MXPA01005176A - Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation - Google Patents
Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferationInfo
- Publication number
- MXPA01005176A MXPA01005176A MXPA/A/2001/005176A MXPA01005176A MXPA01005176A MX PA01005176 A MXPA01005176 A MX PA01005176A MX PA01005176 A MXPA01005176 A MX PA01005176A MX PA01005176 A MXPA01005176 A MX PA01005176A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- phenyl
- chloro
- methyl
- pharmaceutically acceptable
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 15
- 210000000329 Myocytes, Smooth Muscle Anatomy 0.000 title abstract description 17
- 239000003112 inhibitor Substances 0.000 title abstract description 10
- 230000004663 cell proliferation Effects 0.000 title abstract description 9
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 title description 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 257
- 239000011780 sodium chloride Substances 0.000 claims description 186
- 150000003839 salts Chemical class 0.000 claims description 185
- 150000001875 compounds Chemical class 0.000 claims description 169
- -1 3-acetylamino-4-chloro-benzoyloxy Chemical group 0.000 claims description 151
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 124
- 238000000034 method Methods 0.000 claims description 98
- 125000000217 alkyl group Chemical group 0.000 claims description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 72
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 72
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 45
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 42
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 40
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 125000002252 acyl group Chemical group 0.000 claims description 36
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 33
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 30
- 150000002148 esters Chemical class 0.000 claims description 27
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 20
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 239000005711 Benzoic acid Substances 0.000 claims description 12
- 125000005252 haloacyl group Chemical group 0.000 claims description 12
- 150000004702 methyl esters Chemical class 0.000 claims description 11
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N P-Anisic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 claims description 10
- 235000001968 nicotinic acid Nutrition 0.000 claims description 10
- 239000011664 nicotinic acid Substances 0.000 claims description 10
- 229960003512 nicotinic acid Drugs 0.000 claims description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 239000011570 nicotinamide Substances 0.000 claims description 9
- 125000004971 nitroalkyl group Chemical group 0.000 claims description 9
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 200000000008 restenosis Diseases 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 230000002792 vascular Effects 0.000 claims description 5
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000033115 angiogenesis Effects 0.000 claims description 3
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- 125000004429 atoms Chemical group 0.000 claims description 3
- PYHXGXCGESYPCW-UHFFFAOYSA-N diphenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-M pyridine-3-carboxylate Chemical compound [O-]C(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-M 0.000 claims description 3
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 132
- 238000001819 mass spectrum Methods 0.000 description 114
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- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 111
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- 239000012267 brine Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 16
- 239000000969 carrier Substances 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
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- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 10
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- 239000004480 active ingredient Substances 0.000 description 9
- 230000035755 proliferation Effects 0.000 description 9
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- HEVMDQBCAHEHDY-UHFFFAOYSA-N dimethoxymethylbenzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 4
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- 150000003138 primary alcohols Chemical group 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
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Abstract
This invention provides smooth muscle cell proliferation inhibitors of formula (I), having structure (I), wherein X, R1, R2, R3, R4, R5, R6, R7, R8 and R9 have the meaning given in the claims and description.
Description
ACCIDAL BENZYLMALTOSIDES AS SMOOTH MUSCLE CELL PROLIFERATION INHIBITORS
BACKGROUND OF THE INVENTION
This invention relates to the use of substituted 4 ', 6'-acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation and as therapeutic compositions for treating diseases and conditions which are characterized by excessive proliferation of smooth muscle such as restenosis. . All forms of vascular reconstruction such as angioplasia and venous bypass procedures carry out a response to damage that eventually leads to smooth muscle cell (SMC) proliferation and subsequently, deposition of profuse amounts of extracellular matrix. (Clowes, A. W.: Reidy, M.A. J. Vasc. Surg 1991, 13, 885). These events also have central processes in the pathogenesis of atherosclerosis (Raines EW, Ross, R. Br, Heart J. 1993, 69 (supplement), S. 30) as well as transplant arteriosclerosis (Isik, FF, McDonald, T. 0 Ferguson, M., Yamanaka, E., Gordon Am. J. Pathol, 1992, 141, 1139). In the case of restenosis after angioplasia, the solution is clinically important to control the
Ref: 129138 proliferation of SMC through pharmacological intervention have remained elusive to date (Herrman, J. P. R., Hermans, R.M., Vos, J., Serruys P., Drugs 1993, 4, 18 and 249). Any successful approach for the inhibition of selective SMC proliferation should not interfere with endothelial cell repair or the normal proliferation and function of other cells (eissberg, PL, Grainger, DJ, Shanahan CM, Metcalfe, JC, Cardiovascular Res. , 27, 1191). The glycosaminoglycans heparin and heparin sulfated are endogenous inhibitors of SMC proliferation, although they are able to promote the growth of endothelial cells (Castellot, JJ Jr.; right, TC: Karnovsky, MJ Seminar s in Thromobosis and Hemos tas is 1987, 13, 489). However, the full clinical benefits of heparin, heparin fragments, chemically modified heparin, low molecular weight heparins, and other anionic polysaccharides that mimic heparin may be compromised due to other pharmacological abilities (excessive bleeding arising from the effects of anticoagulation in particular) coupled with heterogeneity of the various preparations
(Borman, S. Chemical and Engineering News 1993, June 28, 27). WO 96/14325 describes acylated benzyl glycosides as inhibitors of smooth muscle cell proliferation. The compounds of the present invention differ in that the substituents of the carbohydrate backbone are different. Zehavi, U.; Herchman, M. in Carbohyd. Res. 1986, 151, 371, describes 4-0-α-D-glucopyranosyl-β-D-glucopyranoside of 4-carboxy-2-nitrobenzyl which binds to a polymer for study as an acceptor in the reaction of glycogen synthase. The compounds of the present invention differ in that the substituents on the benzyl groups are different and the use (antiproliferation of smooth muscle) is different. United States Patents Numbers 5,498,775,
W096 / 14324 and US 5,464,827 describe benzyl polyanionic glycosides or cyclodextrins as inhibitors of smooth muscle cell proliferation to treat diseases and conditions which are characterized by excessive proliferation of smooth muscle. Β-cyclodextrin tetradecasulfate has been described as an inhibitor of smooth muscle cell proliferation and is an effective inhibitor of restenosis (Reilly, CF; Fujita, T.; McFall, RC; Stabilito, II; Wai-se E .; Johnson, RG Drug Development Research 1993, 29, 137). US 5019562 discloses anionic derivatives of cyclodextrins for treating pathological conditions associated with undesirable cell or tissue growth. WO 93/09790 describes antiproliferative polyanionic derivatives of cyclodextrins having at least two anionic residues per carbohydrate residues. Meinetsberger (EP 312087 A2 and EP 312086 A2) describes antithrombotic and anticoagulant properties of bis-aldone sulphated acid amides. US 4431637 describes polysulphated phenolic glycosides as modulators of the complement system. The compounds of the present invention differ from all those of the prior art in that the compounds (a) are benzylesterolamides which have no structural similarity to heparin, sulphated cyclodextrins or dimers of lactobionic sulfated acid, (b) contain at most two contiguous sugar residues
(disaccharides), (c) are of a defined structure, (d) and are not sulphated.
DESCRIPTION OF THE INVENTION
This invention provides benzyl maltosides of formula I
where X is O or S; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, pyridyl substituted with R8, furyl substituted with R8, thienyl substituted with R8 and substituted thiazolyl with R8; R2 is hydrogen, acyl of 2 to 6 carbon atoms, haloacyl of 2 to 6 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or fluoromethylcyl of 3 to 8 carbon atoms, carboalkoxyacyl from 4 to 12 carbon atoms,
R3, R4, R5 and R6 are each independently hydrogen, acyl of 2 to 7 carbon atoms, benzoyl wherein the phenyl portion is mono-, di- or trisubstituted with R8, haloacyl of 2 to 7 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 carbon atoms; R7 is hydrogen, methyl or phenyl; R8 is hydrogen, alkoyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN. -N02, halogen or -CF3;
s hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, -NHR3, -NR3R3, -NR3R14, -NHC02R14, -NHS02R14,
R10, R11 and R12 are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen, -CF3 or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halogen; R14 is alkyl of 1 to 6 carbon atoms: R15 is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or
-C02R16; . R16 is alkyl of 1 to 6 carbon atoms, benzyl, phenyl or fluorenyl; n = 0-3; p = 0.6; or a pharmaceutically acceptable salt thereof. The term "alkyl" includes both straight chain as well as branched portions. The term halogen means bromine, chlorine, fluorine and iodine. When a compound of this invention contains a group containing the same portion more than once (ie, when R9 is -NR3R3), each of the portions may be the same or different. The pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric. , methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic and acceptable acids known in a similar manner. The salts can also be formed from organic and inorganic bases, preferably alkali metal salts, for example sodium, lithium or potassium. The acid addition salts can be prepared when Y is nitrogen or the compound of formula I contains a basic nitrogen and the acid addition salts can typically be prepared when the compound of formula I contains a hydroxyl group. The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and therefore may generate optical isomers or diastereomers. Although shown irrespective of the stereochemistry in formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and separated stereoisomers, enantiomerically pure R and S; as well as other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof. Preferred compounds of this invention are benzyl maltosides of the formula I
where X is O or S; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, pyridyl substituted with R8, furyl substituted with R8, thienyl substituted with R8 and substituted thiazolyl with R8;
R2 is hydrogen, acyl of 2 to 6 carbon atoms, carboalkoxyacyl of 4 to 12 carbon atoms,
R3, R4, R5 and R6 are each independently hydrogen or acyl of 2 to 7 carbon atoms; R7 is hydrogen, methyl or phenyl;
R8 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of
1 to 6 carbon atoms, phenyl, -CN. -N02, halogen or -CF3; R9 is hydrogen, -N02, halogen, -CF3, -NHR3, -NR3R3, -NR3R14,
-NHC02R14, -NHS02R14,
R10, R11 and R12 are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of
1 to 6 carbon atoms, -CN, -N02, halogen, -CF3 or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halogen; R 14 is alkyl of 1 to 6 carbon atoms; R15 is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or -C02R16; R16 is alkyl of 1 to 6 carbon atoms, benzyl, phenyl or fluorenyl; n = 0-3; p = 0.6; or a pharmaceutically acceptable salt thereof. The most preferred compounds of this invention are benzyl maltosides of formula I
where X is O; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, or pyridyl substituted with R8; R2 is hydrogen, acyl of 2 to 6 carbon atoms, carboalkoxyacyl of 4 to 12 carbon atoms,
R3, R4, R5 and R6 are each independently hydrogen or acyl of 2 to 7 carbon atoms; R7 is hydrogen; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, -CN or halogen; R9 is hydrogen, -N02, halogen, -CF3, -NHR3, -NR3R3, -NR3R14,
-NHC02R14, -NHS02R14,
R10, R11 and R12 are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms carbon or halogen; R14 is alkyl of 1 to 6 carbon atoms: R15 is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or
- COJÍR1 R is is alkyl of 1 carbon atoms f luorenilo; n = 0-3;
p = 0-6; or a pharmaceutically acceptable salt thereof. The specifically preferred compounds of this invention are: N-. { 2-chloro-5 - [(4 ', 6' -0-ethylidene) -β-D-maltosyloxymethyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [5- [[[6-0-benzoyl-4-0- (4,6-o-ylidene-α-glucopyranosyl) -β-D-glucopyranosyl] oxy] methyl] -2- chlorofenyl] acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[2, 3-di-0-acetyl-6-0-benzoyl-4-0 ~ (2,3-di-0-acetyl-4,6 -O-ethylidene-α-D-glucopyranosyl) - β-D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; N-. { 2-Chloro-5- [(4 ', 6' -O-propylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(6-0-Benzo-4 ', 6'-O-propylidene-β-D-maltosyl] -oxido-methyl] -2-chloro-f-enyl] acetamide or a pharmaceutically acceptable salt thereof; N- (5- { [4 ', 6'-0-benzylidene-6-0- (4-toluensulfonyl) -β-D-maltosyl}.,. -oxy-methyl] -2-chloro-phenyl] acetamide or a pharmaceutically acceptable salt thereof;
N- (5- { [2,3,2 ', 3'-tetra-0-acetyl-4', 6'-O-benzylidene-6-O- (4-toluenesulfonyl) - ß-D-maltosyl .}. -oxi-methyl.} -2-chloro-phenyl) acetamide or a pharmaceutically acceptable salt thereof; N-. { [(6-0-benzyl-4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(6-0-benzyl-4 ', 6'-O-ethylidene-β-D-maltosyl] -oxo-methyl] -2-chloro-phenyl] acetamide or a pharmaceutically acceptable salt thereof; - (2-chloro-5- { [4,6 '-O- (-nitro) -benzylidene-β-D-maltosyl] -oxi-methyl} - phenyl) -acetamide or a pharmaceutically acceptable salt thereof same; N- (5- { [6-0-benzo-4 *, 6 '-O- (4-nitro) -benzylidene-β-D-maltosyl] -oxy-methyl] -2-chloro-phenyl .) - acetamide or a pharmaceutically acceptable salt thereof: N- [2-chloro-5- [(4 ', 6' -O- (4-chloro) -benzylidene-β-D-maltosyl) -oxi-methyl ] - phenyl.} .acetamide or a pharmaceutically acceptable salt thereof: N-. {5- [6-0-benzoyl-4 ', 6' -O- (4-chloro) -benzylidene-β-D- maltosyl) -oxi-methyl] -2-chloro-phenyl] -acetamide or a pharmaceutically acceptable salt thereof: N-. {2-chloro-5- [(4 ', 6' -O-isobutylidene-β -D-maltosyl) -oxi-methyl] -phenyl.}. -acetamide or a pharmaceutically acceptable salt thereof;
N-. { 5- [(6-0-benzoyl-4 ', 6'-O-isobutylidene-B-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(', 6' -O- ((IR) -2-phenyl-ethylidene) -β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(6-0-Benzoyl-4 ', 6' -O- ((IR) -2-phenyl-ethylidene) -β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 2-Chloro-5- [(4 ', 6' -O- (IR) -3-cyano-propylidene) -β-D-maltosyloxy) -methyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5-. { [6-0-benzoyl-4 ', 6' -O- ((IR) -3-cyanopropylidene) -β-D-maltosyloxy] methyl-2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 2-Chloro-5- [(4 ', 6' -O- ((IR) -3-ethoxy-propylidene) -β-D-maltosiloxy) -met-il] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5-. { [6-0-benzoyl-4 ', 6' -O- ((IR) -3-ethoxypropylidene) -β-D-maltosyloxy] -methyl} -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N- (2-chloro-5 { [4 ', 6' -O- (4-pyridinmethylidene) -β-D-maltosyl] -oxi-methyl} - phenyl) -acetamide or a pharmaceutically acceptable salt of the same;
6- (3-Acetylamino-4-chloro-benzoyloxy) -3- (7,8-dihydroxy-2-pyridin-4-yl-hexahydro-pyran [3.2-d] [1, 3] dioxin-6-yloxy) ester ) -4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl benzoic acid; N-. { 5- [(4,6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6' -O-benzylidene-2,2 ', 3,3', 6-penta-O-acetyl-β-D-maltosyl-oxy) -methyl] -2-chloro-f-enyl } -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosiloxy) -met-il] -2-chloro-phenyl} acetamide or a pharmaceutically acceptable salt thereof; (R) -N- (2-chloro-5- [[[2, 3-di-0-acetyl-6-0-benzoyl-4-0- [2,3-di-0-asethyl-4,6 -0- (f-enylmethylene) -aD-glucopyranosyl] -oxy] methyl] -phenyl] acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[6-0- ( 5-methoxy -1,5-dioxopentyl) -4-0- [4,6-0- (phenylmethylene) -aD-glucopyranosyl] -β-D -glucopyranosyl] oxy] methyl] -phenyl] acetamide or a pharmaceutically acceptable salt 4-chloro-3-n-tro-benzyl-, 6 '-O-benmylidene-β-D-maltoside or a pharmaceutically acceptable salt thereof;
4-chloro-3-nitro.benzyl-6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltoside or a pharmaceutically acceptable salt thereof; (R) - (4-chloro-3-nitrophenyl) methyl-2,3-di-0-acetyl-6-0-benzoyl-4-O- [2,3-di-0-acetyl-4,6- 0- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranoside or a pharmaceutically acceptable salt thereof; 6- (4-chloro-3-nitro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydropyran [3,2-d] [1,3] dioxin-6-yloxy) -4,5- ester dihydroxy-tetrahydro-pyran-2-ylmethyl nicotinic acid or a pharmaceutically acceptable salt thereof; 4- [2,3-di-0-acetyl-4,6-0- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranoside 2,3-diacetate 6- (3-pyridinecarboxylate) of (R) - (4 -chloro-3-nitrophenyl) methyl or a pharmaceutically acceptable salt thereof; 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexane-pyran [3.2-d] [1.3] dioxin-6-yloxy) -4.5- ester dihydroxy-tetrahydropyran-2-ylmethyl 4-methoxybenzoic acid or a pharmaceutically acceptable salt thereof; 4, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3 - (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-d] [1, 3] dioxin-6 ester -l yloxy) -tetrahydro-pyran-2-ylmethyl of 4-methoxy-benzoic acid; 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3.2-d] [1,3] dioxin-6-yloxy) -4 ester 5-Dihydroxy-tetrahydropyran-2-ylmethyl 4-chloro-benzoic acid or a pharmaceutically acceptable salt thereof; 4-, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3 - (7,8-diacetoxy-2-pheny1-hexahydro-pyran [3.2-d] [1.3] dioxin-6-yloxy) ester ) -tetrahydro-pyran-2-ylmethyl of -chloro-benzoic acid or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[6-0- (4-chloro-3-nitrobenzoyl) -4-0- [4,6-0- (phenylmethylene) -aD-glucopyranosyl] b -D-glucopyranosyl] oxy] methyl] -phenylacetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(2,2 ', 3, -tri-0-acetyl-6-0- (4-chloro-3-nitrobenzoyl) -4', 6 '-O- (benzylidene) -β-D-maltoside Oxymethyl] -2-chloro-phenyl) -acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[6-0- (4-cyanobenzoyl) -4-0- [4,6-0- (f -enylmethylene) -α-D-glucopyranosyl] -β] -D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[6-0- (4-nitrobenzoyl) -4-0- [4,60- (f-enylmethylene) -α-D -glucopyranos]] - ß - D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[6-0- (3-trifluoromet-ilbenzoyl) -4-O- [4,60- (phenylmethylene) -aD-glucopyranosyl] -β-D- glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6' -0-benzylidene-6-0- (2-iodo) -benzoyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl) -acetamide or a pharmaceutically salt acceptable thereof; N-. { 5- [(4 ', 6' -0-benzylidene-6-0- (3-iodo) -benzoyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6' -0-benzylidene-6- (4-iodo-benzoyl) -oxy-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [-2-chloro-5- [[[6-0- (phenylacetyl) -4-0- [4,6-0- (phenylmethylene) -α-D-glucopyranosyl] -β-D -glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[2, 3-di-O-acetyl--O- [2,3-di-O-acetyl-4, 6, 0- (phenylmethylene) - α-D-glucopyranosyl] -6-0- (phenylacetyl) -β-D-glucopyranosyl] -oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6'-O-benzylidene-6-O-phenyl-ethyl-carboxyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6' -0-benzylidene-6-0-phenyl-propyl-carboxyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof;
6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl) -hexahydro-pyranol [3,2-d] [1,3] dioxin-6-yloxy) -4 ester , 5-dihydroxy-tetrahydro-pyran-2-ylmethyl of the dif-enyl-acetic acid or a pharmaceutically acceptable salt thereof; ester, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-d] [1, 3] dioxin-6-) iloxy) tetrahydro-pyran-2-ylmethyl of the diphenyl-acetic acid or a pharmaceutically acceptable salt thereof; 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3,2-d] [1,3] dioxin-6-yloxy) -4 ester 5-Dihydroxy-tetrahydro-pyran-2-ylmethyl (3,4-dimethoxy-phenyl) -acetic acid or a pharmaceutically acceptable salt thereof; 4, 5-diacetoxy-6 - (3-acetylamino-4-chloro-benzyloxy) -3 - (7, 8 -di-ac-ethoxy-2-phenyl-hexahydro-pyran [3,2-d] [1,23] ester ] dioxin-6-yloxy) -tetrahydro-pyran-2-ylmethyl acid
(3,4-dimethoxy-f-enyl) -acetic acid or a pharmaceutically acceptable salt thereof; 6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenylhexahydro-3-cyano [3,2-d] [1, 3] dioxin-6-yloxy) -4 ester 5-dihydroxy-tetrahydro-pyran-2-ylmethyl nicotinic acid acid or a pharmaceutically acceptable salt thereof;
4-, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-d] [1, 3] dioxin-6-ester) -iloxy) -tetrahydro-pyran-2-ylmethyl of nicotinic acid or a pharmaceutically acceptable salt thereof; (R) -N- [5- [[[6-0- (4-benzoylbenzoyl) -4-0- [4,6-0- (f enylmethyl) -α-D-glucopyranos]] β-D -glucopyranosyl] oxy] methyl] -2-chlorofenyl] acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6'-O-benzylidene-β-maltosyl) -oxy-methyl] -2-methyl-phenyl] -acetamide or a pharmaceutically acceptable salt thereof; N-acetyl-. { 5- [(2,2 ', 3,3', 6 -penta -O-acetyl-4-, 6'-0-benzylidene-β-D-maltosyl) -oxy-methyl] -2-methyl-f-enyl } acetamide or a pharmaceutically acceptable salt thereof; N- (5- { [4 ', 6'-0-benzylidene-6-0- (4-toluensulf onyl) -β-D-maltosyl] -oxy-methyl.} -2-methyl-phenyl ) -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6' -0-benzylidene-6-0-phenyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [2-chloro-5- [[[4-0- [4 •, 6 '-O- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] phenyl] - 3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof;
(R) -N- [5- [[[6-0-benzoyl-4-0- [4 ', 6' -O- (phenylmethylene) -a-D-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] -2-chlorophenyl] -3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof; . { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} furan-2-carboxylic acid amide or a pharmaceutically acceptable salt thereof; . { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} furan-2-carboxylic acid amide or a pharmaceutically acceptable salt thereof; N-. { 2-Chloro-5- [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -pent-4-enamide or a pharmaceutically acceptable salt thereof; N-. { 2-Chloro-5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -pent-4-enamide or a pharmaceutically acceptable salt thereof; 5- (6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxi-methyl-2-chloro-phenylamine or a pharmaceutically acceptable salt thereof; (4-chloro) -benzyl-4 ', 6'-benzylidene-β-D-maltoside or a pharmaceutically acceptable salt thereof; 1-0- (4-chloro) -benzyl-4 ', 6'-0-benzylidene-6-deoxy-β-D-malto-6-yl ester of benzoic acid;
4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} benzamide or a pharmaceutically acceptable salt thereof; 4-benzoyl-N- amide. { 5- [(6-benzoyl-oxy-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzoic acid or a pharmaceutically acceptable salt thereof; 4-benzoyl-N-. { 5- [(4 ', 6' -0-benzylidene-6-0- (2-iodo) -benzoyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzamide or a pharmaceutically acceptable salt thereof; 4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-6-O- (3-iodo-benzoyl) -β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzamide or a pharmaceutically acceptable salt thereof; 4-benzoyl-N- amide. { 5- [(4 ', 6'-O-benzylidene-6- (4-iodo-benzoyl) -oxy-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzoic acid or a pharmaceutically acceptable salt thereof; 9H-Fluoren-9-ylmethyl ester of (L-. {5 - [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenylcarbamoyl}. ethyl) -carbamic or a pharmaceutically acceptable salt thereof; N- (9H-fluoren-9-ylmethoxycarbonyl) -N '-. { 5- [(6-0-benzoyl- ', 6' -O-benzylidene-β-D-maltosyl) -oxi-methyl] -2-chloro-phenyl} -L-alaninamide or a pharmaceutically acceptable salt thereof;
N '-. { 5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -L-alaninamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -N-methyl acetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -N-methylacetamide or a pharmaceutically acceptable salt thereof; Methyl ester of N- acid. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl] -carbamic acid or a pharmaceutically acceptable salt thereof; Methyl ester of N- acid. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -carbamic or a pharmaceutically acceptable salt thereof; Methyl ester of N- acid. { 5- [(6-0- (3-benzyl-l-oxo-propyl) -4 ', 6'-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl] -carbamic acid or pharmaceutically acceptable salt thereof, - N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -metanesulfonamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-cyano-phenyl} -acetamide or a pharmaceutically acceptable salt thereof;
N-. { 5- [(6-Benzoyl-4 *, 6 '-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-methyl-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; 6- [6- (4-chloro-3-nitro-benzylsulfanyl) -4,5-dihydroxy-2-hydroxymethyl-tetrahydropyran-3-yloxy] -2-phenyl-hexahydro-pyran [3.2-d] [1, 3 ] dioxin-7,8-diol or a pharmaceutically acceptable salt thereof; 6-0-benzoyl-4 ', 6'-0-benzoyl-4', 6'-O-beylidene-1-thio-β-D-maltoside or a pharmaceutically acceptable salt thereof. The compounds of this invention are prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. This reaction scheme shows the preparation of representative compounds of this invention. Acetobromomaltose 1 is coupled with benzyl alcohol 2 in the presence of a catalyst such as mercuric bromide, mercuric cyanide, silver triflate or silver perchlorate in an aprotic solvent such as acetonitrile, dichloromethane, ether, toluene or nitromethane at temperatures varying from - 40 ° C to reflux temperature to provide glycoside 3 (Reaction Scheme 1). This glycosidation can also be carried out using the coupling of Schmidt's trichloroacetimidate, with zinc bromide in a solvent such as dichloromethane. The reduction of the nitro group of 3 can be carried out with a reducing agent such as stannous chloride in a polar aprotic solvent such as ethyl acetate at room temperature to reflux to provide the aniline compound 4. The coupling of 4 with a The acid may be completed in the presence of an amine base such as triethylamine or diisopropylethylamine or using a stronger base such as sodium hydride (for sterically hindered systems) in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from 0 ° C to the room temperature to provide the objective compound 5. The peracetylated compound 5 can be converted to the heptahydroxy compound 6 with catalytic sodium methoxide in methanol or aqueous sodium hydroxide in methanol at temperatures ranging from room temperature to reflux. As illustrated in Reaction Run 2, an acetal (7) is formed at positions C-4 ', 6' of the disaccharide of the heptahydroxy compound 6 using an appropriate dimethyl or diethylacetal aldehyde and a source of acid such as p-acid. toluenesulfonic monohydrate or camphorsulfonic acid in a polar aprotic solvent such as N, -dimethylformamide at 60 ° C. In difficult cases, an aldehyde and sulfuric acid in DMF can be used at higher temperatures to obtain the acetyl product. In this point, the primary alcohol in position 6 is acylated selectively using an acid chloride in a 1: 1 mixture of tetrahydrofuran and the hindered base 2, 4, 6-collidine at -40 ° C initially to room temperature overnight to generate compound 8. The remaining four disaccharide secondary alcohols can then be protected with acetic anhydride and triethylamine in a solvent such as dichloromethane to provide peracetylated compound 9. On the other hand, acetal 7 can first be converted to a tosylate using tosyl chloride and pyridine in a solvent such as dichloromethane (Reaction Scheme 3); the resulting intermediate is then peracyl as mentioned above to generate compound 10. Through the total displacement of the tosylate at position 6 (formation of alcohol with sodium formate followed either by formation of benzyl 2, 2-trichloroacetimidate), an ether bond is incorporated in this site in the molecule. The benzylidene acetal is then removed under strongly acidic conditions such as 1M etheral HCl to provide compound 11. A new acetal is then formed at the C-4 ', 6' positions using the above-mentioned conditions or only one aldehyde and the source of acid in benzene at elevated temperature (60 ° C). Finally, the four secondary acetates are removed with sodium methoxide in methanol or aqueous sodium hydroxide in methanol at temperatures ranging from room temperature to reflux to obtain the hydroxy compound 12.
Reaction Scheme 1
reduction
acylation If R2 = Bz, then:
Reaction Scheme 2
C-6 acylation
Yes R2 = Bn, then:
Reaction Scheme 3
er such
acetal
The compounds of this invention are useful as antiproliferative agents. The following procedures show the evaluation of the representative compounds of this invention in a standard pharmacological test procedure which measures the ability of the evaluated compound to inhibit the proliferation of smooth muscle cells.
Effects of the Compounds on Cell Proliferation Using 3H Thymidine Incorporation
Human and porcine smooth muscle cells are tested in an early passage (generally passage 3-7) under subconfluence conditions. The cultures are grown in 16-mm multiple well culture dishes (24 wells) in medium 199 supplemented with 10% fetal bovine serum and 2% antibiotic / antimicrobial. In the subconfluence, the cells are placed in a defined serum-free medium (AIM-V, Gibco) for 24-48 h before initiating the experimental protocol. Although it has been found that the compounds are more effective with longer preincubations, in general, the procedures are. begin with the addition of the compound, 3H-thymidine and serum / growth factor for synchronized cells lacking serum and the results are presented accordingly. The compounds are added to each well in a 50-fold dilution (20 μl / well) and the plates are incubated for 24-36 h at 37 ° C in 5% C02. The compounds initially dissolve in 50% ethanol and are diluted serially in medium. The compounds are evaluated systematically at concentrations of 1 to 100 μM. As a control, heparin of porcine intestinal mucosa grade II (sodium salt) is systematically evaluated in all cell preparations at concentrations of 0.1 to 100 μg / ml. Upon completion of the test procedure, plates are placed on ice, washed three times with ice-cold phosphate buffered saline (PBS) and incubated in ice-cold 10% trichloroacetic acid (TCA) for 30 minutes to remove proteins. soluble in acid. The solution is transferred to scintillation flasks containing 0.4 N HCl (500 μl / bottle to neutralize NaOH) and each well is rinsed twice with 500 μl of water for a total volume of 2 ml / vial. The data is obtained in triplicate for both control and experimental samples. Control data (100%) are obtained from maximally stimulated cells, as a result of growth factor or serum stimulation. Experimental data are obtained from cells maximally stimulated with growth factor or serum and treated with compound. The data are expressed as IC50 or percent inhibition in Table I below.
