO-N(CH 3 ) 2 ,
-NH-CO-N(C 2 H 5 J 2 , -NH-CO-N(C 3 H 7 J 2 , -NH-CO-N(cyclo-C 3 H 5 ) 2 ,
-NH-CO-N[CH(CH 3 ) 2 ] 2 , -NH-CO-N[C(CH 3 J 3 J 2 , -NH-CS-NH 2 ,
-NH-CS-NHCH 3 , -NH-CS-NHC 2 H 5 , -NH-CS-NHC 3 H 7 ,
-NH-CS-NH-cyclo-C 3 H 5 , -NH-CS-NH[CH(CH 3 J 2 ], -NH-CS-NH[C(CH 3 J 3 ], -NH-CS-N(CHa) 2 , -NH-CS-N(C 2 H 5 ) 2 , -NH-CS-N(C 3 Hr) 2 ,
-NH-CS-N(cyclo-C 3 H 5 ) 2 , -NH-CS-N[CH(CH 3 ) 2 ] 2 , -NH-CS-N[C(CH 3 ) 3 ] 2 , -NH-C(=NH)-NH 2 , -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC 2 H 5 ,
-NH-C(=NH)-NHC 3 H7, -NH-C(=NH)-NH-cyclo-C 3 H 5 , -NH-C(=NH)-NH[CH(CH 3 ) 2 ], -NH-C(=NH)-NH[C(CH 3 ) 3 ],
-NH-C(=NH)-N(CH 3 ) 2 , -NH-C(=NH)-N(C 2 H5)2, -NH-C(=NH)-N(C 3 H7) 2 , -NH-C(=NH)-N(cyclo-C 3 H5) 2 , -NH-C(=NH)-N[CH(CH 3 ) 2 ]2 I
-NH-C(=NH)-N[C(CH3)3] 2 , -0-CO-NH 2 , -0-CO-NHCH 3 , -0-CO-NHC 2 H 5 , -0-CO-NHC 3 H 7 , -0-CO-NH-CyCIo-C 3 H 5 , -O-CO-NH[CH(CH 3 ) 2 ], -O-CO-NH[C(CH 3 ) 3 ], -O-CO-N(CH 3 ) 2 , -O-CO-N(C 2 H 5 ) 2 ,
-0-CO-N(C 3 Hz) 2 , -O-CO-N(cyclo-C 3 H 5 ) 2 , -O-CO-N[CH(CH 3 ) 2 ] 2 ,
-O-CO-N[C(CH 3 ) 3 ] 2 , -0-CO-OCH 3 , -0-CO-OC 2 H 5 , -0-CO-OC 3 H 7 , -0-CO-O-CyCIo-C 3 H 5 , -O-CO-OCH(CH 3 ) 2 , -O-CO-OC(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CI, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 CI, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, cyclo-C 3 H 5 , cyclo-C 4 H 7 ,
CyClO-C 5 H 9 , CyCIo-C 6 H 11 , cyclo-C 7 H 13 , cyclo-C 8 H 15 , -Ph, -CH 2 -Ph, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-C 2 H 5, -C(CH 3 ) 3 , -C 5 H 11 , -CH(CH 3 )-C 3 H 7 , -CH 2 -CH(CH 3 >-C 2 H 5 , -CH(CH 3 )-CH(CH 3 ) 2 , -C(CH 3 ) 2 -C 2 H 5 , -CH 2 -C(CH 3 ) 3 , -CH(C 2 H 5 ) 2 , -C 2 H 4 -CH(CH 3 ) 2 , -C 6 H 13 , -C 3 H 6 -CH(CH 3 ) 2 , -C 2 H 4 -CH(CHs)-C 2 H 5 ,
-CH(CH 3 )-C 4 H 9 , -CH 2 -CH(CHa)-C 3 H 7 , -CH(CH 3 )-CH 2 -CH(CH 3 ) 2 ,
-CH(CH 3 )-CH(CH 3 )-C 2 H 5 , -CH 2 -CH(CH 3 )-CH(CH 3 ) 2 , -CH 2 -C(CH 3 )Z-C 2 H 5 , -C(CH 3 ) 2 -C 3 H 7 , -C(CH 3 ) 2 -CH(CH 3 ) 2 , -C 2 H 4 -C(CH 3 ) 3 , -CH(CHs)-C(CHs) 3 , -CH=CH 2 , -CH 2 -CH=CH 2 , -C(CH 3 )=CH 2 , -CH=CH-CH 3 , -C 2 H 4 -CH=CH 2 , -C 7 H 15 , -C 8 H 17 , -CH 2 -CH=CH-CH 3 , -CH=CH-C 2 H 5 , -CH 2 -C(CH 3 )=CH 2 ,
-CH(CH 3 )-CH=CH, -CH=C(CH 3 ) 2 , -C(CH 3 )=CH-CH 3 , -CH=CH-CH=CH 2 , -C 3 H 6 -CH=CH 2 , -C 2 H 4 -CH=CH-CH 3 , -CH 2 -CH=CH-C 2 H 5 ,
-CH=CH-C 3 H 7 , -CH 2 -CH=CH-CH=CH 2 , -CH=CH-CH=CH-CHs,
-CH=CH-CH 2 -CH=CH 2 , -C(CH 3 )=CH-CH=CH 2 , -CH=C(CHs)-CH=CH 2 , -CH=CH-C(CHs)=CH 2 , -C 2 H 4 -C(CHs)=CH 2 , -CH 2 -CH(CHs)-CH=CH 2 ,
-CH(CHs)-CH 2 -CH=CH 2 , -CH 2 -CH=C(CHs) 2 , -CH 2 -C(CH 3 )=CH-CH 3 , -CH(CH 3 )-CH=CH-CH 3 , -CH=CH-CH(CH 3 ) 2 , -CH=C(CHs)-C 2 H 5 ,
-C(CHs)=CH-C 2 H 5 , -C(CHs)=C(CHs) 2 , -C(CHs) 2 -CH=CH 2 ,
-CH(CH 3 )-C(CH 3 )=CH 2 , -C(CHs)=CH-CH=CH 2 , -CH=C(CHs)-CH=CH 2 , -CH=CH-C(CH 3 )=CH 2 , -C 4 H 8 -CH=CH 2 , -CsH 6 -CH=CH-CH 3 ,
-C 2 H 4 -CH=CH-C 2 H 5 , -CH 2 -CH=CH-C 3 H 7 , -CH=CH-C 4 H 9 ,
-C 3 H 6 -C(CH 3 )=CH 2 , -CH 2 -CH 2 -CH 2 -OCHs, -C 2 H 4 -CH(CH S )-CH=CH 2 , -CH 2 -CH(CH S )-CH 2 -CH=CH 2 , -CH 2 NH 2 , -CH(CH 3 )-C 2 H 4 -CH=CH 2 ,
-C 2 H 4 -CH=C(CH 3 ) 2 , -C 2 H 4 -C(CHs)=CH-CH 3 , -CH 2 -CH(CH S )-CH=CH-CH 31 -CH(CHS)-CH 2 -CH=CH-CH 3 , -CH 2 OH, -CH 2 SH, -CH2-CH=CH-CH(CH 3 ) 2I -CH 2 -CH=C(CHa)-C 2 H 5 , -CH 2 -CH 2 -CH 2 NH 2 , -CH 2 -C(CHa)=CH-C 2 H 5 , -CH(CHa)-CH=CH-C 2 H 5 , -CH 2 -CH 2 NH 2 , -CH=CH-CH2-CH(CH 3 )2,
-CH=CH-CH(CH 3 )-C 2 H 5 , -CH=C(CHa)-C 3 H 7 , -C(CH 3 )=CH-C 3 H 7 , -CH2-CH(CH 3 )-C(CH 3 )=CH2, -CH 2 -CH 2 SH, -CH(CH 3 )-CH2-C(CH3)=CH2 I
-CH(CH 3 )-CH(CH 3 )-CH=CH 2 , -CH 2 -CH 2 -CH 2 OH, -CH 2 -C(CHa) 2 -CH=CH 2 , -C(CHa) 2 -CH 2 -CH=CH 2 , -CH 2 -C(CH 3 )=C(CH 3 ) 2 , -CH(CH 3 )-CH=C(CH 3 ) 2 , -C(CH 3 ) 2 -CH=CH-CH 3 , -CH 2 -CH 2 -CH 2 SH, -CH(CH 3 )-C(CH 3 )=CH-CH 3 , -CH=C(CHa)-CH(CHa) 2 , -C(CH 3 )=CH-CH(CH 3 ) 2 , -C(CH 3 )=C(CH 3 )-C 2 H 5 , -CH=CH-C(CH 3 ) 3 , -C(CHa) 2 -C(CHa)=CH 2 , -CH(C 2 Hs)-C(CHa)=CH 2 ,
-C(CH 3
)(C 2
Hs)-CH=CH 2
, -CH(CH 3
)-C(C 2
H 5
)=CH 2)
-CH 2
-C(C 3
Hr)=CH 2
, -CH 2
-C(C 2
Hs)=CH-CH 3
, -CH(C 2
Hs)-CH=CH-CH 3
, -C(C 4
Hg)=CH 2
,
-C[C(CH 3 ) 3 ]=CH 2 , -C[CH(CH 3 )(C 2 Hs)]=CH 2 , -C[CH 2 -CH(CH 3 ) 2 ]=CH 2 , -C 2 H 4 -CH=CH-CH=CH 2 , -C 6 H 4 -OCH 3 , -CH 2 -CH=CH-CH 2 -CH=CH 2 ,
-CH=CH-C 2 H 4 -CH=CH 2 , -C 6 H 4 -OH, -CH 2 -CH=CH-CH=CH-CH 3 ,
-CH=CH-CH 2 -CH=CH-CH 3 , -CH 2 -CH 2 -OCH 3 , -CH=CH-CH=CH-C 2 H 5 , -CH 2 -CH=CH-C(CH 3 )=CH 2 , -CH 2 -CH 2 OH, -CH 2 -CH=C(CH 3 )-CH=CH2, -CH 2 -C(CHs)=CH-CH=CH 2 , -CH 2 -OCH 3 , -CH(CH 3 )-CH=CH-CH=CH 2 , -CH=CH-CH 2 -C(CH 3 )=CH 2 , -CH=CH-CH(CH 3 )-CH=CH 2 ,
-CH=C(CH 3 )-CH 2 -CH=CH 2 , -C(CHs)=CH-CH 2 -CH=CH 2 ,
-CH=CH-CH=C(CHa) 2 , -CH 2 -C 6 H 4 -OCH 3 , -CH=CH-C(CHs)=CH-CH 3 , -CH=C(CHs)-CH=CH-CH 3 , -CH 2 -C 6 H 4 -OH, -C(CHs)=CH-CH=CH-CH 3 , -CH=C(CH 3 )-C(CH 3 )=CH 2 , -C(CH 3 )=CH-C(CH 3 )=CH 2 , -C(CHa)=C(CHs)-CH=CH 2 , -CH=CH-CH=CH-CH=CH 2 , -C≡CH,
-C=C-CH 3 , -CH 2 -C=CH, -C 2 H 4 -C=CH, -CH 2 -CsC-CH 3 , -C=C-C 2 H 5 , -C 3 H 6 -C=CH, -C 2 H 4 -C≡C-CH 3 , -CH 2 -C=O-C 2 H 5 , -C=C-C 3 H 7 ,
-CH(CHs)-C=CH, -CH 2 -CH(CH 3 )-C=CH, -CH(CHs)-CH 2 -C=CH,
-CH(CH 3 )-C≡C-CH 3 , -C 4 H 8 -C≡CH, -C 3 H 6 -CsC-CH 3 , -C 2 H 4 -C=C-C 2 H 5 , -CH 2 -CEC-C 3 H 7 , -C≡C-C 4 H 9 , -C≡C-C(CH 3 ) 3 , -C 2 H 4 -CH(CH S )-C=CH,
-CH 2 -CH(CHs)-CH 2 -C=CH, -CH 2 -C=C-CH(CH 3 ) 2 , -CH(CHs)-C 2 H 4 -CsCH, -CH 2 -CH(CH 3 )-C≡C-CH 3 , -CH(CHa)-CH 2 -CsC-CH 3 , -CH(CHa)-C=C-C 2 H 5 , -C≡C-CH(CH 3 )-C 2 H 5 , -C≡C-CH 2 -CH(CH 3 ) 2 , -CH(C 2 H S )-CEC-CH 3 ,
-C(CH 3 ) 2 -C≡C-CHs, -CH(C 2 Hs)-CH 2 -CsCH, -CH 2 -CH(C 2 Hs)-C=CH, -C(CHs) 2 -CH 2 -CsCH, -CH 2 -C(CHa) 2 -CsCH, -CH(CH 3 )-CH(CHs)-CsCH,
-CH(C 3 H 7 )-CsCH, -C(CH 3 )(C 2 H S )-CSCH, -CSC-CSCH,
-CH 2 -CsC-CsCH, -CSC-CSC-CH 3 , -CH(CSCH) 2 , -C 2 H 4 -CSC-CSCH, -CH 2 -CSC-CH 2 -CSCH, -CSC-C 2 H 4 -CSCH, -CH 2 -CSC-CSC-CH 3 ,
-CsC-CH 2 -CsC-CH 3 , -CSC-CSC-C 2 H 5 , -CξC-CH(CH 3 )-CξCH, -CH(CH 3 )-C≡C-C≡CH, -CH(C≡CH)-CH 2 -C≡CH, -C(CECH) 2 -CH 3 ,
-CH 2 -CH(C=CH) 2 , -CH(C≡CH)-C≡C-CH 3 ;
R 81 - R 84 represent independently of each other hydrogen or -CH 3 , -C 2 H 5 , -C 3 H 7 ;
m is the integer 1 , 2, 3, 4, 5, 6, 7 or 8; n is the integer 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is an integer selected from 1 , 2, 3 or 4; q is an integer selected from 0 or 1 ; r is an integer selected from 0, 1 , 2, 3 or 4; s is an integer selected from 0 or 1 ; t is an integer selected from 0, 1 , 2, 3 or 4; and wherein at least one substituent R 1 - R 5 is different from hydrogen, and stereoisomeric forms, enantiomers, diastereomers, tautomers, anomers, keto-forms, deoxy-forms, prodrugs, solvates, hydrates and pharmaceutically acceptable salts thereof; wherein the following compounds are excluded: p-Aminophenyl-1 -thio-β-D-galactopyranoside, p-Aminophenyl-1 -thio-β-D- glucopyranoside, p-Methylphenyl-1-thio-β-D-glucopyranoside, A-
Methylphenyl-tetraacetyl-β-D-glucothioside, 4-Methylphenyl-β-D- glucothioside, 4-Methoxyphenyl-tetraacetyl-β-D-glucothioside, A-
Methoxyphenyl-β-D-glucothioside, 4-Ethoxyphenyl-tetraacetyl-β-D- glucothioside, 4-Ethoxyphenyl-β-D-glucothioside, 4-Acetylphenyl-tetraacetyl- β-D-glucothioside, 4-Acetylphenyl-β-D-glucothioside, 4-Bromphenyl- tetraacetyl-β-D-glucothioside, 4-Bromphenyl-β-D-glucothioside, A-
Chlorphenyl-tetraacetyl-β-D-glucothioside, 4-Chlorphenyl-β-D-glucothioside, 2,5-Dichlorphenyl-tetraacetyl-β-D-glucothioside, 2,5-Dichlorphenyl-β-D- glucothioside, 3-Chlor-4-methylphenyl-tetraacetyl-β-D-glucothioside, 3-Chlor- 4-methylphenyl-β-D-glucothioside, 2-Amino-4-chlorphenyl-tetraacetyl-β-D- glucothioside, 2-Amino-4-chlorphenyl-β-D-glucothioside, 2-Acetamino-4- chlorphenyl-tetraacetyl-β-D-glucothioside, 4-Dimethylaminophenyl- tetraacetyl-β-D-glucothioside, 4-Dimethylaminophenyl-β-D-glucothioside, A- Diethylaminophenyl-tetraacetyl-β-D-glucothioside, 4-Diethylaminophenyl-β-D- glucothioside, 4-Di-n-propylaminophenyl-tetraacetyl-β-D-glucothioside, 4-Di- n-propylaminophenyl-β-D-glucothioside, 4-(N-Methyl-N-benzylamino)phenyl- tetraacetyl-β-D-glucothioside, 4-(N-Methyl-N-benzylamino)phenyl-β-D- glucothioside, p-(N,N-Di-2-chloroethylamino)phenyl-β-D-thioglucoside, p- (N,N-Di-2-bromethylamino)phenyl-β-D-glucothioside, p-Bromophenyl-1-thio- β -D-galactopyranoside, p-Bromophenyl-tetraacetyl-1 -thio-β-D- galactopyranoside, p-Chlorophenyl-1 -thio- β -D-galactopyranoside, p- Chlorophenyl-tetraacetyl-1 -thio- β -D-galactopyranoside, p-Methylphenyl-1 - thio-β-D-galactopyranoside, p-Methylphenyl-tetraacetyl-1 -thio-β-D- galactopyranoside, p-tert-Butylphenyl-1 -thio-β-D-galactopyranoside, p-tert- Butylphenyl-tetraacetyl-1 -thio- β -D-galactopyranoside, p-Methoxyphenyl-1 - thio-β-D-galactopyranoside, p-Methoxyphenyl-tetraacetyl-1 -thio-β-D- galactopyranoside, p-Nitrophenyl-1 -thio-β-D-galactopyranoside, p-
Nitrophenyl-tetraacetyl-1 -thio- β -D-galactopyranoside, p-Acetylphenyl-1 -thio-β- D-galactopyranoside, p-Acetylphenyl-tetraacetyl-1 -thio-β-D- galactopyranoside, p-Nitrophenyl-1 -thio-β-D-mannopyranoside, p- Aminophenyl-1 -thio-β-D-mannopyranoside, p-Methoxyphenyl-1 -thio-β-D- mannopyranoside, p-Acetamidophenyl-1 -thio-β-D-mannopyranoside, p- Nitrophenyl-1 '-thio-mannoside.