Table 1
a a with inuaci n
The compounds of this invention are useful for treating or inhibiting diseases which are characterized by excessive proliferation of smooth muscle cells.
(hyperproliferation of smooth muscle cells). The compounds are particularly useful for treating hyperproliferative vascular diseases which are characterized by hyperproliferation of smooth muscle cells, such as restenosis, which arise more frequently from vascular reconstructive surgery and transplantation, eg balloon angioplasty, vascular graft surgery , coronary artery bypass surgery and cardiac transplant. Other disease states in which there is "unwanted" cell proliferation include hypertension, asthma and congestive heart failure. The compounds of this invention are also useful as inhibitors of angiogenesis. Angiogenesis (neovascularization), the process by which new capillaries are formed, is of fundamental importance for numerous pathological processes that include chronic inflammation and malignant cancer processes. Therefore, the compounds of this invention are useful as antineplasic agents.
The compounds of this invention can be formulated pure or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard or conventional pharmacological practice. The pharmaceutical carrier can be a solid or a liquid. A solid carrier may include one or more substances which also act as flavoring agents, lubricants, solubilizers, suspension improving agents, fillers, fluidizers, compression aids, binders or tablet disintegrating agents; It can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with a finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the size and shape desired. The powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, waxes with a low melting point and exchange resins. ionic. Liquid carriers are used for the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water or an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspension improving agents, thickening agents, colors, viscosity regulators, stabilizers and osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (which partially contains additives as in the above, for example cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, lecithins and oils (for example fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in compositions in sterile liquid form for parenteral administration. The liquid carrier for pressurized compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be given intravenously. The compounds of this invention can also be administered orally in either a liquid or a solid composition form. The compounds of this invention can be administered rectally or vaginally in the form of a conventional suppository. For administration by inhalation or intranasal or intrabronchial insufflation, the compounds of this invention can be formulated in an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally by the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is not toxic to the skin and allows the delivery of the agent for systemic absorption within the body. the bloodstream via the skin. The carrier can take many of the forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be a viscous liquid or semi-solid emulsions either oil-in-water or water-in-oil type. Pastes made of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. Various occlusive devices can be used to release the active ingredient into the bloodstream such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. Dosage requirements vary with the particular compositions used, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in standard pharmacological test procedures, the daily dosages presented of the active compound would be 0.1 to 10 mg / kg administered parenterally (preferred intravenously) with a projected daily oral dosage of approximately 10 times greater. Early intravenous administration can last for approximately 5-30 days after acute vascular damage (ie, balloon angioplasty or transplantation) and for a longer duration for the treatment of chronic disorders. The treatment will usually begin with dosages less than the optimum dose of the compound. Subsequently the dosage is increased until the optimum effect is reached under the circumstances; The precise dosages for oral, parenteral, nasal or intrabronchial administration will be determined by the doctor performing the administration based on the experience with the individual subject treated. Preferably, the pharmaceutical composition is in a unit dosage form, for example as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage forms may be packaged compositions, for example packaged powders, flasks, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The following provides the preparation of representative compounds of this invention.
EXAMPLE 1
N-. { 2-Chloro-5- \ (4 ', 6' -O-ethylidene) -β-D-maltosyloxymethyl] -phenyl} -acetamide
Stage 1
4-Chloro-3-nitro-benzyl-β-D-maltoside heptaacetate To a stirred solution of 4-chloro-3-nitrobenzyl alcohol (6.70 g, 35.7 mmol) and HgBr2 (14.2 g, 39.3 mmol) in 239 ml of Freshly distilled CH3CN is added, in one portion, Hg (CN) 2 (9.02 g, 35.7 mmol). After 0.5 h, acetobromomaltose (25.0 g, 35.7 mmol) is added and the mixture is stirred for 18 h at room temperature (rt). Subsequently the reaction is suspended with a mixture of H20: brine (1: 1, 100 ml) and extracted with CH2C12 10% CH2C12: EtOAc. The combined organic extracts are dried with MgSO 4 and concentrated. Purification by flash chromatography (10:90 to 80:20 gradient of EtOAc: petroleum ether) gives 51.9 g (90%) of the title compound as a glassy oil which recrystallizes from Et20: petroleum ether to provide a white solid - vitreous, pf 107-111 ° C; XH NMR (CDC13) d 2.00 (s, 3H), 2.02 (s, 3H), 2.03, (s, 3H), 2.04 (s, 6H), 2.11 (s, 3H), 2.15 (s, 3H), 3.70 (ddd, J = 2.9, 4.2, 9.7 Hz, ÍH), 3.94-3.98 (m, ÍH), 4.01-4.07 (m, 2H), 4.20-4.28 (m, 2H), 4.54 (dd, J = 2.9, 12.3 Hz, ÍH), 4.63-4.68 (m, 2H), 4.84-4.94 (m, 3H), 5.06 (t, J = 10.1 Hz, ÍH), 5.26 (t, J = 9.2 Hz, ÍH), 5.36 ( dd, J = 9.7, 10.3 Hz, 1H), 5.42 (d, J = 4.2 Hz, HH), 7.43 (d, J = 2.2, 8.3 Hz, HH), 7.53 (d, J = 8.3 Hz, HH), 7.83 (d, J = 2.0 Hz, ÍH); IR (KBr) 3450, 2950, 1755, 1550, 1375, 1230 and 1050 cm "1; mass spectrum [(+) ESI], m / z 823/825 (M + NH4 +), 828/830 (M + Na ) +; / Analysis Calculated for C35H40ClNO20: C, 49.17; H, 5.00; N, 1.74, Found: C, 49.16; H, 4.88; N, 1. 71.
Stage 2
2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine
A solution containing 4-chloro-3-nitro-benzyl-β-D-maltoside heptaacetate (19.3 g, 23.9 mmol) and tin (II) chloride dihydrate (37.7 g, 167 mmol) in 479 mL of EtOAc is subjected to reflux for 2 h. The reaction is cooled to rt
(room temperature), carefully suspended with saturated aqueous NaHCO3 (until it becomes basic), diluted with
250 ml of EtOAc, stir for 0.5 h and filter. The biphasic filtrate is separated and the aqueous phase is extracted with
EtOAc. The combined organic extracts are dried with Na 2 SO 4 and concentrated. Purification by flash chromatography
(gradient from 0 to 12% acetone / CHCl 3) gives 17.8 g 96 ^) of 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine as a glassy solid, m.p. 78-79 ° C; 1 H NMR (CDC13) d 2.00 (s, 9H), 2.026 (s, 3H), 2.032 (s, 3H), 2.11, 3H), 2.16
(s 3H), 3.00-5.00 (s broad, 2H), 3.64-3.68 (m, ÍH), 3.97 (ddd,
J = 2.4, 4.2, 10.1 Hz, HH), 4.024.07 (m, 2H), 4.24 (dd, J =
2. 2, 3.7. ÍH), 4.27 (dd, J = 2.6, 4.0 Hz, 1H), 4.50-4.57 (m, 3H), 4.74 (d, J = 12.1 Hz, ÍH), 4.83-4.90 (m, 2H), 5.05 (t , J = 10.1 Hz, 1H), 5.22 (t, J = 9.2 Hz, ÍH), 5.35 (dd, J = 9.7, 10.5 Hz, ÍH), 5.42 (d, J = 4.0 Hz, ÍH), 6.62 (dd) , J = 2.0, 8.1 Hz, 1H), 6.76 (d, J = 2.0 Hz, ÍH), 7.21 (d, J = 8.1, ÍH); IR (KBr) 3450, 3350, 2950, 1755, 1650, 1425, 1375, 1230 and 1050 cm "1; mass spectrum [(+) ESI], m / z 776/778 (M + H) +, 798 / 800 (M + Na) +; Analysis calculated for C35H42C1N018; C, 51.07; H, 5.45; N, 1.80, Found: C, 50.94; H, 5.52; N, 1.60.
Stage 3
N- [2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenyl] -acetamide
To a stirred solution of 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine (20.6 g, 26.5 mmol) and triethylamine (8.13 ml, 58.3 mmol) in 265 ml of THF a 0 ° C acetyl chloride (2.26 ml, 31.8 mmol) is added dropwise.
After 0.5 h at this temperature, heat to rt and stir for an additional 6 h. At this point, the reaction is concentrated and taken up in 700 ml of EtOAc. This organic solution is washed with 70 ml of 1N HCl, 70 ml of saturated aqueous NaHCO 3 and
70 ml of brine and then dried with MgSO4. After concentration, the residue is purified by flash chromatography (gradient from 22:80 to 100: 0 EtOAc: petroleum ether) to give the product (16.2 g, 75%) as a glassy solid, m.p. 84-86 ° C XH NMR (CDC13) d 2.00 (s, 6H), 2.020
(s, 3H), 2027 (s, 3H), 2.03 (s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.24 (s, 3H). 3.66-3.69 (m, 1H), 3.94-3.98 (m, ÍH), 4.00-4.06 (m, 2H), 4.22-4.28 (m, 2H), 4.50-4.61 (m, 3H), 4.80-4.91
(m, 3H), 5.05 (t, J = 10.1 Hz, 1H), 5.22 (t, J = 9.2 Hz, ÍH), 5.35 (dd, J = 9.4, 10.5 Hz, ÍH), 5.41 (d, J 4.0 Hz, ÍH), 6.99
(dd, J = 2.0, 8.1 Hz, ÍH), 7.34 (d, J = 8.1 Hz, ÍH), 7.62 (s, ÍH), 8.32 (s, ÍH); IR (KBr) 3400, 2950, 1750, 1690, 1600, 1540, 1425, 1375, 1230 and 1050 cm "1; mass spectrum [(+) ESI], m / z 818/820 (M + H) \ 840 (M + Na) +; Analysis calculated for C35H44C1N019: C, 51.38; H, 5.42; N, 1.71, Found: C, 51.03; H, 5.36; N, 1.59.
Stage 4
N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl) -acetamide
A solution containing N- [2-chloro-5-hepta-0-acetyl-β-D-maltosyloxymethyl) -phenyl] -acetamide (0.945 g, 1.12 mmol) and 25% by weight of NaOMe in MeOH (19.2 μl, 0.036 mmol) in -27.6 ml of MeOH, refluxed for 2.5 h. The reaction is cooled to room temperature and concentrated, and the resulting residue is triturated with Et20 to provide the product (0.583 g, 99%) as a foam; XH NMR (DMSO-d6) d 2.07 (s, 3H), 3.03-3.16 (m 2H), 3.19-3.49 (m, 7H), 3.55-3.62 (m, 2H), 3.67-3.73 (m, ÍH), 4.28 (d, J = 7.7 Hz, ÍH), 4.33-5.76
(s broad, 7H), 4.67 (ABc, J = 12.5 Hz,? d = 0.22, 2H), 5.01
(d, J = 3.7 Hz, ÍH), 7.21 (dd, J = 1.8, 8.1 Hz, ÍH), 7.44 (d,
J = 8.1 Hz, ÍH), 7.64 (d, J = 1.5 Hz. ÍH), 9.33-9.69 (s broad, ÍH); IR (KBr) 3400, 2900, 1680, 1600, 1540, 1430, 1375,
1310, 1150 and 1035 cm "1, mass spectrum [(+) ESI], m / z 524/526
(M + H) +, 546 (M + Na) +; Analysis calculated for C21H30ClNO12 1.0
MeOH: C, 47.53: H, 6.16. N, 2.52. Found: C. 47.94; H,
6. 3. 4; N, 2.42.
Stage 5
N-. { 2-chloro-5- [(41, 6 • -O-ethylidene-D-maltosiloxy -me il] -phenyl.} Acetamide
To a stirred solution of N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide (0.500 g, 0.954 mmol) in 12.5 ml of DMF at rt is added acetaldehyde dimethylacetal drops ( 0.202 mL, 1.91 mmol) followed by TsOH.H20 (0.0907 g, 0.477 mmol). The reaction mixture is heated at 60 ° C for 6 h and then suspended with K2C03 (0.0659 g, 0.477 mmol) and with additional heating of 0.5 h at this temperature. At this point, the solution is filtered hot and the solvent is removed by distillation using high vacuum. The residue is purified by flash chromatography (80: 2: 1 EtOAc: EtOH: H2O) to give the product (0.323 g, 62%) as an off-white powder, m.p. 144-146 ° C: XH NMR (DMSO-d6) d 1.22 (d, J = 5.1 Hz, 3H), 2.07 (s, 3H, 3.05-3.11 (m, ÍH), 3.11 (t, J = 9.4 Hz, 1H), 3.25-3.37 (m, 3), 3.39-3.58 (m, 5H), 3.65-3.71 (m, ÍH), 3.92 (dd, J = 4.8, 9.9 Hz, 1H), 4.28 (d, J = 7.7 Hz, 1H), 4.65
(t, J = 5.7 Hz, ÍH), 4.67 (ABc, J = 12.3 Hz,? d = 0.22, 2H), 4.69 (d, J = 4.8, 9.9 Hz, ÍH), 5.09 (d, J = 4.0Hz , ÍH), 5.23
(t, J = 5.7 Hz, 2H), 5.47 (d, J = 3.5 Hz, HH), 5.57 (d, J = 6.6 Hz, ÍH), 7.22 (dd, J = 1.8, 8.3 Hz HH), 7.44 (d, J = 8.3 Hz, ÍH), 7.65 (s, ÍH), 9.52 (s, ÍH): IR (KBr) 3400, 2910, 2880. 1675, 160O, 1535. 14550, 1420, 1375. 1310. 1150, 1120, 1060, and 1020 cm "1. mass spectrum [(+), FAB], m / z 550/552 (M + H) ', 572/574 (M + Na) + -. Analysis calculated for C23H32ClN012
. 1.0 H20: C, 48.64: H. 6.03; N, 2.47. Found C, 48.55. H. 5.90: N, 2.41.
Example 2
(R) -N- [5-1-R6-0-benzoyl-4-0- (4,6-O-ethylidene-a-D-glucopyranosyl) -β-D-glucopyranosyl] oxylmethyl-2-chlorofenyl] acetamide
To a stirred solution of N-. { 2-Chloro-5- [(4 ', 6' -0-ethylidene) -β- (...) methyl] phenyl} acetamide (0.323 g, 0.587 mmol) in 4.0 ml of THF at -40 ° C collidine (4.0 ml, 30.3 mmol) is added dropwise, followed by the dropwise addition of BzCl (0.818 ml, 0.704 mmol). After 2 h at this temperature, heat to rt and stir for an additional 18 h. At this point, the solvent is distilled off using high vacuum, and the residue is diluted with 200 ml EtOAc. This layer is washed with 20 ml of 1N HCl, 20 ml of saturated NaHCO 3 and 20 ml of brine, and then dried with MgSO 4. After concentration, the oily residue is purified by flash chromatography (gradient from 1% to 11% MeOH: CHCl3) and recrystallization (EtOAc: Et20) to give the product (0.209 g, 54%) as a white vitreous solid, m.p. 166-160 ° C, XH NMR (DMSO-d6) d 1.19 (d, J 5.1 Hz, 3H), 2.04 (s, 3H), 3.09 (t, J = 9.4 Hz, ÍH), 3.14-3.21 (m, ÍH), 3.27-336 (m, 2H), 3.45-3.52 (m, 2H), 3.52-3.60 (m. ÍH), 3.73 (ddd, J = 1.5, 5.1, 9.4 Hz, ÍH), 3.89 (dd, J = 4.8, 9.9 Hz, 1H), 4.30 (dd, J = 5.5, 12.1 Hz, ÍH), 4.38 (d, J = 7.7 Hz, ÍH), 4.53-4.61 (m, 2H), 4.65 (c, J = 5.1, 1H), 4.73 (d, J = 12.5 Hz, 1H), 5.07 (d, J = 4.0 Hz, ÍH), 5.28 (d, J = 5.3 Hz, ÍH), 5.34 (d, J = 5.3 Hz , ÍH), 5.55 (d, J = 2.9 Hz, 1H), 5.77 (d, J = 5.9 Hz, 1H), 7.18 (d, J = 2.0, 8.1 Hz, 1H), 7.40 (d, J = 8.1 Hz , 1H), 7.50-7.55 (m, 2H), 7.62-7.68 (m, 2H), 7.96-8.00 (m, 2H), 9.50 (s, ÍH); IR (KBr) 3450, 3360, 2990, 2910, 2860, 1725, 1750, 1600, 1520, 1450, 1420, 1385, 1260, 1230, 1130, 1110, 1075, 1055, and 1020 cm "1: mass spectrum [ (+) FAB] m / z 654/656 (M + H) +, 076/678 (M + Na) +, 692/694 (M + K) +, Analysis calculated for C C30H3SClNO13; C, 55.09; H, 5.55; N, 2.14, Found C, 54.76: H, 5.40; N, 2.00.
Example 3
(R) -N- f2-chloro-5-? \ 2, 3-di-0-acetyl-6-0-benzoyl-4-0- (2,3-di-O-acetyl-4,6-O-ethylidene-aD-glucopyranosyl) - ß-D-crlcopyranosyl oxy] methyl] f enylacetamide
a stirred solution of (R) -N- [5- [[[6-0-benzoyl-4, O-benzoyl-4-O-ethylidene-aD-glucopyranosyl) -β-D-glucopyranosyl] oxy] methyl] - 2-chlorofenyl] acetamide (0.086 g, 0.131 mmol) and triethylamine (0.161 ml, 1.15 mmol) in 6 ml of CH2C12 at rt was added dropwise acetic anhydride (0.0544 ml, 0.576 mmol) followed by a catalytic amount of DMPA ( 0.0064 g, 0.0524 mmol). After 18 h, the mixture is diluted with 200 ml of EtOAc. This layer is washed with 20 ml of 1 N HCl, 20 ml of saturated aqueous NaHCO 3 and 20 ml of brine, and then dried with Na 2 SO 4. After concentration, the residue is purified by preparative plate chromatography (10:90 MeOH: CHCl 3) to give the product (0.071 g, 66 ^) as a white material, m.p. > 87 ° C
(decomposition); NMR (DMSO-d6) d 1.13 (d, J = 4.8 Hz, 3H).
1. 92 (s, 3H), 1.95 (s, 3H). 1.97 (s, 3H), 1.99 (s, 3H), 2.05
(s, 3H), 3.31-3.39 (m, 1 H), 3.55-3.67 (m, 3H), 4.10-4.19 (m, 2H), 4.41 (dd, J = 3.1, 12.3 Hz, ÍH), 4.54 ( d, J = 12.7 Hz, 1H), 4.64-4.74 (m, 3H), 4.77 (dd, J = 8.3, 9.4 Hz, ÍH), 4.82 (dd, J = 4.0, 10.1 Hz, ÍH), 4.89 (d , J = 7.9 Hz, ÍH), 5.18 (t, J = 9.7 Hz, 1H), 5.29 (d, J = 4.2 Hz, ÍH), 5.33 (t, J = 9.0 Hz, ÍH), 7.04 (dd, J = 1.5, 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.61 (s, ÍH), 7.68 (t, J = 7.5 Hz, ÍH) ), 8.01-8.07 (m, 2H), 9.45 (s, ÍH): IR (KBr) 3410, 2940, 2850, 1755, 1690, 1590, 1530, 1440, 1420, 1370, 1240, 1135, 1060 and 1030 cm "1, mass spectrum [(+) FAB], m / z 823/824 (M + H) +) 844/846 (M + Na) +, Analysis calculated for C38H22C1N017 1.5 H20: C, 53.74; H, 5.58, N, 1.65, Found C, 53.69; H, 5.14; N, 1.57.
Example 4
N-. { 2-Chloro-5-T (4 ', 6'-O-propi 1 ide-ß-D-maltosyl.}. -oxymethyl] phenyl.} - acetamide
The title compound is prepared as a white solid (0.309 g, 57%) from N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide using propionaldehyde diethylacetal and a similar procedure to that of stage 5 of
Example 1, p.f. > 64 ° C (decomposition): XH NMR (DMSO-d6) d 0.86
(t, J = 7.5 Hz, 3H). 1.48-1.58 (m, 2H), 2.07 (s, 3 H), 3.04- 3.14 (m, 2H), 3.25-3.58 (m, 8H), 3.68 (dd, J = 6.2, 10.5 Hz, 1H), 3.95 (dd, J = 4.6, 9.9 Hz, 1H), 4.28 (d, J = 7.7 Hz, ÍH), 4.48 (t, J = 5.1 Hz, 1H), 4.65 (t, J = 5.9 Hz, 1H), 4.67 (ABc, J. = 12.5 Hz,? D = 0.22, 2H), 5.08 (d, J = 4.0 Hz, ÍH), 5.20 (d, J = 5.3 Hz, ÍH), 5.24 (d, J = 5.3) Hz, HH), 5.48 (d, J = 3.3 Hz, HH), 5.57 (d, J = 6.6 Hz, HH), 7.22 (dd, J = 1.8, 8.3 Hz, HH), 7.44 (d, J = 8.3 Hz, ÍH), 7.65 (s, ÍH), 9.52 (s, 1H), IR (KBr) 3400, 2980, 2920, 2840, 1675, 1580, 1530, 1460, 1425, 1375, 1310, 1275, 1150 , 1060, and 1020 cm "1, mass spectrum [(+) FAB], m / z 586/588 (M + Na) +: Analysis calculated for C ^ H ^ CINO ^. 1.0 H20: C, 49.53. , 6.23: N, 2.41, Found C, 49.89: H, 6.38, N, 2.19.
Example 5
N-. { 5- [(6-Q-benzoyl-4 ', 6'-O-propylidene-β-D-maltosyl}.,., -oxi-methyl] 2-chloro-phenyl] acetamide
The title compound is prepared as a white solid (0.140 g, 47%) from N-. { 2-Chloro-5- [(4 ', 6' -O-propylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -acetamide using a procedure similar to Example 2, p.f. > 88 ° C (decomposition); XH NMR (DMSO-d6) d 0.84 (t, J = 7.5 Hz, 3H), 1.45-1.57 (m, 2H), 2.04 (s, 3H), 3.08 (t, J = 5.1 Hz, ÍH), 3.17 ( dd, J = 8.3, 13.2 Hz, ÍH), 3.26-3.37 (m, 2H), 3.45-3.59 (m, 4H), 3.70-3.77 (m, ÍH), 3.91 (dd, J = 4.6, 9.7 Hz, ÍH), 4.30 (dd, J = 5.3, 12.1 Hz, ÍH), 4.38 (d, J = 7.7 Hz, ÍH), 4.43 (t, J = 4.8 Hz, 1H), 4.53-4.61 (m, 2H), 4.73 (d, J = 12.3 Hz, HH), 5.07 (d, J = 3.5 Hz, HH), 5.25 (d, J = 5.3 Hz, HH), 5.34
(d, J = 5.1 Hz, HH), 5.56 (d, J = 2.2 Hz, HH), 5.77 (d, J = 5.9 Hz, HH), 7.18 (d, J = 8.1 Hz, HH), 7.39 (d , J = 8.3 Hz, HI), 7.53 (t, J 7.7 Hz, 2H), 7.61-7.68 (m, 2H), 7.98 (d, J = 7.5 Hz, 2H), 9.45 (s, ÍH), IR ( KBr) 3410, 2970, 2920, 2860, L720, 1675, 1590, 1530, 1450, 1420 1375, 1270, 1060, 1020, and 720 cm "1: mass spectrum [(-) FAB], m / z 666 ( M-H) +; Analysis calculated for C31H48C1N013: C. 55.73; H, 5.73: N. 2.09. Found C. 55.67: H, 5.71: N, 2.09.
Example 6
N- (5- { [4 ', 6'-O-benzylidene-6-O- (4-toluenesulf onyl) - ß-D-maltosyl] -oxy-methyl} -2-chloro-f-enyl .}. -acetamide
stage 1
N-. { 5 - [(4 ', 6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide
To a stirred solution of N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide (14.15 g, 27.0 mmol) in 325 ml of DMF at rt is added benzaldehyde dimethylacetal (8.11 ml, 54.0 mmol) dropwise followed by TsOH.H20 (2.57 g, 13.5 mmol). The reaction mixture is heated at 60 ° C for
6 h and then it is suspended with K2C03 (1.87 g, 13.5 mmol) with an additional heating of 0.5 h at this temperature. At this point, the solution is filtered hot and the solvent is distilled off using high vacuum. The residue is purified by flash chromatography (gradient of 80: 2: 1 a
: 2: 1 EtOAc: EtOOH: H20) to provide the product
(10.8 g, 65%) as a white solid, m.p. 143-147 ° C. ? H NMR
(DMS0-d6) d 2.08 (s, 3H), 3.07-3.12 (m, 1H), 3.28-3.50 (m, 5H), 3.51-3.60 (m, 9H), 3.64-3.75 (m, 3H). 4.10-4.12 (m, ÍH), 4.30
(d, J = 7.9 Hz, 1H), 4.67 (t, 5.9 Hz, ÍH), 4.68 (ABc, J = 12.5
Hz,? D = 0.22, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.25 (d, J = 5.1
Hz, 1H), 5.30 (d, J = 5.3 Hz, ÍH), 5.51 (d, J = 3.3 Hz, ÍH),
. 57 (s, ÍH), 5.63 d, J = 6.8 Hz, ÍH), 7.22 (dd, J = 1.5, 8.3 Hz, ÍH), 7.35-7.38 (m, 3H), 7.42-7.46 (m, 3H), 7.66 (s, ÍH), 9.53 (s, ÍH): IR (KBr) 3500, 3410, 2910, 2850, 1700, 1600, 1550, 1440, 1425, 1375, 1310, 1230, 1150, 1070, and 1030 cm " 1, mass spectrum [(+) FAB], m / z 634 (M + Na) *; Analysis calculated for C28H34C1N012: 1.0 H20: C, 53.38, H, 5.76; N, 2.22, Found C, 53.58: H , 5.62, N, 2.25.
stage 2
N-. { 5- . { [4 ', 6'-O-benzylidene-6-O- (4-toluensulf onyl) - ß-D-maltosyl] oxy-methyl} -2-chloro-phenyl} -acetamide At 0 ° C, to a stirred solution of N-. { 5- [(4 ', 6' -0-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide (1.81 g, 2.96 mmol) in 6.0 ml of pyridine was added a solution of p-toluenesulfonyl chloride (0.686 g, 3.60 mmol) in 3.75 ml of CH2C12. After 2 h, p-toluenesulfonyl chloride (0.686 g, 3.60 mmol) in 3.75 mL of additional CH2C12 is added and the mixture is stirred at 0 ° C for 2 h. The reaction is suspended with 50 ml of ice-cooled H20 and extracted with EtOAc. The combined organic extracts are washed successively with saturated aqueous NaHCO3 (2x), saturated aqueous CuSO4 (2x), brine (2x), dried with Na2SO4 and concentrated. Purification by flash chromatography (gradient of 5-10% MeOH: CH 2 Cl 2) gives 0.930 g (41%) of a colorless solid, m.p. 105-120 ° C, XH NMR (DMS0-d6) d 2.08 (s, 3H), 2.33 (s, 3H). 3.04-3.09 (m. ÍH), 3.27.-3.45 (m, 4H), 3.49-3.53 (m, 1H), 3.60-3.65 (m, 3H), 3.95 (d, 1H), 4.13 (dd, ÍH) , 4.29-4.33 (m, 2H), 4.46 (d, ÍH), 4.62 (d, 1H), 5.05 (d, ÍH), 5.33-5.35 (m, 2H). 5.55 (d, 1H), 5.57 (s, ÍH), 5.75 (d, ÍH), 7.18 (d, 1H), 7.35-7.47 (m, 8H), 7.78 (d, ÍH). 9.53 (s, 1H), mass spectrum [(+) ESI] m / z 766/768 (M + H) +. 783/785 (M + NH2) +. Analysis calculated for C35H40ClNO14S: C. 53.60: H. 5.40: N. 1.79. Found C, 53.46. H. 5.18: N, 1.80.
Example 7
N- (5- { [2,3,2 ', 3'-tetra-Q-acetyl-4', 6'-O-benzylidene-6-0-toluensul f onui 1) - ß - D - mal t os ill - oxy - me ti 1} - 2 - chloro-phenyl} acetamide
The title compound is prepared as a colorless solid (0.942 g, 99%) from N- (5 { [4 ', 6'-O-benzylidene-6-0- (4-toluenesulfonyl) -β -D-maltosyl] -oxi-methyl.} -2-chloro-phenyl) -acetamide using a procedure similar to that of Example 3, mp. 116-122 ° C; X H NMR (DMSO-d 6) d 1.91 (s, 3H). 1.92 (s, 3H), 1.96 (s, ÍH), 2.00 (s, 3H). 2.08 (s, 3H,), 2.29 (s, 3H), 3.68 (dd, 1H), 3.77 (t, ÍH), 3.85 (t, ÍH), 3.90 (t, 1H), 3.97-4.00 (m, 1H ), 4.21 (dd, 1H), 4.32 (s, 2H), 4.39 (d, ÍH), 4.56 (d, ÍH), 4.60 (d, 1 H), 4.78 (d, ÍH), 4.86 (dd, ÍH) ), 5.17-5.30 (m, 3H), 5.65 (s, ÍH), 7.03 (d, 1H), 7.34-7.41 (m, 7H), 7.46 (d, ÍH), 7.59 (s, 1H), 7.80 ( d, 2H), 9.52 (s, ÍH): mass spectrum [(+) ESI], m / z 934/936 (M + H) +. Analysis calculated for C23H48C1N018: S: C. 55.27, H. 5.17: N, 1.50, Found C. 55.07.14. 5.05: N. 1.47.
Example 8
N- (5- [(6-O-benzyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl] -acetamide step 1
N-. { 5 - [(2,2I, 3,3'-tetra-O-acetyl-4 ', 6 • -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide
A solution that contains N-. { 5- . { [2, 3, 2 ', 3' -tetra-O-acetyl-4 ', 6' -0-benzylidene-6-0- (4-toluenesulfonyl) -β-D-maltosyl] oxy-methyl} -2-chloro-phenyl} -acetamide (1.021 g, 1.093 mmol) and sodium formate (0.1858 g, 2.732 mmol) in EtOH: DMSO: H20 (2: 2: 1.21.9 ml) is heated at 100 ° C for 2 days. The reaction is cooled to room temperature, diluted with 100 mL of 10% CH2C12: EtOAc, washed with brine (3x), dried with MgSO4 and concentrated in vacuo. Purification by flash chromatography (gradient of 1, 2 and 3% MeOH: CHCl2) gives 0.446 g (52%) of the title compound as a colorless solid: XE NMR (DMS0-d6) d 1.93 (s, 3H), 1.95 (s, 3H). 1.98 (s, 3H), 2.01 (s, 3H), 2.08 (s, 3H), 3.68-3.99 (m, 7H), 4.19-4.22 (m, ÍH), 4.57 (d, J = 12.7 Hz, ÍH) , 4.64-4.87 (m, 4H), 5.00 (s broad, ÍH), 5.21-5.33 (m, 3H), 5.63 (s. ÍH), 7.08 (dd, J = 8.3, 1.8 Hz, ÍH), 7.38 ( s, 5H), 7.47 (d, J = 8.2 Hz, ÍH), 7.64 (s, ÍH), 9.53 (s, ÍH).
Stage 2 N-. { 5- [(2,2 ', 3,3' -tetra-O-acetyl-β-O-benzyl-41,6 '-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro -phenyl} acetamide
At room temperature, to a stirred solution containing N-. { 5- [(2,2 *, 3,3'-tetra-0-acetyl-4 ', 6'-O-benzylidene-β-D-maltosyl) oxy-methyl] -2-chloro-phenamyl} -acetamide (0.221 g, 0.283 mmoles (and 2, 2, 2-benzyl trichloroacetimidate (0.105 ml, 0.567 mmol) in 10 ml of CH2C12 10%: benzene is added one drop of trifluoromethanesulfonic acid.After 16 h, the reaction it is diluted with 10 ml of 5% MeOH: CHC13, filtered through a pad of silica gel of 2.54 cm (1") eluting with 5% MeOH: CHC13, and concentrated in vacuo.Purification by flash chromatography ( gradient of 1 and 2% MeOH: CHCl3) gives 0.134 g (54%) of the title compound as a colorless solid: 1H NMR (DMS0-d6) d 1.94 (s, 3H), 1.96 (s, 3H), 1.98 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 3.69-4.07 (m, 8H), 4.54-4.59 (m, 3H), 4.69-4.77 (m, 2H), 4.82-4.86 (m, 2H), 5.23-5.34 (m, 3H), 5.61 (s, ÍH), 7.09 (dd, J = 8.3, 1.7 Hz,
ÍH), 7.27-7.37 (m, lOH), 7.46 (d, J = 8.2 Hz, ÍH), 7.65 (s, 1H), 9.52 (s, ÍH).
stage 3
N-. { 5- [(6-0-Benzyl-4 ', 6'-O-benzylidene-β-D-maltosyl) oxy-methyl] -2-chloro-phenyl} acetamide The title compound is prepared as a colorless solid (0.085 g, 65%) from N-. { 5- [(2, 2 •, 3, 3 '-tetra-O-acetyl-6-0-benzyl-4', 6 '-O-benzylidene-β-D-maltosyl) -oxi-methyl] -2- chlorine-phenyl} -acetamide using a procedure similar to that of step.4 of Example 1, p.f. 98-105 ° C: XH NMR (DMSO-d6) d 2.06 (s, 3H), 3.09-3.11 (m, HH), 3.28-3.75 (m.lOH). 3.99
(dd, ÍH), 4.33 (d, J = 7.7 Hz, ÍH), 4.50 (s, ÍH), 4.51 (s, ÍH). 4.66 (ABc, J = 12.6 Hz,? D = 0.08, 2H), 5.14 (d, J = 3.7 Hz, ÍH), 5.30 (d, J = 9.0 Hz, 1H), 5.31 (d, J = 9.0 Hz, ÍH). 5.56-5.57 (m, 2H), 5.70 (d, J = 6.6 Hz, 1H), 7.21-7.'38 (m, 9H). 7.42 - 7.45 (m 3H), 7.66 (s, ÍH), 9.52 (s, 1H), mass spectrum
[(+) F7AB], m / z 724 (M + H) +, Analysis calculated for C35H40ClNO12: 0.5 H2 O: C. 59.11. H. 5.81: N, 1.97, Found C. 59.12: H. 5.76: N, 1.98.
Example 9
N-. { 5- [(6-Q-benzyl-4 ', 6' -O-ethylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide
stage 1
N-. { 5- [(2,2 ', 3,3 · -tetra-O-asethyl-6-O-bensuyl-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -acetamide At room temperature, to a stirred solution of N-. { 5- [(2,2 ', 3,3' -tetra-0-acetyl-6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxi-methyl] -2- chlorine-phenyl} Acetamide (0.202 g, 0.232 mmol) in 5 ml of MeOH is added with 1 M ethereal HCl. After 2 h, the reaction is suspended with 25 ml of saturated aqueous NaHS03, diluted with 25 ml of H20, extracted with EtOAc. , dried with Na2SO4 and concentrated. Purification by flash chromatography (MeOH: 5%: CHC13) gives 0.136 g (75%) of the title compound; ? NMR (DMSO-d6) d 1.92 (s, 3H), 1.95 (s, 6H), 2.00 (s, 6H), 2.07, s, 3H), 3.49-3.56 (m, 4H), 3.75-3.94 (m, 4H), 4.50-4.59 (m, 5H), 4.67-4.76 (m, 2H), 4.83 (d, J = 7.9 Hz, ÍH). 5.06-5.13 (m, ÍH), 5.21-5.29 (m, 2H), 5.44 (d, J = 6.0 Hz, ÍH), 7.08 (dd, J = 8.1, 1.5 Hz, ÍH), 7.26-7.36 (m, 5H), 7.45 (d, J = 8.2 Hz, 1H), 7.64 (s, ÍH), 9.52 (s, 1H).
stage 2
N-. { 5- [(2,2 ', 3,3' -tetra-0-acetyl-6-0-benzyl-4 ', 6'-O-ethylidene-β-D-maltosyl) -oxi-methyl] -2- chlorine-phenyl} -acetamide
A stirred solution containing N-. { 5 - [(2,2 ', 3,3'-tetra-O-acetyl-6-O-benzyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} acetamide (0.274 g, 0.350 mmol), propionaldehyde (45.5 μl, 0.630 mmol) and camphorsulfonic acid (18.3 mg, 0.0787 mmol) in 6.3 ml of benzene, is refluxed with azeotropic water removal with Dean-Stark equipment. After 2.5 h, the reaction is cooled to room temperature, suspended with 25 ml of NaHCO 3, extracted with EtOAc and dried with Na 2 SO 4. Purification by flash chromatography (gradient of 1, 2 and 3% Me0H: CHCl3) gives 0.346 g (96%) of the title compound: U NMR (DMSO-d6) d 0.082 (t, 3H), 1.48-1.53 ( m, 2H), 1.92 (s, 3H), 1.95 (s, 3H), 1.97 (s, 3H), 2.01
(s, 3H), 2.07 (s, 3H), 3.51-3.48 (m, ÍH), 3.60-3.64 (m, 2H), 3.71-4.03 (m, 5H), 4.49-4.69 (m, 4H), 4.70 -4.85 (m, 4H), 5.14-5.32 (m, 3H), 7.07-7.36 (m, 6H), 7.46 (d, J = 8.2 Hz, ÍH), 7.64
(s, 1H), 9.52 (s, ÍH)
stage 3
N-. { 5- [(6-0-bensyl-4 ', 6' -O-ethylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide
A solution that contains N-. { 5- [(2, 2 ', 3, 3' -tetra-O-acetyl-6-0-benzyl-4 ', 6' -O-ethylidene-β-D-maltosyl) -oxi-methyl] -2- chlorine-phenyl} -acetamide (0.217 g, 0.264 mmol) and 25% by weight of NaOMe in MeOH (0.0285 g, 0.132 mmol) in 5.3 ml of MeOH is refluxed for 3 h. The reaction is cooled to room temperature and concentrated. Purification by flash chromatography (gradient of 10% MeOH / CH2Cl2) gives the product (0.100 g, 58%) as a white solid; XH NMR (DMSO-ds) d 0.85 (t, J = 7.5 Hz, 3H), 1.21-1.55 (m, 2H), 1.05 (s, 3H), 3.05-3.13 (m, 2H), 3.24-3.70 (m , 9H). 3.83 (dd, J = 9.8, 4.7 Hz, 1H), 4.30 (d, J = 7.7 Hz, ÍH), 4.43-4.49 (m, 3H), 4.63 (ABc, J = 12.4 Hz,? D = 0.07, 2H ), 5.07 (d, J 3.5 Hz, 1H), 5.24 (d, J = 5.3 Hz, ÍH), 5.31 (d, J = 5.3 Hz, ÍH), 5.55 (d, J = 2.6 Hz, 1H), 5.65 (d, J = 6.6 Hz, ÍH), 7.17-7.34 (m, 6H), 7.41 (d, J = 8.3 Hz, ÍH), 7.63 (s, ÍH), 9.55 (s, ÍH), mass spectrum [ (+) ESI] 671 (M + NH 4) +; Analysis calculated for C ^ H ^ NCIO ^; C. 56.92; H, 6.16: N, 2.14, Found C, 56.69, H. 6.33; N, 1.99.
Example 10
N- (2-chloro-5- { F4 ', 6' -O- (4-nitro) -benzylidene-β-D-maltosyl "oxymethyl) -phenyl-acetamide
To a stirred solution of N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide (0.500 g, 0.954 mmol) in 30 ml of DMF at rt is added 3-nitro-benzaldehyde dimethylacetal (0.752 g,
3. 82 mmol) followed by CSA (0.111 g, 0.477 mmol). The reaction mixture is heated at 60 ° C for 18 h and approximately
% complete by CCD. Another 0.5 equivalents of CSA are added
(0.11 g) and heated at 90 ° C for 3 h. The reaction is then suspended with K2C03 (0.132 g, 0.954 mmol) with additional heating for 0.5 h at 60 ° C. At this point, the solution is filtered hot and the solvent is removed by distillation using high vacuum. The residue is purified by flash chromatography (gradient from 40: 2: 1 to 20: 2: 1 EtOAc: EtOH: H20) to give the product (0.262 g, 42%) as a white solid, m.p. 221-223 ° C XH NMR (DMS0-d6) d 2.07 (s, 3H), 3.06-3.12 (m, ÍH), 3.26-3.49 (m, 5H), 3.49-3.62 (m, 2H), 3.68-3.77
(m, 3H), 4.11-4.20 (m, 1H), 4.30 (d, J = 7.7 Hz, 1 H), 4.67
(t, J = 5.7 Hz, ÍH). 4.68 (ABc, J = 12.3 Hz,? D, = 0.22, 2H), 5.16 (d, J = 3.7 Hz, ÍH), 5.25 (d, J = 4.8 Hz, ÍH), 5.36 (d, J = 4.8 Hz , HH), 5.49 (d, J = 3.1 Hz, HH), 5.62 (d, J = 6.6 Hz, 1H), 5.74 (s, HH), 7.22 (dd, J = 1.8, 8.1 Hz, HH) , 7.44 (d, J = 8.3 Hz, ÍH), 2.65 (s, ÍH), 7.73 (d, J = 8.8 Hz, 2H), 8.25
(dt, J = 2.2, 9.0 Hz, 2H), 9.52 (s, ÍH), IR (KBr) 3410, 2910, 2870, 1670, 1610, 1590, 1530, 1440, 1420, 1355, 1320, 1265, 1140, 1075, and 1035 cm "1: mass spectrum [(-) FAB], m / z 655 (M - H) +." Analysis calculated for C28H33C1N2014: C, 51.19: H, 5.06.N, 4.26, Found C. 50.87 : H, 4.87, N. 4.32.
Example 11
N- (5- { [6-0-benzoyl-4!, 6 '-O- (4-nitro) -benzylidene-β-D-maltosyl] oxy-methyl.} -2-chloro-phenyl) -acetamide The title compound is prepared as a white solid (0.080 g, 35%) from N- (2-chloro-5- { [4 ', 6' -O- (4-nitro) -benzylidene) -β-D-maltosyl] -oxi-methyl.}. phenyl) -acetamide using the procedure of Example 2, mp. > 167 ° C
(decomposition):? H NMR (DMSO-d6) d 2.04 (s, 3H), 3.15-3.22 (m,
ÍH), 3.37-3.43 (m, 2H), 3.51 (td, J = 2.9, 8.8 Hz, ÍH), 3.57- 3.64 (m, 3H), 3.70-3.78 (m, 2H), 4.09 (dd, J = 4.6, 9.9 Hz,
1H), 4.35 (dd, J = 5.1, 12.3, Hz, ÍH), 4.39 (d, J = 7.7 Hz,
ÍH), 4.57-4.63 (m, ÍH), 4.65, (ABc, J = 12.3 Hz,? + D = 0.14,
2H), 5.15 (d, J = 4.0 Hz, ÍH), 5.36 (d, J = 5.3 Hz, 1H), 5.41
(d, J = 5.3 Hz, ÍH,), 5.57 (d, J = 3.1 Hz, ÍH), 5.70 (s, ÍH),
. 81 (d, J = 6.2 Hz, 1H), 7.19 (dd, J = 1.8, 8.1 Hz, ÍH), 7.40
(d, J = 8.1 Hz, ÍH), 7.50-7.56 (m, 2H), 7.62-7.72 (m, 4H),
7. 97-8.01 (m, 2H), 8.24 (dt, J = 2.4, 9.2 Hz, 2H), 9.45 (s,
ÍH), IR (KBr) 3410, 2850, 1725, 1660, 1610, 1590, 1530, 1445,
1420, 1355, 1270, 1120, 1075, 1025 and 715 cm "1; mass spectrum
[(+) FAB]. m / z 783 (M + Na) +: Analysis calculated for
CasH ^ ClNOaOj. . 1.0 H20: C. 53.95; H, 5.05; N. 3.60, Found
C. 53.86, H, 4.75: N. 3.51.
Example 12
N-. { 2-Chloro-5- [(4 ', 6' -O- (4-chloro) -benzylidene-β-D-maltosyl) -oxymethyl] -phenyl} acetamide The title compound is prepared as a white glass (0.315 g, 51%) from N- [2-cñprop-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide using p-chlorobenzaldehyde dimethylacetal and the procedure of Example 10, mp > 97 ° C (decomposition): X H NMR (DMSO-d 6) d 2.07 (s, 3 H), 3.09 (t, J = 8.8 Hz, ÍH), 3.28-3.48 (m, 5 H), 3.49-3.61 (m , 2H), 3.61-3.75 (m, 3H), 4.11 (d, J = 5.3 Hz, ÍH), 4.30 (d, J = 7.7 Hz, ÍH), 4.63-4.72 (s broad, ÍH), 4.68 (ABc , J = 12.3 Hz,? D = 0.22, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.21-5.36 (s broad, 2H), 5.47-5.53 (s broad, ÍH), 5.57-5.66 ( s broad, 1H), 5.59 (s, ÍH), 7.22 (dd, J = 2.0, 8.3 Hz, ÍH), 7.42-7.48 (m, 5H), 7.65 (s, ÍH), 9.52 (s, ÍH), IR (KBr) 3390, 2920, 9850, 1670, 1590, 1530, 1500, 1450, 1420, 1365, 1300, 1140, 1070, 1030, and 815 crn "1; mass spectrum [(+) FAB], m / z 668 (M + Na) +, Analysis calculated for C ^ H ^ C ^ NO ^. 0.5 H20: C. 51.31, H, 5.23, N, 2.14, Found C, 51.13, H, 5.44, N. 1.92.
Example 13
N-. { 5- [(6-0-Benzoyl-4 ', 6' -O- (4-chloro) -benzylidene-β-D-maltosyl) oxy-methyl] -2-chloro-phenyl} -acetamide
The title compound is prepared as a white solid (0.158 g, 50%) from N-. { 2-Chloro-5- [(4 ', 6' -O- (4-chloro) -benzylidene-β-D-maltosyl) -oxi-methyl] -phenyl} -acetamide using a procedure similar to that of Example 2, p.f. > 182 ° C (decomposition); XH NMR (DMSO-d6) d 2.05 (s, 3H), 3.15-3.22 (H), 3.28-3.43 (m, 2H), 3.48-3.63 (m, 4H), 3.67-3.73 (m, ÍH), 3.73- 3.78 (m, 1 H). 4.03-4.07 (m, ÍH), 4.32-4.37 (m, 1H), 4.39 (d, J = 7.9 Hz, ÍH), 4.57-4.63 (m, ÍH), 4.65 (ABc, J = 12.5 Hz,? D = 0. 14, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.36 (dd, J = 2.6, 5.1 Hz, 2H), 5.54 (s, ÍH), 5.56 (d, J = 3.1 Hz, 1H), 5.79 (d, J = 6.4 Hz, ÍH), 7.19 (dd, J = 2.0, 8.3 Hz, ÍH), 7.40 (d, J = 8.3 Hz, ÍH), 7.43 (s, 4H), 7.53 ( t, J = 7.9 Hz, 2H), 7.63-7.68 (m, 2H), 7.99 (dd, J = 0.9, 7.9 Hz, 2H), 9.50 (s, ÍH), IR (KBr) 3450, 3380, 2960, 2900, 2860, 1730, 1700, 1665, 1590, 1530, 1495, 1440, 1415, 13.65, 1310, 1280, 1140, 1075, 1050, 1035, 1015, 820, and 720 cm "1; mass spectrum [ (+) FAB], m / z 7.50 (M + H) +, 772 (M + Na) +: Analysis calculated for C3SH37C12N013: C. 56.01: H. 4.97, N. 1.87. Found C, 55.67.H, 4.91 , N, 1.87.
Example 14
N- (2-Chloro-5- [(4 ', 6' -O-isobutylidene-β-D-maltosyl) -oxy-methyl] phenyl] -acetamide
The title compound is prepared as a white solid (0.250 g, 45%) from N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide using isobutyraldehyde dimethylacetal and the process of Example 10, pf > 122 ° C
(decomposition): XH NMR (DMSO-d6) d 0.87 (dd, J = 5.5, 6.6 Hz, 6H), 1.68-1.78 (m, HI), 2.07 (s, 3H), 3.04-3.13 (m, 2H) , 3.24-3.55 (m, 8H), 3.68 (dd, J = 6.2, 10.5 Hz, ÍH), 3.97 (dd, J = 49.7 Hz, ÍH), 4.27 (s, ÍH), 4.28 (d, J = 3.7 Hz, ÍH), 4.65 (t, J = 5.9 Hz, ÍH), 4.67 (ABc, J = 12.5 Hz,? D = 0.22. ÍH), 5.06
(d, J = 4.0 Hz, HH), 5.17 (d, J = 5.3 Hz, ÍH), 5.24 (d, J = 5.3 Hz, HH), 5.50 (d, J = 3.3 Hz, HH), 5.59 (d , J = 6.6 Hz, 1H), 7.22 (dd, J = 1.5, 7.9 Hz, 1H), 7.44 (d, J = 8.3 Hz, ÍH), 7.65 (s, 1H), 9.52 (s, ÍH); IR (KBr) 3420, 2960, 2910, 2830, 1670, 1590, 1530, 1466, 1420, 1370, 1310, 1255, 1145, 1080, 1055, and 1030 cm "1; mass spectrum [(-) ESI], m / z 576 (M - H) +, Analysis calculated for CF ^ H ^ ClNO ^ 0.5 H20: C, 51.15, H, 6.35, N. 2.39, Found C. 51.06, H. 6.5) 6; N, 2.45 .
Example 15
N-. { 5- [(6-O-benzoyl-4 ', 6'-O-isobutylidene-β-D-maltosyl) -oxi-methyl-2-chloro-phenyl} -acetamide
The title compound is prepared as a white solid (0.079 g, 41%) from N-. { 2-Chloro-5- [(4 ', 6' -0-isobutylidene-β-D-mal-trosyl) -oxy-methyl] -phenyl} -acetamide using the procedure der Example 2, p.f. > 123 ° C
(decomposition): XH NMR (DMSO-d6) d 0.85 (t, J = 6.4 Hz, 6H), 1.66-1.75 (m, ÍH), 2.05 (s, 3H), 3.07 (t, J = 9.4 Hz, ÍH ), 3.15-3.21 (m, ÍH), 3.26-3.36 (m, 2H), 3.46-3.60 (m, 4H), 3.72-3.77 (m, 1H), 3.92 (dd, J = 4.8, 10.1 Hz, ÍH) ), 4.23 (d, J = 4.8 Hz, 1H), 4.30 (dd, J = 5.1, 12.1 Hz, 1H), 4.38 (d, J = 7.7 Hz, 1H), 4.57 (d, J = 10.5 Hz, ), 4.64 (ABC, J = 12.5 Hz,? D = 0.14, 2H), 5.06 (d, J = 4.0 Hz, ÍH), 5.21 (d, J = 4.8 Hz, ÍH), 5.34 (d, J = 5.1 Hz, ÍH), 5.57 (d, J = 2.2 Hz, ÍH), 5.76 (d, J = 5.9 Hz, 1H), 7.18 (dd, J = 1.5, 8.3 Hz, ÍH), 7.40 (d, J = 8.3 Hz, ÍH), 7.53 (t, J = 7.9 Hz, 2H), 7.61-7.68 (m, 2H), 7.96-8.01 (m, 2H), 9.50 (s, ÍH): IR (KBi,) 3410, 2960 , 2910, 2840, 1725, 1660, 1610, 1590, 1530, 1425, 1375, 1270, 1055, 1025 and 715 cm "1: mass spectrum [(-) APC]; m / z 681.0 / 683.1 (M) +, Analysis calculated for C 32 H 40 ClNO 13, 1.0 H 20, C. 54.90: H, 6.05, N, 2.00, Found C. 54.95, H. 5.90, N. 1.94.
Example 16
N- (5- [(4 ', 6' -O- ((IR) -2-phenyl-ethylidene) -β-D-maltosyloxy) -methyl-2-chloro-phenyl] -acetamide
The title compound is prepared as a white solid (0.210 g, 35%) from N- [2-chloro-5- (β-D-maltosyl) -oxymethyl) -phenyl] -acetamide using phenylacetaldehyde dimethylacetal and the procedure of Example 10, pf > 106 ° C
(decomposition): XU NMR (DMSO-d6) d 2.07 (s, 3H), 2.81 (dd, J = 6.4, 14.1, ÍH), 2.91 (dd, J = 4.0, 14.1 Hz, ÍH), 3.04-3.11 ( m, ÍH), 3.16 (t, J = 9.4 Hz, ÍH), 3.26-3.54 (m, 7H), 3.58 (td, J = 5.1, 10.1 Hz, ÍH), 3.65-3.72 m, ÍH), 3.93 ( dd, J = 4.8, 9.9 Hz, ÍH), 4.29 (d, J = 7.7 Hz, ÍH), 4.65 (t, J = 5.9 Hz, ÍH), 4.67 (ABc, J = 12.3 Hz,? d = 0.22, 2H), 4.75 (dd, J = 4.2, 6.2 Hz, HH), 5.09 (d, J = 3.7 Hz, HH), 5.23 (dd, J = 5.3, 10.1 Hz, 2H,), 5.47 (d, J = 3.5 Hz, 1H), 5.57 (d, J = 6.6 Hz, ÍH), 7.17-7.30 (m, 6H), 7.44 (d, J = 8.1 Hz, ÍH), 7.65 (s, ÍH), 9.52 (s, ÍH); IR (KBr) 3400, 2920, 1850. 1670, 1590, 1530, 1450, 1420, 1375, 1310, 1250, 1150, 1130, 1060, 1025, and 750 cm "1; mass spectrum [(+) FAB], m / z 648 (M + Na) +, Analysis calculated for
C29H36C1N012. H20: C, 51.56, H, 6.19; N, 2.07, Found C. 51.47; H. 5.52; N. 2.13.
Example 17
N- (5- r (6-Q-benzoyl-4 ', 6' -O- ((IR) -2-phenyl-ethylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl}. -acetamide
The title compound is prepared as a white solid (1.25 g, 63%) from N-. { 5- [(4 ', 6' -O- ((IR) -2-phenyl-ethylidene) -β-D- -maltosiloxy) methyl] -2-chloro-phenyl} -acetamide using the procedure of Example 2, p.f. 153-156 ° C, XK NMR (DMSO-de) d 2.05 (s, 3H), 2.78 (dd, J = 6.2, 14.1 Hz, ÍH), 2.89 (dd, J = 4.2, 14.3 Hz, ÍH), 3.10 -3.21 (m, 2H), 3.26-3.37 (m, 2H), 3.47-3.64 (m, 4H), 3.71-3.77 (m, ÍH), 3.89 (dd, J = 4.8, 9.9 Hz, ÍH), 4.31 (dd, J = 5.3, 12.1 Hz, ÍH), 4.38 (d, J = 7.7 Hz, ÍH), 4.53-4.60 (m, ÍH), 4.68-4.77 (m, 2H), 5.07 (d, J = 4.0 Hz, ÍH), 5.27 (d, J = 5.5 Hz, 1 H), 5.34 (d, J = 5.3 Hz, 1H), 5.55 (d, J = 2.9 Hz, ÍH), 5.77 (d, J = 6.2 Hz , ÍH), 7.16-7.28 (m, 6H), 7.40 (d, J = 8.1 Hz, ÍH), 7.52 (t, J = 7.7 Hz, 2H), 7.62-7.67 (m, 2H), 7.98 (dd, J = 0.7, 7.9 Hz, ÍH), 9.50 (s, 1H): IR (KBr) 3480, 3370, 2910, 1725, 1695, 1590. 1525, 1450, 1425, 1380, 1355, 1310, 1275, 1250, 1235 , 1149, 1120, 1075, 1050, 1035 and 715 cm "1; Analysis calculated for C36H40C1N013; C. 59.22; H, 5.52; N, 1.92. Found: C, 58.93; H, 5.45; N, 1.86
Example 18
N-. { 2-chloro-5- [(4 ', 6' -O- ((IR) -3-cyano-propipiden-β-D-maltosyloxy) -methyl] -phenyl.}. -acetamide
The title coppa was prepared as a tan solid (0.101 g, 18%) from N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] acetamide using 3-cyanopropaldehyde dimethylacetal and the procedure of Example 10, pf 185-188 ° C: U NMR (DMS0-d6) d 1.82-1.89 (m, 2H), 2.07 (s, 3H), 2.47-2.55 (m, 2H), 3.04-3.11 (m, ÍH), 3.15 ( t, J = 9.2 Hz, ÍH), 3.24-3.59 (m, 8H), 3.65-3.71 (m, ÍH), 3.99 (d, J = 4.6, 9.9 Hz, ÍH), 4.28 (d, J = 7.7 Hz , ÍH), 4.62-4.67 (m, 2H). 4.67
(7ABc, J = 12.5 Hz,? D = 0.22, 2H), 5.10 (d, J = 3.7 Hz, ÍH), 5.24 (d, J = 5.3, 7.2 Hz, 2H), 5.48 (d, J = 3.3 Hz , ÍH), 5.58
(d, J = 6.6 Hz, HH), 7.22 (d, J = 1.8, 8.1 Hz, HH), 7.44 (8.1 Hz, HH), 7.65 (s, HH), 9.52 (s, HH): IR (KBr) 3540, 3410, 3120, 2930, 2850, 2230, 1685, 1590, 1540, 1450, 1425, 1420, 1370, 1320, 1255, 1150, 1130, 1100, 1065, 1050, 1020, 995, and 890 cm "1; mass spectrum [(+) FAB], m / z 611 (M + Na) +: Analysis calculated for C25H23C1N012 0.5 H20: C, 50.21, H. 5.73: N, 4.68. Found C. 50.32 : H. 5.51, N, 4.84.