2. Compound according to claim 1 having the general formula (II):
wherein the substituents R * , R ** , R 80 - R 84 and the integers p, q, r, s, t have the meanings as disclosed in claim 1.
3. Compound according to claim 1 having the general formula (Vl):
wherein the substituents R*, R ** , R 1 - R 5 have the meanings as disclosed in claim 1.
4. Compound according to claim 1 having the general formula (IX):
wherein the substituents R * , R ** , R 1 - R 5 have the meanings as disclosed in claim 1.
5. Compound according to claim 1 having the general formula (XII):
wherein the substituents R * , R ** , R - R have the meanings as disclosed in claim 1.
6. Compound according to any previous claim for use as a pharmaceutically active agent.
7. Use of a compound having the general formula (I):
wherein
A is -(CH 2 )p-(CR B1 =CR
R * and R** represent independently of each other hydrogen or -CHO 1 -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC 4 H 9 , -CO-CyCIo-C 4 H 7 , -COCH 2 CH(CH 3 ) 2) -COCH(CH 3 )-C 2 H 5 , -COC(CHs) 3 , -COC 5 H 11 , -CO-CyClO-C 5 H 9 , -COCH 2 CH(CH 3 )-C 2 H 5 , -COC(CH 3 ) 2 -C 2 H 5 , -COCH 2 CH 2 CH(CH 3 ) 2 , -COCH 2 C(CH 3 ) 3 , -COC 6 H 13 , -COCH(CH 3 )-CH(CH 3 ) 2 , -COCH(CH 3 )-C 3 H 7> -CO-CyCIo-C 6 H 11 ,
-COCH 2 CH(CH 3 )-C 3 H 7 , -COC(CH 3 ) 2 -C 3 H 7 , -COCH 2 CH 2 CH(CHa)-C 2 H 5 , -COCH 2 CH 2 C(CHs) 3 , -COCH(CH 3 )-C(CH 3 ) 3 , -COCH(CH 3 )-CH 2 -CH(CH 3 ) 2 , -COCH(CH 3 )-C 4 H 9 , -COCH 2 CH 2 CH 2 CH(CH 3 ) 2 , -COCH 2 CH(C 2 Hs) 2 ,
-COCH 2 -CH(CH 3 )-CH(CH 3 ) 2l -COCH(CH 3 )-CH(CH 3 )-C 2 H 5 ;
R 1 - R 5 represent independently of each other
-R S 1 _ R 7 _ ,R S 1 _ R9> _ R i0 f _ NH R 1 \ -NHR 12 , -NR 13 R 14 , -NR 15 R 16 ,
-OR 17 -OR 18 -COR 19 -COR 20 -CONH-R 21 -CONH-R 22
-COOR 23 , -COOR 24 , -OOC-R 25 , -OOC-R 26 , -NHCO-R 27 , -NHCO-R 28 ,
-R 29 -R 30 -R 31 -R 32 -R 33.
R 6 - R 28 represent independently of each other
-R 34 , -R 35 , -R 36 , -R 37 , -R 38 , -CH 2 -R 39 , -C 2 H 4 -R 40 , -C 3 H 6 -R 41 , -C 4 H 8 -R 42 ,
-C 5 H 1 Q-R 43 -C 6 H 12 -R 44 -C 7 H 14 -R 45 -CHR 4 4 0 6R D 47 -CR 48 R 49 R 50 , -CHR 51 -CHR 52 R 53 , -CR^-CR^R 58 , -CHR 59 -CHR 60 -CHR 61 R 62 ,
_ CR 63 R 64_ CR 65 R 66_ CR 67 R 68 R 69.
-(C
R 29 - R 80 represent independently of each other
-H, -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-cyclo-C 3 H 5 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-CyCIo-C 3 H 5 , -SCH(CH 3 ) 2 , -SC(CH 3 ) 3 , -NO 2 , -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC(CH 3 ) 3 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH(CH 3 ) 2 , -COOC(CH 3 ) 3 , -0OC-CH 3 , -0OC-C 2 H 5 , -0OC-C 3 H 7 , -OOC-cyclo-C 3 H 5 , -OOC-CH(CH 3 ) 2 , -OOC-C(CH 3 ) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-CyCIo-C 3 H 5 , -CONH[CH(CH 3 ) 2 ], -CONH[C(CH 3 ) 3 ], -CON(CH 3 ) 2 , -CON(C 2 Hs) 2 , -CON(C 3 H 7 ) 2 , -CON(cyclo-C 3 H 5 ) 2 ,
-CON[CH(CH 3 ) 2 ] 2 , -CON[C(CH 3 )s] 2 , -NHCOCH 3 , -NHCOC 2 H 5 ,
-NHCOC 3 H 7 , -NHCO-CyClO-C 3 H 5 , -NHCO-CH(CH 3 ) 2 , -NHCO-C(CH 3 ) 3 , -NHCO-OCH 3 , -NHCO-OC 2 H 5 , -NHCO-OC 3 H 7 , -NHCO-O-CyCIo-C 3 H 5 , -NHCO-OCH(CHs) 2 , -NHCO-OC(CH 3 ) 3 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 , -NH-CyCIo-C 3 H 5 , -NHCH(CH 3 ) 2 , -NHC(CH 3 ) 3> -N(CH 3 ) 2 , -N(C 2 Hg) 2 , -N(C 3 H 7 ) 2 , -N(cyclo-C 3 H 5 ) 2 , -N[CH(CH 3 ) 2 ] 2> -N[C(CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo-C 3 H 5 , -SOCH(CH 3 ) 2 , -SOC(CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -cyclo-C 3 H 5 , -SO 2 CH(CHs) 2 , -SO 2 C(CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 , -SO 3 -cyclo-C 3 H 5 , -SO 3 CH(CHs) 2 , -SO 3 C(CH 3 ) 3 , -OCF 3 , -OC 2 F 5 , -0-COOCH 3 , -0-COOC 2 H 5 , -0-COOC 3 H 7 , -0-COO-CyCIo-C 3 H 5 , -O-COOCH(CH 3 ) 2l -0-COOC(CHs) 3 , -NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHCsH 7 , -NH-CO-NH-cyclo-CsHs,
-NH-CO-NH[CH(CH 3 ) 2 ], -NH-CO-NH[C(CH 3 ) 3 ], -NH-CO-N(CH 3 ) 2 ,
-NH-CO-N(C 2 Hs) 2 , -NH-CO-N(C 3 H 7 ) 2l -NH-CO-N(cyclo-C 3 H 5 ) 2 ,
-NH-CO-N[CH(CH 3 ) 2 ] 2 , -NH-CO-N[C(CH 3 )s] 2 , -NH-CS-NH 2 ,
-NH-CS-NHCH 3 , -NH-CS-NHC 2 H 5 , -NH-CS-NHC 3 H 7 ,
-NH-CS-NH-CyCIo-C 3 H 5 , -NH-CS-NH[CH(CH 3 ) 2 ], -NH-CS-NH[C(CH 3 ) 3 ],
-NH-CS-N(CHs) 2 , -NH-CS-N(C 2 Hs) 2 , -NH-CS-N(C 3 H 7 ) 2 ,
-NH-CS-N(cyclo-C 3 Hs) 2 , -NH-CS-N[CH(CH 3 ) 2 ] 2 , -NH-CS-N[C(CH 3 ) 3 ] 2 , -NH-CC=NH)-NH 2 , -NH-CC=NH)-NHCH 3 , -NH-CC=NH)-NHC 2 H 5 ,
-NH-CC=NH)-NHC 3 H 7 , -NH-CC=NH)-NH-CyCIo-C 3 H 5 ,
-NH-C(=NH)-NH[CH(CH3) 2 ], -NH-C(=NH)-NH[C(CH 3 ) 3 ],
-NH-CC=NH)-N(CHa) 2 , -NH-CC=NH)-N(C 2 Hs) 2 , -NH-C(=NH)-N(C 3 H 7 ) 2 , -NH-C(=NH)-N(cyclo-C 3 H 5 ) 2 , -NH-C(=NH)-N[CH(CH 3 ) 2 ] 2 ,
-NH-C(=NH)-N[C(CH 3 ) 3 ] 2 , -0-CO-NH 2 , -0-CO-NHCH 3 , -0-CO-NHC 2 H 5 , -0-CO-NHC 3 H 7 , -0-CO-NH-CyCIo-C 3 H 5 , -O-CO-NH[CH(CH 3 ) 2 ],
-O-CO-NH[C(CH 3 ) 3 ], -O-CO-N(CH 3 ) 2 , -O-CO-N(C 2 H 5 ) 2 ,
-O-CO-N(C 3 H 7 ) 2 , -O-CO-N(cyclo-C 3 H 5 ) 2 , -O-CO-N[CH(CH 3 ) 2 ] 2 , -O-CO-N[C(CH 3 ) 3 ] 2 , -0-CO-OCH 3 , -0-CO-OC 2 H 5 , -0-CO-OC 3 H 7 ,
-0-CO-O-CyCIo-C 3 H 5 , -O-CO-OCH(CH 3 ) 2 , -O-CO-OC(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CI, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 CI, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, cyclo-C 3 H 5 , cyclo-C 4 H 7 , cyclo-C 5 H 9 , cyclo-C 6 Hii, cyclo-C 7 H 13 , cyclo-C 8 H 15 , -Ph, -CH 2 -Ph, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CH 3 ) 2 ,
-CH(CH 3 )-C 2 H 5, -C(CH 3 ) 3 , -C 5 Hn, -CH(CH 3 )-C 3 H 7) -CH 2 -CH(CHa)-C 2 H 5 , -CH(CH 3 )-CH(CH 3 ) 2 , -C(CHs) 2 -C 2 H 5 , -CH 2 -C(CH 3 )S, -CH(C 2 Hs) 2 , -C 2 H 4 -CH(CHs) 2 , -C 6 H 13 , -CsH 6 -CH(CH 3 ) 2 , -C 2 H 4 -CH(CHs)-C 2 H 5 , -CH(CH 3 )-C 4 H 9 , -CH 2 -CH(CHa)-CsH 7 , -CH(CHa)-CH 2 -CH(CHs) 2 , -CH(CH 3 )-CH(CH 3 )-C 2 H 5 , -CH 2 -CH(CH 3 )-CH(CH 3 ) 2 , -CH 2 -C(CHs) 2 -C 2 H 5 ,
-C(CHs) 2 -C 3 H 7 , -C(CHs) 2 -CH(CHs) 2 , -C 2 H 4 -C(CH 3 ) 3 , -CH(CH 3 )-C(CHs)s, -CH=CH 2 , -CH 2 -CH=CH 2 , -C(CH 3 )=CH 2 , -CH=CH-CH 3 , -C 2 H 4 -CH=CH 2 , -C 7 H 15 , -C 8 H 17 , -CH 2 -CH=CH-CH 3 , -CH=CH-C 2 H 5 , -CH 2 -C(CHs)=CH 2 , -CH(CH 3 )-CH=CH, -CH=C(CHs) 2 , -C(CHs)=CH-CH 3 , -CH=CH-CH=CH 2 , -C 3 H 6 -CH=CH 2 , -C 2 H 4 -CH=CH-CH 3 , -CH 2 -CH=CH-C 2 H 5 ,
-CH=CH-C 3 H 7 , -CH 2 -CH=CH-CH=CH 2 , -CH=CH-CH=CH-CH 3 ,
-CH=CH-CH 2 -CH=CH 2 , -C(CHs)=CH-CH=CH 2 , -CH=C(CH 3 )-CH=CH 2) -CH=CH-C(CH 3 )=CH 2 , -C 2 H 4 -C(CH 3 )=CH 2 , -CH 2 -CH(CH 3 )-CH=CH 2 , -CH(CHs)-CH 2 -CH=CH 2 , -CH 2 -CH=C(CH 3 ) Z , -CH 2 -C(CH 3 )=CH-CH 3 , -CH(CHa)-CH=CH-CHs, -CH=CH-CH(CHa) 2 , -CH=C(CH 3 )-C 2 Hs,
-C(CHs)=CH-C 2 H 5 , -C(CH 3 )=C(CHs) 2 , -C(CHa) 2 -CH=CH 2 ,
-CH(CH 3 )-C(CH 3 )=CH 2 , -C(CHs)=CH-CH=CH 2 , -CH=C(CH 3 )-CH=CH 2l -CH=CH-C(CH 3 )=CH 2 , -C 4 H 8 -CH=CH 2 , -C 3 H 6 -CH=CH-CH 3 ,
-C 2 H 4 -CH=CH-C 2 H 5 , -CH 2 -CH=CH-C 3 H 7 , -CH=CH-C 4 H 9 , -C 3 H 6 -C(CHs)=CH 2 , -CH 2 -CH 2 -CH 2 -OCH 3 , -C 2 H 4 -CH(CHs)-CH=CH 2 ,
-CH 2 -CH(CH 3 )-CH 2 -CH=CH 2 , -CH 2 NH 2 , -CH(CHs)-C 2 H 4 -CH=CH 2 ,
-C 2 H 4 -CH=C(CHs) 2 , -C 2 H 4 -C(CHs)=CH-CH 3 , -CH 2 -CH(CHa)-CH=CH-CHs, -CH(CH S )-CH 2 -CH=CH-CH 3 , -CH 2 OH, -CH 2 SH, -CH2-CH=CH-CH(CH 3 ) 2) -CH 2 -CH=C(CHs)-C 2 H 5 , -CH 2 -CH 2 -CH 2 NH 2 , -CH 2 -C(CHa)=CH-C 2 H 5 , -CH(CHa)-CH=CH-C 2 H 5 , -CH 2 -CH 2 NH 2 , -CH=CH-CH 2 -CH(CH 3 ) 2 ,
-CH=CH-CH(CHa)-C 2 H 5 , -CH=C(CHa)-C 3 H 7 , -C(CH 3 )=CH-C 3 H 7>
-CH2-CH(CH 3 )-C(CH3)=CH2, -CH 2 -CH 2 SH, -CH(CH 3 )-CH2-C(CH3)=CH2, -CH(CH 3 )-CH(CH 3 )-CH=CH 2> -CH 2 -CH 2 -CH 2 OH, -CH 2 -C(CHa) 2 -CH=CH 2 , -C(CHa) 2 -CH 2 -CH=CH 2 , -CH 2 -C(CHa)=C(CHa) 2 , -CH(CH 3 )-CH=C(CH 3 ) 2 ,
-C(CHa) 2
-CH=CH-CH 3
, -CH 2
-CH 2
-CH 2
SH, -CH(CH 3
)-C(CH 3
)=CH-CH 3>
-CH=C(CH 3
)-CH(CH3)2, -C(CH 3
)=CH-CH(CH 3
) 2
, -C(CHa)=C(CHa)-C 2
H 5
, -CH=CH-C(CH 3
) 3
, -C(CH 3
) 2
-C(CH 3
)=CH 2
,
-C(CH 3 )(C 2 Hs)-CH=CH 21 -CH(CH 3 )-C(C 2 H 5 )=CH 2l -CH 2 -C(C 3 H 7 )=CH 2 , -CH 2 -C(C 2 Hs)=CH-CH 3 , -CH(C 2 Hs)-CH=CH-CH 3 , -C(C 4 Hg)=CH 2 ,
-C(C 3 H 7 )=CH-CH 3 , -C(C 2 Hs)=CH-C 2 H 5 , -C(C 2 H 5 )=C(CH 3 ) 2 ,
-C[C(CH 3 ) 3 ]=CH 2 , -C[CH(CH 3 )(C 2 Hs)]=CH 2 , -C[CH 2 -CH(CH 3 ) 2 ]=CH 2 ,
-C 2 H 4 -CH=CH-CH=CH 2 , -C 6 H 4 -OCH 3 , -CH 2 -CH=CH-CH 2 -CH=CH 2 , -CH=CH-C 2 H 4 -CH=CH 2 , -C 6 H 4 -OH, -CH 2 -CH=CH-CH=CH-CH 3 , -CH=CH-CH 2 -CH=CH-CH 3 , -CH 2 -CH 2 -OCH 3 , -CH=CH-CH=CH-C 2 H 5 ,
-CH 2 -CH=CH-C(CH 3 )=CH 2 , -CH 2 -CH 2 OH, -CH 2 -CH=C(CHs)-CH=CH 2 , -CH 2 -C(CH 3 )=CH-CH=CH 2 , -CH 2 -OCH 3 , -CH(CH 3 )-CH=CH-CH=CH 2 , -CH=CH-CH 2 -C(CH 3 )=CH 2 , -CH=CH-CH(CHa)-CH=CH 2 ,
-CH=C(CHa)-CH 2 -CH=CH 2 , -C(CH 3 )=CH-CH 2 -CH=CH 2 , -CH=CH-CH=C(CH 3 ) 2 , -CH 2 -C 6 H 4 -OCH 3 , -CH=CH-C(CH 3 )=CH-CH 3 ,
-CH=C(CHa)-CH=CH-CHa, -CH 2 -C 6 H 4 -OH, -C(CH 3 )=CH-CH=CH-CH 3 , -CH=C(CH 3 )-C(CH 3 )=CH 2 , -C(CH 3 )=CH-C(CH 3 )=CH 2 ,
-C(CH 3 )=C(CH 3 )-CH=CH2, -CH=CH-CH=CH-CH=CH 2 , -C≡CH,
-CEC-CH 3 , -CH 2 -C=CH, -C 2 H 4 -C=CH, -CH 2 -C=C-CH 3 , -C=C-C 2 H 5 , -C 3 H 6 -C=CH, -C 2 H 4 -C=C-CH 3 , -CH 2 -C=C-C 2 H 5 , -C=C-C 3 H 7 ,
-CH(CH 3 )-C≡CH, -CH 2 -CH(CHa)-C=CH, -CH(CHa)-CH 2 -C=CH,
-CH(CH 3 )-C≡C-CH 3 , -C 4 H 8 -C=CH, -C 3 H 6 -C=C-CH 3 , -C 2 H 4 -C=C-C 2 H 5 , -CH 2 -C=C-C 3 H 7 , -C=C-C 4 H 9 , -C≡C-C(CH 3 ) 3 , -C 2 H 4 -CH(CH 3 )-C≡CH, -CH 2 -CH(CHa)-CH 2 -C=CH, -CH 2 -C=C-CH(CHa) 2 , -CH(CH 3 )-C 2 H 4 -C≡CH, -CH 2 -CH(CHs)-C=C-CH 3 , -CH(CHs)-CH 2 -C=C-CH 3 , -CH(CH 3 )-C≡C-C 2 Hs,
-C≡C-CH(CH 3 )-C 2 H 5 , -C=C-CH 2 -CH(CHs) 2 , -CH(C 2 Hs)-C=C-CHs,
-C(CHa) 2 -C=C-CH 3 , -CH(C 2 Hs)-CH 2 -C=CH, -CH 2 -CH(C 2 Hs)-C=CH, -C(CHa) 2 -CH 2 -C=CH, -CH 2 -C(CHs) 2 -C=CH, -CH(CH S )-CH(CH S )-C=CH, -CH(C 3 H 7 )-C≡CH, -C(CH 3 )(C 2 Hs)-C=CH, -C≡C-C≡CH, -CH 2 -C=C-C=CH, -C=C-C=C-CH 3 , -CH(C=CH) 2 , -C 2 H 4 -C=C-C=CH,