Example 19
N-Í5- ([6-0-benzoyl-4 ', 6' -O- ((IR) -3-cyanopropylidene) -β-D-maltosyloxy] -methyl] -2-chloro-phenyl}. -acetamide
The title compound is prepared as a white solid (0.038 g, 46%) of N-. { 2-Chloro-5- [(4 ', 6' -O- ((IR) -3-cyano-propylidene-β-D-maltosiloxy) -methyl] -phenyl] -acetamide using the procedure of Example 2, mp 164-166 ° C; 1H NMR (DMSO-d6) d 1.79-1.86 (m, 2H), 2.04 (s, 3H), 2.48-2.52 (m, 2H), 3.13 (t, J = 9.2 Hz, ), 3.14-3.20 (m, ÍH), 3.27-3.40 (m, 2H), 3.46-3.60 (m, 4H), 3.71-3.77 (m, ÍH), 3.93 (dd, J = 4.6, 9.9 Hz, ÍH) ), 4.30 (dd, J = 5.3, 12.1 Hz, ÍH), 4.38 (d, J = 7.9 Hz, ÍH), 4.55-4.62 (m, 2H), 4.64 (ABc, J = 12.5 Hz,? D = 0.14 , 2H), 5.08 (d, J = 3.7 Hz, HH), 5.28 (d, J = 5.1 Hz, HH), 5.35 (d, J = 5.3 Hz, HH), 5.55 (d, J = 2.9 Hz, HH ), 5.77 (d, J = 6.2 Hz, ÍH), 7.18 (dd, J = 1.5, 8.1 Hz, ÍH), 7.40 (d, J = 8.1 Hz, 1H), 7.53 (t, J = 7.9 Hz, 2H ), 7.62-7.68 (m, 2H), 7.98 (dd, J = 1.5, 8.3 Hz, 2H), 9.50 (s, ÍH), IR (KBr) 3450, 3380, 3320, 2920, 2880, 2240, 1725, 1710. 1670, 1610, 1590, 1530, 1440, 1420, 1370, 1310, 1275, 1125, 1100, 1060, 1030, 1020 and 720 cm "1; mass spectrum [(-) FAB], m / z 691 (M-H) +: Analysis calculated for C32H37C1N2013: C, 55.45; H. 5.38: N. 4.04, Found: C. 55.25; H, 5.44: N. 3.90.
Example 20
N-. { 2-chloro-5-f (4 ', 6'-0- ((IR) -3-ethoxy-propi 1 iden) - ß-D maltosiloxy) -methyl] -phenyl} acetamide
The title compound is prepared as a white solid (0.080 g, 14%) from N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide using 3-chloropropionaldehyde diethylacetal and the procedure of Example 10, mp 149.5- 153 ° C: XH NMR (DMSO-d6) d 1.08 (t, J = 7.0 Hz, 3H), 1.70-1.81
(m, 2H), 2.07 (s, 3H), 2.44-2.54 (m, 2H), 3.04-3.17 (, 2H),
3. 24-3.60 (m, 10H), 3.64-3.71 (m, ÍH), 3.95 (dd, J = 4.8, 9.9
Hz, ÍH), 4.28 (d, J = 7.7 Hz, 1H), 4.63 (dd, J = 5.7, 9.7 Hz, 2H), 4.67 (ABc, J = 12.3 Hz,? D 0.22, 2H), 5.09 (d , J = 3.7 Hz, 1H), 5.19 (d, J = 5.3 Hz, ÍH), 5.23 (d, J = 5.3 Hz, ÍH), 5.46
(d, J = 3.3 Hz, 1H), 5.56 (d, J = 6.6 Hz, ÍH), 7.22 (dd, J = 1.8, 8.1 Hz, HH), 7.44 (d, J = 8.3 Hz, 1H), 7.65 (s, ÍH), 9.51
(Yes H); IR (KBr.) 3500, 3420, 2970, 2920, 2840, 1690, 1590, 1530, 1440, 1420, 1370, 1320, 1250, 1110, 1070, and 1020 cm "1; mass spectrum [(-) FAB] , m / z 606 (M-H) +, Analysis calculated for C26H38C1N013, 1.5 H20: C, 49.17, H, 6.51, N. 2.21, Found C, 48.89: H. 5.93; N, 2.27.
Example 21
N-. { 5- . { [6-0-benzoyl-4 ', 6' -O- ((IR) -3-ethoxypropylidene) -β-D-maltosiloxy-1-methyl} -2-chloro-phenyl} -acetamide
The title compound is prepared as an off-white solid (0.015 g, 26%) from N-. { 2-chloro-5- [. { 4 ', 6' -O- ((IR) -3-ethoxy-propylidene) -β-D-maltosyloxy) -methyl] -phenyl} -acetamide using the procedure of Example 2. p.f. > 94 ° C
(decomposition): XH NMR (DMSO-d6) d 1.07 (t, J = 7.0 Hz, 3H), 1.69-1.78 (m, 2H), 2.04 (s, 3H), 2.44-2.54 (m, 2H), 3.09 (t, J = 9.7 Hz, ÍH), 3.14-3.21 (m, ÍH), 3.26-3.42 (m, 4H), 3.45-3.60 (m, 4H), 3.71-3.76 (m, ÍH), 3.91 (dd) , J = 4.4, 9.7 Hz, ÍH), 4.30 (dd, J = 5.3, 12.3 Hz, ÍH), 4.37 (d, J = 7.7 Hz, ÍH), 4.54-4.61 (m, 2H), 4.64 (ABc, J = 12.5 Hz,? D = 0.14, 2H), 5.07 (d, J = 4.0 Hz, ÍH), 5.25 (d, J = 5.3 Hz, ÍH), 5.34 (d, J = 5.3 Hz, ÍH), 5.55 (d, J = 2.6 Hz, HH), 5.77 (d, J = 6.2 Hz, ÍH), 7.18 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.1 Hz, HH), 7.53 (t , J = 7.9 Hz, 2H), 7.62-7.68 (m, 2H), 7.98 (d, J = 7.2 Hz, 2H), 9.50 (s, ÍH); IR (KBr) 3410, 2910, 2850, 1720, 1670, 1590, 1530, 1440, 1420, 1370, 1280, 1115, 1060, 1025, and 720 cm "1: mass spectrum [(+) FAB], m / z 734 (M + Na) +: Analysis calculated for C33H42C1N014, 4.0 H20: 50.54: H. 6.43, N, 1.79, Found C. 50.22, H. 5.28: N, 1.77.
Example 22
N- (2-chloro-5- { [4 ', 6' -O- (4-pyridinmethylidene) -β-D-maltosyl] -oxymethyl.} - phenyl) -acetamide
To a stirred solution of N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide (0.500 g, 0.954 mmol) in 25 ml of DMF at rt is added 4-pyridinecarboxaldehyde (0.446 ml). , 4.67 mmoles) followed by concentrated H2SO4 (0.105 ml, 3.78 mmoles). The reaction mixture is heated at 110 ° C for 18 h. The reaction is then suspended with K2C03 (1.40 g, 10.1 mmol) and with an additional 0.5 h of heating at 60 ° C. At this point, the solution is filtered hot and the solvent is removed by distillation using high vacuum. The residue is purified by flash chromatography (gradient of 80: 6: 3 to 5: 2: 1 of EtOAc: EtOH: H20) to give the product (0.050 g, (9%) as a yellow solid, mp> 112 ° C
(decomposition); XH NMR (DMSO-d6) d 2.07 (s, 3H), 3.05-3.13 (m, HH), 3.27-3.49 (m, 4H), 3.49-3.62 (m, 3H), 3.66-3.75 (m, 3H) , 4.14 (dd, J = 12.5, 17.5 Hz, ÍH), 4.29 (d, J = 7.7 Hz, ÍH), 4.67 (t, J = 5.9 Hz, ÍH), 4.67 (ABc, J = 12.3 Hz,? D = 0.22, 2H), 5.16 (d, J = 3.7 Hz, 1H), 5.25 (d, J = 5.3 Hz, ÍH), 5.35
(d, J = 4.8 Hz, HH), 5.50 (d, J = 3.3 Hz, HH), 5.61-5.65 (m, 2H), 7.22 (dd, J = 1.8, 8.3 Hz, ÍH), 7.42-7.47 ( m, 3H), 7.65
(s, ÍH), 8.60 (d, J = - 5.9 Hz, 2H), 9.52 (s, ÍH); IR (KBr): 3390, 2920, 2830, 1670, 1620, 1590, 1530, 1450, 1420, 1380, 1310, 1270, 1245, 1180, 1145, 1075, 1055, 1030, and 755 cm "1: mass spectrum [(-) FAB], m / z 611 (MH): Analysis calculated for C27H21C1N2012 4.25H20; C, 47.03; H, 6.07; N, 4.06. Found: C. 46.63; H, 5.00; N, 3.60.
Example 23
6- (3-acetylaminium-4-chloro-benzoyloxy) -3- (7,8-dihydroxy-2-pyridin-4-yl-hexahydro-pyran [3 .2 -d] Ti, 31 dioxin-6-yloxy ester ) -4, 5-dihydroxy-tetrahydro-pyran-2-methylmethyl benzoic acid
The title compound is prepared as an off-white solid (0.025 g, 46%) from N- (2-chloro-5 { [4 ', 6' -O- (4-pyridinmethylidene) -β- D-maltosyl] -oxi-methyl.}. Phenyl) -acetamide using the procedure of Example 2, mp. 260-261.5 ° C:
? NMR (DMSO-d6) d 2.04 (s, 3H), 3.15-3.22 (m, 1H), 3.25-3.43 (m, 2H), 3.51 (td, J = 2.9, 8.8 Hz, ÍH), 3.55-3.64 ( m, 3H), 3.68-3.77 (m, 2H), 4.07 (dd, J = 4.6, 9.7 Hz, ÍH), 4.34 (dd, J = 5.3, 12.3 Hz, ÍH), 4.39 (d, J = 7.7 Hz , ÍH), 4.56-4.62 (m, ÍH), 4.65 (ABc, J = 12.3, Hz,? D = 0.14, 2H), 5.15 (d, J = 4.0 Hz, ÍH), 5.35 (d, J = 5.3 Hz, ÍH), 5.39 (d, J = 5.1 Hz, ÍH), 5.56 (d, J = 3.1 Hz, 1H), 5.58 (s, ÍH), 5.79 (d, J = 6.2 Hz, 1H), 7.18 ( dd, J = 2.0, 8.3 Hz, ÍH), 7.38-7.45 (m, 3H), 7.53 (t, J = 7.9 Hz, 2H), 7.62-7.68 (m, 2H), 7.97-8.01 (m, 2H) , 8.59 (d, J = 4.6 Hz, 2H), 9.49 (s, ÍH): IR (KBr) 3460, 3310, 3240, 2910, 2830, 1725, 1665, 1620, 1590, 1530, 1420, 1375, 1275, 1140, 1075, 1055, 1030 and 715 cm "1: mass spectrum [(+) FAB], m / z 717 (M + H) + .739 (M + Na) + M; Analysis calculated for C34H37C1N2013. 1.5 H2o : C, 54.88; H, 5.42; N, 3.76, Found: C, 54.55; H, 4.98; N, 3.68.
Example 24
N-. { 5 - [(4 ', 6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide
To a stirred solution of N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] -acetamide (14.15 g, 27.0 mmol) in 325 ml of DMF at rt is added benzaldehyde dimethyl acetal (8.11) to drops. ml, 54.0 mmol) followed by TsOH.H20 (2.57 g, 13.5 mmol). The reaction mixture is heated at 60 ° C for 6 h and then suspended with K2C04 (1.87 g, 13.5 mmol) with additional heating for 0.5 h at this temperature. At this point, the solution is filtered hot and the solvent is distilled off using high vacuum. The residue is purified by flash chromatography (gradient from 80: 2: 1 to 20: 2: 1 EtOAc: EtOH: H20) to give the product (10.8 g, 65%) as a white solid, m.p. 143-147 ° C; * H NMR (DMSO-d6) d 2.08
(s, 3H), 3.07-3.12 (m, ÍH); 3.28-3.50 (m, 5H), 3.512-3.60 (m, 2H), 3.64-3.75 (m, 3H), 4.10-4.12 (m, ÍH), 4.3? "(D, J = 7.9 Hz, 1H), 4.67 (t, 5.9 Hz, ÍH), 4.68 (ABc, J = 12.5 Hz,? D = 0.22, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.25 (d, J = 5.1 Hz, ÍH) 5.30
(d, J = 5.3 Hz, ÍH), 5.51 (d, J = 3.3 Hz, ÍH), 5.57 (s, ÍH), 5.63 (d, J = 6.8 Hz, ÍH), 7.22 (dd, J = 1.5, 8.3 Hz, 1H), 7.35-7.38 (m, 3H), 7.42-7.46 (m, 3H), 7.66 (s, ÍH), 9.53 (s, 1H), IR (KBr) 3500, 3410, 2910, 2850, 1700, 1600, 1550, 1440, 1425, 1375, 1310, 1230, 1150, 1070 and 1030 cm "1: mass spectrum C. 53.38; H, 5.76; N, 2.22, Found: C, 53.58; H, 5.62; N, 2.25.
Example 25
N-. { 5-r (4 ', 6' -O-benzyl iden- 2, 2 ', 3, 3', 6-penta-O-acetyl-β-D-maltosyl-oxy) -metill-2-chloro-f-enyl } -acetamide a stirred solution of N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide (0.230 g, 0.376 mmol) and triethylamine (0.576 ml, 4.14 mmol) in 5 ml of DMF at rt is added dropwise acetic anhydride (0.195 ml, 2.07 mmol) followed by a catalytic amount of DMAP (0.023 g, 0.188 mmoles). After 18 h, the mixture is concentrated and the resulting residue is diluted with 100 ml of EtOAc. This layer is washed with 10 ml of 1 N HCl, 10 ml of saturated aqueous NaHCO 3 and 10 ml of brine and then dried with Na 2 SO 3. After concentration, the residue is purified by flash chromatography (10:90 to 80:20 gradient of EtOAc: petroleum ether) to give the product (0.181 g, 59%) as an off-white solid, m.p. 99-102 ° C X H NMR (DMSO-d 6) d 1.92 (s, 3 H), 1-94 (s, 3 H) 1.97 (s, 3 H), 1.98 (s, 3 H), 1.99 (s, 3 H), 2.08 (s, 3H), 3.67-3.75 (m; ÍH), 3.89 (t, J = 9.4 Hz, ÍH), 395-4.04 (m, 3H), 4.12-4.19 (m, 2H), 4.39 (dd, J = 1.5, 11.9 Hz, ÍH), 4.54 (d, J = 12.7 Hz, ÍH), 4.68-4.74 (m, 2H), 4.85-4.89 (m, 2H), 5.24 (t, J = 10.1Hz, ÍH) , 5.28 (d.J = 4.0 Hz, ÍH), 5.32 (d, J = 9.4 Hz, ÍH), 5.62 (s, ÍH), 7.07 (dd, J = 1.8, 8.1Hz, ÍH), 7.36 (s, 5H), 7.45 (d, J = 8.3 Hz, ÍH), 7.62 (s, ÍH), 9.50 (s, ÍH): IR (KBr) 3390, 2920, 2850, 1755, 1690, 1600, 1530, 1410, 1375 , 1230 and 1050 cm "1; mass spectrum [(+) FAB] .m / z 822 (M + H) +, 844 (M + Na) +: Analysis calculated for C18H44C1N017 .1.0 H20: C, 54.32; H 5.52M; N, 1.67 Found: C, 54.68; H, 5.44; N, 1.57.
Example 26
N-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl-oxy) -methyl] -2-chloro-enyl} -acetamide
The title compound is prepared as a white solid (4.04 g, 69%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide using a procedure similar to that of Example 2, p.f. 185-187 ° C; 1H NMR
(DMSO-d6) d 2.05 (s, 3H), 3.16-3.22 (m, ÍH), 3.32-3.42 (, 2H), 3.48-3.64 (m, 4H), 3.71 (dd, J = 4.8, 9.7 Hz, ÍH), 3.74-3.79
(m, ÍH), 4.05 (dd, J = 4.8, 10.3 Hz, ÍH), 4.35 (dd, J = 5.3, 123 Hz, ÍH), 4.39 (d, J = 7.7 Hz, ÍH), 4.58-4.63 ( m, ÍH), 4.65 (ABc J = 12.5 Hz,? d = 0.14, 2H), 5.14 (d, 4.0 Hz, ÍH), 5.34 (t, J = 5.1Hz, 2H), 5.52 (s, ÍH) , 5.57 (d, J = 3.1, ÍH), 5.79 (d, J = 6.2 Hz, ÍH), 7.19 (dd, -J = 2.0, 8.3 Hz, 1H), 7.32-7.38 (m, 3H), 7.387. 45 (m, 3H), 7.51-755 (m, 2H), 7.63-7.68 (m, 2H), 7.98-8.01 (m, 2H), 9.49 (s, ÍH); IR (KBr) 3380, 3290, 2890. 2870, 1730, 1670, 1600, 1540, 1440, 1420, 1375, 1275, 1070, 1050, 1025, 975 and 710 cm "1; mass spectrum [(+) FAB] , m / z 716/718 (M + H) +, 738/740 (M + Na) + Analysis calculated for C35H38C1N013: C, 58.70; H, 5.35, N. 1.96 Found: C, 58.53; H, 5.36; N, 1.94.
Example 27
(E) -N- [2-chloro-5- r \ \ 2,3-di-0-acetyl-6-0-benzoyl-4-0- [2,3-di-O-acetyl-4, 6-0 - (Phenylmethylene) -aD-glucopyranosyl] -β-D-alucopyranosyl oxy] -methyl-phenyl] acetamide
The title compound is prepared as a glassy white solid (0.048 g, 86%) from N-. { 5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl-oxy) -methyl] -2-chloro-phenyl} -acetamide using a procedure similar to that of Example 25, p.p. 101-104 ° C. X H NMR (DMSO-d 6) d 1.94 (s, 3 H), 1.95 (s, 3 H), 1.98 (s, 3 H), 1.99 (s, 3 H), 2.05 (s, 3 H), 3.61 (t, J = 9.7 Hz, ÍH), 3.70-3.76 (m, ÍH), 3.80 (dd, J = 4.6 Hz, ÍH), 3.86 (t, J = 9.4 Hz ÍH), 4.13-4.22 (m, 2H), 4.46 (dd, J = 3.7, 12.5 Hz, ÍH), 4.64 (ABc, J = 12.7 Hz? D = 0. 14. 2H), 4.68 (d, J = 10.5 Hz, 1H), 4.79 (dd, J = 8.1, 9.4 Hz , ÍH), 4.87-4.91 (m, 2H), 5.27 (t, J = 9.9 Hz, ÍH), 5.33-5.38 (m, 2H), 5.54 (s, ÍH), 7.04 (dd, J = 1.8, 8.1 Hz, ÍH), 7.28-7.36 (m, 5H), 7.41 (d, J = 8.3 Hz, ÍH), 7.52-7.57 (m, ÍH), 7.65-7.71 (m, 1H), 8.03-8.07 (m, 2H), 9.48 (s, 1H); IR (KBr) 3400, 1755, 1600, 1540, 1440, 1420, 1375, 1240, 1070, and 1030 cm "1, mass spectrum FAB], m / z 884 (M + H) + 906 (M + Na) +, Analysis calculated for C43H46C1N017: C, 58.41 H. 5.24, N. 1.58, Found: C. 58.24; H, 5.3 1: N, 1.59.
Example 28
(R) -N- [2-chloro-5- [[6-0- (5-methoxy-1, 5-dioxopentyl) -4-0- [4,6,0- (phenylmethylene) - a -D- glucopyranosyl l] - ß - D-cylcopyranosyl] oxy] methyl] phenyl acetamide
The title compound is prepared as a white foam (0.149 g, 50%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using methyl-4- (chloroformyl) butyrate as the acid chloride and a procedure similar to that of Example 2, p.f. 79-81 ° C: XH NMR
(DMS0-d6) d 1.90-1.98 (m, 2H), 2.13 (s, 3H), 2.352.43 (m, 4H),
3. 41 (t, J = 9.4 Hz, ÍH), 3.47-3.73 (m, 6H), 3.65 (s, 3H),
3. 82-3.89 (m, 2H), 3.93 (t, d = 9.4 Hz, ÍH), 4.06-4.26 (s broad, ÍH), 4.20 (dd, J = 4.6, 12.3 Hz, ÍH), 4.28 (c, J = 10.5 Hz, ÍH), 4.34-4.40 (m, 2H), 4.70 (ABc, J = 12.5 Hz,? D = 0.23, 2H), 4.76-4.94 (s broad, 1H), 5.04 (d, J = 4.0 Hz, ÍH), 5.20-5.36 (s broad, ÍH), 5.47 (s, ÍH), 7.01 (dd, J = 1.8, 8.6 Hz, ÍH), 7.30 (d, J = 8.3 Hz, ÍH), 7.33- 7.35 (m, 3H), 7.46-7.48 (m, 2H), 7.64 (s, ÍH), 8.32 (s, ÍH): IR (KBr) 3400, 293O, 2880, 1735, 1600, 1540, 1450, 1420, 1375, 1310, 1250, 1200, 1160, 1070, and 1025 was "1, mass spectrum [(+) FAB] m / z 740 (M + H) +, 762 (M + Na) +; Analysis calculated for C34H42C1N015 1.0 H20: C. 53.86: M 5.85; N, 1.85, Found: C, 53.51, H. 5.80, N, 1.73.
Example 29
-chloro-3-nitro-benzyl-4 ', 6' -O-benzylidene-β-D-maltoside
stage 1
4 - . 4-chloro-3-nor ro-benzyl-β-D-maltoside
The title compound is prepared as a yellow powder (1.04 g, 97%) from 4-chloro-3-nitro-benzyl-β-D-maltoside heptaacetate using a procedure similar to step 4 of Example 1, m.p. 168-169 ° C; XH NMR (DMS0-d6) d 3.03-3.13 (m, 2H), 3.20-3.38 (m, 4H), 3.41-3.49 (m, 3H), 3.55-3.64 (m, 2H), 3.68-3.75 (m, ÍH), 4.00-5.50 (s broad, 7H), 4.31 (d, J = 7.7 Hz, ÍH), 4.79 (ABc, J = 13.6 Hz,? D = 0. 17. 2H), 5.00 (d, J = 3.7 Hz, HH), 7.70-7.78 (m, 2H), 8.09 (d, J = 1.8 Hz, HH); IR (KBr) 3380, 2900, 1720, 1625, 1550, 1365, 1140, 1080 and 1030 cm "1; mass spectrum [(+) FAB], m / z 533/535 (M + Na) +: Calculated analysis for C19H26C1N013, 1.0 H20:: C. 43.07: H. 5.33: N, 2.64, Found: C. 43.11, H, 5.23, N. 2.58.
stage 2
4-chloro-3-nitro-benzyl-4 ', 6'-O-benzylidene-β-D-maltoside The title compound is prepared as a yellow solid (0.869 g, 74%) from 4-chloro-3 -nitro-benzyl-β-D-maltoside using a procedure similar to that of Example 24, mp > 122 ° C (decomposition) XH NMR (DMSO-d6) d 3.11 (dd, J = 4.8, 8.8 Hz, 1H), 3.30-3.42 (m, 4H), 3.46 (dd, J = 3.3, 9.0 Hz, ÍH) , 3.49-3.60 (m, 2H), 3.64-3.75 (m, ÍH), 4.12 (dd, J = 2.9, 8.1 Hz, ÍH), 4.33 (d, J = 7.7 Hz, ÍH), 4.65 (t, J = 5.7 Hz, 114), 4.80 (ABc, J = 13.6 Hz,? D = 0.16, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.29 (d, J = 5.1Hz, ÍH), 5.34 ( d, J = 5.1Hz, 1H), 5.53 (d, J = 3.1Hz, ÍH), 5.57 (s, ÍH), 5.62 (d, J = 6.6 Hz, 1H), 7.34-738 (m, 3H), 7.42-7.46 (m, 2H), 7.70-7.77 (m, 2H), 8.10 (d, J = 1.6 Hz, ÍH); IR (KBr) 3390, 2920, 2870, 1625, 1610, 1590, 1550, 1440, 1420, 1360, 1200, 1140, 1070, and 1030 cm "1: mass spectrum [(+) FAB], m / z 600 / 602 (M + H) + 622/624 (M + Na) +; Analysis calculated for C 26 H 30 ClNO 13 0.5 H 20: C, 51.28; H, 5.13; N, 2.30 Found: C, 51.13; H, 5.21; N, 2.30
Example 30
4-chloro-3-nitro-benzyl-6-0-benzoyl-4 ', 6'-O-benzyl iden-β-D-maltoside
The title compound is prepared as a whitish glass (0.155 g, 49%) from 4-chloro-3-nitro-benzyl-4 ', 6'-O-benzylidene-β-D-maltoside using a procedure similar to of Example 2, pf 111-114 ° C: XH NMR (DMS0-d6) d 3.19-3.26 (m, ÍH), 3.28-3.43 (m, 2H), 3.51-3.65 (m, 4H), 3.68-3.75 (m, ÍH), 3.77-3.81 (m, ÍH), 4.04 (dd, J = 4.6, 9.9 Hz, ÍH), 4.34 (dd, J = 5.1, 12.3 Hz, ÍH), 4.45 (d, J = 7.9 Hz, ÍH), 4.59 (d, J = 12.3 Hz, ÍH), 4.79 (ABc, J = 13.6 Hz,? d = 0.10, 2H), 5.14 (d, J = 3.7 Hz, ÍH), 5.35 (d, J = 5.3 Hz, ÍH) ), 5.46 (d, J = 5.1 Hz, ÍH), 5.52 (s, 1H), 5.60 (d, J = 3.1Hz, ÍH), 5.80 (d, J = 6.2 Hz, ÍH), 7.33-7.37 (m , 3H), 7.39-7.43 (m, 2H), 7.50-7.55 (m, 2H), 7.63-7.68 (m, ÍH), 7.68-7.73 (m, 2H), 7.97 (dd, J = 1.1, 8.1 Hz , 2H), 8.08 (s, ÍH): IR (KBr) 3400, 2910, 2860, 1725, 1610, 1540, 1440, 1360, 1325, 1275, 1070, and 1025 cm "1: mass spectrum [(+) FAB], m / z 704 (M + H) + .726 (M + Na) +: Analysis calculated for C33H34C1N014 1.0 H20: C, 54.89; H, 5.03; N, 1.94 Found: C, 54.72; H, 4.56; N, 1.91.
Example 31
(R) - (4-chloro-3-nitrophenyl) methyl-2,3-di-0-acetyl-6-0-benzoyl-4-O- [2,3-di-O-acetyl-4,6- 0- (phenylmethylene) -aD-glucopyranosyl-1-β-D-glucopyranoside
The title compound is prepared as an off-white solid (0.0773 g, 84%) from 4-chloro-3-nitro-benzyl-6-O-benzoyl-4 ', 6'-O-benzylidene-β-D- maltoside using a procedure similar to that of Example 25, mp 138-140 ° C; XH NMR
(DMSO-d6) d 1.95 (s, 3H), 1.96 (s, 3H), 1.98 (s, 3H), 1.99 (s, 3H), 3.61 (t, J = 9.4 Hz, ÍH), 3.69-3.77 ( m, ÍH), 3.79 (dd, J = 4.6, 9.4 Hz, ÍH), 3.86 (t, J = 9.4 Hz, ÍH), 4.13-4.25 (m, 2H), 4. (dd, J = 3.5, 12.3 Hz, ÍH), 4.66-4.69 (m, ÍH), 4.71
(d, J = 13.6 Hz, ÍH), 4.80-4.84 (m, 2H), 4.89 (dd, J = 4.2, 10.3 Hz, 1H), 4.96 (d, J = 7.9 Hz, ÍH), 5.27 (t, J = 9.9 Hz, 1H), 5.34-5.40 (m, 2H), 5.54 (s, ÍH), 7.27-7.37 (m, 3H), 7.51-7.56 (m 2H), 7.57 (dd, J = 2.0. Hz, ÍH), 7.65-7.70 (m, ÍH), 7.72 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 2.0 Hz, ÍH), 8.01-8.05
(m, 2H); IR (KBr) 3440, 2950, 2830, 1755, 1620, 1550, 1440, 1410, 1370, 1320, 1240, 1160, 1120, 1070, 1030, and 990 cm "1: mass spectrum [(+) FAB], m / z 872 (M + H) +, 894 (M + Na) +, Analysis calculated for C41H42C1N018, 0.5 H20: C, 55.88: H. 4.92, N. 1.59, Found: C. 55.90, H 4.80, N. 1-56.
Example 32
6- (4-Chloro-3-nitro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3.2-d] [1,3] dioxin-6-yloxy) -4 ester 5-dihydroxy-tetrahydro-pyran-2-ylmethyl nicotinic acid
The title compound is prepared as a white foam (0.211 g, 45%) from 4-chloro-3-nitro-benzyl-4 ', 6'-O-benzylidene-β-D-maltoside using sodium chloride hydrochloride. nicotinoyl and a procedure similar to that of Example 2
(except that the compound is purified directly by flash chromatography), m.p. > 105 ° C (decomposition): 1H
NMR (DMSO-d5) d 3.21-3.28 (m, ÍH), 3.32-3.42 (m, 2H), 3.51- 3.60 (m, 3H), 3.65 (t, J = 9.2 Hz, ÍH), 3.67-3.74 ( m, ÍH), 3.78-3.83 (m, ÍH), 4.01-4.06 (m, ÍH), 4.38 (dd, J = 5.1, 12.3 Hz, ÍH), 4.45 (d, J = 7.9 Hz ÍH), 4.58- 4.64 (m, 1H), 4.79 (ABc, J = 13.6 Hz,? D = 0.09, 2H), 5.17 (d, J = 3.7 Hz, ÍH), 5.35
(d, J = 5.3 Hz, ÍH), 5.46 (d, J = 5.3 Hz, ÍH), 5.52 (s, ÍH),
. 61 (d, J = 3.1Hz, ÍH), 5.82 (d, J = 6.2 Hz, ÍH), 7.34-7.37 (m, 3H), 7.39-7.43 (m, 2H); 7.54-7.59 (m, ÍH), 7.68-7.71 (m,
2H), 8.08 (d, J = 1.3 Hz, HH), 8.31 (d, J = 7.9 Hz, HH), 8.78-8.88 (broad s, HH), 9.05-9.19 (broad s, 1H); IR (KBr) 3400. 2900, 2870, 1725, 1600, 1540, 1440, 1410, 1360, 1285, 1070, 1030, 740, and 690 cm "1; mass spectrum [(+) FAB], m / z 705 / 707 (M + H) +: Analysis calculated for C32H33C1N2014, 1.0 H20: C. 53.15: H.4.88, N.3.87, Found: C, 53.33: H. 4.78: N. 3.72.
Example 33
4 - . 4 - [2,3-di-0-acetyl-4-6- (phenylmethylene) -aD-glucopyranosyl] - β-D-glucopyranoside 2,3-diacetate 6- (3-pyridinecarboxylate) of (R) - (4-chloro-3-nitrophenyl) methyl The title compound is prepared as a white foam (0.123 g, 95%), from the ester 6- (4-chloro-3-nitro-benzyloxy) -3 - ( 7,8-Dihydroxy-2-phenyl-hexahydro-pyrano [3.2-d] [1,3] dioxin-6-yloxy) -4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl of nicotinic acid using a similar procedure to that of Example 25, pf >101 ° C (decomposition) 1 H NMR (DMS0-d 6) d 1.95 (s, 3 H), 1.96 (s, 3 H), 1.98 (s, 3 H), 1.99 (s, 3 H), 3.64 (t, J = 9.4 Hz, ÍH), 3.69-3.81 (m, 2H), 3.87 (t, J = 9.4 Hz, ÍH), 4.17 (dd, J = 3.1, 5.7 Hz, ÍH), 4.27 (t, J = 9.4 Hz, ÍH) ), 4.47 (dd, J = 4.0, 12.5Hz, ÍH), 4.69-4.75 (m, 2H), 4.80-4.91 (m, 3H), 4.96 (d, J = 8.1Hz, ÍH), 5.26 ( t, J = 10.1Hz, ÍH), 5.33-5.39 (m, 2H), 5.55 (s, ÍH), 7.29-7.36 (m, 5H), 7.55-7.59 (m, 2H), 7.72 (d, J = 8.3 Hz, ÍH), 7.93 (d, J = 2.0 Hz, ÍH), 8.36 (d, J = 2.2, 7.9 Hz, ÍH), 5, 84 (dd, J = 1. 8. 4.8 Hz, ÍH), 9.16 (dd, J = 0.9, 2.2 Hz, ÍH): IR (KBr) 3440, 2930, 2860, 1755, 1600, 1540, 1420, 1375, 1280, 1240, 1140, 1070, 1060, 1030, and 995 cm " 1; mass spectrum [(+) FAB], m / z 873/875 (M + H) +. 895/897 (M + Na) +, Analysis calculated for C40H41ClN2O18 1.25 H20: C. 53.64; H, 4.89; N, 3.13, Found: C, 53.46; H, 4.5 1; N, 2.96.
Example 34
6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran-L3.2- • di p.33 dioxin-6-yloxy) ester 4, 5-Dihydroxy-tetrahydro-pyran-2-ylmethyl 4-methoxybenzoic acid
The title compound is prepared as a white foam (0.284 g, 47%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide using p-anisoyl chloride and a procedure similar to that of Example
2, p.f. > 117 ° C (decomposition): XH NMR (DMS0-d6) d 2.05 (s,
3H), 3.15-3.21 (m, ÍH), 3.35 (d, J = 9.4 Hz, ÍH), 3.35-3.42)
(m, ÍH), 3.48-3.61 (m, 4H), 3.67-3.76 (m, ÍH), 3.82 (s, 3H), 4.05 (dd, J = 4.8, 9.9 Hz, ÍH), 4.29 (dd, J = 5.5, 12.3 Hz, ÍH), 4.38 (d, J = 7.9 Hz, ÍH), 4.55-4.60 (m, ÍH), 4.65 (ABc = 12.5 Hz,? D = 0. 14. 2H), 5.13 (d , J = 3.7 Hz, HH), 5.34 (dd, J = 4.0, 5.3 Hz, 2H), 5.52 (s, HH), 5.56 (d, J = 2.9 Hz, HH), 5.77 (d, J = 6.2 Hz , ÍH), 7.02-7.06 (m, 2H), 7.19 (dd, J = 2.0, 8.3 Hz, HH), 7.33-7.37 3H), 7.39-7.44 (m, 3H), 7.64
(s, ÍH), 7.94 (dt, J = 2.9, 9.9 Hz, 2H), 9.50 (s, ÍH); GO
(KBr) 3410, 3000, 2910, 1880, 1720, 1610, 1580, 1530, 1515,
1450, 1420, 1375, 1255, 1160, 1070, and 1025 c "1; mass spectrum [(+) FAB], m / z 746/748 (M + H) \ 768/770 (M + Na) +, 784/786 (M + K) +: Analysis calculated for C36H40ClNO14-2.0 H20: C, 55.2, H. 5.67: N, 1.79. Found: C. 55.38, H. 5.28: N, 1.72.
Example 35
4-, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetQXI-2-phenyl-hexahydro-pyran [3.2 -di], dioxin- 6 - ester iloxy) -tetrahydro-pyran-2-ylmethyl of 4-methoxy-benzoic acid
The title compound is prepared as a white foam (0.142 g, 81%) from 6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-f-enylhexahydro) ester. -pirano [3,2-d] [1, 3] dioxin-6-yloxy) -4,5-dihydroxy-tetrahydropyran-2-ylmethyl 4-methoxy-benzoic acid using the procedure similar to that of Example 25, mp > 110 ° C
(decomposition): X H NMR (DMSO-d 6) d 1.94 (s, 3 H), 1.95 (s,
3H), 1.98 (s, 3H), 1.99 (s, 3H), 2.06 (s, 3H), 3.61 (t, J = 9.7
Hz, ÍH), 3.68-3.75 (m, ÍH), 3.80 (dd, J = 4.6, 9.4 Hz, ÍH),
3. 82 (s, 3H), 3.82-3.89 (m, ÍH), 4.11-4.16 (m, ÍH), 4.17 (c, 9..7 Hz,] H), 4.40 (dd, J = 3.3, 12.3 Hz, ÍH), 4.63 (ABc, J =
12. 7 Hz,? D = 0.15, 2H), 4.64 (d, J = 10.8 Hz, ÍH), 4.77 (dd, J = 7.9, 9.4 Hz, ÍH), 4.86-4.91 (m, 2H), 5.26 (t, J = 9.9 Hz, ÍH), 5.32-5.38 (m, 2H), 5.54 (s, ÍH), 7.06 (dt, J = 2.9, 9.7 Hz, 3H), 7.29-7.37 (m, 5H), 7.42 (d , J = 8.1Hz, ÍH), 7.61 (s, ÍH), 7.99 (dt, J = 2.9, 9.9 Hz, 2H), 9.49 (s, ÍH): IR (KBr) 3400, 2950, 2840, 1755, 1700 , 1600, 1580, 1535, 1515, 1450, 1420, 1375, 1240, 1165, 1110, 1070, 1055, and 1030 cm "1: mass spectrum [(+) FAB], m / z 914/916 (M + H) \ 936/938 (M + Na) +, Analysis calculated for C44H48C1N018, 1.0 H20: C, 56.68: H, 5.41: N, 1.50, Found: C. 56.37: H, 5.08, N, 1.48.
Example 36
6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran T3.2-d] [1,31 dioxin-6-yloxy) -4 ester 5-dihydroxy-tetrahydro-pyran-2-ylmethyl 4-chloro-benzoic acid
The title compound is prepared as a white foam (0.372 g, 61%) from N-. { 5- [(4 •, 6 '-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide using 4-chlorobenzoyl chloride and a procedure similar to that of
Example 2. p.f. > 113 ° C (decomposition); XH NMR (DMSO-d6) d
2. 05 (s, 3H), 3.16-3.21 (m, ÍH), 3.28-3.41 (m, 2H), 3.48-3.62 (m, 4H), 3.69 (dd, J = 5.1, 9.9 Hz, ÍH), 3.76 ( ddd, J = 1.5,
4. 6, 9.4 Hz, ÍH), 4.04 (dd, J = 4.8, 9.9 Hz, 1H), 4.33-4.40 (m,
2H), 4.55-4.60 (m, 2H), 4.73 (d, J = 12-5 Hz, ÍH), 5.13 (d,
J = 4.0 Hz, ÍH), 5.35 (t, J = 5.3 Hz, 2H), 5.52 (s, 1H), 5.58
(d, J = 2.9 Hz, ÍH), 5.81 (d, J = 6.2 Hz, ÍH), 7.19 (dd, J = 2.0, 8.3 Hz, ÍH), 7.33-7-37 (m, 3H), 7.38- 7.43 (m, 3H), 7.59 (dt, J = 2.4, 9.2 Hz, 2H), 7.64 (s, ÍH), 7.99 (dt, J = 2.4, 9.0 Hz, 2H), 9.50 (s, ÍH); IR (KBr) 3410, 2910, 2870, 1725, 1590, 1530, 1440, 1420, 1375, 1270, 1070, 1025, and 760 cm "1: mass spectrum [(+) FAB], m / z 750/752 / 754 (M + H) +, 772 (M + Na) \ 788/790/792 (M + K) +; Analysis calculated for C35H37C12N013, 1.5 H20: C, 54.06; H, 5.18, N, 1.80. C. 53.76, H, 4.78, N, 1.77.
Example 37
4-, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-p-enyl-hexahydro-pyran [3.2-dl Ti, 31 dioxin-6-yloxy] ester ) 4-chloro-benzoic acid-tetrahydro-pyran-2-ylmethyl
The title compound is prepared as a white foam (0.225 g, 72%) from the 6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-) ester. [3,2-d] [1, 3] dioxin-6-yloxy) -4,5-dihydroxyethyl-hydroxy-2-methyl-2-methyl-2-methyl-benzoic acid ester using a procedure similar to that of Example 25, pf 114-115 ° C. X H NMR (DMSO-ds) d 1.94 (s, 3 H), 1.95 (s, Í H), 1.98 (2, 3 H), 1.99 (s, 3 H), 2.05 (s, 3 H), 3.62 (t, J = 9.2 Hz, 1H), 3.68-3.74 (m, ÍH), 3.79 (dd, J = 4.2, 9.2 Hz, ÍH), 3.86 (t, J = 9.4 Hz, ÍH), 4.13-4.19 (m, ÍH), 4.18 (c, J = 9.4, ÍH), 4.47 (dd, J = 3.5, 12.3 Hz, ÍH), 4.63 (ABc, J = 12.7 Hz,? d = 0.14, 2H), 4.66 (d, J = 10.8 Hz, ÍH), 4.79 (dd, J = 8.1, 9.2 Hz, ÍH), 4.86-4.91 (m, 2H), 5.26 (t, J = 9.9 Hz, ÍH), 5.32-5.38 (m, 2H), 5.54 (s) , ÍH),
7. 05 (dd, J = 1.8, 8.3 Hz, ÍH), 7.27-7.31 (m, 2H), 7.32-7.36 (m, 3H), 7.42 (d, J = 8.3 Hz, 1H), 7.58-7.63 (m, 3H), 8.02- 8.06 (m, 2H), 9.49 (s, ÍH); IR (KBr) 3410, 2950, 2860, 1755, 1690, 1600, 1530, 1450, 1420, 1375, 1260, 1140, 1070, 1055, and 1030 cm "1: mass spectrum [(+) FAB], m / z 918/920/922 (M + H) +, 940/942/944 (M + Na) +, Analysis calculated for C43H45C12N017, 1.0 H20: 55.13, H. 5.06, N. 1.50, Found: C. 54.77 H. 4.73: N. 1.45.
Example 38
(R) -N- [2-chloro-5- [[[6-0- (4-chloro-3-nitrobenzoyl) -4-0- [4,60- (phenylmethylene) -α-D-glucopyranosyl-1-ß- D-glucopyranosyl] oxy] methyl phenyl] acetamide
The title compound is prepared as a white solid (0.158 g, 52%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide using 4-chloro-3-nitrobenzoyl chloride and a procedure similar to that of Example 2; XR NMR (DMSO-d6) d 2.13 (s, 3H), 3.41 (apparent t, J = 9.4 Hz, ÍH), 3.55-3.69 (m, 6H), 3.77 (apparent t, J = 9.0 Hz, 1H), 3.87-3.97 (m, 3H), 4.29 (dd, J = 10.5, 4.8 Hz, 1H), 4.41 (d, J = 7.7 Hz, ÍH), 4.47 (dd, J = 12.1, 5.3 Hz, ÍH), 4.60 (d, J = 12.7 Hz, 2H), 4.72 (dd, J = 12.0, 2.0 Hz, HH), 4.84 (d, J = 12.5 Hz, HH), 5.08 (d, J 3.7 Hz, HH), 5.14 ( s broad, ÍH), 5.47 (s, ÍH), 6.99 (dd, J = 8.3, 2.0 Hz, ÍH), 7.29 (d, J = 5.3 Hz, ÍH), 7.32-7.44 (m, 3H), 7.45- 7.47 (m, 2H), 7.60 (s, ÍH), 7.64 (d, J = 8.6 Hz, ÍH), 8.16 (dd, J = 8.3, 2.0 Hz, ÍH), 8.34 (s, ÍH), 8.51 (d , J = 2.0 Hz, ÍH), IR (KBr) 3400, 2900, 1750, 1660, 1275, and 1075 cm "1; mass spectrum [(+) FAB], m / z 795/797/799 (M + H) \ 817/819/821 (M + Na) +; Analysis calculated for C35H36C12N2015.1.0 H20: C, 51.67.H, 4.71, N, 3.44, Found: C. 51.87: H. 4.84, N. 3.60.
Example 39
N-. { 5- [(2,2 ', 3-tri-0-acetyl-6-0- (4-chloro-3-nitrobenzoyl) -4', 6'-O- (benzylidene) - ß-D-maltosyl) - oxymethyl-2-chloro-phenyl) -acetamide
The title compound is prepared as a white solid from (R) -N- [2-chloro-5- [[[6-0- (4-chloro-3-nitrobenzoyl) -4-0- [4, 60- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] phenyl] acetamide using a procedure similar to that of Example 25: 1 H NMR (DMSO-d 6) d 2.04 (s, 3H), 2.05 ( s, 3H), 2.06 (s, 3H), 2.22 (s, 3H), 3.11 (d, J = 3.7 Hz, 1H), 3.62 (m, 4H), 3.81-3.99 (m, ÍH), 4.29 (dd) , J = 10.3, 4.8 Hz, 1H), 4.48-4.61 (m, 3H), 4.98 (dd, J = 10.3.
3. 7 Hz, 1H), 5.35 (d, J = 4.0 Hz, ÍH), 5.44-5.52 (m, 2H), 6.99 (dd, J = 8.1, 2.0 Hz, ÍH), 7.31-7.42 (m, 6H), 7.58-7.59 (m, 2H), 7.63 (d, J = 8.3 Hz, ÍH), 8.14 (dd, J = 8.3, 2.0 Hz, ÍH), 8.31 (s broad, ÍH), 8.51 (d, J = 2.0 Hz, ÍH); IR (KBr) 3400, 2900, 1750, 1660, 1275 and 1075 cm "1; mass spectrum [(+) FAB], m / z 921/923/925 (M + H) \ 943/945/947 (M + Na) +, Analysis calculated for C41H42C12N2018: C. 53.43, H. 4.59, N, 3.04, Found: C. 52.88: H, 5.11; N, 2.59.
Example 40
(R) -N- [2-chloro-5- [[[6-0- (4-cyanobenzoyl) -4-0- [4, 60- (f in methyl butyl) - a -D-gl uc op i rano sill - ß - D -glucopyranosyl] oxyl methyl] f enyl acetamide
The title compound is prepared as a white solid from N-. { 5- [(4,6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-f-enyl} -acetamide using 4-cyanobenzoyl chloride and a procedure similar to that of Example 2, p.f. 143-145 ° C; ? NMR (DMS0-d6) d 2.04 (s, 3H), 3.17-3.22 (m, 2H), 3.28-3.41 (m, 3H), 3.48-3.80 (m, 5H), 4.03 (dd, J = 9.4. Hz, 1H), 4.38-4.42 (m, 2H), 4.62 (d, J = 10.8 Hz, ÍH), 4.65 (ABc, J = 12.5 Hz,? D J = 0.13, 2H), 5.14 (d, J = 4.80 Hz, 2H), 5.35 (apparent t, J = 5.3 Hz, 2H), 5.52 (s, 1H), 5.59 (d, J = 2.9 Hz, ÍH), 5.83 (d, J = 6.0 Hz, ÍH), 7.19 (dd, J = 8.3, 2.0 Hz, ÍH), 7.34-7.39 (m, 3H), 7.39-7.42 (m, 2H), 7.63 (s, ÍH), 8.0 (d, J = 8.9 Hz, 2H), 8.13 (d, J = 8.8 Hz, 2H), 9.49 (s, ÍH); IR (KBr) 3400, 2900, 1725, 1660, 1175 and 1075 cm "1: mass spectrum [(-) FAB], m / z 739/741 (M - H) +; Analysis calculated for C36H27C1N2013 .0.5 H20: : C, 57.64, H. 5.11, N. 3.73, Found: C. 57.47, H. 5.08: N. 3-57.
Example 41
(R) -N- [2-chloro-5- [[[6-0- (4-nitrobenzoyl) -4-0- [4, 60- (f enylmethyl) -α-D-gl uc op i rano sill - ß - D -glucopyranosyl] oxy] metill f enill acetamide
The title compound is prepared as a white solid from N-. { 5 - [(4 ', 6' -O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-f-enyl} -acetamide using 4-nitrobenzoyl chloride and a procedure similar to Example 2; H NMR
(DMS0-d6) d 2.14 (s, 3H), 3.41 (apparent t, J = 9.2 Hz, ÍH),
3. 54-3.69 (m, 5H), 3.84-3.99 (m, 5H), 4-30 (dd, J = 10.1 5.1 Hz, 1H), 4.41 (d, J = 7.7 Hz, ÍH), 4.50 (dd, J = 7.5, 4.6 Hz,
2H), 4.72 (dd, J = 12.1, 1.3 Hz, ÍH), 4.73 (ABc, J = 12.5 Hz,
? d = 0. 21. 2H), 4.85 (d, J = 3.4 Hz, 2H), 5.47 (s, ÍH), 6.97-7.0 (m, ÍH), 7.29 (d, J = 2.9 Hz, ÍH), 7.32-7.36 (m, 3H), 7.44- 7.52 (m, 2H), 7.60 (s broad, ÍH), 8.20 (d, J = 9.0 Hz, 2H), 8.29 (d, J = 9.0 Hz, 2H), 8.36 (s broad, ÍH): IR (KBr) 3400, 2900, 1725, 1660, 1275 and 1075 cm "1: mass spectrum [(+) FAB], m / z 761/763 (M + H) +, 783/785 (M + Na) +: Analysis calculated for C35H37C1N2015 2.0 H20: C 52.74: H 5.18; N 3.51, Found: C 52.92 H, 5.07; N, 3.45.
Example 42
(R) -N-r2-chloro-5-ff-O- (3-trifluoromet-il-benzoyl) -4-0-> 4, 60- (f-l-methyl) - a-D-glucopyranos - ß - D -glucopyranosyl] oxy] methyl] phenyl] acetamide
The title compound is prepared as a white solid from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using 3-trif luoromethylbenzoyl chloride and a procedure similar to that of
Example 2, p.f. 194 ° C; XH NMR (DMSO-d6) d 2.11 (s, 3H), 3.40
(apparent t, J = 9.4 Hz, ÍH), 3.53-3.68 (m, 5H), 3.77 (apparent t, J = 8.8 Hz, 1H), 3.88-3.93 (m, 2H), 3.97 (apparent t, J =
9. 4 HZ, 1H), 4.30 (dd, J = 10.3, 5.1Hz, ÍH), 4.40 (d, J = 7.7 Hz, ÍH), 4.71 (ABc J = 12.5 Hz,? D = 0.22, 2H), 4.73 (d, J = 11, Hz, ÍH), 5.09 (d, J = 3.7 Hz, 2H), 5.46 (s, ÍH), 6.95 (dd, J = 8.34, 1.8 Hz, ÍH), 7.26 (d, J = 8-3 Hz, ÍH), 7.30-7.34 (m, 3H), 7.43-7.47 (m, 2H), 7.60 (broad t, 7 Hz, 2H), 7.81 (bd, J = 7.7 Hz, ÍH) , (bd, J = 8.0 Hz, 1H), 8.32 (bd, J = 9.2 Hz, 2H), IR (KBr) 3400, 2900, 1725, 1660, 1250 and 1075 cm "1; mass spectrum [(+) FAB], m / z 784/786 (M + H) +. 806/808 (M + Na) +: Analysis calculated for C3SH49C1N3013, 1.0 H20 :: C. 53.91: H, 490, N. 1.75, Found: C , 54.19: H, 4.67; N, 1.75, Example 43
N-. { 5- [(4 ', 6' -O-Benzylidene-6-0- (2-iodo) -benzoyl-β-D-maltosyl) -oxi-methyl-2-chloro-phenyl) -acetamide
The title compound is prepared as a white solid from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using o-iodobenzoyl chloride and a procedure similar to that of Example 2, p.f. 140-143 ° C; 'H NMR (DMSO-d6) d 2.05 (2, 3H), 3-15-3.17 (m, ÍH), 3.218-3.65 (m, 6H), 3.75-3.79 m, 3H), 4.14 (dd, J = 9.1 Hz, ÍH), 4.35 (dd, J = 12.1 5.7 Hz, ÍH), 4.40 (d, j = 7.9, ÍH), 4.62 (d, J = 10.8 Hz, ÍH), 4.66 (ABc, J = 12.3 Hz ,? d 0. 14. 2H), 5.15 (d, J = 4.0 Hz, ÍH), 5.36 (t, J = 5.3 Hz, 2H), 5.55
(s, ÍH), 5, 60 (d, J = 64 Hz, ÍH), 5.87 (d, J = 6.2 Hz, ÍH), 7.18 (dd, J = 8.1, 2.00 Hz, ÍH), 7.26-7.30 ( m, ÍH), 7.34-7.50
(m, 6H), 7.51-7.53 (m, ÍH), 7.63 (s, ÍH), 7.78 (dd, J = 7.9, 1.5 Hz, ÍH), 8.02 (dd, J = 7.9, 1.1 Hz, ÍH), 9.50 (s, ÍH); GO
(KBr) 3400, 2930, 1750, 1550, 1245 and 1075 cm "1; mass spectrum
[(+) ESI], m / z 842/844 (M + H) +, 859/861 (M + NH4) +: Analysis calculated for C35H37C1N013. 1.0 H20: C, 48.84; H. 4.53: N, 1.66, Found: C.48.59; H. 4.28; N, 1.58.
Example 44
N-. { 5- f (4 ', 6'-O-benzylidene-6-0- (3-iodo) -benzoyl-β-D-maltosyl) -oxi-methyl-2-chloro-phenyl} -acetamide
The title compound is prepared as a white solid from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide using m-iodo-benzoyl chloride and a procedure similar to that of Example 2, p.f. 175-177 ° C; XH NMR (DMSO-d6) d 2.05 (s, 3H), 3.15-3.20 (m, 2H), 3.32-3-42 (m, 2H), 3.50-3.61 (m, 4H), 3.70-3.77 (, 2H) ), 4.00-4.09
(m, 2H), 4.34 (dd, J = 12.1 5.7 Hz, ÍH), 4.40 (d, J = 7.9 Hz, ÍH), 4.62 (d, J = 10.5, Hz, ÍH), 4.66 (ABc, J = 12-3 Hz,? D = 0.14, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.35 (apparent t, J = 5.7 Hz, 2H), 5.53 (s, ÍH), 5.57 (d , J = 2.9 Hz, HH), 5.79 (d, J = 6.4 Hz, HH), 7.01 (dd, J = 8.3, 1.8 Hz, 1H), 7.32-7.37 (m, 3H), 7.40-7.42 (m, 2H), 7.65 (s, ÍH), 7.99-8.03 (m, 2H), 8.26
(t, J = 1.8 Hz, ÍH), 9.50 (5. ÍH); IR (KBr) 3400, 2930, 1700, 1250 and 1075 cm "1, mass spectrum [(-) FAB], m / z 840 (M-H) +; Analysis calculated for C35H37C1N013, 1.0 H20: C, 48.88; H. 4.57: N. 1.63, Found: C. 49.02, H. 4.49: N. 1.54.
Example 45
N-. { 5 - [(4 ', 6' -0-benzylidene-6- (4-iodo-benzoyl-oxy-β-D-maltosyl] oxy-methyl] -2-chloro-phenyl] -acetamide
The title compound is prepared as a white solid (0.410 g, 60%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using p-iodobenzoyl chloride and a procedure similar to that of Example 2, p.f. > 187 ° C (decomposition), E NMR (DMSO-d6) d 2.05 (s, 3H), 3.15-3.22 (m, ÍH), 3.28-3.42 (m, 2H), 3.48-3.62 (m, 4H), 3.66 -3.73 (m, ÍH), 3.75 (ddd, J = 1.5, 4.8, 9.7 Hz, ÍH), 4.01 - 4.06 (m, ÍH), 4.35 (dd, J = 5.3, 12.3 Hz, ÍH), 4.39 (d , J = 7.7 Hz, HH), 4.57 (d, J = 10.3 Hz, HH), 4.65 (ABc, J = 12.5 Hz, d d = 0. 14. 2H), 5.12 (d, J = 4.0 Hz, HH ), 5.35 (t, J = 5.3 Hz, 2H), 5.52 (s, ÍH), 5.58 (d, J = 2.9 Hz, ÍH), 5. 81 (d, J = 6.2 Hz, ÍH), 7.19 (dd) , J = 1.8, 8.1Hz, 1H), 7.33-7.38 (m, "3H), 7.38-7.43 (m, 3H), 7.64 (s, 1H), 7.73 (dt, J = 2.0, 8.8 Hz, 2H) , 7.91 (dt, J = 8.8 Hz, 2H), 9.50 (s, ÍH), IR (KBr) 3420, 3270, 2920, 2880, 1725, 1660, 1590, 1530, 1450, 1425, 1385, 1375, 1280, 1140, 1110, 1070, 1050, 1030, 1005, and 750 cm "1; mass spectrum [(+) FAB], m / z 864/866 (M + Na) *, - Analysis calculated for C35H37ClIN013: C. 49.93: H, 4.43: N. 1.66, Found: C, 49.65. H. 4.51, N. 1.77.
Example 46
(R) -N- r-2-chloro-5- [[[6-0- (phenylacetyl) -4-Q- f4, 6-Q- [4,6-0- (phenylmethylene) - a -D- glucopyranosyl l] - ß - D -glucopyranosyl oxy] methyl] phenyl] acetamide
The title compound is prepared as a white glass (0.249 g, 42%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using phenylacetyl chloride and a procedure similar to that of Example 2, p.f. > 98 ° C (decomposition); XH NMR (DMS0-d6) d 2.08 (s, 3H), 3.08-3-13 (m, HH), 3.27-3.49 (m, 4H), 3.54 (dd, J = 5.3, 9.2 Hz, HH) , 3.56-3.63 (m, 2H), 3.66 (dd, J = 4.4, 9.4 Hz, ÍH), 3.71 (s, 2H), 4.06 (dd, J = 4.4, 9.4 Hz, ÍH), 4.12 (dd, J = 5.7, 12.3 Hz, ÍH), 4.32 (d, J = 7.7 HZ, ÍH), 4.37 (d, J = 11.0 Hz, ÍH), 4.58 (ABc, J = 12.5 Hz,? D = 0.16, 2H ), 5.02 (d, J = 3.7 Hz, ÍH), 5.32 (d, J = 5.3 Hz, ÍH), 5.35 (d, J = 5.3 Hz, ÍH), 5.55 (s, ÍH), 5.57 (d, J = 2.9 Hz, HH), 5.83 (6.2 Hz, HH), 7-18-7.31 (m, 6H), 7.34-7.36 (m, 3H), 7.41-7.46 (m, 3H), 7.65 (s, 1H) , 9.53 (s, ÍH); IR KBr) 3390, 2910, 2880, 1740, 1670, 1590, 1535, 1460, 1420, 1375, 1310, 1250, 1140, 1070, and 1025 cm "1. mass spectrum [(+) FAB], m / z 730/732 (M + H) +, 752/754 (M + Na) +. 768/770 (M + K) +; Analysis calculated for C36H40ClNO13, 2.0 H20 :: C. 56.43: H. 5.79: N. 1.83 , Found: C, 56.62: H, 5.35; N, 1.79.