-CH 2 -C=C-CH 2 -C=CH, -C=C-C 2 H 4 -C=CH, -CH 2 -C=C-C=C-CH 3 ,
-C=C-CH 2 -C=C-CH 3 , -C=C-C=C-C 2 H 5 , -C≡C-CH(CH 3 )-C≡CH,
-CH(CH 3 )-C≡C-C≡CH, -CH(C=CH)-CH 2 -C=CH, -C(C=CH) 2 -CH 3 ,
-CH 2 -CH(C=CH) 2 , -CH(C=CH)-C=C-CH 3 ; R 81 - R 84 represent independently of each other hydrogen or -CH 3 , -C 2 H 5 , -C 3 H 7 ;
m is the integer 1 , 2, 3, 4, 5, 6, 7 or 8; n is the integer 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is an integer selected from 1 , 2, 3 or 4; q is an integer selected from 0 or 1 ; r is an integer selected from 0, 1 , 2, 3 or 4; s is an integer selected from 0 or 1 ; t is an integer selected from 0, 1 , 2, 3 or 4; and wherein at least one substituent R 1 - R 5 is different from hydrogen, and stereoisomeric forms, enantiomers, diastereomers, tautomers, anomers, keto-forms, deoxy-forms, prodrugs, solvates, hydrates and pharmaceutically acceptable salts thereof; wherein the following compound is excluded: p-Nitrophenyl-1 '-thio-mannoside; for the manufacture of the pharmaceutical composition useful as an inhibitor of a human sodium dependent glucose transporter 2 (SGLT2).
8. Use of a compound according to claim 7 for prophylaxis and/or treatment of diseases and conditions associated with glucose transport by SGLT2.
9. Use of a compound according to claim 7 or 8 for prophylaxis and/or treatment of hyperglycemia and hyperglycemia related diseases and conditions.
10. Use of a compound according to claim 9 wherein the hyperglycemia and hyperglycemia related disease or condition is selected from the group comprising: type I diabetes; type Il diabetes; diabetic complications including coronary heart disease, retinopathy, nephropathy, neuropathy and delayed wound healing; hyperinsulinemia; insulin resistance; obesity; hyperlipidemia including hypertriglyceridemia; metabolic syndrome X, also called insulin resistance syndrome; atherosclerosis; hypertension and related diseases.
11. Use of a compound according to any one of claims 8 - 9 wherein the hyperglycemia and hyperglycemia related disease or condition is selected from the group comprising: type I diabetes; type Il diabetes; and diabetic complications including coronary heart disease, retinopathy, nephropathy, neuropathy and delayed wound healing.
12. Use of a compound according to claim 7 in combination with an anti-diabetic or anti-hyperglycemic agent such as insulin and insulin analogues, insulin sensitizers, meglitinides, bigaunides, sulfonyl ureas, PPAR inhibitors, glucagon- like peptide-1 (GLP-1 ), PTP1 B inhibitors, glycogen phosphorylase inhibitors and glucose-6-phosphatase inhibitors or agents for treating diabetic complications such as PKC inhibitors or AGE inhibitors.
13. Use of a compound according to claim 7 in combination with a lipid-lowering agent such as HMG CoA reductase inhibitors, MTP inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipooxygenase inhibitors, cholesterol absorption inhibitors, ileal Na + /bile acid cotransporter inhibitors, upregulators of LDL receptor activity, bile acid sequestrants, and nicotinic acid
14. Use of a compound according to claim 7 in combination with an anti-obesity agent such as beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, and thyroid receptor beta drug.
15. Pharmaceutical composition comprising at least one compound according to claim 7 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents. |
Thioglycosides as pharmaceutically active agents
Specification
The present invention relates to thioglycosides and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts of these compounds, as well as pharmaceutical compositions containing at least one of these thioglycosides together with pharmaceutically acceptable carrier, excipient and/or diluents. Said thioglycosides have been identified as specific inhibitors of the sodium dependent glucose transporter 1 (SGLT1 ) and 2 (SGLT2), respectively, and are useful for the prophylaxis and/or treatment of hyperglycemia and hyperglycemia related diseases and conditions.
Background of the invention The transport of glucose into epithelial cells is regulated by a secondary active transport system, the sodium-dependent D-glucose transporters (SGLT1 and SGLT2), driven by a sodium-gradient formed by Na7K + -ATPase. Glucose accumulated in the epithelial cell is further transported into the blood across the membrane by facilitated diffusion through GLUT transporters. In the kidney, glucose is filtered in the glomerulus and reabsorbed into the renal proximal tubular epithelial cells by SGLT2 in the S1 and S2 tubular segments. Much smaller amounts of glucose are recovered by SGLT1 in the later segment of the tubule. In the small intestine SGLT1 is the transporter mainly involved in sugar absorption.
Considering the physiologic effect of glucose reabsorption in the kidney and absorption in the intestine, they represent important therapeutic targets for the regulation of blood glucose concentration, thus, controlling hyperglycemia.
The role of glucose analogues in SGLT inhibition has been well demonstrated in in vitro animal models (Oku et al., Diabetes 48(9), 1794 -1800 (1999); Ohsumi et al., Bioorganic & Medicinal Chemistry Letters 13(14), 2269-2272 (2003)) and in vivo animal models (Oku et al., Biological and Pharmaceutical Bulletin 23(12), 1434-1437 (2000); Ueta et al., Life Science 76(23), 2655-68 (2005)). The most studied substance is phlorizin (Ehrenkranz et al., Diabetes Metab Res Rev 21 (1 ), 31 -8 (2005)) an O-glucoside derivative. The clinical application of O-glucoside derivatives, however, is restricted due to hydrolysis by β-glucosidases in the intestine. To overcome this problem, phlorizin analogues such as T-1095 (3-(benzofuran-5-yl)-2',6' -dihydroxy -4'- methylpropiophenone 2'-O- (6-O-methoxycarbonyl -β-D-glyco-pyrano- side) have been chemically synthesized. T-1095 is absorbed through the small
intestine and is then converted into its active form, resulting in the inhibition of glucose reabsorption in the renal tubules (Ohsumi et al., Bioorganic & Medicinal Chemistry Letters 13(14); Nunoi et al., Clinical and Experimental Pharmacology and Physiology 29(5-6), 386-90 (2002)).
The use of O-glucoside derivatives for the inhibition of SGLT2 has also been described, for example, in WO 01/74834 A1 , WO 03/020737 A1 , WO 2005/011592 A2, WO 2005/012242 A2 and WO 2005/012243 A2 and the use of C-glucoside derivatives for the inhibition of SGLT2 has been described, for example, in WO 01/27128 A1 and WO 02/083066 A2.
Herein, we report the discovery of thioglycoside derivatives which demonstrate selective inhibition of human SGLT1 and SGLT2, respectively.
The production of thioglycoside derivatives has been described, for example, in CH 539071 A, WO 2004/024908 A1 and WO 2005/040371 A1.
Thioglycoside derivatives have been described for use in the prevention of bacterial plaque formation in JP 07126132 A and for use as a growth promoter for animals and microorganisms in JP 62026204 A.
JP 2002069000 A describes the use of a thioglycoside derivative as a liposome surfactant for the production of an insulin containing liposome suitable for oral administration.
None of these prior art documents disclose the use of the claimed thioglycoside derived compounds described in the present application for the inhibition of SGLT 1 and/or SGLT2 for the prophylaxis and/or treatment of hyperglycemia or hyperglycemia related diseases and conditions.
It is the object of the present invention to provide compounds and/or pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially for prophylaxis and/or treatment of hyperglycemia and hyperglycemia related diseases and conditions, as well as compositions comprising at least one of those compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients.
The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are
evident from the dependent claims, the description, and the examples of the present application.
Description of the invention The thioglycoside derivatives according to the present invention are represented by the following general formula (I)
wherein
R * and R ** represent independently of each other hydrogen or
-CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5l -COCH(CH 3 ) 2 , -COC 4 H 9 , -CO-cyclo-C 4 H 7 , -COCH 2 CH(CH 3 ) 2 , -COCH(CH 3 )-C 2 H 5 ,
-COC(CH 3 ) 3 , -COC 5 H 11 , -CO-CyCIo-C 5 H 9 , -COCH 2 CH(CH 3 )-C 2 H 5 ,
-COC(CHs) 2 -C 2 H 5 , -COCH 2 CH 2 CH(CH 3 ) 2 , -COCH 2 C(CH 3 ) 3 , -COC 6 H 13 , -COCH(CH 3 )-CH(CH 3 ) 2 , -COCH(CH 3 )-C 3 H 7 , -CO-CyCb-C 6 H 11 ,
-COCH 2 CH(CH 3 )-C 3 H 7 , -COC(CH 3 ) 2 -C 3 H 7 , -COCH 2 CH 2 CH(CH 3 )-C 2 H 5 ,
-COCH 2 CH 2 C(CH 3 ) 3 , -COCH(CH 3 )-C(CH 3 ) 3 , -COCH(CH 3 )-CH 2 -CH(CH 3 ) 2 , -COCH(CH 3 )-C 4 H 9 , -COCH 2 CH 2 CH 2 CH(CH 3 ) 2 , -COCH 2 CH(C 2 H 5 ) 2 ,
-COCH 2 -CH(CH 3 )-CH(CH 3 ) 2 , -COCH(CH 3 )-CH(CH 3 )-C 2 H 5 ;
R 1 - R 5 represent independently of each other -R 6 , -R 7 , -R 8 , -R 9 , -R 10 , -NHR 11 , -NHR 12 , -NR 13 R 14 , -NR 15 R 16 ,
-OR 17 , -OR 18 -COR 19 -COR 20 , -CONH-R 21 , -CONH-R 22 -COOR 23 , -COOR 24 -OOC-R 25 -OOC-R 26 -NHCO-R 27 -NHCO-R 28
-R 29 -R 30 -R 31 -R 32 -R 33.
R 6 - R 28 represent independently of each other
_ R 34 i _ R 35_ _ R 36_ _ R 3 7j _ R ∞ .CH 2 -R SS 1 .C 2 H 4- RW _c 3 H 6 -R 41 , -C 4 H 8 -R 42 ,
-C 5 H 10 -R 43 , -C 6 H 12 -R 44 , -C 7 H 14 -R 45 , -CHR 46 R 47 , -CR 48 R 49 R 50 , -CHR 51 -CHR 52 R 53 , -CR 54 R 55 -CR 56 R 57 R 58 , -CHR 59 -CHR 60 -CHR 61 R 62 ,
_ C R 63 R 64_ CR 65 R 66_ CR 67 R 68 R 69.