Example 47
(R) -N- [2-chloro-5-f? [2, 3-di-0-acetyl-4-0- [2,3-di-0-acetyl-4,6-0- (f-methylene) -aD-glucopyranosyl] -6-0- (f enylacetyl) -β-D-glucopyranosyl-oxyl methyl] f enyl acetamide
The title comd is prepared as a white foam
(0.125 g, 73%) from (R) -N- [-2-chloro-5- [[[6-0- (phenylacetyl) -4-0- [4-6-0- (phenylmethylene) - aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] phenyl] acetamide using a procedure similar to that of Example 25, mp > 98 ° C XH NMR
(DMS0-d6) d 1.93 (s, 3H), 1.94 (5, 3H), 1.97 (s, 3H), 1.99 (s,
3H), 2.08 (s, 3H), 3.69-3.78 (m, 4H), 3.86-3.94 (m, 2H), 4.01
(ddd, J = 2.6, 4.4, 9.7 Hz, ÍH), 4.10 (d, J = 5.3 Hz, ÍH),
4. 20 (dd, J = 5.1, 12.3 Hz, 1H), 4.44-4.50 (m, 2H), 4.63-4.70
(m, 2H), 4.83 (d, J 8.1Hz, ÍH), 4.88 (dd, J = -4.2, 10.3 Hz,
ÍH), 5.21-5.27 (m, 2H), 5.30 (t, J = 9.2 Hz, ÍH), 5.61 (s, 1H)
7. 05 (dd, J = 1.8, 8.1Hz, ÍH), 7.19-7.30 (m, 5H), 7.35 (s,
5H), 7.45 (d, J = 8.3 Hz, ÍH), 7.62 (s, ÍH), 9.51 (s, ÍH);
IR (KBr) 3400, 3030, 2940, 2840, 1755, 1690, 1600, 1445, 1420,
1375, 1240, 1140, 1060, and 1030 cm "1: mass spectrum [(+) FAB] m / z 898/900 (M + H) +, 920/922 (M + Na) + Analysis calculated for
C44H48C1N017. 1.75 H20: C. 56.84: H, 5.58, N, 1.51. Found:
C. 56.44: H, 5.11; N, 1.59.
Example 48
N-. { 5- [(4 ', 6'-0-benzylidene-6-0-phenyl-ethyl-carboxy-1-β-D-maltosyl) -oxi-methyl-2-chloro-f-enyl] } -acetamide
The title comd is prepared as a white solid (0.352 g, 63%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using hydrocinnamoyl chloride and a procedure similar to that of Example 2, p.f. 192-193: E NMR (DMS0-d6) d 2.06 (s, 3H), 2.66
(t, J = 7.7 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 3.08-3.16 (m, ÍH), 3.33-3.49 (m, 4H), 3.53-3.59 (m, 2H), 3.61-3.72 (m, 2H), 4.05-4.12 (m, 2H), 4.32-4.37 (m, 2H), 4.62 (ABc, J = 12.3 Hz,? D = 0.16, 2H), 5.09 (d, J = 4.0 Hz, ÍH), 5.3.5 (d, J = 5.1Hz, ÍH), 5.33 (d, J = 5.3 Hz, ÍH), 5.54-5.58 (m, ÍH), 5.56 (s, ÍH), 5.82 ( d, J = 6.2 Hz, HH), 7.12-7.18 (m, HH), 7.18-7.26 (m, 5H), 7.34-7.40 (m, 3H), 7.42-7.46 (m, 3H), 7.65
(s, ÍH), 9.51 (s, ÍH): IR (KBr) 3560, 3390, 3260, 3080, 2900, 2880, 1745, 1660, 1590, 1540, 1450, 1425, 1370, 1320, 1280, 1200, 1180 , 1140, 1070, 1050, 1025, 970, 755, and 695 cm "1: mass spectrum [(+) FAB], m / z 744 (M + H) +, 766 (M + Na) +: Calculated analysis for C37H42C1N013: C. 59.72, H. 5.69: N. 1.88, Found: C, 59.75, H. 5.75, N, 2.03.
Example 49
N-. { 5 - [(4 ', 6' -O-benzyl iden-6-o-phenyl-propyl-carboxy 1-ß-D-maltosyl) -oxi-methyl-2-chloro-phenyl} -acetamide
The title comd is prepared as a white solid (0.210 g, 68%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using 4-phenylbutyryl chloride (prepared from 4-phenylbutyric acid and oxalyl chloride) and a procedure similar to that of Example 2, p.f. 184-185 ° C: XH NMR (DMSO-d6) d 1.77-1.86 (m, 2H), 2.07 (s, 3H), 2.34 (t, J = 7.2Hz 2H), 2.58 (t, J = 7.5 Hz, 2H), 3.08-3.16 (m, ÍH), 3.29-3.51 (m, 4H), 3-53-3.73 (m, 4H), 4.07-4.14 (m, 2H), 4.33-4.38 (m, 2H) 4.62 (ABc, J = 12.3 Hz,? D = 0.16, 2H), 5.09 (d, J = 4.0 Hz, ÍH), 5.28-5.37
(s broad, 2H), 5.56 (s, 2H), 5.82 (d, J = 5.3 Hz, ÍH), 7.13- 7.19 (m, 4H), 7.21-7.27 (m, 2H), 7.33-7.37 (m, 3H), 7.40-7.46
(m, 3H), 7.63 (s, ÍH), 9.51 (s, ÍH): IR (KBr) 3560, 3390,
3260, 3080, 2930, 2900, 2880, 1745, 1665, 1590, 1540, 1450, 1420, 1370, 1320, 1275, 1175, 1140, 1070, 1050, 1025, and 690 cm "x, mass spectrum [(+ ) FAB] m / z 780/782 (M + Na) +: Analysis calculated for C ^ H ^ CINO-L 60.20: H, 5.85; N, 1.85.
Found: 60.13. H. 5.73. N. 1.99, Example 50
6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3.2-dl [1,3] dioxin-6-yloxy) -4.5 ester diphenyl-acetic acid dihydroxy-tetrahydro-pyran-2-ylmethyl
The title compound is prepared as a white foam (0.510 g, 77%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using diphenylacetyl chloride and a procedure similar to that of
Example 2, p.f. > 106 ° C (decomposition): E NMR (DMSO-d6) d 2.08
(s, 3H), 3.03-3.09 (m, ÍH), 3.26-3.38 (m, 3H), 3.41-3.47 (m,
ÍH), 3.51-3.62 (m, 3H), 3.66-3.73 (m, 1H), 4.02-4.07 (m, ÍH), 4.15 (c, J = 6.2 Hz, 1H), 4.27 (d, J = 7.7 Hz , 1H), 4.46 (ABc, J = 12.5 Hz,? D = 0.15, 2H), 4.50 (d, J = 10.8 Hz, ÍH, 4.90 (d, J = 4.0 Hz, 1H), 5.27 (s, ÍH) , 5.31 (d, J = 5.3 Hz, ÍH), 5.35 (d, J = 5.3 Hz, ÍH), 5.54-5.56 (m, 2H), 5.81 (d, J = 6.4 Hz, ÍH), 7.14 (dd, J = 1.8, 8.3 Hz, ÍH), 7.19-7.25 (m, ÍH), 7.15-7.34 (m, 8H), 7.34-7.38 (m, 3H), 7.40-7.45 (m, ÍH), 7.61 (s, 1H), 9.52 (s, ÍH): IR (KBr) 3400, 3050, 2900, 2860, 1730, 1680, 16000, 1530, 1500, 1450, 1420, 1375, 1310, 1275, 1240, 1150, 1070, 1025, 750, and 690 cm "1: mass spectrum [(+) FAB], m / z 806/808 (M + H) +, 828/830 (M + Na) +, 844/846 (M + K) + Analysis calculated for C42H44C1N013, 1.0 H20 :: C. 61.20, H, 5.63, N, 1.70, Found: C. 61.17: H. 5.48, N. 1.59, Example 51
4, 5-diacetoxyl-6- (3-acetylamino- -4- -cl'-oro-benzyloxy) -3- (7,, 8-diacetoxy-2-phenyl-hexa.hydro-pyran) T3 .2- ester Di-Di, 31-dioxin-6-yloxy) -tetrahydro-pyran-2-methylmethyl of the di-enyl-acetic acid
The title compound is prepared as a white foam (0.289 g, 76%) from the 6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro) ester. [3.2-d] [1, 3] -dioxin-6-yloxy) -4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl diphenylacetic acid using a procedure similar to that of Example 25, mp. > 99 ° C: (decomposition) 'H NMR (DMSO-d6) d 1.92 (s, 3H), 1.94 (s, 3H), 1.96 (s, 3H), 1.99 (s, 3H), 2.08 (s, 3H) , 3.66 (t, J = 9.9 Hz, 1H), 3.72-3.78 (m, 1H), 3.78 (t, 3 = 9.0 Hz, 1H), 3.87 (t, J = 9.7 Hz, ÍH), 3.98-4.05 ( m, 2H), 4.18-4.24 (m, ÍH), 4.44 (ABc, J = 12.7 Hz,? d = 0.16, 2H), 4.61-4.67 (m, 2H), 4.80 (d, J = 7.9 Hz, ), 4.88 (dd, J = 4.2, 10.3 Hz, 1H), 5.16 (d, J = 4.0 Hz, ÍH), 5.22 (t, J = 9.9 Hz, ÍH), 5.29 (t, J = 9.2 Hz, ÍH) ), 531 (s, ÍH), 5.60 (s, ÍH), 6.99 (dd, J = 1.5, 8.1Hz, ÍH), 7.20-7.25 (m, 2H), 7-27-735 (m, 5H), 7.35 (m, 5H), 7.43 (d, J = 8.1Hz, ÍH), 7.59 (s, ÍH), 9.51 (s, ÍH); IR (KBr) 3410, 3070, 3025, 2930, 2860, 1755, 1690, 1600, 1525, 1450, 1410, 1375, 1240, 1140, 1055, and 1030 cm "1. mass spectrum [(+) FAB], m / z 974 (M + H) +, 996 (M + Na) +, Analysis calculated for C50H52ClNO17, 1.25 H20: C. 6024, H. 5.51, N. 1.40, Found: c, 59.97: H. 5.10 : N, 1.37.
Example 52
6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3.2 -di [1,31 dioxin-6-yloxy) -4,5- ester (3,4-dimethoxy-phenyl) -acetic acid dihydroxy-tetrahydro-pyran-2-methylmethyl
The title compound is prepared as a white foam (0.316 g, 49%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide using 3,4-dimethoxyphenylacetyl chloride and a procedure similar to that of Example 2, p.f. > 106 ° C (decomposition): tE NMR (DMSO-d6) d 2.07 (s, 3H), 3.07-3.14 (m, ÍH), 6H), 3.52-3.65 (m, 4H), 3.67 (s, 3H), 3.68 (5, 3H), 4.4, 9.7 Hz, ÍH), 4.11 (dd, J = 5.5, 12.3 Hz, ÍH), 4.31-4.38 (m, 2H), 4.58 (ABc, J = 12.3 Hz,? D = 0.16, 2H), 4.99 (d, J = 3.7 Hz, 1H), 5.34 (dd, J = 5.3, 9.2 Hz, 2H), 5.55 (s, ÍH), 5.57 (d, J = 2.9 Hz, ÍH), 5.82 (d, J = 6.2 Hz, HH), 6.76 (d, J = 2.0, 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, HH), 6.85 (d, J = 2.0 Hz, HH), 7.19 (dd, J = 2.0, 8.3 Hz, ÍH), 7.34-7.37 (m, 3H 7.41-7.46 (m, 3H), 7.64 (s, ÍH), 9.53 (s, ÍH), IR (KBr) 3410, 2920, 1735, 1675, 1600, 1520, 1450, 1420, 1375, 1265, 1230, 1140, 1070, and 1025 cm "1; mass spectrum [(+) FAB], m / z 790/792 (M + K ) +: Analysis calculated for C38H44C1N015, 0.5 H20: 57.11, H. 5.68, N. 1.75, Found: C, 56.95, H. 5.55, N. 1.71.
Example 53
4-, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-dl Ti, 31 dioxin- -yloxy) ester 3- (4,4-dimethoxy-phenyl) -acetic acid tetrahydr-pyran-2-ylmethyl
The title compound is prepared as a white foam (0.105 g, 89%) from 6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl) ester. 3- (4,4-Dimethoxy-phenyl) -acetic acid hexahydro-pyran [3, 4-dimethoxy-piran-2-ylmethyl] dioxin-6-yloxy) -4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl using a procedure similar to that of Example 25, pf > 98 ° C (decomposition): t E NMR (DMS0-d6) d 1.92 (s, 3 H), 1.94 (s, 3 H), 1.97 (s, 3 H), 1.99 (s, 3 H), 2.07 (s, 3 H), 3.62-3.77 (m, 4H), 3.66 (s, 3H), 3.67 (s, 3H), 3.89 (t, J = 9.2 Hz, 2H), 3.99-4.03 (m, ÍH), 4.10 (dd, J = 10.5, 16.0 Hz, ÍH), 4.19 (dd, J = 4.4, 11.9 Hz, ÍH), 4.44-4.50 (m, 2H), 4.64-4.70 (m, 2H), 4.84 (d, J = 5, 1Hz, ÍH), 4.87 (dd, J = 4.0, 10.1Hz, ÍH), 5.21 (d, J = 3.7 Hz, 1H), 5.25 (d, J = 9.9 Hz, ÍH), 5.30 (t, J 9.2 Hz, ÍH) ), 5.62 (s, ÍH), 6.77 (dd, J = 1.8, 8.1Hz, ÍH), 6.81 (d, J = 8.3 Hz, ÍH), 6.86 (d, J = 1.8 Hz, ÍH), 7.04 (dd) , J = 1.5, 8.3 Hz, ÍH), 7.35 (s, 5H) 7.44 (d, J = 8.1Hz, ÍH), 7.61 (s, ÍH), 9.51 (s, ÍH); IR (KBr) 3370, 2930, 2860, 1755, 1690, 1600, 1520, 1450, 1420, 1370, 1240, 1140, 1055, and 1030 cm "1; mass spectrum I (+) FAB], m / z 958 / 960 (M + H) +, 980/982 (M + Na) +, Analysis calculated for C46H52C1N019 1.75 H20: C, 55.81: H, 5.65; N, 1.41, Found: C. 55.60, H, 5.14; N 1.38.
Example 54
6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-f-n-hexahydro-pyran [3,2-d] [1,3] dioxin-6-yloxy) -4 ester , 5-dihydroxy-tetrahydro-pyran-2-ylmethyl nicotinic acid
The title compound is prepared as a white solid (0.278 g, 47%) from N-. { 5- [(4 ', 6' -O-benzylidene-β-D-maltosyloxy) -methyl] -2-chloro-phenyl} -acetamide using nicotinoyl chloride hydrochloride and a procedure similar to that of Example 2, p.f. > 133 ° C (decomposition): XH NMR
(DMSO-d6) d 2.04 (s, 3H), 3.16-3.23 (m, ÍH), 3.36 (d, J = 9.4 Hz, ÍH), 3.36-3.42 (m, ÍH), 3.48-3.61 (m, 3H ), 3.63 (t, J = 9.4 Hz, 1H), 3.68-3.75 (m, ÍH), 3.76-3.80 (m, ÍH), 4.04 (dd, J = 4.6, 9.9 Hz, ÍH), 4.36-4.41 ( m, 2H), 4.64 (d, J = 10.5 Hz, ÍH), 4.65 (ABc, J = 12.5 Hz,? d = 0.14, 2H), 5.16 (d, J = 4.0 Hz, ÍH), 5.35 (dd, J = 4.0, 5.1, 2H), 5.52 (s, ÍH), 5.58 (d, J = 2.9 Hz, ÍH), 5.82 (d, J = 6.2 Hz, 1H), 7.19 (dd, J = 1.8, 8.3 Hz , ÍH), 7.34-7.38 (m, 3H), 7.39-7.43 (m, 3H), 7.57 (ddd, J = 0.7, 4.8, 7.9 Hz, ÍH), 7.64 (s, 1H), 8.33 (dt, J = 2.0, 7.9 Hz, ÍH), 8.82 (dd, J = 1.8, 4.8 Hz, ÍH), 9.12 (d, J = 2.2 Hz, ÍH), 9.49 (s, ÍH); IR (KBr) 3410, 2910, 2870, 1730, 1625, 1600, 1530, 1455, 1425, 1380, 1290, 1130, 1110, 1070, 1025, 740, and 690 cm "1; mass spectrum [(+) FAB ], m / z 717/719 (M + H) +: Analysis calculated for C34H37C1N2013, 1.0 H20: C, 55.55, H, 5.35, N. 3.81, Found: C, 55.55, H, 5.30, N, 3.78.
Example 55
Ester 4, 5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran-3, 2-dl Fl, 3] -dioxin- 6-yloxy) -tetrahydro-pyran-2-ylmethyl of nicotinic acid
The title compound is prepared as a white foam (0.157 g, 73%) from the 6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro) ester. [3,2-d] [1,3] dioxin-6-yloxy) -4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl of nicotinic acid using a procedure similar to that of Example 25, mp. > 112 ° C (decomposition);
E NMR (DMS0-d6) d 1.94 (s, 3H), 1.95 (s, 3H), 1.98 (s, 3H), 1.99 (s, 3H), 2.05 (s, 3H), 3.64 (t, J = 9.4 Hz, ÍH), 3.69-3.76 (m, ÍH), 3.79 (dd, J = 4.2, 9.2 Hz, ÍH), 3.87 (t, J = 9.4 Hz-1H), 4.13-4.19 (m, ÍH), 4.26 (t, J = 9.4 Hz-> H), 4.48 (dd, J = 4.0, 12.3 Hz, 1H), 4.64 (ABc, J = 12.7 Hz,? d = 0.14, 2H), 4.71-4.76 (m, ÍH) , 4.82 (dd, J = 8.1, 9.2 Hz, ÍH), 4.87-4.92 (m, 2H), 5.26 (t, J = 10.1Hz, ÍH), 5.32-5.38 (m, 2H), 5.55 (s, ÍH) ), 7.04 (dd, J = 1.8, 8.1Hz, ÍH), 7.29-7.36 (m, 5H), 7.42 (d, J = 8, 1Hz, 1H), 7.58 (dd, J = 4.8, 8.1Hz, ), 7.61 (s, ÍH), 8-39 (dt J = 2.0, 7.9 Hz, ÍH), 8.84 (dd, J 1.5, 4.6 Hz, ÍH), 9.17-9.19 (m, 1H), 9.49 (s, ÍH): IR (KBr) 3410. 2940. 2860, 1755, 1690, 1600, 1530, 1450, 1420, 1380, 1290, 1240, 1140, 1055, 1030, and 995 cm "1; mass spectrum [(+) FAB], m / z 885 (M + H) '. 907 (M + Na) '; Analysis calculated for C42H45C1N2017 • 1.0 H20: C, 55.85, H 5.24: N, 3.10. Found: C, 55.61, H. 4.89, N, 2.99.
Example 56
(R) -N- F5- FF F6-Q- (4-Benzoylbenzoyl) -4-0- F4, 6-0- (phenylmethylene) -D-glucopyranosyl-D-glucopyranosyl -ß oxyl metill clorof -2-enyl] Acetamide The title compound is prepared as a white powder (0.347 g, 52%) from N-. { 5- [(4 ', 6' -O-benzylidene-β-D-maltosiloxy) -methyl] -2-chlorophenyl} -acetamide using p-benzoylbenzoyl chloride (prepared from p-benzoylbenzoic acid and oxalyl chloride) and a procedure similar to that of Example 2, p.f. > 117 ° C (decomposition); XH NMR
(DMSO-d6) d 2.03 (s, 3H), 3.17-3.23 (m, ÍH), 3.27-3.43 (m,
2H), 3.49-3.66 (m, 4H), 3.70-3.82 (m, 2H), 4.08 (4.8, 10.1Hz,
ÍH), 4.39-4.44 (m, 2H), 4.64 (d, J = 10.5 HZ, ÍH), 4.66 (ABc, J = 12.3 Hz,? D = 0.14, 2H), 5.16 (d, J = 4.0 Hz. ÍH), 5.36 (t, J = 5.3 Hz, 2H), 5.53 (s, ÍH), 5.60 (d, J = 2.9 Hz, 1H), 5.83 (d, J = 6.2 Hz, ÍH), 7.20 (dd, J = 1.8, 8.1 Hz, ÍH), 7.33-7.37 (m, 3H), 7.39-7.43 (m, 3H), 7.54-7.59 (m, 2H), 7.65 (s, ÍH), 7.67- 7.73 (m, ÍH), 7.73-7.77 (m, 2H), 7.82-7.86 (m, 2H), 8.13-8.17 (m, 2H), 9.49 (s, ÍH); IR (KBr) 3410. 3080. 2910, 2850, 1725. 1660, 1600, 1530, 1450, 1420, 1400, 1365, 1270, 1140, 1070 and 1025 cm "1; mass spectrum [(-) E5i], m / z 818.1 (M-H), - Analysis calculated for C42H42CIN014 • 0.5 H2O: C, 60.83: H. 5.23: N. 1.69, Found: C, 60.71; H, 5.28; N, 1.61.
Example 57
N-. { 5-F (4 ', 6'-O-benzyl iden-β-D-maltosyl) -oxi-methyl-2-methyl-f-nyl} -acetamide stage 1
- [(hepta-O-acetyl-β-D-mal osyl) -oxy-methyl] -2-methyl-l-nitrobenzene
The title compound is prepared as a colorless solid (8.02 g, 53%) from 4-methyl-3-nitrobenzyl alcohol and acetobromomaltose using a procedure similar to that of step 1 of Example 1, p.p. 68-74 ° C; 1 H NMR (DMS0-d6) d 1.93 (s, 3 H), 1.94 (s, 3 H), 1.95 (s, 3 H), 1.96 (s, 3 H), 1.97 (s, 3 H), 2012 (s, 3 H), 2.07 (s, 3 H), 3.93 -4.01 (m, 4 H), 4.13 - 4.21 (m, 2 H), 4.37 (d, 2 H), 4.64 - 4.90 (m, 5 H), 4.97 (t, ÍH), 5.20 (dd, ÍH), 5.27 - 5.33 (m, 2 H), 7.48 (d, ÍH), 7.52 (d, ÍH), 7.88 (s, ÍH), IR ( KBr) 2950, 1750, 1230 and 1050 cm "1, mass spectrum [(+ FAB)], m / z 808 (m + H) + Analysis calculated for C34, H43NO20. C, 51.98: H, 5.52: N 1.78 Found: C, 51.59; H, 5.45; N, 1.86.
stage 2
- (hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methylphenylamine
The title compound is prepared as a white foam (5.39 g, 79%) from 5- (hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methyl-1-nitrobenzene using a procedure similar to that of Stage 2 of Example 1; X H NMR (DMS0-d 6) d 1.93 (s, 3 H), 1.94 (s, 3 H), 1.95 (s, 3 H), 1.97 (s, 3 H), 1.98 (s, 3 H), 2, 03 (s, 6 H), 2. 1 0 (s, 3 H), 3.93 -4.03 (m, 4 H), 4.14 - 4.23 (m, 2 H), 4.32 - 4.41 (m, 2 H), 4.58 (d, ÍH), 4.68 (t, ÍH), 4.76 4.88 (m, 4 H), 4.98 (t. ÍH), 5.22 (t, ÍH), 5.28-5.31 (m, 2 H), 6.37 (d, 2 H), 6.49 (s, ÍH), 6.87 (d, ÍH).
stage 3
N- [5- (hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methylf-enyl] -acetamide
The title compound is prepared as a white foam (6.60 g, 91%) from 5- (hepta-O-acetyl) - β-D-maltosyloxymethyl) -2-methylphenylamine using a procedure similar to that of step 3 of Example 1; XH NMR (DMSO-d6) 1.93 (s, 3H), 1.94 (s, 3H), 1.95 (s, 3H), 1.979 (s, 3 H), 1.984 (s, 3H), 2.03 (s , 3 H), 2.10 (s, 3 H), 2.18 (s, 3 H), 3.94-4.02 (m, 4 H), 4.14 - 4.24 (m, 2 H), 4.40 (d, ÍH), 4.48 ( d, 1 H), 4.67 - 4.74 (m 2 H), 4.81 - 4.89 (m, 2 H), 4.98 (t, ÍH), 5.19 - 5.32 (m, 3 H), 6.98 (d, ÍH), 7.17 ( d, 1H), 7.33 (s, ÍH), 9.27 (s, ÍH).
stage 4
N- [5- (ß-D-maltosiloxy-methyl) -2-methyl-phenyl] -acetamide
A solution containing N- [5- (hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methylphenyl] acetamide (6.60 g, 8.27 mmol) and 25% by weight of NaOMe in MeOH (0.893 g, 4.14 mmol) ) in 198 ml of MeOH is refluxed for 2.5 h. The reaction is cooled to room temperature and concentrated to provide 4.09 g (98%) of the product as a white foam. This material is used without any additional purification. An analytical sample is obtained by reverse phase CLAP (C18, 15% CH3CN / H20) to give a white solid, m.p. 115 ° C, X H NMR (DMSO-d 6) d 2.03 (s, 3 H), 2.16 (s, 3 H), 3.04 - 3.09 (m, 2 H), 3.21 - 3.56 (m, 7 H), 3.57 - 3.62 (m, 2
H), 3.70 - 3.73 (m, ÍH), 4.26 (d, ÍH), 4.48 - 4.54 (m, 3 H),
4. 76 (d, ÍH), 4.86 - 4.89 (m, 2 H), 5.01 (d, ÍH), 5.17 (d, ÍH),
. 42 (d, ÍH), 5.49 (d, ÍH), 7. 1 0 (d, ÍH), 7.15 (d, ÍH), 7.35
(s, ÍH), 9.28 (s, ÍH), IR (KBr) 3375, 2900, 1670 and 1025 cm "1, mass spectrum [(+) FAB], m / z 504 (M + H) \ 526 ( M + Na) + Analysis calculated for C22H33N012 • 0.5 H20; C, 51.56; H, 6.67; N, 2.73, Found; C, 51.79; H, 6.81; N, 2.75.
Stage 5 N-. { 5 - [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-methyl-phenyl} -acetamide
A solution that contains N-. { 5- [(ß-D-maltosyl) -oxi-methyl] -2-methyl-phenyl} -acetamide (1.88 g, 3.83 mmol), benzaldehyde dimethylacetal (0.807 ml, 5.36 mmol) and p-toluenesulfonic acid monohydrate (72.7 mg, 0.383 mmol) is heated to 60 ° C. After 4 h, benzaldehyde dimethylacetal (0.403 ml, 2.68 mmol) and additional p-toluenesulfonic acid monohydrate (36.4 mg, 0.192 mmol) are added and the reaction is heated at 60 ° C for 16 h. K2C03 is added to the reaction and heating is continued for 0.5 h. The hot solution is filtered and the filtrate is concentrated. Purification by reverse phase CLAP (C18, 15% CH3CN: H20) gives 1.26 g (56%) of the title compound as a white solid, m.p. 190-197 ° C; XH NMR (DMS0-d6) d 2.04 (s, 3H), 2.16 (s, 3H), 3.08 (t, ÍH), 3.35-3.40 (m, 3H), 3.45 (t, ÍH), 3.53-3.59 (m , 2H), 3.64-3.75 (m, 3H), 4.1 1 (dd, J = 5.1, 2.4 Hz, 1H), 4.28 (d, ÍH), 4.50 (d, ÍH), 4.67 (t - ÍH), 4.77 (d, ÍH), 5, 13 (d, ÍH), 5.21 (s broad, ÍH), 5.29 (s broad, ÍH), 5.49 (s broad, ÍH), 5.57 (s, ÍH), 5.61 (s broad , ÍH), 7.10 (d, 1H), 7.16 (d, HH), 7.34-7.3 8 (m, 4H), 7.42-7.45 (s, 2H), 9.28 (s, HH); IR (KBr) 3400, 2900, 1650 and 1075 cm "1; mass spectrum [(+) ESI], m / z 609 (M + NH4) +, 614 (M + Na) *; Analysis calculated for C29H37N012 • 0.5 H20: C, 57.99, H, 6.30, N, 2.37, Found, C, 57.80, H, 6.39, N, 2.50, Found, C, 57.85, H, 6.33, N, 2.27.