R 29 - R 80 represent independently of each other
_H, -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-cyclo-C 3 H 5 , -OCH(CH 3 ) 2) -OC(CHs) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-CyCIo-C 3 H 5 , -SCH(CH 3 ) 2 , -SC(CH 3 ) 3 , -NO 2 , -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-CyCIo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC(CH 3 ) 3 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-CyCb-C 3 H 5 , -COOCH(CH 3 ) 2 , -COOC(CH 3 ) 3 , -0OC-CH 3 , -0OC-C 2 H 5 , -0OC-C 3 H 7 , -0OC-CyCIo-C 3 H 5 , -OOC-CH(CH 3 ) 2 , -0OC-C(CHs) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-CyClO-C 3 H 5 , -CONH[CH(CH 3 ) 2 ], -CONH[C(CHs) 3 ], -CON(CHs) 2 , -CON(C 2 Hs) 2 , -CON(C 3 H 7 ) 2 , -CON(cyclo-C 3 H 5 ) 2 ,
-CON[CH(CH 3 ) 2 ] 2 , -CON[C(CH 3 ) 3 ] 2 , -NHCOCH 3 , -NHCOC 2 H 5 , -NHCOC 3 H 7 , -NHCO-CyClO-C 3 H 5 , -NHCO-CH(CH 3 ) 2 , -NHCO-C(CHs) 3 , -NHCO-OCH 3 , -NHCO-OC 2 H 5 , -NHCO-OC 3 H 7 , -NHCO-O-CyCIo-C 3 H 5 , -NHCO-OCH(CHs) 2 , -NHCO-OC(CH 3 ) 3 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 , -NH-CyCIo-C 3 H 5 , -NHCH(CH 3 ) 2 , -NHC(CH 3 ) 3 , -N(CHs) 2 , -N(C 2 Hs) 2 , -N(C 3 H 7 ) 2 , -N(cyclo-C 3 H 5 ) 2 , -N[CH(CH 3 ) 2 ] 2 , -N[C(CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo : C 3 H 5 , -SOCH(CH 3 ) 2 ,
-SOC(CHs) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -CyCIo-C 3 H 5 , -SO 2 CH(CH 3 ) 2 , -SO 2 C(CHs) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 , -SO 3 -CyCIo-C 3 H 5 , -SO 3 CH(CH 3 ) 2 , -SO 3 C(CHs) 3 , -OCF 3 , -OC 2 F 5 , -0-COOCH 3 , -0-COOC 2 H 5 , -0-COOC 3 H 7 , -O-COO-cyclo-CsHs, -0-COOCH(CHs) 2 , -O-COOC(CH 3 ) 3 , -NH-CO-NH 2 , -NH-CO-NHCH 3 ,
-NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -N H-CO-N H-cyclo-C 3 H 5 ,
-NH-CO-NH[CH(CHs) 2 ], -NH-CO-NH[C(CH 3 ) 3 ], -NH-CO-N(CHs) 2 ,
-NH-CO-N(C 2 Hs) 2 , -NH-CO-N(C 3 H 7 ) 2 , -NH-CO-N(cyclo-C 3 H 5 ) 2 ,
-NH-CO-N[CH(CHs) 2 ] 2 , -NH-CO-N[C(CH 3 ) 3 ] 2 , -NH-CS-NH 2 ,
-NH-CS-NHCH 3 , -NH-CS-NHC 2 H 5 , -NH-CS-NHC 3 H 7 ,
-NH-CS-NH-CyClO-C 3 H 5 , -NH-CS-NH[CH(CH 3 ) 2 ], -NH-CS-NH[C(CH 3 ) 3 ],
-NH-CS-N(CH 3 ) 2 , -NH-CS-N(C 2 Hg) 2 , -NH-CS-N(C 3 H 7 J 2 ,
-NH-CS-N(cyclo-C 3 H 5 ) 2 , -NH-CS-N[CH(CH 3 ) 2 ] 2 , -NH-CS-N[C(CH 3 ) 3 ] 2 , _NH-C(=NH)-NH 2 , -NH-C(=NH)-NHCH3 I -NH-C(=NH)-NHC 2 H 5 ,
-NH-C(=NH)-NHC 3 H 7 , -NH-C(=NH)-NH-cyclo-C 3 H 5 ,
-NH-C(=NH)-NH[CH(CH 3 ) 2 ], -NH-C(=NH)-NH[C(CH 3 ) 3 ],
-NH-C(=NH)-N(CH 3 ) 2 , -NH-C(=NH)-N(C 2 H5) 2 , -NH-C(=NH)-N(C 3 H 7 ) 2 ,
-NH-C(=NH)-N(cyclo-C 3 H 5 ) 2 , -NH-C(=NH)-N[CH(CH 3 ) 2 ] 2l -NH-C(=NH)-N[C(CH 3 ) 3 ] 2 , -0-CO-NH 2 , -0-CO-NHCH 3 , -0-CO-NHC 2 H 5 , -0-CO-NHC 3 H 7 , -0-CO-NH-CyCIo-C 3 H 5 , -O-CO-NH[CH(CH 3 ) 2 ],
-O-CO-NH[C(CH 3 ) 3 ], -O-CO-N(CH 3 ) 2 , -O-CO-N(C 2 H 5 ) 2)
-O-CO-N(C 3 H 7 ) 2 , -O-CO-N(cyclo-C 3 H 5 ) 2 , -O-CO-N[CH(CH 3 ) 2 ] 2 ,
-O-CO-N[C(CH 3 ) 3 ] 2 , -0-CO-OCH 3 , -0-CO-OC 2 H 5 , -0-CO-OC 3 H 7 , -0-CO-O-CyCIo-C 3 H 5 , -O-CO-OCH(CH 3 ) 2 , -O-CO-OC(CH 3 ) 3 , -CH 2 F,
-CHF 2 , -CF 3 , -CH 2 CI, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 CI, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, cyclo-C 3 H 5 , cyclo-C 4 H 7 , CyCIo-C 5 H 9 , CyCIo-C 6 H 11 , cyclo-C 7 H 13 , cyclo-C 8 H 15 , -Ph, -CH 2 -Ph, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CH 3 ) 2 , -CH(CHa)-C 2 H 5, -C(CH 3 ) 3 , -C 5 H 11 , -CH(CH 3 )-C 3 H 7 , -CH 2 -CH(CHa)-C 2 H 5 , -CH(CH 3 )-CH(CH 3 ) 2 , -C(CH 3 ) 2 -C 2 H 5 , -CH 2 -C(CH 3 ) 3 , -CH(C 2 H 5 ) 2 ,
-C 2 H 4 -CH(CHa) 2 , -C 6 H 13 , -C 3 H 6 -CH(CH 3 ) 2 , -C 2 H 4 -CH(CH 3 )-C 2 H 5 ,
-CH(CHa)-C 4 H 9 , -CH 2 -CH(CH 3 )-C 3 H 7 , -CH(CH 3 )-CH 2 -CH(CH 3 ) 2 ,
-CH(CH 3 )-CH(CH 3 )-C 2 H 5 , -CH 2 -CH(CH 3 )-CH(CH 3 ) 2 , -CH 2 -C(CH 3 ) 2 -C 2 H 5 , -C(CH 3 ) 2 -C 3 H 7 , -C(CH 3 ) 2 -CH(CH 3 ) 2 , -C 2 H 4 -C(CH 3 ) 3 , -CH(CH 3 )-C(CH 3 ) 3 , -CH=CH 2 , -CH 2 -CH=CH 2 , -C(CH 3 )=CH 2 , -CH=CH-CH 3 , -C 2 H 4 -CH=CH 2 , -C 7 H 15 , -C 8 H 17 , -CH 2 -CH=CH-CH 3 , -CH=CH-C 2 H 5 , -CH 2 -C(CHa)=CH 2 , -CH(CH 3 )-CH=CH, -CH=C(CH 3 ) 2 , -C(CH 3 )=CH-CH 3 , -CH=CH-CH=CH 2 , -C 3 H 6 -CH=CH 2 , -C 2 H 4 -CH=CH-CH 3 , -CH 2 -CH=CH-C 2 H 5 , -CH=CH-C 3 H 7 , -CH 2 -CH=CH-CH=CH 2 , -CH=CH-CH=CH-CH 3 ,
-CH=CH-CH 2 -CH=CH 2 , -C(CH 3 )=CH-CH=CH 2 , -CH=C(CH 3 )-CH=CH 2 ,
-CH=CH-C(CH 3 )=CH 2 , -C 2 H 4 -C(CHs)=CH 2 , -CH 2 -CH(CH 3 )-CH=CH 2 ,
-CH(CHa)-CH 2 -CH=CH 2 , -CH 2 -CH=C(CH 3 ) 2 , -CH 2 -C(CH 3 )=CH-CH 3 ,
-CH(CH 3 )-CH=CH-CH 3 , -CH=CH-CH(CH 3 ) 2 , -CH=C(CH 3 )-C 2 H 5 , -C(CH 3 )=CH-C 2 H 5 , -C(CH 3 )=C(CH 3 ) 2 , -C(CHa) 2 -CH=CH 2 ,
-CH(CH 3 )-C(CH 3 )=CH 2 , -C(CH 3 )=CH-CH=CH 2 , -CH=C(CHa)-CH=CH 2 ,
-CH=CH-C(CHa)=CH 2 , -C 4 H 8 -CH=CH 2 , -C 3 H 6 -CH=CH-CH 3 ,
-C 2 H 4 -CH=CH-C 2 H 5 , -CH 2 -CH=CH-C 3 H 7 , -CH=CH-C 4 H 9 ,
-C 3 H 6 -C(CH 3 )=CH 2 , -CH 2 -CH 2 -CH 2 -OCH 3 , -C 2 H 4 -CH(CHa)-CH=CH 2 ,
-CH 2 -CH(CHa)-CH 2 -CH=CH 2 , -CH 2 NH 2 , -CH(CHa)-C 2 H 4 -CH=CH 2 ,
-C 2
H 4
-CH=C(CHs) 2
, -C 2
H 4
-C(CHs)=CH-CH 3
, -CH 2
-CH(CHS)-CH=CH-CH 3
,
-CH 2 -CH=C(CHs)-C 2 H 5 , -CH 2 -CH 2 -CH 2 NH 2 , -CH2-C(CH 3 )=CH-C 2 H 5 , -CH(CHs)-CH=CH-C 2 H 5 , -CH 2 -CH 2 NH 2 , -CH=CH-CH2-CH(CH 3 ) 2 , -CH=CH-CH(CHs)-C 2 Hs, -CH=C(CHs)-C 3 H 7 , -C(CHa)=CH-C 3 H 7 , -CH2-CH(CH 3 )-C(CH 3 )=CH 2 , -CH 2 -CH 2 SH, -CH(CH 3 )-CH 2 -C(CH 3 )=CH 2l -CH(CH 3 )-CH(CH 3 >-CH=CH 2 , -CH 2 -CH 2 -CH 2 OH, -CH 2 -C(CH 3 ) 2 -CH=CH 2 , -C(CHa) 2 -CH 2 -CH=CH 2 , -CH2-C(CH 3 )=C(CH 3 ) 2 , -CH(CH 3 )-CH=C(CH 3 ) 2 , -C(CHa) 2 -CH=CH-CH 3 , -CH 2 -CH 2 -CH 2 SH, -CH(CH 3 )-C(CH 3 )=CH-CH 3 , -CH=C(CH 3 >-CH(CH 3 ) 2 , -C(CH 3 )=CH-CH(CH 3 ) 2 , -C(CHs)=C(CHa)-C 2 H 5 , -CH=CH-C(CH 3 )S, -C(CH 3 )2-C(CH 3 )=CH 2 , -CH(C 2 H 5 )-C(CH 3 )=CH 2 , -C(CH 3 )(C 2 Hs)-CH=CH 2 , -CH(CH 3 )-C(C 2 H 5 )=CH 2 , -CH 2 -C(C 3 H 7 )=CH 2 , -CH 2 -C(C 2 Hs)=CH-CH 3 , -CH(C 2 H 5 )-CH=CH-CH 3 , -C(C 4 Hg)=CH 2 , -C(C 3 H 7 )=CH-CH 3 , -C(C 2 Hs)=CH-C 2 H 5 , -C(C 2 Hs)=C(CHa) 2 , -C[C(CH 3 ) 3 ]=CH 2 , -C[CH(CH 3 )(C 2 Hs)]=CH 2 , -C[CH2-CH(CH 3 ) 2 ]=CH 2 , -C 2 H 4 -CH=CH-CH=CH 2 , -C 6 H 4 -OCH 3 , -CH 2 -CH=CH-CH 2 -CH=CH 2 , -CH=CH-C 2 H 4 -CH=CH 2 , -C 6 H 4 -OH, -CH 2 -CH=CH-CH=CH-CH 3 , -CH=CH-CH 2 -CH=CH-CH 3 , -CH 2 -CH 2 -OCH 3 , -CH=CH-CH=CH-C 2 H 5 , -CH 2 -CH=CH-C(CHs)=CH 2 , -CH 2 -CH 2 OH, -CH 2 -CH=C(CHs)-CH=CH 2 , -CH 2 -C(CHs)=CH-CH=CH 2 , -CH 2 -OCH 3 , -CH(CH S )-CH=CH-CH=CH 2 , -CH=CH-CH 2 -C(CH 3 )=CH 2 , -CH=CH-CH(CH S )-CH=CH 2 , -CH=C(CHs)-CH 2 -CH=CH 2 , -C(CHs)=CH-CH 2 -CH=CH 2 , -CH=CH-CH=C(CHs) 2 , -CH 2 -C 6 H 4 -OCH 3 , -CH=CH-C(CH 3 )=CH-CH 3 , -CH=C(CHs)-CH=CH-CH 3 , -CH 2 -C 6 H 4 -OH, -C(CH 3 )=CH-CH=CH-CH 3 , -CH=C(CH 3 )-C(CHs)=CH 2 , -C(CH 3 )=CH-C(CH 3 )=CH 2 , -C(CHs)=C(CHs)-CH=CH 2 , -CH=CH-CH=CH-CH=CH 2 , -C≡CH, -C=C-CH 3 , -CH 2 -C=CH, -C 2 H 4 -C=CH, -CH 2 -C=C-CH 3 , -C=C-C 2 H 5 , -C 3 H 6 -C=CH, -C 2 H 4 -C=C-CH 3 , -CH 2 -C=C-C 2 H 5 , -C=C-C 3 H 7 , -CH(CH 3 )-C≡CH, -CH 2 -CH(CHs)-C=CH, -CH(CHs)-CH 2 -C=CH,
-CH(CH 3 )-C≡C-CHs, -C 4 H 8 -C=CH, -C 3 H 6 -C=C-CH 3 , -C 2 H 4 -CEC-C 2 H 5 , -CH 2 -C=C-C 3 H 7 , -C≡C-C 4 H 9 , -C≡C-C(CH 3 )s, -C 2 H 4 -CH(CH 3 )-C=CH, -CH 2 -CH(CHa)-CH 2 -CsCH, -CH 2 -C=C-CH(CHs) 2 , -CH(CHs)-C 2 H 4 -C=CH,
-CH 2 -CH(CHs)-C=C-CH 3 , -CH(CHs)-CH 2 -C=C-CH 3 , -CH(CH 3 )-C≡C-C 2 Hs, -C≡C-CH(CH 3 )-C 2 Hs, -C=C-CH 2 -CH(CH 3 ) 2 , -CH(C 2 Hs)-C=O-CH 3 , -C(CHa) 2 -C=C-CH 3 , -CH(C 2 Hs)-CH 2 -C=CH, -CH 2 -CH(C 2 Hs)-C=CH, -C(CHa) 2 -CH 2 -C=CH, -CH 2 -C(CH S ) 2 -CECH, -CH(CH 3 )-CH(CH 3 )-C≡CH, -CH(C 3 H 7 )-C≡CH, -C(CH 3 )(C 2 Hs)-C=CH, -C≡C-C≡CH, -CH 2 -C=C-CECH, -C=C-C=C-CH 3 , -CH(C=CH) 2 , -C 2 H 4 -C=C-C=CH,
-CH 2 -CSC-CH 2 -CSCH, -C≡C-C 2 H 4 -C≡CH, -CH 2 -CEC-CEC-CH 3 ,
-CsC-CH 2 -CsC-CH 3 , -C≡C-C≡C-C 2 H 5 , -C≡C-CH(CH 3 )-C≡CH,
-CH(CH 3 )-C≡C-C≡CH, -CH(CECH)-CH 2 -CSCH, -C(CSCH) 2 -CH 3 ,
-CH 2 -CH(C≡CH) 2 , -CH(C≡CH)-C≡C-CH 3 ;
R 81 - R 84 represent independently of each other hydrogen or -CH 3 , -C 2 H 5 , -C 3 H 7 ;
m is the integer 1 , 2, 3, 4, 5, 6, 7 or 8; n is the integer 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is an integer selected from 1 , 2, 3 or 4; q is an integer selected from 0 or 1 ; r is an integer selected from 0, 1 , 2, 3 or 4; s is an integer selected from 0 or 1 ; t is an integer selected from 0, 1 , 2, 3 or 4;
and wherein at least one substituent R 1 - R 5 is different from hydrogen, and stereoisomer^ forms, enantiomers, diastereomers, tautomers, anomers, keto- forms, deoxy-forms, prodrugs, solvates, hydrates and pharmaceutically acceptable salts thereof.
Preferably R ** represents hydrogen or an acetyl group (-COCH 3 ) while R * is preferably hydrogen, acetyl, propionyl, isoproprionyl and linear or branched butanoyl.
R * and R * * in position 4 of the sugar moiety and especially R * are preferably independently of each other selected from
-CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-CyCIo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC 4 H 9 , -CO-cyclo-C 4 H 7 , -COCH 2 CH(CH 3 ) 2 , -COCH(CH 3 )-C 2 H 5 ,
-COC(CH 3 ) 3 , -COC 5 H 11 , -CO-CyCIo-C 5 H 9 , -COCH 2 CH(CH 3 )-C 2 H 5 , -COC(CHs) 2 -C 2 H 5 , -COCH 2 CH 2 CH(CH 3 ) 2 , -COCH 2 C(CH 3 ) 3 , -COC 6 H 13 , -COCH(CH 3 )-CH(CH 3 ) 2 , -COCH(CH 3 )-C 3 H 7 , -CO-CyCIo-C 6 H 11 ,
-COCH 2 CH(CH 3 )-C 3 H 7 , -COC(CH 3 ) 2 -C 3 H 7 , -COCH 2 CH 2 CH(CH 3 )-C 2 H 5 ,
-COCH 2 CH 2 C(CH 3 ) S , -COCH(CHs)-C(CHs) 3 , -COCH(CH 3 )-CH 2 -CH(CH 3 ) 2 , -COCH(CH 3 )-C 4 H 9 , -COCH 2 CH 2 CH 2 CH(CH 3 )2, -COCH 2 CH(C 2 Hs) 2 , -COCH 2 -CH(CH 3 )-CH(CH 3 ) 2 , -COCH(CH 3 )-CH(CH 3 )-C 2 H 5 ;
In the case R** in positions 2, 3 and 4 are hydrogen, R * is preferably selected from the afore-mentioned acyl groups and is different from hydrogen.
The moiety A represents preferably a substituted phenyl group:
In another set of preferred compounds A represents an linear or cyclic or branched and a substituted or unsubstituted alkyl chain comprising preferably 4 to 14 carbon atoms and preferably one heteroatom such as nitrogen, oxygen or sulfur. Most preferred is a residue A comprising between 6 and 12 carbon atoms and optionally one heteroatom.
Furthermore, the residue A preferably comprises one or two double bonds which may be further substituted by an short alkyl chain having 1 to 3 carbon atoms.
A preferred general subformula for A is: -(CH 2 ) p -(CR 81 =CR 82 ) q -(CH 2 )r- (CR 83 =CR 84 )s-R 80 , -(CH 2 )p-(CR 81 =CR 82 ) q -(CH 2 )r-R 80 or -(CH 2 ) p -(CR 81 =CR 82 ) q -R 80 .
Consequently, preferred subformula of general formula (I) are:
Formula ( Il )
Formula ( III )
Formula ( IV )
Formula ( V )
The substituents R * , R ** , R 80 - R 84 and the integers p, q, r, s, t have the meanings as disclosed above.
Another preferred set of compounds is represented by the general subformula (Vl) - (VIII) wherein A is a substituted phenyl residue:
Formula ( Vl )
Formula ( VII ) Formula ( VIII )
Preferred are these compounds wherein a substituent in ortho position is present.
Also preferred are compounds wherein a substituent in meta position is present.
Still preferred are compounds wherein two or three or four substituents in ortho and/or meta position are present.
The glycose moiety (the term "glycose" refers to any six carbon containing sugar) in the above general formula (I) can be any of the following six carbon glycoses:
As sugar moiety glucose and galactose are the most preferred sugars so that the thioglucose compounds of general subformula (IX) - (Xl) and the thiogalactose compounds of general subformula (XII) - (XIV) are the most preferred thioglycosides.
Preferred are the thioglycoside derivatives wherein the glycoside is glucose as shown in the following general formula (IX) - (Xl):
Formula ( IX )
Formula ( X )
Formula ( Xl )
Compounds wherein the -S-phenyl residue is below the plane of the sugar ring are called α-anomers or α-glycosides and wherein the -S-phenyl residue is above the plane of the sugar ring are called β -anomers or β-glycosides. Preferred are the compounds wherein the -S-phenyl residue is in equatorial position.
Also preferred are the thioglycoside derivatives wherein the glycoside is galactose as shown in the following general formula (XII) - (XIV):
Formula ( XIV )
Also preferred are the thioglycoside derivatives wherein R 1 and/or R 5 represents -CH 2 OH 1 -CH 2 -CH 2 OH, -CH 2 -CH 2 NH 2 , -CH 2 -CH 2 SH, -CH 2 NH 2 , -CH 2 SH and most preferred -CH 2 OH.
Furthermore, for all compounds of general formula (I) the β-glycosidic forms (β- anomers) are more preferred than the α-glycosidic forms (α-anomers).
The above-mentioned thioglycoside derivatives are especially useful as pharmaceutically active agents, most especially for prophylaxis and/or treatment of hyperglycemia and hyperglycemia related diseases and conditions.
The present invention also comprises pharmaceutically acceptable salts of the compounds according to the general formula (I), all stereoisomeric forms of the compounds according to the general formula (I) as well as solvates, especially hydrates thereof.
In the case the inventive compounds bear basic and/or acidic substituents, they may form salts with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-tolueπesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen- benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. In case, the compounds bear acidic substituents, the formation of salts with inorganic or organic bases may be possible. Examples for such bases are NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
Some of the compounds of the present invention may be crystallized or recrystallized from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilization.
Some compounds of the general formula (I) may exist in the form of optical isomers, e.g. enantiomers, diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. Where a compound according to the general formula (I) contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof. When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1 % w/w of the other isomer(s).
Another aspect of the present invention relates to the use of the inventive thioglycoside derivatives as drugs, i.e. as pharmaceutically active agents applicable in medicine.
Inhibition of human sodium dependent glucose transporter 2 (SGLT2) mediated glucose reabsorption in the kidney represents a promising therapeutic target. SGLT2 is responsible for most of the reabsorption of glucose in the kidney.
It was found that the thioglycoside derivatives of the present invention are specific inhibitors of human SGLT2. Inhibitors of SGLT2 or the inhibition of SGLT2 cause the inhibition of glucose reabsorption in the kidney.
Thus, the thioglycoside derivatives disclosed herein are especially useful for the manufacture of a pharmaceutical compositions useful as inhibitors of the human SGLT2.
Further, the thioglycoside derivatives disclosed herein are especially useful for the prophylaxis and/or treatment of diseases and conditions associated with glucose transport by SGLT2.
Inhibition of glucose transport in the kidney represents a different mechanism of action from the other agents commonly used in clinical practice to decrease blood glucose concentration (anti-hyperglycemic agents). Inhibition of glucose transport in the kidney leads to increased urinary glucose excretion and consequently decreases blood glucose concentration. The decrease of glucose transport induced by thioglucosides leads to reduction of blood glucose concentration with subsequently decrease of glomerular filtration. Thus, the effect of these thioglucosides in the kidney is auto-regulated by the blood glucose concentration avoiding a significant reduction of blood glucose concentration, which represents a common complication observed when using other anti-hyperglycemic agents.
Diabetes mellitus is characterized by reduced insulin secretion from pancreatic b- cells (type 1 diabetes) or deficient insulin action (type 2 diabetes), both causing an increase in the blood glucose concentration (hyperglycemia). Hyperglycemia represents the main pathogenic factor for the development of diabetic complications including coronary heart disease, retinopathy, nephropathy, and neuropathy.
In addition, chronic hyperglycemia leads to progressive impairment of insulin secretion and to insulin resistance of peripheral tissues (referred to as glucose toxicity).
Thus, the thioglycoside derivatives disclosed herein are especially useful for the treatment of hyperglycemic diseases and conditions such as type I diabetes, type Il diabetes and diabetic complications including coronary heart disease, retinopathy, nephropathy, neuropathy and delayed wound healing.
As further hyperglycemic diseases and conditions the following can also be mentioned: hyperinsulinemia; insulin resistance; obesity; hyperlipidemia including hypertriglyceridemia; metabolic syndrome X, also called insulin resistance syndrome; atherosclerosis; hypertension and related diseases.
Preferred as SGLT2 inhibitors and preferred for prophylaxis and/or treatment of hyperglycemic diseases and conditions are the compounds of general formula (I) wherein the glycose moiety is glucose. Also preferred are the compounds of general formula (I) wherein the glycose moiety is galactose.
Preferred are also the compounds of general formula (I) wherein R 1 or R 5 represents -CH 2 OH.
Thioglycosides and especially thioglucosides (thioglucopyranosides) and thiogalactosides (thiogalactopyranosides) according to general formula (I) are preferred wherein R * is different from hydrogen.
In general R * stands for hydrogen, formyl, acetyl, propionyl, isopropionyl, n-butanoyl, s-butanoyl, iso-butanoyl, t-butanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclohexylcarbonyl, n-pentanoyl, s-pentanoyl, iso-pentanoyl, t-pentanoyl, n-hexanoyl, s-hexanoyl, iso-hexanoyl, t-hexanoyl, or any other linear, cyclic or branched acyl group comprising 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group referred to as R 29 - R 80 .
Disclaimed as substances as such are the following compounds:
- p-Aminophenyl-1 -thio-β-D-galactopyranoside,
- p-Aminophenyl-1 -thio-β-D-glucopyranoside, - p-Methylphenyl-1 -thio-β-D-glucopyranoside,
- 4-Methylphenyl-tetraacetyl-β-D-glucothioside,
- 4-Methylphenyl-β-D-glucothioside,
- 4-Methoxyphenyl-tetraacetyl-β-D-glucothioside,
- 4-Methoxyphenyl-β-D-glucothioside, - 4-Ethoxyphenyl-tetraacetyl-β-D-glucothioside,
- 4-Ethoxyphenyl-β-D-glucothioside,
- 4-Acetylphenyl-tetraacetyl-β-D-glucothioside,
- 4-Acetylphenyl-β-D-glucothioside,
- 4-Bromphenyl-tetraacetyl-β-D-glucothioside, - 4-Bromphenyl-β-D-glucothioside,
- 4-Chlorphenyl-tetraacetyl-β-D-glucothioside,
- 4-Chlorphenyl-β-D-glucothioside,
- 2,5-Dichlorphenyl-tetraacetyl-β-D-glucothioside,
- 2,5-Dichlorphenyl-β-D-glucothioside, - 3-Chlor-4-methylphenyl-tetraacetyl-β-D-glucothioside,
- 3-Chlor-4-methylphenyl-β-D-glucothioside,
- 2-Amino-4-chlorphenyl-tetraacetyl-β-D-glucothioside,
- 2-Amino-4-chlorphenyl-β-D-glucothioside,
- 2-Acetamino-4-chlorphenyl-tetraacetyl-β-D-glucothioside, - 4-Dimethylaminophenyl-tetraacetyl-β-D-glucothioside,
- 4-Dimethylaminophenyl-β-D-glucothioside,
- 4-Diethylaminophenyl-tetraacetyl-β-D-glucothioside,
- 4-Diethylaminophenyl-β-D-glucothioside,
- 4-Di-n-propylaminophenyl-tetraacetyl-β-D-glucothioside,
- 4-Di-n-propylaminophenyl- β -D-glucothioside,
- 4-(N-Methyl-N-benzylamino)phenyl-tetraacetyl-β-D-glucothios ide,
- 4-(N-Methyl-N-benzylamino)phenyl-β-D-glucothioside,
- p-(N,N-Di-2-chloroethylamino)phenyl-β-D-thioglucoside, - p-(N,N-Di-2-bromethylamino)phenyl-β-D-glucothioside,
- p-Bromophenyl-1 -thio-β-D-galactopyranoside,
- p-Bromophenyl-tetraacetyl-1 -thio-β-D-galactopyranoside,
- p-Chlorophenyl-1 -thio-β-D-galactopyranoside,
- p-Chlorophenyl-tetraacetyl-1 -thio-β-D-galactopyranoside, - p-Methylphenyl-1 -thio-β-D-galactopyranoside,
- p-Methylphenyl-tetraacetyl-1 -thio-β-D-galactopyranoside,
- p-tert-Butylphenyl-1 -thio- β -D-galactopyranoside,
- p-tert-Butylphenyl-tetraacetyl-1 -thio-β-D-galactopyranoside,
- p-Methoxyphenyl-1 -thio-β-D-galactopyranoside, - p-Methoxyphenyl-tetraacetyl-1 -thio-β-D-galactopyranoside,
- p-Nitrophenyl-1 -thio-β-D-galactopyranoside,
- p-Nitrophenyl-tetraacetyl-1 -thio-β-D-galactopyranoside,
- p-Acetylphenyl-1 -thio-β-D-galactopyranoside,
- p-Acetylphenyl-tetraacetyl-1 -thio-β-D-galactopyranoside, - p-Nitrophenyl-1 -thio-β-D-mannopyranoside,
- p-Aminophenyl-1 -thio-β-D-mannopyranoside, p-Methoxyphenyl-1 -thio-β-D-mannopyranoside,
- p-Acetamidophenyl-1 -thio-β-D-mannopyranoside,
- p-Nitrophenyl-1 '-thio-mannoside.
The last compound, the p-nitrophenyl-1 '-thio-mannosid, is also disclaimed in regard to the pharmaceutical compositions.
However none of the afore-mentioned compounds which as disclaimed as compounds as such are disclaimed in regard to the uses disclosed herein.
In further preferred embodiments of the present invention, at least one compound of general formula (I) - (III) is applied in combination with existing anti-hyperglycemic agents for the treatment or prophylaxis of type I diabetes, type Il diabetes, or diabetic complications including coronary heart disease, retinopathy, nephropathy, neuropathy, delayed wound healing, hyperinsulinemia; insulin resistance; obesity; hyperlipidemia including hypertriglyceridemia; metabolic syndrome X, also called insulin resistance syndrome; atherosclerosis; hypertension and related diseases.
The mechanisms of action of existing anti-hyperglycemic agents have been focused on improved glucose disposal, controlled hepatic glucose release or inhibition of intestinal glucose absorption.
It is preferred to use at least one compound of general formula (I) - (III) in combination with an anti-diabetic or anti-hyperglycemic agent such as insulin and insulin analogues, insulin sensitizers, meglitinides, bigaunides, sulfonyl ureas, PPAR inhibitors, glucagon-like peptide-1 (GLP-1 ), PTP1 B inhibitors, glycogen phosphorylase inhibitors and glucose-6-phosphatase inhibitors.
It is also preferred to use at least one compound of general formula (I) - (III) in combination with agents for treating diabetic complications such as PKC inhibitors or AGE inhibitors.
It is also preferred to use at least one compound of general formula (I) - (III) in combination with a lipid-lowering agent such as HMG CoA reductase inhibitors, MTP inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipooxygenase inhibitors, cholesterol absorption inhibitors, ileal Na+/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, bile acid sequestrants, and nicotinic acid.
It is further preferred to use at least one compound of general formula (I) - (III) in combination with an anti-obesity agent such as a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, and thyroid receptor beta drug.
Still another aspect of the present invention relates to pharmaceutical compositions comprising at least one compound according to general formula (I) - (III) as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient, binders, disintegrates, glidents, diluents, lubricants, coloring agents, sweetening agents, flavoring agents, preservatives or the like. The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way.
The preferred preparations are adapted for oral application. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations, powders and deposits.
Furthermore, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient. Preparations for oral use are preferred.
The pharmaceutical compositions according to the present invention containing at least one compound according to the present invention and/or a pharmaceutically acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, aerosol preparations consistent with conventional pharmaceutical practices. The pharmaceutical formulation may further contain a cytotoxic and/or cytostatic drug. Other suitable formulations are gels, elixirs, dispersible granules, syrups, suspensions, creams, lotions, solutions, emulsions, suspensions, dispersions, and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
As pharmaceutically acceptable carrier, excipient and/or diluents can be used lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules).
Suitable binders include starch, gelatine, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate.
Lubricants such as boric acid, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride,
sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D 1 L- leucine may be used within the pharmaceutical preparations.
Disintegrating agents (disintegrates) such as starch, methylcellulose, guar gum, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures can be used.
Furthermore, coloring agents, sweetening agents, flavoring agents and/or preservatives may be present in the pharmaceutical formulations.
Glidents which can be used are for example silicon dioxide and talc; suitable adsorbent are clay, aluminum oxide.