Example 58
Ñ-Acetyl- (5- F (2,2 '-3,3', 6-penta-0-acetyl-4 ', 6' -O-benzylidene-β-D-maltosyl) -oxi-methyl] -2 -methyl-phenyl.} acetamide
At 0 ° C, a stirred solution, containing N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxi-methyl] -2-methyl] -phenyl} acetamide (0.406 g, 0.686 mmol), pyridine (1.66 ml, 20.6 mmol) and 4-dimethylaminopyridine (0.768 g, 6.86 mmol) is added to acetic anhydride drops (1.28 ml, 13.7 mmol). After 6 h, with a reaction finally heated to room temperature, the solution is diluted with 100 ml of diethyl ether, washed successively with H20 (2x), aqueous NaHC03 saturated (2x), aqueous CuS04 saturated (2x) brine (2x), dried with Na2SO4 and concentrated. Purification by flash chromatography (gradient of 3, 4 and 5% MeOH: CHCl3) gives 0.194 g (34%) of a white solid after crystallization from CH2C12: petroleum ether, m.p. 97 ° C; X H NMR (DMSO-d 6) d 1.90 (s, 3 H), 1.92 (s, 3 H), 1.98
(s, 3H), 1.99 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 2.13 (s,
3H), 1.17 (s, 3H), 3.71-3.80 (m, 2H), 3.95-4.02 (m, 2H), 4.12-4.18 (m, 2H), 4.39 (dd, J = 9.9, 2.2 Hz, ÍH) , 4.56 (d, ÍH), 4.67-4.75 (m, 2H), 4.86-4.90 (m, 2H), 5.22-5.33 (m, 3H), 5.61 (s, ÍH), 7.11 (s, ÍH), 7.24 (d, ÍH), 7.34 (d, ÍH), 7.36 (s, 5H), IR (KBr) 3450, 2900, 1750 and 1240 cm "1; mass spectrum [(+) FAB], m / z 844 ( M + H) +, 866 (M + Na) + Analysis calculated for C41H49N018; C, 58.36, H, 5.85, N, 1.66, Found; C, 57.99; H, 5.76, N, 1.67.
Example 59
N- (5 - { F4 ', 6' -O-benzylidene-6-O- (toluenesulfonyl) - ß-D-maltosyl oxy-methyl) -2-methyl-phenyl} -acetamide
At 0 ° C, to a stirred solution of N-. { 5- [4 ', 6' -0-benzylidene-β-D-maltosyl) -oxi-methyl] -2-methyl-phenyl} -acetamide (0.711 g, 1.20 mmol) in 2.4 ml of pyridine was added a solution of p-toluenesulfonyl chloride (0.275 g, 1.44 mmole) in 1.5 ml of CH2C12. After 2 h, p-toluenesulfonyl chloride (.2275 g, 1.44 mmol) is added in 1.5 mL of additional CH2Cl2, and the solution is stirred at 0 ° C for 2 h. The reaction is suspended with 50 ml of H20 of cold ice and extracted with EtOAc. The combined organic extracts are washed successively with saturated aqueous NaHCO3 (2x), saturated aqueous CuSO4 (2x), brine (2x), dried with Na2SO4) and concentrated. Purification by reverse phase CLAP (C18, 50% CH3CN: H20) gives 0.421 g, (47%) of a colorless solid, m.p. 115-121 ° C; XH NMR (DMSO-d6) d 2.05 (s, 3H), 2-17 (s, 3H), 2.33 (s, 3H), 3.05 (t, ÍH), 3.243.44 (m, 4H), 3.52 (t , HI), 3.5 8-3.62 (m, 3H), 3.95 (d, ÍH) 4.13 (dd, 1H), 4.28 (d, 1H), 4.33 (d, ÍH), 4.41 (d, ÍH), 4.59 ( d, ÍH), 5.05 (d, 1H), 5.57 (s, ÍH), 7.06 (d, ÍH), 7.16 (d, 1H), 7.33-7.47 (m, 8H), 7.78 (d, 2H), 9.29 (Yes H); IR (KBr) 3375, 2900, 16.50, 1350, 1175 and 1075 cm "1; mass spectrum [(+) FAB], m / z 746 (M + H) +, 768 (M + Na) +; Calculated analysis for C36H13N014S-H20; C, 56.61; H, 5.94; N, 1.83, Found; C, 56.61; H, 5.77, N, 1. 80.
Example 60
N-. { 5- [(4 ', 6'-O-benzylidene-6-O-phenyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide
At room temperature, to a stirred solution of phenol (0.0784 g, 0.833 mmoles) in 10 ml of DMF is added potassium t-butoxide (0.0982 g, 0.833 mmole). After 0.5 h, a solution of N- (5- {[2, 3, 2 ', 3' -tetra-O-acetyl-4 ', 6'-O-benzylidene-6 is added to the reaction. -O- (4-toluenesulfonyl) -β-D-maltosyl] -oxi.} -2-chloro-phenyl) -acetamide (0.389 g, 0.417 mmol) in 4 ml of DMF and the reaction is heated to 65 ° C for 3 h. The reaction is cooled to room temperature, suspended with 40 ml of H20, extracted with EtOAc, dried with Na2SO4 and concentrated. The crude product is dissolved in 10 ml of MeOH and treated with 25% by weight of NaOMe in 45 mg of MeOH at 65 ° C for 3 hours. The reaction is. cool to room temperature and concentrate. Purification by flash chromatography
(gradient of 5 and 10% MeOH: CHCl3) gives 0.149 g (39%) of the title compound as a solid: H NMR (DMSO-d6) d 2.05
(s, 3H), 3.13-3.19 (m, iH,), 3.17-3.40 (m, 2H), 3.44-3.66 (m, 5H), 3.70-3.73 (m, 2H), 4.14 (dd, J = 10.8 , 4.4 Hz, ÍH), 4.23
(d, J = 10.9 Hz, 1H), 4.39 (d, J = 7.7 Hz, ÍH), 4.64 (ABc, J = 12.3 Hz,? d = 0.08, 2H), 5.16 (d, J = 3.17 Hz, ), 5.28
(d, J = 5.1 Hz, 1H), 5.33 (d, J = 5.3 Hz, ÍH), 5.47 (s, ÍH), 5.56 (d, J = 3.3 Hz, ÍH), 5.67 (d, J = 6.4 Hz , ÍH), 6.90-6.97
(m, 3H), 7.20 (dd, J = 8.2, 1.9 Hz, ÍH), 7.25-7.29 (m, 2H), 7.32-7.36 (m, 5H), 7.42 (d, J = 8.3 Hz, ÍH), 7.65 (s, ÍH), 9.50
(s, ÍH),, IR (KBr) 3400, 1650 and 1070 cm "1; mass spectrum
[(+) FAB], m / z 710 (M + Na) +; Analysis calculated for C34H38NCI012; C, 59.34; H, 5.57; N, 2.03. Found; C, 59.96; H, 5.78; N, 2.16.
Example 61
(R) -N- F 2 -chloro-5-F F F 4-0-F 4 ', 6'-O- (phenylmethylene) -a-D-glucopyranosyl 1-ß-D-glucopyranosyl] oxy 1-methyl phenyl-3-pyridinecarboxamide
Stage 1 N- [2-chloro-5- [[[2, 3, 6-tri-0-acetyl-4-0- (2, 3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl ) -β-D-glucopyranosyl] oxy] methyl] phenyl] -3-pyridinecarboxamide
To a stirred solution of 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine (0.200 g, 0.258 mmol) and triethylamine (0.119 g, 0.310 mmol) in 3 ml of THF a 0 ° C nicotinoyl chloride hydrochloride (0.0551 mg, 0.310 mmol) is added. After 0.5 h at this temperature, heat to rt and stir for an additional 18 h. At this point, the solid is filtered off and washed with 10 ml of additional THF. The filtrate is then concentrated and taken up in 100 ml of EtOAc. This organic solution is washed with 10 ml of H20 and 10 ml of brine and then dried with Na2SO4. After concentration, the residue is purified by preparative plate chromatography (10:90 MeOH: CHCl 3) to give the product (0.183 g, 80%) as a white foam, m.p. 83-86 ° C, E NMR (CDC3) d 1.99 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.10 (s) , 3H), 2.16 (s, 3H), 3.67-3.72 (m, ÍH), 3.93-3.98 (m, 1H), 4.04 (dd, J = 2.2, 11.9 Hz, 2H), 4.25 (dt, J = 3.7 , 12.5
Hz, 2H), 4.53 (dd, J = 2.9, 12.3 Hz, ÍH), 4.60 (d, J = 7.7 Hz,
ÍH), 464 (d, J = 17. 12.5 Hz, ÍH), 4.83-4.93 (m, 3H, 5.05, t,
(10.1 Hz, 1H), 5.23 (t, J = 9.4 Hz, ÍH), 5.34 (dd, J = 9.7,
. 5 Hz, 1H), 5.41 (d, J = 4.2 Hz, HH), 7.07 (dd, J = 2.0 Hz, HH), 7.41 (d, J = 8.1 Hz, 1H), 7.48 (ddd, J = 0- 9, 4.8, 7.9 Hz, ÍH), 8.23 (ddd, J = 1.5, 2.2, 7.9 Hz, 1H), 8.43 (s, ÍH), 8.48 (d, J = 2.0 Hz, ÍH), 8.82 (dd, J = 1.5, 4.8 Hz-> H), 9.15 (.dd, J = 0.7, 2.2 Hz, 1H); IR (KBr) 3400. 1950. 1755, 1675, 1600, 1550, 1420, 1375, 1235, and 1050 cm "1; mass spectrum [(+) FAB] m / z 881 (M + H) +, 903 ( M + Na) +; Analysis calculated for C39H4SC1N2019 • 2.0 H20: C, 51.07; H, 5.38; N, 3.05, Found; C, 50.80 H, 4.83; N, 2.89.
stage 2
N- [2-sloro-5- [[(4-0-a-D-glucopyranosyl-β-D-glucopyranosyl) oxy] methyl] phenyl] -3-pyridinecarboxamide
The title compound is prepared as a white foam (1.97 g, 57%) from N- [2-chloro-5- [[[2, 3, 6-tri-O-acetyl-4-O- (2 , 3,4, 6- tetra-O-acetyl-aD-glucopyranosyl) - ß-D-glucopyranosyl] oxy] methyl] phenyl] -3-pyridicarboxamide using a procedure similar to that of step 4 of Example 1, mp >106 ° C (decomposition) ^ H NMR (DMSO-d6) d 3.02-3.13 (m, 2H), 3.19-3.29 (m, 2H), 3.31-3.39 (m, ÍH), 3.39-3.50 (m, 3H ), 3.55-3.63 (m, 2H), 3.70-3.76 (m, ÍH), 4.09 (c, J = 5.3 Hz, ÍH), 4.31 (d, J = 7.9 Hz, ÍH), 4.49-4.55 (m, 2H), 4.60 (d, J = 12.5 Hz, ÍH), 4.84-4.91 (m, 3H), 5.01 (d, J = 3.7 Hz, ÍH), 5.26 (d, J = 5.1Hz, ÍH), 5.43 ( d, J = 6.4 Hz, HH), 5.52 (d, J = 3.1Hz, ÍH), 7.35 (d, J = 2.0, 8.3 Hz, HH), 7.54 (d, J = 8.1Hz, HH), 7.56- 7.60 (m, 2H), 8.31 (dt, J = 2-0, 7.9 Hz, ÍH), 8.77 (dd, J = 1.5, 4.8 Hz, 1H), 9.12-9.14 (m, ÍH), 10.34 (s, ÍH); IR (KBr) 3390, 2910, 2320, 1660, 1590, 1525, 1475, 1450, 1420, 1360, 1310, 1190, 1140, 1080, and 1030 cm "1, mass spectrum [(+) FAB], m / z 587 (M + H) +, 609 (M + Na) +, Analysis calculated for C25H31CIN2012 • 1.5H20; C, 48.90; H, 5.58; N, 4.56, Found; C, 49.18.H, 5.52; N, 4.32 .
stage 3
(R) -N- [2-chloro-5- [[[4-0- [41,6 '-O- (phenylmethylene)-aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] phenyl] - 3-pyridinecarboxamide
The title compound is prepared as a white solid (1.25 g, 57%) from N- [2-chloro-5- [[(4-Oa-glucopyranosyl-β-D-glucopyranosyl) oxy] methyl] phenyl] - 3-pyridinecarboxamide using a procedure similar to that of Example 24, mp 208-210 ° C, XH NMR (DMSO-d6) d 3.08-3.15 (m, HH), 3.30-3.42 (m, 4H), 3.42-3.51 (m, HH), 3.51 - 3.60 (m, 2H),
3. 64-3.76 (m, 3H), 4.12 (dd, J = 3.3, 8.6 Hz, ÍH), 4.33 (d, J = 7.7 Hz, 1H), 4.68 (t, J = 5.7 Hz, ÍH), 4.74 (ABc , J = 12.5 Hz,? D = 0.22, 2H), 5.14 (d, J = 3.7 Hz, ÍH), 5.30 (t, J = 4.4 Hz, 2H), 5-52 (d, J = 3.3 Hz, ÍH) ), 5.57 (s, ÍH), 5.63 (d, J = 6.6 Hz, ÍH), 7.34-738 (m, 4H), 7.42-7.46 (m, 2H), 7.54 (d, J = 8.3 Hz, ÍH) , 7.55-7.60 (m, 2H), 8.31 (d, J = 1.8, 7.9 Hz, ÍH), 8.77 (dd, J = 1.8, 4.8 Hz, ÍH), 9.13 (dd, J = 0.7, 0.22 Hz, ÍH) ), 10.34 (s, ÍH); IR (KBr) 3530, 3400, 2920, 2830, 1680, 1590, 1540, 1460, 1420, 1380, 1320, 1275, 1150, 1120, 1070, and 1025 cm "1; mass spectrum [(+) FAB], m / z 675/677 (M + H) +, 697/699 (M + Na) +; Analysis calculated for C32H3SC1N2012 • 0.5 H20: C, 56.18; H, 5.30; N, 4.09, Found; C, 56.31; H , 5.13; N, 4.19.
Example 62
(R) -N- F5- FF rβ-O-benzoyl-4-O-F4 ', 6'-O- (phenylmethylene) -aD-glucopyranosyl-β-D-glucopyranosyl] oxyl methyl -2-chlorophenyl -3- pyridinecarboxamide
The title compound is prepared as a whitish vitreous solid (0.628 g, 44%) from (R) -N- [2-chloro-5- [[[4-0- (phenylmethylene) -aD-glucopyranosyl] - β-D-glucopyranosyl] oxy] methyl] phenyl] -3-pyridinecarboxamide using a procedure similar to that of Example 2, mp 190-193 ° C; 1 H NMR (DMS0-d6) d 3.17-3.24 (m, HH), 3.30-3.43 (m, 2H), 3.50-3.64
(m, 4H), 3.68-3.76 (m, 1H), 3-78 (ddd, J = 1.5, 5.1, 9.7 Hz-1H), 4.-50 (dd, J = 4.8, 9.9 Hz, 1H ), 4.36 (dd, J = 5.1, 12.1Hz, ÍH), 4.43 (d, J = 7.7Hz, ÍH), 4.59-4.64 (m, ÍH), 4.71
(ABc, J = 12.7 Hz,? D = 0.14, 2H), 5.14 (d, J = 3.7Hz, ÍH), 5.35 (d, J = 5, 1Hz, ÍH), 5.39 (d, J = 5.3 Hz, 1H), 5.52 (s, 1H), 5.59 (d, J = 3.1Hz, ÍH), 5.80 (d, J = 6.4 Hz, ÍH), 7.31-7.37 (m, 4H), 7.39-7.43 (m , 2H), 7.51 (dd, J = 5.9, 7.9 Hz, 3H), 7.54-7.58 (m, 2H), 7.60- 7.66 (m, ÍH), 7.98 (dd, J = 1.1, 8.1Hz, 2H), 8.29 (dt, J = 1.8, 7.9 Hz, ÍH), 8.77 (dd, J = 1.8, 4.8 Hz, ÍH), 9.11 (d, J = 2.0 Hz, 1H), 10.31 (s, ÍH); IR (KBr) 3410. 3080, 2900, 2850, 1720, 1680, 1590, 1530, 1440, 1420, 1375, 1320, 1275, 1070, 1025, 755, and 710 c "1; mass spectrum [(+) FAB ] m / z 779/781 (M + H) +. 801/803 (M + Na) - Analysis calculated for C39H39C1N2013 0.5 H20; C, 59.43, H, 5.12, N, 3.55 Found: C, 59.34; H, 4.91; N, 3.45.
Example 63
. { 5-T (4 ', 6'-O-benzyl iden-β-D-maltosyl) -oxi-met i 11-2-chloro-phenyl} -furan-2-carboxylic acid amide
stage 1
. { 5 - [(2,2,, 3,3,4 ', 6,6l-hepta-O-acetyl-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -furan-2-carboxylic acid amide
The title compound is prepared as a white foam (1.4 g, 94%) from 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine using a procedure similar to that of Stage 3 of Example 1. pf > 85 ° C
(decomposition); H NMR (DMSO-d6) d 1.93 (5, 6H), 1.94 (s, 3H), 1969 (s, 3H), 1972 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 3.92-4.02 (m, 4H), 4.12-4.23 (m, ZH), 4.38 (dd, J = 2.2, 12.1Hz, 1H), 4.67 (ABc, J = 13.0 Hz,? D = 0.15, 2H) , 4.73 (dd, J = 7.9, 9.4 Hz, ÍH), 4.83-4.90 (m, 2 H), 4.97 (t, J = 9.7 Hz, ÍH), 5.21 (t, J = 10.1 Hz, ÍH), 5.27 (d, J = 4.2 Hz, ÍH), 5.31
(d, J = 9.2 Hz, HH), 6.70 (c, J = 1.8 Hz, HH), 7.18 (dd, J = 2.0, 8.3 Hz 1H), 7.32 (d, J = 3.5 Hz, HH), 7.53 ( d, J = 8.1Hz, 1H), 7.57 (d, J = 2.0 Hz, ÍH), 7.93-7.95 (m, ÍH), 9.84 (s, ÍH), IR (KBr) 3390, 3130, 2950, 1755, 1690, 1590, 1530, 1445, 1420, 1375, 1320, 1230, 1140, and 1040 cm "1; mass spectrum [(+) FAB] m / z 970 (M + H) \ 892 (M + Na) + , Analysis calculated for C38CINO20 • 1.0 H2; C, 51.39; H, 5.22; N, 1.59, Found; C, 51.00; H, 4.93; N, 1.51.
stage 2
. { 2-Chloro-5- [(ß-D-maltosyl) -oxy-methyl] -phenyl} -furan-2-carboxylic acid amide
A solution that contains. { 5 - [(2,2'-3,3 ', 4', 6,6'-hepta-O-acetyl-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} Furan-2-carboxylic acid amide (1.36 g, 1.56 mmol) and 25% by weight of NaOMe in MeOH (26.8 μL, 0.468 mmol) in 41 mL of MeOH is stirred at rt for 18 h. At this point, the mixture is concentrated and the resulting residue is triturated with Et20 to provide the product (0.890 g, 99%) as a white foam, m.p. > 127 ° C
(decomposition); XH NMR (DMSO-d6) d 3.01-3.12 (m, 2H), 3.21
(dd, J = 3.7, 9.7 Hz, Í.H), 3.24-3.29 (m, ÍH), 3.29-3.38 (m, 2H), 3.38-3.50 (m, 3H), 3.54-3.63 (m, 2H) , 3.73 (d, J = 12.3 Hz, ÍH), 4.30 (d, J = 7.7 Hz, ÍH), 4.45-4.58 (m, ÍH), 4.71
(ABC, J = 12.5 Hz,? D = 0.22.2H), 4.83-4.93 (s broad 2H), 5.01 (d, J = 4.0 Hz, ÍH), 5, 18-5.32 (s broad H), 5.34- 5.58
(s broad 1H), 6.69 (dd, J = 1.5, 3.3 Hz, ÍH), 7.26-7.33 (m, 2H), 7.50 (d, J = 8.3 Hz, ÍH), 7.62 (d, J = 2.0 Hz, ÍH), 7.92-7.94 (m, 1H), 9.82-9.94 (s broad, ÍH); IR (KBr) 3400, 2920, 2880, 1675, 1590, 1530, 1445, 1425, 1365, 1315, 1140, 1080, 1030 and 755 cm "1; mass spectrum [(+) FAB), m / z 5981600 ( m + Na) *, Analysis calculated for C24H30C1N13 • 0.5H20; C, 49.28, H, 5.34; N, 2.39, Found; C, 49.06; H, 5.34; N, 2.21.
stage 3
. { 5 - [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -furan-2-carboxylic acid amide
The title compound is prepared as a white solid (0.352 g, 63%) from. { 2-Chloro-5- [(ß-D-maltosyl) -oxy-methyl] -phenyl} furan-2-carboxylic acid amide using a procedure similar to that of Example 24, p.f. 224-226 ° C, E NMR (DMS0-d6) d 3.07-3.14 (m, HH), 3.27-3.42 (m, 4H), 3.42-3.49 (m, HH), 3.51-3.59 (m, 2H) , 3.63-3.76 (M, 3H), 4.11 (dd, J = 2.4.7.9 Hz, ÍH), 4.32 (d, J = 7.7 Hz, ÍH), 4.67 (t, J = 5.9 Hz, ÍH), 4.72 ( ABC, J = 12.5 Hz,? D = 0.22, 2H), 5.14 (d, J = 3.7 Hz, 1H), 5.29 (t, J = 6.2 Hz, 2H), 5.51 (d, J = 3.3 Hz, ÍH) , 5.57 (s, ÍH), 5.62 (d, J = 6.8 Hz, ÍH), 6.68-6.72 (M, ÍH), 7.30-7.34 (m, 2H), 7.34-7.38 (m, 3H), 7.41-7.46 (m, 2H), 7.51 (d, J = 8.1 Hz, ÍH), 7.62 (s, ÍH), 7.94 (LJ = 0.9 Hz, 1H), 9.88 (s, ÍH); IR (K.Br) 3390, 2920, 2850, 1680, 1600, 1590, 1530, 1455, 1430, 1385, 1320, 1280, 1140, 1070, 1050, 1025 and 750 cm "1, - mass spectrum [(- ) F? D 1, m / z 662 (M-H) +; Analysis calculated for C31H34CIN013 • 1.0H20; C, 54.59; H, 5.32; N, 2.05, Found; C, 54.82, H, 4.91; N, 2.03 .
Example 64
. { 5-F F 6 -O-benzoyl-4 ', 6'-O-benzylidene-β-D-benzylidene-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} furan-2-carboxylic acid amide
The title compound is prepared as a white solid (0.130 g, 47%) from the. { 5- [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} furan-2-carboxylic acid amide using a procedure similar to that of Example 2, p.f. > 142 ° C (decomposition); E NMR (DMSO-d6) d 3.16-3.23 (m, ÍH), 3.27-3.42 (m, 2H), 3.49-3.64 (m, 4H), 3.71
(dd,) = 5, 1. 1 0. 1Hz, ÍH), 3.75-3.80 (m, ÍH), 4.05 (dd, J = 4.8, 9-9 Hz, EH), 4-36 (dd, J = 5.3, 12.1 Hz, HH), 4.42 (d, J = 7.9 Hz- HH), 4.58-4-63 (m, 2H), 4.7R (d, 1 = 12.7Hz, HH), 5, 14 (d, J = 3.7 Hz, HH), 5.34 (d, J = 5.3 Hz, HH), 5.38 (d, J = 5.3 Hz, HH), 5.52 (,, HH), 5.58 (d, J = 2.9 Hz, HH) 5.79
(d, J = 6.2 Hz, ÍH), 6.69 (c, J = 1. 18 Hz, ÍH), 7.26-7.32 (m, 2H), 7.33-7.38 (m, 3H), 7.38-7.44 (m, 2H ), 7.47 (d, J = 8.3 Hz, ÍH), 7.51 (t, J = 7.9 Hz, 2H), 7.61 (d, J = 2.0 Hz, ÍH), 7.61-7.66 (m, ÍH), 7.93 (dd) , J = 0.7, 2.6 Hz, ÍH), 7.99 (dd, J = 5.3, 7.0 Hz, 2H), 9.85 (s, ÍH); IR (KBr) 3460, 3380, 3140, 3080, 2880, 1730, 1660, 1590, 1535, 1445, 1425, 1375, 1320, 1275, 1140, 1120, 1075, 1025, 980 and 715 cm "1; mass spectrum
[(+) ESI], m / z 768 (M + H) +, 790 (M + Na) +; Analysis calculated for C38CIN014 - 1.0 H20; C, 58.05; H, 5.13; N, 1.78, Found; C, 57.96; H, 4.93; N, 1.76.
Example 65
N- (2-chloro-5- F (4 ', 6' -O-benzylidene-β-D-maltosyl) -oxi-methylylethyl) pent-4-enamide
Step 1 N- [2-chloro-5- [[[2, 3, 6-tri-0-acetyl-4-0- (2, 3,4, 6-tetra-O-acetyl-aD-glucopyranosyl) - β-D-glucopyranosyl] oxy] methyl] phenyl] -4-pentanamide
To a stirred solution of 4-pentenoic acid
(57.9 μl, 0.567 mmol) and DMF (catalytic amount) in 3 ml of
CH2C12 at rt oxalyl chloride (49.4 μl, 0.567 mmol) is added dropwise. After 5 min at this temperature, it is heated to
40 ° C for an additional 10 min. This completes the preparation of the initial acid chloride material. At this point, a second solution of NaH (0.0206 g, 0.515 mmol) and 3 ml of CH2C12 at rt is added 2-chloro-5- (hepta-O-acetyl-D-maltosyl-oxymethyl) -phenylamine (0.400 mg, 0.515 mmol). After 10 min, the acid chloride solution is added to this solution, dropwise. The reaction is stirred at rt for 1 h and then diluted with 100 mL EtOAc. This layer is washed with 10 ml of 1 N HCl, 10 ml of saturated NaHCO 3 and 10 ml of brine and then dried with MgSO 4. After concentration, the oily residue is purified by flash chromatography (10:90 to 70:30 gradient of EtOAc: petroleum ether to give the product (0.321 g, 73%) as a white foam, mp> 68 ° C (decomposition); XE NMR (DMSO-d6) d 1.93 (s, 3H),
1. 94 (s, 6H), 1969 (s, 3H), 1972 (s, 3H), 2.01 (5, 3H), 2.08
(s, 3H), 2.29-2.36 (m, 2H), 2.44-2.49 (m, 2H), 3.92-4.02 (m, 4H), 4.13-4.22 (m, 2H), 4.38 (d, J = 10.1Hz) , ÍH), 4.53 (d, J = 12.7 Hz, ÍH), 4.69-4.75 (m, 2H), 4.84 (d, J = 3.7 Hz, ÍH), 4.87 (d, J = 2.9 Hz, ÍH), 4.94 -5.01 (m, 2H), 5.07 (dd, J = 2.0, 17.4 Hz, ÍH), 5.21 (t, J = 9.7 Hz, ÍH), 5.27 (d, J = 3.7 Hz, ÍH), 5.31 (d, J = 8.8 Hz, HH), 5.80-5.91 (m, HH), 7.08 (dd, J = 2.0, 8.3 Hz, HH), 7.46 (d, J = 8.1 Hz, HH), 7.61 (s, HH), 9.49 (s, ÍH); IR (KBr) 3400, 2950, 1755, 1690, 1630, 1590, 1525, 1420, 1370, 1235, and 1050 cm "1. mass spectrum [(+) FAB] m / z 858/860 (M + H) +. 880/882 (M + Na) \ Analysis calculated for C3aH48CIN019, 0.5 H20, C, 52.63, H, 5.69, N, 1.62, Found, C, 52.65, H, 5.66, N, 1.59.
stage 2
N-. { 2-Chloro-5- [(ß-D-maltosyl) -oxy-methyl] -phenyl} -pent-4-enylamide
The title compound is prepared as an off-white solid (0.0614 g, 93%) from N- [2-chloro-5- [[[2, 3, 6-tri-O-acetyl-4-O- (2 , 3,4, 6-tetra-O-acetyl-aD-glucopyranosyl) -β-D-glucopyranosyl] oxy] methyl] phenyl] -4 -pentenamide and a procedure similar to that of step 4 of Example 1, p. > 103 ° C (decomposition); XH NMR (DMSO-d6) d 2.30-2.37 (m, 2H), 2.43-2.49 (m, 2H), 3.02-3.10 (m, 2H), 3.19-3.18 (m, 2H), 3.30-3.49 (m, 5H), 3.54-3.63 (m, 2H), 3.72 (d, J = 10.8 Hz, 1H), 4.28 (d, J = 7.7 Hz, 1H), 4.40-4.67 (m, 2H), 4.54 (d, J = 12.3 Hz, ÍH), 4.72-4.96 (m, 2H), 4.80 (d, J = 12.3 Hz, 1H), 4.96-5.04 (m, 2H), 5.09 (dd, 1 = 1.5, 17.1Hz, ÍH) , 5.13-5.33 (s broad 1H), 5.33-5.59 (s broad 2H), 5.80-5.92 (m, ÍH), 7.22 (dd, J = 1.5, 8.1Hz, ÍH), 7.44 (d, J = 8.1Hz , ÍH), 7.63 (s, 1H), 9.51 (s, ÍH); IR (KBr) 3400, 2910, 1665, 1590, 1530, 1440, 1420, 1370, 1310, 1140, 1070, and 1035 cm "1, mass spectrum [(+) FAB], m / z 564/566 (M + H) \ 586/588 (M + Na) +, Analysis calculated for C24H34CIN012; C, 51.11; H, 6.06; N, 2.48, Found; C, 51.17; H 6.06; N, 2.36.
stage 3
N-. { 2-chloro-5- [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -pent-4-enamide
The title compound is prepared as a white powder (0.102 g, 88%) from. { 2-Chloro-5- [(ß-D-maltosyl) -oxy-methyl] -phenyl} -pent-4-enylamide using a procedure similar to that of Example 24, p.f. 191-193 ° C, XH NMR (DMSO-d6) d 2.30-2.37 (m, 2H), 1.43-2.49 (m, 2H), 3.06-3.13 (m, ÍH), 3.28-3.33 (m, ÍH), 3.34-3.41 (M, 3H), 3.43-3.49 (m, ÍH), 3.51 -3.60 (m, 2H), 3.64-3.75 (m, 3H), 4.11 (dd, J = 2.9, 8.1Hz, ÍH), 4.30 (d, J = 7.7 Hz, ÍH), 4.67 (L, J = 5.9 Hz, ÍH), 4.68 (ABc, J = 12.3 Hz,? D = 0.22, 2H), 4.99 (dd, J = 2.0, 10.3 Hz, ÍH), 5.08 (dd, J = 1.8, 17.1Hz, 'lH), 5.14 (d, J = 3.7 Hz, ÍH), 5.25 (d, 1 = 5.3 Hz, ÍH), 5.30 (d, J = 5.3 Hz, ÍH), 5.51 (d, J 3.3 Hz, ÍH), 5.57 (s, ÍH) 9 5.63 (d, J = 6.6 Hz, ÍH), 5.81-5.91 (m, 1H), 7.23 (dd, J = 2.0, 8.3 Hz, ÍH), 7.34-7.38 (, 3H), 7.42-7.47 (m, 3H), 7.64 (d, J = 1.5 Hz, ÍH), 9.51 (s, 1H); IR (KBr) 3410. 2900, 2870, 1670, 1640, 1590, 1535, 1445, 1420, 1375, 1370, 1325. 1310, 1270, 1150, 1070 and 1030 cm "1; mass spectrum [(+) FAB] , m / z 652/654 (M + H) +, 674/676 (M + Na) \ - Analysis calculated for C31H38CIN012; C, 57.10, H, 5.87, N, 2.15 Found: C, 56.76; H, 5.8 1; N, 2.31.