Suitable diluents are water or water/propylene glycol solutions for parenteral injections, juice, sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
Said pharmaceutical compositions may further comprise at least one of the above- mentioned anti-hyperglycemic agents, anti-diabetic agents, agents for treating diabetic complications, lipid-lowehng agents or anti-obesity agents.
Description of the figures:
Figure 1 Determination of SGLT translocation activity assessed using fluorescence resonance energy transfer (FRET). FRET signal obtained by each thioglycoside, D-glucose and phlorizin on human SGLT1 and SGLT2 expressed as relative fluorescence units.
Figure 2 [ 14 C]AMG-uptake obtained in human SGLT1 or SGLT2 treated with thioglycosides 1 through 8 or phlorizin (10 μM each). Results represent the mean of 16 determinations (four experiments) and are expressed as % of inhibition.
EXAMPLES
Materials and Methods
Cell Culture Stable transfected Chinese hamster ovary (CHO) cells that express human SGLT1 or human SGLT2 were seeded at a concentration of 1 x 10 3 cells/ml and maintained in culture for 2 days to allow the cells to form a confluent monolayer culture. For transport studies cells were seeded in 96-well microtiter scintiplates (PerkinElmer, Weisbaden, German). For fluorescence resonance energy transfer (FRET) analysis cells were seeded in flat-bottom, poly-D-lysine black-wall, clear bottom, 96-well plates (Becton Dickinson; Heidelberg, Germany).
SGLT Activity
SGLT activity, as indicated by membrane translocation, was assessed using fluorescence resonance energy transfer (FRET). Cells were incubated for 48 hours ar 37 0 C in a 5% CO 2 atmosphere in growth medium. Cells were washed with 0.2 ml Dulbecco ' s phosphate-buffered saline (Invitrogen, Karlsruhe, Germany) and then incubated with 0.1 ml of a solution containing 5 μm CC2-DMPE and 0.02% pluronic acid in PBS. After incubation in the dark for 30 min at 25 0 C, cells were washed twice with 0.2 ml PBS. Afterwards, cells were incubated in the dark at 25 0 C for 30 minutes with 0.1 ml of a solution containing 1 Mm DiSBAC 2 (3). A t the end of the incubation period 1 mM of each thioglucoside was added and excited by 390 nm. Fluorescence emission was recorded at 460 and 580 nm. After a 20 second baseline reading, 0.1 ml of PBS containing 10 μM of each compound was added, and the fluorescence was calculated as the ratio F/F o = [(A 46 o/A58o)/(l46o/l58o)] where A and I represent the reading after or before addition of each thioglucoside, respectively. For I, the readings form 2-5 seconds were averaged; and for A, readings from 3 seconds after the signal that had reached a plateau level (usually within 2-5 seconds) were also averaged. FRET values were expressed as relative fluorescence units (RFU).
Inhibition of SGLT Transport
Sodium-dependent D-glucose transport was determined by means of α-methyl [ 14 C]D-glucopyranoside ([ 14 C]AMG, spec. Radioactivity 300 mCi/mmol) purchased from NEN (Bad Homburg, Germany). For the purpose of this study, Krebs-Ringer- Henseleit (KRH) solution containing 120 mM NaCI, 4.7 mM KCI, 1.2 mM MgCI 2 , 2.2 mM CaCI 2 , 10 mM Hepes (pH 7.4 with Tris) was used to assess sodium-dependent D-glucose transport. For sodium free conditions, KRH solution containing 120 mM N-methyl-glucamine (NMG) instead of NaCI (Na + ) was used to assess sodium-
independent D-glucose transport. All chemicals were purchased from Sigma (Deisenhof, Germany).
Briefly, cells were rinsed three times with 200 μl KRH-Na + or KRH-NMG. Then, 100 μl per well of transport buffer containing KRH-Na + or KRH-NMG plus [ 14 C]AMG (0.1 μCi/μl) were added and incubated for 1 hour. At the end of the uptake period, [ 14 C]AMG-uptake was stopped by adding 100 μl of ice-cold stop buffer (KRH-Na + , containing 0.5 mM phlorizin). Then, the cells were solubilized by adding 100 μl of ATPIite substrate solution (PerkinElmer, Boston, USA) and luminescence ATP detection was assessed using a MicroBeta Trilux (PerkinElmer). A standard curve was used to determine the amount of ATP as mg of protein. After 24 hours the microtiter plate was taken for scintillation counting of radioactive [ 14 C]AMG-uptake using a MicroBeta Trilux (PerkinElmer). Subsequently, the mean counts per minute (cpm) were calculated and converted to picomolar (pmol). The obtained radioactive counts were expressed as pmol/mg/hour. Sodium-dependent [14C]AMG-uptake was calculated by subtracting uptake under sodium-free conditions from the uptake obtained in the presence of sodium.
Kinetic parameters, IC 5O values and apparent inhibition constant (Ki), were calculated using the Kinetic Enzyme Module (SigmaPlot 8.02, Systat Software, Erkrath,
Germany). The inhibitory effect on SGLT transport was also analyzed by IC 50 values.
Dixon plot analysis was used for both estimation of the inhibition constant (Ki) and for identification of the mechanism of enzyme inhibition. Ki was determined by the point of intersection of two different substrate concentrations. Plots of the reciprocal of rate of metabolite formation (1/Rate) versus inhibitor concentration at each substrate concentration were prepared.
RESULTS
Table 1.
Thioglucosides tested for inhibitory effect on human SGLT1 and SGLT2.
SGLT Activity
The activity of the sodium-dependent D-glucose cotransport system was studied by changes in membrane potential induced by each of the eight thioglucosides (see Table 1 ) (10 μm). FRET values were normalized using the fluorescence signal obtained from non-transfected CHO cells. Fluorescence response ratio lower than 1 indicated that such compounds were not significantly transported, while a ratio higher than 1 demonstrated transport across the plasma membrane mediated by SGLT. As shown in Figure 1 , hSGLTI thioglucosides 3, 4, 5, and 7 showed fluorescence signal ratios of 1.15, 2.14. 1.01 and 2.64 (n=16; p<0.01 ), respectively, while hSGLT2 thioglucosides 3, 4, 6 and 7, had fluorescence ratios significantly higher than one (1.21 , 1.63, 1.32 and 4.22, respectively; n=16, p<0.01 ). These results demonstrate that the thioglucosides 3, 4 and 7 are significantly transported through both hSGLTI and hSGLT2. Thioglucoside 1 , 2 and 8 were not transported by either hSGLTI or by hSGLT2. The maximal effect was observed with thioglucoside 4 with FRET values higher than 2 for hSGLTI . Thioglucoside 7 had the highest plasma membrane depolarization for hSGLT2 as shown by a FRET value of 4.22. These data clearly demonstrate the presence of electrogenic uptake of some thioglucosides, specifically, thioglucosides 4 and 7, across the plasma membrane. The FRET values of phlorizin demonstrated that this glucose analogue was not transported by hSGLTI or hSGLT2, thus serving as a control.
Inhibition of SGLT Transport
The inhibitory effect of all eight thioglucosides (see Table 1 ) on sodium-dependent D- glucose co-transport, was evaluated using [ 14 C]AMG-uptake. Figure 2 shows the uptake values for all thioglucosides and phlorizin (10μM each) expressed as % inhibition. The inhibitory effect of thioglucosides 1 , 2, 3 and 4 was stronger for hSGLTI , while thioglucosides 5 through 8 had a higher inhibitory effect for hSGLT2 (n=16, p<0.001 ). These values were comparable to that obtained with phlorizin (10μM) (n=16), suggesting a strong inhibitory effect for the tested thioglucosides. The inhibitory effect of thioglucosides 4 and 7, both with a maximal transport across the plasma membrane, was above 70% for hSGLTI and hSGLT2, respectively.
IC50 and Ki values To analyze further the inhibitory effect of each thioglucosides 1 through 8, kinetic studies were performed. As shown in Table 2, IC50 values for hSGLTI were between 30 μM and 120 μM. The only exception was compound 3 with a value of 4
μM, indicating a strong inhibitory effect. The inhibition of hSGLT2 transport was more pronounced as shown by IC50 values between 9 μM and 18 μM. Thioglucoside 4 and 7, however, showed lower inhibitory effect with IC 50 values equal to 30 μM and 52 μM for hSGLTI and 18 μM and 32 μM for hSGLT2, respectively. Thus, thioglucoside 4 and 7 were significantly transported but the inhibitory effect was reduced. However, these values were similar to those obtained with phlorizin with values of 28 μM and 62 μM for hSGLTI and hSGLT2, respectively.
The apparent inhibition constants (Ki) for all eight thioglucosides are also shown in Table 2. The order of inhibition (lower Ki to higher Ki) of hSGLTI was compound 3>1 >5>8>4, while of hSGLT2 was 6>2>5>8>1.
Table 2.
IC 50 values and apparent inhibitory constant (Ki) of thioglucosides 1 - 8 on hSGLTI and hSGLT2, values are expressed as μM.
Thioglucosides 2 and 6 showed a Ki higher than 100 μM for hSGLTI , while both compounds had a Ki of 0.01 μM for hSGLT2, demonstrating a strong inhibitory effect on hSGLT2 but not on hSGLTI . In addition, the Ki of phlorizin for hSGLTI and hSGLT2 was 15 μM and 10 μM, respectively, suggesting a stronger inhibitory effect of these thioglucosides as compared to phlorizin. These results demonstrate the significant therapeutic effect of thioglucosides 2 and 6, based on a strong inhibitory effect on hSGLT2 (with Ki = 0.01 μM).
The following thioglucosides were synthesized and tested for inhibitory effect on human SGLT1 and SGLT2 according to the methods described above.
Synthesis and spectrometric data of the compounds
Coupling according to Koeniqs Knorr 2 mmol 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide and 4 mmol triethylamine were dissolved in 4 ml acetonitrile. Thereafter 2 mmol of the phenolic aglycons (component) were added. After 2h stirring at room temperature 50 ml chloroform was added and the remaining solution was washed three times with water. Purification was made by recrystallisation from ethanol. Compounds which did not form crystals were purified by MPLC (RP-18 Lichroprep, MeOH / water = 1/1).
2-Methoxycarbonyl-phenylsulfanyl-2',3',4',6'-tetra-O-acetyl- 1'-thio- > g-D- glucopyranoside
Yield: 91% 1 H-NMR (CDCI 3 ) δ [ppm]: 7,81 (d, 1H, J=7,6, H3); 7,52 (d, 1H, J=8,2, H6); 7,38 (t, 1H, J=7,6, H4); 7,28 (t, 1H, J=7,6, H5); 5,21 (t, 1H, J=9,1, H3 1 ); 5,09 (dd, 1H, J=9,5, H274 1 ); 5,08 (dd, 1H, J=9,5, H274 1 ); 4,82 (d, 1H, J=10,1, H1 1 ); 4,17 (dd, 1H, Ji=12,6, J2=5,7, H6 1 ); 4,10 (d, 1H, J=12,0, H6'); 3,82 (s, 3H, H8); 3,75 (ddd, 1H, Ji=8,7, J2=6,5, J3=1,7, H5 1 ); 2,01 (s, 3H, CH3); 1,97 (s, 3H, CHs); 1,96 (s, 3H, CHs); 1,94 (s, 3H.CH3)
13 C-NMR (CDCI 3 ) ) δ [ppm]: 170,5; 170,2; 169,4; 169,1; 166,8; 136,5; 132,2; 130,9; 130,7; 129,5; 126,4; 84,4; 75,7; 74; 69,8; 68,3; 62,3; 52,2; 20,7; 20,6; 20,6; 20,5 MS (70 eV) m/z (%): 467(15), 332(50), 331 (100), 271 (17), 229(17), 211 (16), 187(15), 170(39), 169(55), 167(57), 152(25), 145(28), 139(40), 137(37), 136(68), 127(73), 115(29), 109(71), 97(34), 81(24), 69(17)
HR-MS m/z [M+]: calculated: [C22H26θnS+hf] 499,1274; measured: 499,1278
S-Methoxycarbonyl-phenylsulfanyl^'.S'^'.β'-tetra-O-acety l-i'-thio-yg-D- qlucopyranoside Yield: 93%
1H-NMR (CDCI3) δ [ppm]: 8,14 (t, J=1,6, 1H); 7,97 (dt, J1=7,8; J2=1,3, 1H); 7,67
(ddd, J1=7,9; J2=1,6; J3=1,3, 1H); 7,38 (t, J=7,8, 1H); 5,21 (t, J=9,4, 1H); 5,03 (t,
J=9,8, 1H); 4,96 (dd, J1=9,8; J2=9,4, 1H); 4,72 (d, J=10,1, 1H); 4,22 (dd, J1=12,3;
J2=5,1, 1H); 4,15 (dd, J1=12,3; J2=2,4, 1H); 3,90 (s, 3H); 3,73 (ddd, J1=10,0; J2=5,2, J3=2,3, 1 H); 2,08 (s, 3H); 2,05 (s, 3H); 2,00 (s, 3H); 1 ,97 (s, 3H)
13C-NMR (CDCI3) £[ppm]: 170,6; 170,1; 169,3; 169,2; 166,2; 137,2; 133,8; 132,4;
131,0; 129,4; 128,9; 85,5; 75,9; 73,9; 69,9; 68,1; 62,1; 52,3; 20,7; 20,6;
20,5; 20,5
MS (70 eV) m/z (%): 467(4); 332(10); 331(57); 170(10); 169(100); 168(5); 145(6);
139(8); 137(7); 127(20); 115(6); 110(5); 109(62); 97(7); 81(5)
HR-MS m/z [M+]: calculated: C21 H23O1 OS 467,101194; measured: 467,101577
4-Methoxycarbonyl-phenylsulfanyl-2',3',4',6 > -tetra-0-acetyl-1'-thio-^-D- qlucopyranoside
Yield: 63%
1 H-NMR (CDCI3) £[ppm]: 7,90 (dt, J1=8,7; J2=1,9, 2H); 7,44 (dt, J1=8,7; J2=1,9,
2H); 5,19 (t, J=9,4, 1H); 5,00 (t, J=9,7, 1H); 4,97 (dd, J1=10,1; J2=9,3, 1H); 4,76 (d, J=10,1, 1H), 4,18 (dd, J1=12,4; J2=5,5, H); 4,12 (dd, J1=12,3; J2=2,4, 1H); 3,85 (s,
3H); 3,72 (ddd, J1=10,1; J2=5,3; J3=2,5, 1H); 2,03 (s, 3H); 2,01, (s, 3H); 1,97 (s, 3H);
1,93 (s, 3H)
13C-NMR (CDCI3) £[ppm]: 170,1; 169,3; 169,2; 166,4; 138,6; 130,9; 130,0;
129,4; 85,0; 76,0; 73,8; 69,8; 68,1; 62,1; 52,2 MS (70 eV) m/z (%): 67(3); 332(8); 331 (39); 271 (5); 170(7); 169(100); 168(5);
145(7); 139(9); 137(7); 127(16); 115(5); 109(59); 97(7)
HR-MS m/z [M+]: calculated: C21H23O10S 467,101194 ; measured: 467,102913.
3-Tolyl-2',3',4',6'-tetra-O-acetyl-1'-thio-/g-D-qlucopyra noside Yield: 83%
1 H-NMR (CDCI 3 ) δ [ppm]: 7,28 (s, 1H); 7,27 (d, J=7,3, 1H); 7,18 (td, Ji=7,3; J2=1,0, 1H); 7,11 (dd, Ji=7,3; J2=<1, 1H); 5,20 (t, J=9,35, 1H); 5,03 (t, J=9,6, 1H); 4,95 (dd, Ji=9,3; J2=10,0, 1H); 4,68 (d, J=10,3, 1H); 4,21 (dd, Ji=12,3; J2=5,1, 1H); 4,15 (dd, Ji = 12,3; J2=2,6, 1H); 3,71 (ddd, Ji=IO 1 O; J2=5,1; J3=2,5, 1H); 2,37 (s, 3H); 2,07 (s, 3H); 2,06 (s, 3H); 2,00 (s, 3H); 1 ,97 (s, 3H).
13C-NMR (CDCI 3 ) )δ [ppm]: 170,5; 170,2; 169,4; 169,2; 138,8; 133,6; 131,5; 130,0; 129,2; 128,8.
MS (70 eV) m/z (%): 381(5); 332(8); 331(57); 243(10); 231(15); 181(6); 181(56); 170(7); 169(100); 162(14); 139(5); 131(61); 127(18); 119(16); 109(31); 100(10). HR-MS m/z [M+]: calculated: C14H19O9331, 102908; measured: 331,102386
2-Tolyl-2',3',4',6'-tetra-O-acetyl-1'-thio- / g-D-qlucopyranoside
Yield: 83%
1H-NMR (CDCI 3
) £[ppm]: 7,49 (d, J=7,6, 1H); 7,17 (d, J=0,8, 1H); 7,18 (ddd, Ji=9,8;
128,4; 126,5; 86,4; 74,0; 70,2; 68,4; 62,2; 20,8; 20,6; 20,5; 20,5; 20,4 MS (70 eV) m/z (%): 332(12); 331 (69); 289(4); 271 (8); 229(8); 211 (5); 187(5); 170(13); 169(100); 145(11 ); 139(9); 127(34); 124(8); 123(7); 1 15(10); 1 10(7);109(76); 103(8); 99(4); 98(4); 97(10); 91 (8); 85(5); 81 (1 1 ); 69(4) HR-MS m/z [M+]: calculated: CUHIθOθ 331 ,0102908 ; measured: 331 ,102325
4-Tolyl-2',3',4',6'-tetra-O-acetyl-1 '-thio-/g-D-qlucopyranoside
Yield: 84%
1 H-NMR (CDCI 3 ) δ [ppm]: 7,34 (d, J=8,1 , 2H); 7,07 (d, J=7,6, 2H); 5,16 (t, J=9,4, 1 H); 4,96 (dd, Ji = 10,0; J2=9,5, 1 H); 4,87 (dd, Ji=9,7; J2=9,5, 1 H); 4,59 (d, J=10,0,
1 H); 4,16 (dd, Ji = 12,3; J2=5,0, 1 H); 4,12 (dd, Ji=12,3; J2=2,8, 1 H); 3,65 (ddd,
Ji = 10,1 ; J2=4,9; J 3 =2,8, 1 H); 2,29 (s, 3H); 2,03 (s, 3H); 2,01 (s, 3H); 1 ,96 (s, 3H);
1 ,92 (s, 3H)
13C-NMR (CDCIs) <? [ppm]: 170,3; 169,9; 169,2; 169,0; 138,6; 133,7; 129,5; 127,5; 85,7; 75,7; 74,0; 69,9; 68,2; 62,1 ; 21 ,0; 20,6; 20,6; 20,4; 20,4
MS (70 eV) m/z (%): 331 (61 ); 271 (7); 229(5); 21 1 (4); 187(3); 170(11 ); 169(100);
145(7); 139(8); 127(27); 124(9); 123(10); 1 15(6); 109(69); 103(5); 97(8); 91 (7); 81 (7)
HR-MS m/z [M+]: calculated: C14H19O9331 , 102908 ; measured: 331 ,102733
Benzyl-2',3',4',6'-tetra-O-acetyl-1 '-thio-/?-D-qlucopyranoside
Yield: 69%
1 H-NMR (CDCI3) δ [ppm]: 7,29 (m, 5H); 5,09 (m, 3H); 4,28 (d, J=9,6, 1 H); 4,23 (q, J=12,3, 1 H); 4,12 (q, J=12, 1 H); 3,88 (q, 2H); 3,59 (m, 1 H); 2,1 1 (s, 3H); 2,01 (s, 6H); 1 ,99 (s, 3H)
13C-NMR (CDCI3) δ [ppm]: 170,7; 170,3; 169,5; 136,9; 129,2; 128,7; 127,5; 82,0; 75,9; 73,9; 69,9; 68,5; 62,3; 33,9; 20,9; 20,8; 20,7
Oxidation of qeranyl acetate with selenium dioxide
To a suspension of 3.2 mmol selenium dioxide in 30 ml dichlormethane, 14 mmol geranyl acetate and 16.5 mmol of a 5.5 M water-free solution of f-butylhydroperoxide in nonane were added. After stirring the mixture for three hours at room temperature the mixture was filtered and the solvent was removed under reduced pressure. The obtained yellow oil was dissolved in diethylether and was washed two times with brine (saturated sodium chloride solution). Purification was performed by column chromatography on silica gel using Et 2 O / PE (petrol ether) = 1/1 ).
(2E,6a-8-Hvdroxy-3.7-dimethyl-2,6-octadienylacetate
Yield: 52%
1 H-NMR (CD 3 CI) £ [ppm]: 9.33 (S 1 1 H, H7); 6,39 (t, 1 H, J=7,2, H6); 5,33 (t, 1 H, J=7,0, H2); 4,53 (d, 2H, J=7,0, H1 ); 2,44 (q, 2H, J=7,5, H5); 2,18 (t, 2H, J=7,5, H4); 1 ,99 (s, 3H, CH3); 1 ,69 (s, 6H, H9, H10)
13C-NMR (CD3CI) δ [ppm]: 195,0; 170,9; 153,3; 140,3; 139,6; 1 19,5; 61 ,0; 37,7; 26,9; 20,9; 16,2; 9,1
Mitsunobu-Couplinq
7.4 mmol of 1 ,1 '-(azodicarbonyl)dipiperidine dried in high vacuum was dissolved in 40 ml dry (absolute) THF and 7.4 mmol trimethylphosphane were added at 0 0 C. The solution was stirred for about 30 minutes until the color disappeared and a light yellow solution remained. 5 mmol 2,3,4,6-tetra-O-acetyl-thio-α-D-glucopyranose which was dried in oil vacuum was added at room temperature together with 3.7 mmol aglycon dissolved in 20 ml THF to this solution. The mixture was stirred for 2 hours at room temperature. The white precipitate was filtered off and the solvent was removed under reduced pressure. The remainder was redissolved in ethylacetate and the hydrazide was precipitated with petrolether. The precipitate was filtered off and the solvent was removed under reduced pressure. The remainder was then taken up in dichlormethane and was washed twice with water and once with a saturated solution of sodium hydrogencarbonate. Purification was performed by column chromatography on silica gel using Ethylacetate / Petrolether = 1/2).
(2E,6a-8-Acetoxy-2,6-dimethyl-octa-2,6-dienyl-2',3',4'.6' -tetra-0-acetyl-1 '-thio-
/?-D-glucopyranoside
Yield: 79%
1 H-NMR (CDCI3) δ [ppm]: 5,34 (t, 1 H, J=6,9, H7); 5,26 (t, 1 H, J=6,8, H3); 5,17 (dd, 1 H, J=9,3, H3 1 ); 5,06 (dd, 1 H, J=9,1 , H4 1 ); 5,02 (dd, 1 H, J=10,3, H2 1 ); 4,58 (d, 2H, J=6,9, H8); 4,38 (d, 1 H, J=10,1 , HV); 4,21 (dd, 1 H, J1 =12,0, J2=5,0, H6 1 ); 4,10 (dd, 1 H, J1 =1 1 ,5, J2=2,5, H6 1 ); 3,57 (ddd, 1 H, J1 =9,6, J2=4,9, J3=2,1 , H5 1 ); 3,35 (d, 1 H, J=12,9, H1 ); 3,11 (d, 1 H, J=12,9, H1 ); 2,21 -2,12 (m, 2H, H4); 2,12-1 ,97 (m, 2H, H5); 2,06 (s, 3H, CH3); 2,03 (s, 3H, CH3); 2,01 (s, 3H, CH3); 2,00 (s, 3H, CH3); 1 ,98 (s, 3H, CH3); 1 ,70 (s, 3H, C9/10); 1 ,66 (s, 3H, C9/10)
13C-NMR (CDCI3) £ [ppm]: 171 ,0 (C=O); 170,5 (C=O); 170,2 (C=O); 169,3 (C=O); 169,28 (C=O); 141 ,5 (C6); 130,5 (C2); 128,6 (C3); 118,7 (C7); 81 ,8 (C1 1 ); 75,7 (C5 1 ); 73,9 (C3 1 ); 69,8 (C2 1 ); 68,4 (C4 1 ); 62,2 (C6 1 ); 61 ,2 (C8); 39,4 (C5); 39,2 (C1 ); 26,3
(C4); 21 ,0 (CH3); 20,7 (CH3); 20,6 (CH3); 20,56 (CH3); 20,5 (CH3); 16,5 (C10); 14,7 (C9)
MS (MassSpec, El) m/z (%): 332(9), 331 (57, C6H7O6(C2H3O)4), 271 (12), 229(6), 21 1 (7), 169(100, C10H14S), 142(10), 139(9), 129(6), 127(16), 109(34), 97(9), 43(40) HR-MS (Quattro) measured: 581 ,2034; calculated: 581 ,2033 [C26H38O11 S+Na]
(Z)-3-Hexenyl-2',3',4',6'-tetra-O-acetyl-1 '-thio-/7-D-qlucopyranoside
Yield: 82%
1 H-NMR (CDCI3) £[ppm]: 5,44-5,15 (m, 2H); 5,09 (td, J1 =9,4; J2=1 ,6, 1 H); 4,91 (td, J2=9,9; J3=0,7, 1 H); 4,78 (ddd, J1 =10,0; J2=9,4; J3=1 ,0, 1 H); 4,40 (dd, J1 =10,0;
J2=5,6, 1 H); 4,1 1 (ddd, J1 = 12,4; J2=5,0; J3=2,1 , 1 H); 4,01 (ddd, J1 =12,3; J2=1 ,9;
J3=1 ,5, 1 H); 3,60 (dddd, J1 =10,0; J2=5,0; J3=2,4; J4=1 ,2, 1 H); 2,60-2,44 (m, 2H);
2,22-2,03 (m, 2H); 1 ,83 (s, 3H); 1 ,82 (q, J=7,5, 3H); 1 ,81 (s, 3H); 1 ,78 (s, 3H); 1 ,76
(s, 3H) 13C-NMR (CDCI3) δ [ppm]: 170,1 ; 169,7; 169,0; 168,9; 133,3; 126,2; 83,2; 75,7;
73,7; 69,7; 68,2; 62,0; 29,6; 27,4; 25,2; 20,3; 20,3; 20,2; 20,2; 13,9
MS (70 eV) m/z (%): 331 (31 ); 21 1 (10); 169(100); 145(7); 139(9); 127(24); 115(15);
109(67); 103(5); 97(6); 81 (7); 55(10)
HR-MS m/z [M+]: calculated: C20H30O9S 446,161055; measured: 446,160927.
Deprotection and reduction with lithium aluminium hydride
In a 50 ml two-necked round bottom flask 15 ml tetrahydrofurane was added. 3.2 mmol lithium aluminium hydride was added. Under cooling with ice water 1 mmol of the protected glycoside dissolved in 15 ml THF was slowly added (dropwise). Thereafter the reaction mixture was heated under reflux for 2 hours. The solution was allowed to cool to room temperature and under cooling with ice water 0.15 ml water, 0.15 ml of a 15 % solution of sodium hydroxide and 0.45 ml water were added subsequently. A white precipitate was formed which was filtered off and was washed thereafter several times with methanol. Purification was performed via MPLC using a RP-18 column and a mixture of water and methanol (2:3).
Deprotection with sodium methanolate
0.73 mmol of the protected thioglycoside was dissolved in 10 ml methanol. 3 mmol of a solution of 30% sodium methanolate in MeOH was added and the reaction mixture was stirred at room temperature for 12h. Thereafter the mixture was neutralized using an ion exchange resin (Amberlite IRC 50 Oder Amberlite IRC 86) and the neutralized mixture was filtered. Purification was conducted via MPLC (RP- 18 Lichroprep, MeOH / water = 3/2).
Compound 8
M=440g/mol
Phenyl-tetra-O-acetyl-thioglucoside
Phenyl-1'-thio-β-D-glucopyranoside
(3Z)-Hex-3-en-1 -yl-6'-O-2CH.vbutyrate-1 '-thio-yg-D-glucopyranoside compound 9
Yield: 66%
IH-NMR(CDCb) J[ppm]:
13C-NMR (CDCIa) £[ppm]: 177.7, 133.8, 126.3, 86.0, 79.4, 77.9, 72.4, 69.9, 63.4,
40.9, 30.4, 27.9, 26.6, 20.7, 16.5, 14.3, 11.7
MS (70 eV) m/z (%): 362(2), 331(7), 247(52), 229(54), 217(35), 187(25), 169(52),
145(51), 127(52), 115(57), 103(53), 97(41), 85(88), 69(62), 57(100).
HR-MS m/z [M+]: calculated: C 17 H 30 O 6 S 362.176311; measured: 362.175453
(Z)-3-Hexenylthioglucoside-6-O-2-CH3-butyrate (3Z)-Hex-3-en-1-yl-6'-O-(2-Methylpropanyl)-1'-thio-β-D-gluc opyranoside
Benzyl-i'-thio-ib-D-glucopyranoside - compound 10 Yield: 96%
1H-NMR (D2O) £[ppm]: 7,28-7,19 (m, 4H); 7,18-7,12 (m, 1H); 4,11 (d, J=9,4, 1H);
3,83 (d, J=13,1, 1H); 3,74 (d, J=13,4, 1H); 3,66 (dd, J1=12,5; J2=2,2, 1H); 3,49, (dd,
J1=12,5, J2=5,5, 1H); 3,21-3,18 (m, 1H); 3,17-3,10 (m, 3H)
13C-NMR (D2O) J[ppm]: 138,1; 129,3; 128,8; 127,8; 84,1; 79,9; 77,4; 72,3; 69,7; 61,1; 33,6
MS (70 eV) m/z (%): 286(0,3); 268(0,35); 195(0,4); 145(45); 124(58); 91(100);
85(48); 73(45)
HR-MS m/z [M+]: calculated: C13H18O5S: 286,087496; measured: 286,087578
(2E,6E)-8-Hvdroxy-2,6-dimethyl-octa-2,6-dienyl-1'-thio-/g -D-glucopyranoside compound 11
Yield: 72%
1H-NMR (CD3OD) £[ppm]: 5,37 (t, J=5,8, 1H); 5,35 (t, J=6,8, 1H); 4,26 (d, J=9,8,
1H); 4,10 (d, J=6,3, 2H); 3,85 (dd, J1 = 12,1; J2=2,1, 1H); 3,65 (dd, J1 = 12,0; J2=5,8,
1H); 3,51 (d, J=12,9, 1H); 3,37-3,30 (m, 2H); 3,24 (dd, J=8,4, 1H); 3,19 (ddd,
J1=8,58; J2=6,2; J3=1,8, 1H); 3,11 (d, J=12,9, 1H); 2,27-2,12 (m, 2H); 2,09 (t, J=7,1,
2H); 1,74(s, 3H); 1,68 (s, 3H)
13C-NMR (CD3OD) £[ppm]: 139,0; 132,1; 129,3; 125,2; 84,9; 81,9; 79,8; 74,2; 71,6;
63,0; 59,5; 40,4; 39,8; 27,4; 16,4; 15,2
MS (70 eV) m/z (%): 330(2); 262(18); 239(14); 185(21); 168(28); 167(25); 153(14);
152(15); 145(50); 135(28); 134(36); 127(34); 121(37); 119(20); 107(26); 101(43);
100(27); 99(36); 97(43); 93(32); 91(24); 87(53); 85(100); 84(56); 81(29); 73(66);
69(31); 68(31); 67(36); 61(38); 57(39)
HR-MS m/z [M+]: calculated: C16H28O6S: 348,150096 ; measured: 348,150075
8-OH-geranylthioglucoside δ-Hydroxy^.δ-dimethyl-octa^.θ-dienylsulfanyM'-thio-β-D-g lucopyranoside
3-Tolyl-1'-thio-/?-D-qlucopyranoside - compound 12
Yield: 99% 1H-NMR (CD 3 OD) £[ppm]: 7,36 ( s, 1H); 7,30 (d, J=7,6, 1H); 7,13 (t, J=7,6, 1H); 7,02 (d, J=7,6, 1H); 4,54 (d, J=10,1, 1H); 3,82 (dd, Ji=12,2; J2=1,8, 1H); 3,62 (dd, Ji = 12,2; J2=5,5, 1H); 3,35 (t, J=8,7, 1H); 3,28 (ddd, Ji=9,2; U2=5,9; U3=1,9, 1H); 3,25 (dd, Ji=9,3; J2=8,7, 1H); 3,18 (dd, Ji=9,8; J2=8,9, 1H); 2,22 (s, 3H)
13C-NMR (CD 3 OD) δ [ppm]: 140,1; 135,3; 133,4; 130,0; 129,3; 89,7; 82,3; 79,9;
74,1; 71,7; 63,2; 21,6
MS (70 eV) m/z (%): 286(4); 145(10); 127(8); 126(5); 125(10); 124(100); 123(6);
97(5); 91(21); 87(10); 85(18); 73(13); 69(7); 61(9); 57(9)
HR-MS m/z [M+]: calculated CisHisOsS: 286,087496; measured: 286,087410
m-Kresolthioglucoside 3-Tolyl-r-thio-β-D-glucopyranoside
2-ToIyM '-thio-yg-D-qlucopyranoside -compound 13
Yield: 98%
1H-NMR (CDaOD) δ [ppm]: 7,52 (dd, M=I ,2; J2=1,7, 1H); 7,21 (dd, Ji=7,8; J2=1,4,
1H); 7,18 (td, Ji=7,2; U2=1,9, 1H); 7,15 (td, Ji=7,4; J2=1,8, 1H); 4,69 (d, J=10,1, 1H);
3,78 (dd, Ji=12,5; J2=2,1, 1H); 3,60 (dd, Ji=12,5; J2=5,5, 1H); 3,35 (t, J=8,7, 1H);
3,48 (ddd, Ji=9,6; J2=5,5; U3=2,1, 1H); 3,45 (d, Ji=6,1, 1H); 3,43 (dd, Ji=8,5; U2=7,6,
1H); 2,42 (S 1 3H)
13C-NMR (CD 3 OD) δ [ppm]: 140,0; 135,2; 132,7; 131,1; 128,2; 127,7; 89,3; 82,0;
79,7; 74,2; 71,4; 62,9; 21,1
MS (70 eV) m/z (%): 286(3); 145(12); 124(100); 97(6); 91(21); 87(13); 85(22);
73(15); 69(9); 61(10); 57(12)
HR-MS m/z [M+]: calculated: C13H18O5S: 286,087496; measured: 286,087761
o-Kresolthioglucoside 2-Tolyl-1'-thio-β-D-glucopyranoside
4-Tolyl-1'-thio-/?-D-qlucopyranoside - compound 14
Yield: 96%
1H-NMR (CD 3 OD) £[ppm]: 7,37 (d, J=8,2, 2H); 7,14 (d, J=8,2, 2H); 4,59 (d, J=9,8,
1H); 3,77 (dd, Ji = 12,5; J 2
=2,1, 1H); 3,59 (dd,
1H); 3,33 (ddd, Ji=9,8; U2=5,5; Ja=2,1, 1H); 3,27 (t, J=9,6, 1H); 3,21 (q, J=9,0, 1H);
2,22 (s, 3H)
13C-NMR (CD 3 OD) £[ppm]: 139,0; 133,8; 131,4; 130,8; 89,9; 82,2; 79,9; 73,9; 71,6;
63,1; 21,4
MS (70 eV) m/z (%): 286(6); 145(8); 127(6); 124(100); 123(10); 97(5); 91(22);
87(10); 85(15); 73(13); 69(7); 61(8); 57(9)
HR-MS m/z [M+]: calculated: C13H18O5S: 286,087496; measured: 286,087404
p-Kresolthioglucoside (4-ToIyI-I '-thio-β-D-glucopyranoside)
Enzymatic acylation of thioqlucosides
The reaction was carried out under an inert atmosphere. 100 mg thioglucoside was dissolved in 10 ml tert.-butanol. 1 g molecular sieve 4A was added. Thereafter 10 ml of a 12.5% solution of ethylisobutyrate or ethyl-2-CH 3 -butyrate in tert.-butanol was added slowly. The reaction was started through addition of 100 mg Candida
Antarctica lipase B. The reaction mixture was stirred for 24h at 40 0 C and thereafter filtered. The filtrate is evaporated to dryness. The raw product was purified by column chromatography on silica gel using EtOAc / MeOH = 4/1.
3-Tolyl-6'-O-(2-methylpropanyl)-1'-thio-/?-D-qlucopyranos ide - compound 15
Yield: 69% 1H-NMR (CD 3 OD) £[ppm]: ): 7,33 (s, 1H), 7,32 (d, 1H), 7,15 (t, 1H), 7,07 (d, 1H), 4,80 (s, OH), 4,55 (d, 1H), 4,40 (dd, 1H), 4,14 (dd, 1H), 3,47 (m, 1H), 3,36 (t, 1H), 3,25 (t, 1H), 3,17 (dd, 1H), 2,54 (h, 1H), 2,30 (s, 3H), 1,11 (m, 3H) 13C-NMR (CD 3 OD) £[ppm]: ): 177,2; 138,3; 133,1 ; 132,3; 128,8; 128,3; 127,9; 87,8; 78,1; 77,8; 72,3; 70,1; 63,5; 33,8; 19,9; 17,9 MS (70 eV) m/z (%): 356(20); 233(46); 215(41); 145(13); 124(32); 91(22); 71(100) HR-MS m/z [M+]: calculated: CMHUOSS: 356,129361; measured: 356,128136
m-Cresolthioglucoside-6-O-isobutyrate io-β-D-glucopyranoside
3-Tolyl-6'-0-(2-methylbutanyl)-1'-thio-/?-D-glucopyranosi de - compound 16
Yield: 30%
1 H-NMR (CD 3 OD) δ [ppm]: ): 7,23 (s, 1H 1 7,22 (d, 1H), 7,15 (t, 1H), 7,07 (d, 1H,
4,80 (s, OH), 4,54 (d, 1H), 4,42 (dd, 1H) 1 4,14 (dd, 1H), 3,47 (m, 1H, 3,37 (t, 1H), 3,25 (t, 1H), 3,17 (dd, 1H), 2,37 (h, 1H), 2,30 (s, 3H), 1,64 (m, 1H), 1,45 (m, 1H),
1,10(m,3H)
13C-NMR (CD 3 OD) δ [ppm]: ): 176,8; 138,3; 133,1 ; 132,4; 128,9; 128,3; 127,9;
87,8; 78,1; 77,8; 72,3; 70,2; 63,4; 26,39; 19,9; 15,6; 10,5
MS (70 eV) m/z (%): 370(51); 247(100); 229(66); 145(20); 124(42); 91(26); 85(91); 57(88)
HR-MS m/z [M+]: calculated: CisZ-fceOeS: 370,145011; measured: 370,146307
m-Cresolthioglucoside-θ-O^-CHS-butyrate -β-D-glucopyranoside
(Z)-3-hexenyl-1'-thio-/7-D-glucopyranoside -compound 17
Yield: 67% 1 H-NMR (CD3OD) δ [ppm]: 5,80-5,55 (m, 2H); 4,67 (dd, J1=9,8; J2=4,5, 1H); 4,03 (d, J=12,5, 1H); 3,88 (dd, J1=12,2; J2=4,3, 1H); 3,65-3,57 (m, 3H); 3,48 (td, J1=9,5; J2=1,6, 1H); 2,94-2,91(m, 2H); 2,57-2,46 (m, 2H); 2,25-2,12 (m, 2H); 1,11 (t, J=7,5, 3H)
13C-NMR (CD3OD) £[ppm]: 134,2; 127,4; 85,7; 80,2; 77,7; 72,8; 69,9; 61,3; 30,2; 27,7; 20,7; 14,1
MS (70 eV) m/z (%): 278(2); 234(1); 229(1); 205(2); 198(4); 187(3); 169(5); 163(13); 162(18); 145(78); 127(53); 117(18); 116(43); 115(100); 103(13); 99(14); 97(21); 91 (27); 87(92); 85(90); 83(18); 82(22); 81 (12); 73(65); 71(18); 69(34); 67(17); 61 (39); 60(30); 57(41); 55(43) HR-MS m/z [M+]: calculated: C12H22O5S: 278,118796; measured: 278,118609.
(Z)-3-Hexenylthioglucoside (3Z)-Hex-3-en-1 -yl-1 '-thio-β-D-glucopyranoside
2-Tolyl-6'-O-(2-methylbutanyl)-1 '-thio-/?-D-glucopyranoside - compound 18
Yield: 66%
1 H-NMR (CD 3 OD) J[ppm]: 7,30 (m, 4H), 4,80 (s, OH), 4,58 (d, 1H), 4,45 (dd, 1H), 4,14 (dd, 1H), 3,49 (m, 1H), 3,40 (t, 1H), 3,3 (m), 2,45 (s, 3H), 2,43 (h, 1H), 1,65 (m, 1H), 1,47 (m, 1H), 1,13 (m, 3H), 0,90 (m, 3H) 13C-NMR (CD 3 OD) £[ppm]: ): 178,2; 141 ; 134,4 ; 133,4; 131,1; 128,6; 127,4; 89,3; 79,7; 79,2; 74,0; 71,6; 64,9; 42,4; 27,8; 21,2; 17,0; 11,9
MS (70 eV) m/z (%): 370(10); 358(8); 247(37); 229(26); 145(13); 124(20); 91(16); 85(81); 69(15); 57(100) HR-MS m/z [M+]: calculated: CieZ-feeOeS: 370,145011; measured: 370,143501
o-Cresolthioglucoside-6-O-2-CH3-butyrate 2-Tolyl-6'-O-(2-methylbutanyl)-1 '-thio-β-D-glucopyranoside
4-Tolyl-6'-O-(2-methylpropanyl)-1'-thio-/?-D-qlucopyranos ide - compound 19
Yield: 64%
1 H-NMR (CD 3 OD) δ [ppm]: ): 7,30 (dd, 4H), 4,80 (s, OH), 4,53 (d, 1H), 4,44 (dd,
1H), 4,18 (dd, 1H), 3,48 (m, 1H), 3,39 (t, 1H), 3,27 (t, 1H), 3,19 (dd, 1H), 2,55 (h, 1H),
2,38(s, 3H), 1,15 (d, 6H)
13C-NMR (CDSOD) δ [ppm]: ): 177,2; 139,0; 134,0; 130,8; 130,5; 89,4; 79,5; 79,3;
73,7; 71,5; 64,9; 35,3; 21,1; 19,3
MS (70 eV) m/z (%): 356(19); 233(46); 215(50); 145(13); 124(44); 91(21); 71(100)
HR-MS m/z [M+]: calculated: C17H24O6S: 356,129361; measured: 356,127945
p-Cresolthioglucoside-6-O-isobutyrate -β-D-glucopyranoside
4-Tolyl-6'-O-(2-methylbutanyl)-1'-thio-/?-D-glucopyranosi de - compound 20
Yield: 44%
1 H-NMR (CD 3 OD) δ [ppm]: 7,30 (dd, 4H), 4,80 (s, OH), 4,51 (d, 1H), 4,46 (dd, 1H), 4,17 (dd, 1H), 3,48 (m, 1H), 3,40 (t, 1H), 3,27 (t, 1H), 3,18 (dd, 1H), 2,43 (h, 1H), 2,36 (s, 3H), 1,68 (m, 1H), 1,50 (m, 1H), 1,15 (d, 3H), 0,93 (t, 3H) 13C-NMR (CD 3 OD) δ [ppm]: ): 178,2; 139,0; 134,0; 130,8; 130,5; 89,3; 79,6; 79,3; 73,7; 71,5; 64,8; 42,4; 27,8; 21,1; 16,9; 12,0
MS (70 eV) m/z (%): 370(17); 247(47); 229(44); 145(16); 124(41); 91(21); 85(93); 57(100) HR-MS m/z [M+]: calculated: frβHiβOsS: 370,145011; measured: 370,144441
p-Cresolthioglucoside-6-O-2-CH3-butyrate
4-Tolyl-6'-O-(2-methylpropanyl)-1'-thio-β-D-glucopyranos ide
0
2-Methoxycarbonyl-phenylsulfanyl-1'-thio-/7-D-qlucopyrano side - compound 21
Yield: 50%
1 H-NMR (CD 3 OD) £[ppm]: 7,74 (dd, 1H, Ji=7,6, J2=1,3, H6); 7,46 (dd, 1H, J=7,6, 1,3, H3); 7,32 (td, 1H, Ji=7,5, J2=1,4, H5); 7,27 (td, 1H, Ji=7,5, J2=1,5, H4); 4,88 (d, 1H, J=12,8, H7); 4,74 (d, 1H, J=12,8, H7); 4,49 (d, 1H 1 J=9,8, H1'); 3,85 (dd, 1H, Ji=11,9, J2=2,1, H6') ; 3,65 (dd, 1H, Ji=12,2, J2=5,5, H6'); 3,36 (dd, 1H, J=8,7, H3'); 3,30-3,22 (m, 2H, H2', H5'); 3,16 (dd, 1H, Ji=9,6, J2=8,7, H4')
13 C-NMR (CD 3 OD) £[ppm]: 144,9 (C2); 135,8 (C1); 132,8 (C5); 129,8 (C3); 129,5 (C6); 129,2 (C4); 89,8 (CV); 82,2 (C5 1 ); 79,7 (C3 1 ); 73,8 (C2 1 ); 71,5 (C4 1 ); 63,8 (C7); 63,0 (C6 1 )
MS (LCQ/APCI) m/z (%): 303,9(20), 285,0(8), 267,1(24), 249,1(29), 231,2(23),
213,3(5), 164,3(100), 140(57)
HR-MS m/z [M+]: calculated: C13H18O6S: 303,0902; measured: 303,0902
3-Methoxycarbonyl-phenylsulfanyl-1'-thio-/g-D-qlucopyrano side - compound 22
Yield: 40%
1 H-NMR (D 2 O) S[ppm]: 7,60 (s, 1H); 7,55 (d, J=7,8, 1H); 7,30 (dd, J1=7,9; J2=7,7,
1H); 7,24 (d, J=7,8, 1H); 4,69 (d, J=9,8, 1H); 4,52 (s, 2H); 3,78 (dd, J1=12,5; J2=2,1, 1H); 3,60 (dd, J1=12,5; J2=5,8, 1H); 3,42 (t, J=9,2, 1H); 3,38
(ddd, J1=9,8; J2=6,0; J3=2,1, 1H); 3,30 (t, J=9,4, 1H); 3,24 (t, J=9,4, 1H)
13 C-NMR (D 2 O) ±[ppm]: 142,7; 133,6; 131,9; 131,4; 130,7; 128,2; 88,4; 81,2;
78,5; 73,0; 70,6; 64,7; 62,1
MS (70 eV) m/z (%): 302(2); 162 (6); 145(14); 141(8); 140(100); 139(5); 127(9); 123(7); 109(5); 107(7); 97(5); 91(9); 87(14); 85(20); 79(7); 77(11); 73(17)
HR-MS m/z [M+]: calculated: C13H18O6S: 302,082410; measured: 302,082123.
4-Methoxycarbonyl-phenylsulfanyl-1'-thio-/?-D-glucopyrano side - compound 23 Yield: 57%
1 H-NMR (D2O) δ [ppm]: 7,46 (d, J=8,2, 2H); 7,27 (d, J=8,2, 2H); 4,67 (d,
J=10,1,1H); 4,52 (s, 2H); 3,78 (dd, J1=12,4; J2=1,7, 1H); 3,60 (dd, J1=12,4; J2=5,6,
1H); 3,41 (t, J=9,0, 1H); 3,37 (ddd, J1 = 10,0; J2=5,9; J3=1,0, 1H); 3,29 (t, J=9,6, 1H);
3,23 (dd, J1 =9,5; J2=9,6, 1H) 13C-NMR (D2O) δ [ppm]: 142,9; 134,5; 133,9; 130,8; 89,9; 82,6; 79,9; 74,4; 72,0;
66,0; 63,5
MS (70 eV) m/z (%): 302(3); 145(14); 142(5); 141(8); 140(100); 139(5); 127(10);
123(9); 122(7); 111(8); 109(4); 107(13); 97(6); 91(8); 87(12); 85(21); 79(8); 78(4);
77(12); 73(17); 71(3); 69(9); 61(10); 60(9); 57(6)
HR-MS m/z [M+]: calculated: C13H18O6S: 302,082410; measured: 302,082756.
Compound 24
M=302g/mol
Thiosalicin
2-Hydroxymethyl-phenyl-1'-thio-β-D-glucopyranoside
Compound 25
M=302g/mol m-Thiosalicin
3-Hydroxymethyl-phenyl-1 '-thio-β-D-glucopyranoside
Compound 26
M=302g/mol p-Thiosalicin
4-Hydroxymethyl-phenyl-1 '-thio-β-D-glucopyranoside