Example 66
N-. { 2-Chloro-5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -pent-4 -enamide
The title compound is prepared as a white solid (1.10 g, 84%) from N-. { 2-Chloro-5- [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -pent-4 -enamide using a procedure similar to that of Example 2, p.f. > 110 ° C (decomposition); XH NMR (DMSO-d6) d 2.28-2.35 (m, 2H), 2.41-2.46 (m, 2H), 3-16-3.23 (m, ÍH), 3.28-3.43 (m , 2H), 3.48-3.64 (m, 4H), 3.68-3.73 (m, ÍH), 3.73-3.79 (m, ÍH), 4.03-4.08 (m, ÍH), 4.33-4.38 (m, ÍH), 4.39 (d, J = 7.7 Hz, ÍH), 4.58-4.63 (m, 1H), 4.65 (ABc, J = 12.5 Hz,? d = 0.14, 2H), 4.95-4.99 (m, ÍH), 5.06 ( dd, J = 2.0, 17.4 Hz, ÍH), 5.13 (d, J = 4.0 Hz, lH), 5.35 (t, 3 = 4.8 Hz, 2H), 5-52 (s, ÍH), 5.57 (d, J = 2.9 Hz, ÍH), 5, 80 (d, J = 6.4Hz, ÍH), 5.81-5.90 (m, ÍH), 7.20 (dd, J = 2.0, 8.1Hz, 1H), 7.33-7.37 (m, 3H), 7.38-7.43 (m, 3H), 7.50-7.55 (m, 2H), 7.62 (d, J = 1.5 Hz, ÍH), 7.63-7.68 (m, ÍH), 7.99 (dd, J = 1. 1. 8.3 Hz, 2H), 9.49 (s, ÍH), IR (KBr) 3400, 3270. 3080, 2910, 2880, 1725, 1660, 1590, 1530, 1445, 1425, 1375, 1325, 1275, 1140, 1070 , 1025, 990, and 715 cm "1; mass spectrum [(+) FAB], m / z 756/758 (M + H) \ 778/780 (M +
Na) +; Analysis calculated for C38H42CIN013 • 0.5 H20; C, 59.65; H, 5.66; N, 1.83. Found; C, 59.73; H, 5.64; N, 1.75.
Example 67
- (ß-O-benzoyl-4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl-2-chloro-phenylamine
To a stirred solution of N-. { 2-chloro-5- [(6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -pent-4-enamide (0.681 g, 0.901 mmol) in THF: H20 (1: 1, 50 mL) at rt is added iodine (0.685 g, 2.70 mmol). After 5 min at this temperature, it is suspended with solid Na2S203 until the brown color becomes clear. The mixture is diluted with 100 ml of EtOAc, washed with 10 ml of brine and then dried with Na 2 SO 4. After concentration, the oily residue is purified by flash chromatography (gradient from 1:99 to 13:87 of MeOH: CHCl 3) to give the product (0.483 g, 80%) as a white solid, m.p. 168-171 ° C; NMR (DMSO-d6) d 3.17 (t, J = 8.3 Hz, ÍH), 3.31-3.43 (m, 2H), 3.48-3.63 (m, 4H), 3.68-3.77 (m, 2H), 4.05 (dd, J = 4.8, 9.9 Hz, ÍH), 4.32-4-38 (m, 2H), 4.52 (ABc, J = 11.9 Hz,? D = 0.18, 2H), 4.61 (d, J = 10.5 Hz, ÍH), 5.14 (d, J = 3.7 Hz, HH), 5.22-5.32 (s broad 3H), 5.32-5.39 (s broad ÍH), 5.52 (s, lH), 5.57 (s, HH), 5.76-5.83 (s broad ÍH), 6.53 (dd, J = 1.8, 8.1Hz, ÍH), 6.75 (d, J = 2.0Hz, 1H), 7.08 (7.9 Hz, ÍH), 7.33-7.37 (m, 3H), 7.38-7.44 ( m, 2 H), 7.51-7.56 (m, 2H), 7.63-7.69 (m, ÍH), 8.00 (dd, J = 0.7, 7.9 Hz, 2H), IR (KBr) 3390, 1920, 2860, 1730, 1620. 1-590. 1495, 1440, 1430, 1370. 1315, 1270, 1070, 1025, 100, and 710 cm "1; mass spectrum [(+) FAB], m / z 674/676 (M + H) +, 696/698 (M + Na) +, Analysis calculated for CIN012 • 1.0 H20, C, 57.27, H, 5.53, N, 2.02, Found, C, 57.28, H, 5.39 N, 1.99.
Example 68
(4-chloro) -benzyl-4 ', 6' -O-benzylidene-β-D-maltoside
stage 1
(4-chloro-benzyl) -2, 2'-3, 3 •, 4 ', 6,6' -hepta-O-acetyl-β-D-mal-osido The title compound is prepared as white needles (3.96 g. , 73%) from acetobromomaltose using 4-chlorobenzyl alcohol and a procedure similar to stage 1 of Example 1, mp. 138-141 ° C; XH NMR (DMSO-d6) d 1994
(s, 3H), 1999 (s, 3H), 2.00 (s, 3H), 2,025 (s, 3H), 2,029 (s,
'3H), 2.10 (s, 3H), 2.16 (s, 3H), 3.66 (ddd, J = 2.9, 4.4, 9.9
Hz, ÍH), 3.96 (ddd, J = 2.4, 4.0, 10.1Hz, 1H), 4.00-4.07 (m,
2H), 4.21-4. n (m, 2H), 4.51 (dd, J = 2.9, 12.3 Hz, ÍH), 4.56
(d, J = 2.4 Hz, HH), 4.58 (d, J = 6.8 Hz, ÍH), 4.80-4.92 (m, 3H), 5.05 (t, J = 9.9 Hz, HH), 5.22 (t, J = 9.2 Hz, ÍH), 5.35
(dd, J = 9.4, 10.3 Hz, HH), 5.41 (d, J = 4.0 Hz, HH), 7.21 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 9.3 Hz, 2H); IR (KBr) 3480, 2960, 2880, 1755, 1650, 1610, 1495, 1440, 1375, 1335, 1240, 1170, 1135, 1050, 935, 910, 820 and 615 cm "1; mass spectrum [(+) FAB], m / z 761/763 (M + H)? 783/785 (M + Na) +, Analysis calculated for C33H41C10? A; C, 52.08; H, 5.43; N, 0.00. Found; C, 51.88; H, 5.37; N, 0.01.
stage 2
(4-chloro-benzyl) -β-D-maltoside
The title compound is prepared as a white foam (1.55 g, 95%) from (4-chloro-benzyl) -2,2 ', 3, 3', 4 ', 6,6' -hepta-O- acetyl-β-D-maltoside using a procedure similar to step 4 of Example 1, mp > 102 ° C
(decomposition); XH NMR (DMSO-d6) d 3.02-3.11 (m, 2H), 3.19-3.26
(m, 2H), 3.29-3.36 (m, 2H), 3.37-3.49 (m, 3H), 3.54-3.64
(m, 2H), 3.72 (d, J = 1 1.0 Hz, 1H), 4.27 (d, J = 7.7 Hz, 1H),
4. 39-4.65 (s broad 2H), 4.69 (ABc, J = 12.5 Hz,? D = 0.20, 2H),
4. 76-5.03 (s broad H), 5.01 (d, J = 3.7 Hz, ÍH), 5.10-5.63 (s broad 4H), 7.37-7.43 (m, 4H); IR (KBr) 3340, 2920, 2890, 1625,
1600, 1490, 1450, 1400, 1365, 1150, 1075, 1030 and 820 cm "1; mass spectrum [(+) ESI], m / z 484.4 / 486.4 (M + NH4) +; Analysis calculated for C ^ H ^ CIO ^ • 0.5 H20; C, 47.96; H, 5.93; N, 0.00.
Found; C, 47.62; H, 5.82; N, 0.24.
stage 3
(4-chloro) -benzyl-4 ', 6' -O-benzylidene-β-D-maltoside
The title compound is prepared as a white foam (1.20 g, 65%) from 4-chloro-benzyl) -β-D-maltoside using a procedure similar to that of Example 24, p.p. 187-188 ° C: 1 H NMR (DMSO-d 6) d 3.10 (t J = 8.3 Hz, ÍH), 3.17-3.41 (m, 4H), 3.46 (t, J = 8.8Hz, ÍH), 3.51-3.59 ( m, 2H), 3.64-3.75 (m, 3H), 4.12 (dd, J = 3.1, 8.1Hz, ÍH), 4.29 (d, J = 7.7 Hz, 1H), 4.62-4.71 (s broad H), 4.70 (ABc, J = 12.5 Hz,? D = 0.20, 2H), 5.14 (d, J = 3.7 Hz, ÍH), 5.21-5.36 (s broad 2H), 5.47-5.55 (s broad 1H), 5.57 (s, ÍH), 5.59-5.67 (s broad H), 7.34-7.39 (m, 3H), 7.39-7.46 (m, 6H), IR (KBr) 3570, 3430, 3080, 2870, 1615, 1495, 1450, 1435, 1375, 1360, 1340, 1255, 1160, 1120, 1070, 1030, 1000 and 755 cm "1; mass spectrum, [(+) ESI]. M / z 555/557 (M + H) +, 572/574 (M + NH 4) +; 1126/1128 (2M + NH,) +; Analysis calculated for C 26 H 31 ClO:: L; C, 56.27; H, 5.63; N, 0.00 Found: C, 56.09; H, 5.73; N, 0.23.
Example 69
ster 1-0- (4-chloro) benzyl-4 ', 6'-benzylidene-6-deoxy-β-D-malto-6-yl benzoic acid
The title compound is prepared as a white solid (0.800 g, 66%) from (4-chloro) -benzyl-4 ', 6' -O-benzylidene-β-D-maltoside using a procedure similar to that of Example 2, pf > 110 ° C (decomposition): 1 H NMR (DMSO-d 6) d 3.16-3.23 (m, H H), 3.27-3.43 (m, 2 H), 3.49-3.64 (m, 4 H), 3.68-3.78 (m, 2 H) , 4.02-4.08 (m, ÍH), 4.35 (dd, J = 5.5, 12.5 Hz, ÍH), 4.39 (d, J = 7.9 Hz, ÍH), 4.57-4.62 (m, ÍH), 4.67 (ABc, J = 12.5 Hz,? D = 0.14, 2H), 5.14 (d, J 3.7 Hz, ÍH), 5.36 (dd, J = 5.1, 10.5 Hz, 2H), 5.52 (s, ÍH), 5.58 (d, J = 2.9 Hz, ÍH), 5.80 (d, J = 6.2 Hz, ÍH), 7.33-7.43 (m, 9H), 7.53, (t, J = 7.5 Hz, 2H), 7.66 (td, J = 1.1, 7.7 Hz , ÍH), 7.99 (dd, J = 0.9, 8.1Hz, 2H); IR (KBr) 3410, 2890, 1725, 1630, 1610, 1495, 1440, 1380, 1320, 1275, 1075, 1025, and 710 cm "1; mass spectrum [(-) FAB], m / z 657/659 (M-H) +; Analysis calculated for C33H35CI012-1.0H20; C, 58.54; H, 5.51; N, 0.00, Found; C, 58.75; H, 5.36; N, 0.14.
Example 70
4-benzoyl- [N- (5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl] -benzamide
stage 1
4-benzoyl-N-. { 2-Chloro-5- [(2, 2 ', 3, 3', 41, 6, 6 '-hepta-O-acetyl-β-D-maltosyl) -oxi-methyl] -phenyl} -benzamide
The title compound is prepared as a white foam (0.240 g, 94%) from 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine using p-benzoylbenzoic acid and a procedure similar to the step of Example 65, mp > 84 ° C (decomposition); X H NMR (DMSO-d 6) d 1.93 (s, 3 H), 1.94 (s, 6 H), 1.97 (s, 6 H), 2.01 (s, 3 H), 2.08 (3. 3 H), 3.93-4.03 (m, 4 H) ), 4.15 (dd, J = 4.6, 12.3 Hz, ÍH), 4.21 (dd, J = 4.6, 12.1Hz, ÍH), 4.39 (dd, J = 2.2, 11.9 Hz, 1H), 4.70 (ABc, J = 12.7 Hz,? D = 0.14, 2H), 4.74 (dd, J = 8.1, 9.7 Hz, ÍH), 4.86 (dd, J 4.0, 10.5 Hz, ÍH), 4.90 (d, J = 8.1Hz, ÍH) ), 4.98 (t, J = 9.7 Hz, ÍH), 5.21 (dd, J = 9.7, 10.5 Hz, ÍH), 5.28 (d, J = 4.0 Hz, 1H), 5.31 (dd, J = 8.6, 9.4 Hz) , HH), 7.22 (dd, J = 2.0, 8.3 Hz, HH), 7.52 (d, J = 2.0 Hz, HH), 7.55-7.62 (m, 3H), 7.69-7.74 (m, HH), 7.76-7.80 (m, 2H), 7.85-7.88
(m, 2H), 8.11-8.14 (, 2H), 10.30 (s, ÍH); IR (KBr) 3400, 3010, 2950, 1755, 1675, 1650, '1590, 1530, 1440, 1420, 1370, 1230, 1130, and 1040 cm "1; mass spectrum [(+) FAB] m / z 984 / 986
(M + H) \ 1006/1008 (M + Na) +, Analysis calculated for C47H50CINO20; C, 57.35, H, 5.12; N, 1.42. Found; C, 57.11, H, 5.03; N, 1.32.
stage 2
4-benzoyl-N-. { 2-Chloro-5- [3,4-dihydroxy-6-hydroxymethyl-5- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy) -tetrahydro-pyran-2-yloxymethyl] - phenyl } benzamide
The title compound is prepared as a whitish vitreous solid (1.50 g, 95%) from 4-benzoyl-N-. { 2-chloro-5- [(2, 2 ', 3, 3', 4 ', 6,6' -hepta-O-acetyl-β-D-maltosyl) -oxymethyl] -phenyl} -benzamide using a procedure similar to that of step 4 of Example 1, p.f. > 131 ° C (decomposition); E NMR (DMSO-d6) d 3.02-3.32 (m, 4H), 3.32-3.40 (m, 2H), 3.40-3.50 (m, 3H), 3.55-3.64 (m, 2H), 3.73 (d, J = 10.8 Hz, HH), 4.31 (d, J = 7.9 Hz, HH), 4.48-4.53 (s broad ÍH), 4.53-4.59 (s broad ÍH), 4.61 (d, J = 12.5 Hz, ÍH), 4.83- 4.92 (m, 3H), 5.02 (d, J 4.0 Hz, ÍH), 5.21-5.31 (s broad ÍH), 5.36-5.48 (s broad ÍH), 5.48-5.56 (s broad ÍH), 7.32 (dd, J = 2.0, 8.3 Hz, 1H), 7.53 (d, J = 8.1Hz, ÍH), 7.56-7.62 (m, 3H), 7.69-7.74 (m, ÍH), 7.78 (dd, J = 1.3, 8.3 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 8.14 (d, J = 8.6 Hz, 2H), 10.33 (s, ÍH); IR (KBr) 3410, 2910, 1660, 1590, 1530, 1440, 1420, 1370, 1325, 1275, 1140, 1100, 1080, 1030, 910 and 710 cm "1; mass spectrum [(+) FAB], m / z 690/692 (M + H) +. 712/714 (M + Na) + Analysis calculated for C33H36CIN013 • 1.0 H20; C, 55.97; H, 5.41; N, 1.98 Found: C, 55.98, H, 5.36, N, 1.97.
stage 3
4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzamide
The title compound is prepared as a white solid (1.07 g, 66%) from 4-benzoyl-N-. { 2-Chloro-5- [3,4-dihydroxy-6-6-hydroxymethyl-5- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy) -tetrahydro-pyran-2-yloxymethyl] -phenyl ester } -benzamide using a procedure similar to that of Example 24, p.f. 208-211 ° C; XH NMR (DMSO-d6) d 3.09-3.15 (m, 1H), 3.29-3.42 (m, 4H), 3.47 (td, J = 3.1, 8.8 Hz, ÍH), 3.52-3.60 (m, 2H), 3.64 -3.76 (m, 3H), 4.12 (dd, J = 3.1, 8.3 Hz, ÍH), 4.34 (d, J = 7.7 Hz, ÍH), 4.68 (t J = 7.5 Hz, ÍH), 4.75 (ABc. J = 12.5 Hz,? D = 0.22, 2H), 5.14 (d, J = 4.0 Hz, ÍH),
. 30 (dd, J = 1.8, 5.3 Hz, 2H), 5.52 (d, J = 3.3 Hz, ÍH), 5.57
(s, ÍH), 5.63 (d, J = 6.6 Hz, ÍH), 7.34-7.38 (m, 4H), 7.42-7.46
(m, 2H), 7.55 (d, J = 8.1Hz, ÍH), 7.56-7.62 (m, 3H), 7.69-7.74
(m, ÍH), 7.76-7.80 (m, 2H), 7.87 (d, J = 8.3 Hz, 2H), 8.14 (d, j = 8.3 Hz, 2H), 10.33 (s, ÍH); IR (KBr) 3410, 3070, 2920,
2860, 1655, 1590, 1530, 1445, 1425, 1380, 1330. 1275, 1145,
1070, 1030, 1000, 910, and 700 cm "1; mass spectrum [(+) FAB], m / z 778/780 (M + H) +, 800/802 (M + Na) *; Analysis calculated for C40H40CINO13 • 0.5 H20; C, 61.03; H, 5.25; N, 1.78.
Found; C, 61.11; H, 4.86, N, 1.74.
Example 71
Amide of 4-benzoyl-N- acid. { 5- [(6-Benzoyl-oxy-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} benzoic
The title compound is prepared as a white solid (0.352 g, 63%) from 4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzamide using a procedure similar to that of Example 2, p.f. > 135 ° C (decomposition); XH NMR (DMS0-d6 d 3.18-3.24 (m, HI), 3.32-3.43 (m, 2H), 3.50-3.65 (m, 4H), 3.72 (td, J = 5.3, 10.1 Hz, ÍH), 3.77- 3.82 (m, ÍH), 4.05 (dd, J = 4.8, 10.1Hz, 1H), 4.36 (dd, J = 4.8, 12.1 Hz, ÍH), 4.43 (d, J = 7.9 Hz, 1H), 4.62 (d , J = 10.3 Hz, ÍH), 4.72 (ABc, J = 12.7 Hz- d = 0. 14. 2H), 5.14 (d, J = 3.7 Hz, ÍH), 5.32-5.37 (m, ÍH), 5.40 ( d, J = 4.4 Hz, HH), 5.52 (,, HH), 5.59 (s, 1H), 5.80 (d, J = 5.5 Hz, HH), 7.31-7.37 (m, 4H), 7.39-7.43 (m , 2H), 7.48-7.53 (m, 3H), 7.56-7.66 (m, 4H), 7.71 (tt, J = 1. 1, 6.8 Hz, ÍH), 7.77
(dd, J = 1.1, 7.9 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H), 7.99 (dd, J = 0.9, 8.1Hz, 2H), 8.12 (d, J = 8.6 Hz, 2H) , 10.33 (s, ÍH); GO . { KBr) 3420, 3080, 2850, 1720, 1660, 1600, 1530, 1440, 1420, 1370, 1320, 1275, 1140, 1070, 1030, and 715 cm "1; mass spectrum
[(+) FAB], m / z 882 (M + H) +, 904/906 (M + Na) +; Analysis calculated for C47H44CIN014 • 1.0 H20; C, 62.70; H, 5.15; N, 1.56, Found; C, 62.83; H, 5.02. N, 1.70.
Example 72
4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-6-O- (2-vodo) -benzoyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzamide
The title compound is prepared as a white solid (0.145 g, 32%) from 4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzamide using an o-I-BzCl and a procedure similar to that of Example 2, p.f. > 122 (decomposition); X NMR (DMSO-d6) d 3.16-3.23 (m, ÍH), 3.28-3.45 (m, 2H), 3.49-3.6 (m, 4H), 3.75 (dd, J = 4.8, 7.5 Hz, ÍH), 3.78 -3.84 (m, ÍH), 4.14 (dd, J = 4.6, 9.7 Hz 1H), 4.36 (dd, J = 5.5, 12.1Hz, ÍH), 4.44 (d, J = 7.7 Hz, ÍH), 4.61-4.67 (m, ÍH) 4.73 (ABc, J = 1.7 Hz,? d = 0.15, 2H), 5, 16 (d, J = 4.0 Hz, ÍH), 5.38 (dd, J = 5.3, 10.5Hz, 2H ), 5.55 (s, ÍH), 5.60 (d, J = 2.6 Hz, ÍH), 5.88 (d, J = 6.2 Hz, 1H), 7.2 (td, J = 1.8, 7.9 Hz, ÍH), 7.31-7.38 (m, 4H), 7.40-7.45 (m, 2H), 7.48-7.53 (, m, 2H) 7.56-7.62 (m, 3H), 7.71 (tt, J = 1.3, 6.8 Hz, ÍH), 7.75-7.79 (m, 3H), 7.85 (dd, J = 1.8, 6.6Hz, 2H), 8.00 (dd, J = 1.], 8.1Hz, ÍH), 8.12 (dd, J = 1.8, 6.6 Hz, 2H ), 10.30 (s ÍH): IR (KBr) 3410, 3070, 2850, 1730, 1655, 1590, 1525, 1440, 1420, 1375, 1280 1250, 1140, 1070. 1025, and 705 cm "1; mass spectrum [(+) FAB], m / z 1008 (M + H) + 1030 (M + Na) +, Analysis calculated for C47H43CIIN014; • 0.5 H20; C, 55.50; H, 4.36; N 1.38, Found; C, 55.14;; H, 4.22, N, 1.36.
Example 73
4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-6-O- (3-iodo-benzoyl) -β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -benzamide
The title compound is prepared as a white solid (0.244 g, 54%) from 4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzamide using m-I -BzCl (prepared from m-I-benzoic acid and oxalyl chloride) and a procedure similar to that of Example 2, p.f. 185-188.5 ° C; NMR (DMSO-d6) d 3.18-3.24 (m, 1H), 3.27-3.43 (m, 2H), 3.50-3.63 (m, 4H), 3.71 (td, J = 4.6, 9.9 Hz, ÍH), 3.77- 3.82 (m, ÍH), 4.06 (dd, J = 4.8, 9.9 Hz, ÍH), 4.35 (dd, J = 5.5, 12.1 Hz, ÍH), 4.44 (d, J = 7.7 Hz, ÍH), 4.61-4.67 (.m, ÍH), 4.73 (ABc, J = 12.5 Hz, áh = 0. 13, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.34 (d, J = 5.3 Hz, ÍH), 5.39 (d, J = 5.1 Hz, ÍH), 5.53 (s, ÍH), 5.58 (d, J = 2.9 Hz, 1H), 5.79 (d, J = 6.1Hz, ÍH), 7.31 (d, J = 7.9 Hz , ÍH), 7.33-7.37 (m, 4H), 7.38-7.43 (m, 2H), 7.51 (d, J = 8. 1Hz, ÍH), 7.56-7.62 (m, 3H), 7.71 (tt, J = 1.3, 6.8 Hz, 1H), 7.76-7.80 (m, 2H), 7.85 (dd, J = 1.8, 6.6 Hz, 2H), 7.99 (dt, J = 1.5,
7. 7 Hz, 2H), 8.11 (dd, J = 1.8, 6.8 Hz, 2H), 8.25 (t, J =
1. 8 Hz, 1H), 10.29 (s, ÍH); IR (KBr) 3410, 3080, 2910, 2850, 1725, 1650, 1590, 1570, 1530, 1440, 1420, 1375, 1280, 1255, 1140, 1070, 1030, 750 and 700 cm "1 mass spectrum [(+ ) FAB], m / z 1030 (M + Na) *, Analysis calculated for C47H43C1IN014 • 0.5 H20; C, 55.50; H, 4.36; N, 1.38, Found; C, 55.13; H, 4.15; N, 1.38.
Example 74
Amide of 4-benzoyl-N- (5- F (4 ', 6' -O-benzylidene-6- (4-iodo-benzoyl) -β-D-maltosyl) -oxy-methyl-2-chloro-phenyl acid Benzoic acid The title compound is prepared as a white solid (0.378 g, 59%) from 4-benzoyl-N-. {5- [(4 ', 6' -O-benzylidene-β-D)]. -maltosyl) -oxi-methyl] -2-chloro-phenyl] -benzamide using p-iodobenzoyl chloride and a procedure similar to that of Example 2, mp> 151 ° C (decomposition); 1 H NMR (DMSO-d6 ) d 3.18-3.24 (m, ÍH), 3.32-3.42 (m, 2H), 3.49-3.63 (m, 4H), 3.71
(td, J = 4.8, 9.9 Hz, ÍH), 3.78 (ddd, J = 1.1, 4.6, 9.2 Hz,
ÍH), 4.04 (dd, J = 4.8, 9.9 Hz, ÍH), 4.35 (dd, J = 4.8,
12. 1 Hz, ÍH), 4.42 (d, J = 7.7 Hz, ÍH), 4.59 (d, J = 10.8 Hz, 1H), 4.72 (ABc, J = 12.7 Hz,? D = 0.13, 2H), 5.13 (d , J = 4.0Hz, 1H), 5.34 (d, J = 5.3 Hz, ÍH), 5.39 (d, J = 5.1Hz, ÍH), 5.52 (s, ÍH), 5.59 (d, J = 2.4 Hz, ÍH) ), 5.82 (d, J = 5.9 Hz, 1H), 7.31-7.37 (m, 4H), 7.38-7.42 (m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.56-7.61 (m, 3H), 7.69-7.75 (m, 3H), 7.76-7.79 (m, 2H), 7.85 (d, J = 8.6 Hz- 2H), 7.89 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 8.6 Hz, 2H), 10.30 (s, ÍH); IR (KBr) 3420, 3080, 2890, 2840, 1725, 1655, 1590, 1530, 1440, 1420, 1380, 1365, 1325, 1280, 1160, 1120, 1070, 1030, 1005, 750 and 700 cm "1, spectrum mass [(+) FAB] m / z 1030/1032 (M + Na) +, Analysis calculated for C47H43C1IN014; C, 55.01; H, 4.42, N, 1.36, Found; C, 54.99; H, 4.38; N, 1.40.
Example 75
9H-Fluoren-9-methylmethyl (1- {5-F (4 ', 6' -0-benzylidene-β-D-maltosyl) -oxy-methyl-2-chloro-phenyl-carbamoyl} ethyl ester -carbamic
stage 1
N-. { 2-chloro-5- [(2,2 ', 3, 3 «, 4 •, 6, 6') -hepta-O-acetyl-β-D-maltosyl-oxymethyl] -phenyl} - (9H-Fluoren-9-ylmethoxycarbonyl) -L-alaninamide
The title compound is prepared as a white foam (2.50 g, 36%) from 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine using N- (9H-fluoren -9-ylmethoxycarbonylamino) -L-alanine and a procedure similar to that of step 1 of Example 65, mp > 96 ° C (decomposition); p.f. > 96 ° C (decomposition):? NMR (DMSO-d6) d 1.33 (dd, 17.2 Hz, 3H), 1.918 (s, 3H), 1.919 (s, 3H), 1.94 (s, 3H), 1966 (s, 3H), 1.97 (s ^ 2.01 (s, 2.07 (s, 3H), 3.91-4.02 (m, 4H), 4.12-4.24 (m, 3H), 4.24-4.34 (m, 3H), 4.34-4.40 (m, ÍH), 4.53 (d, J = 12.7 Hz, ÍH), 4.68-4.75 (m, 2H), 4.84 (d, J = 4. 0 Hz, ÍH), 4.86 (d, J = 2.6 Hz, ÍH), 4.97 (t, J = 9.7 Hz, ÍH), 5.21 (t, J = 9.7 Hz, ÍH), 5.27 (d, J = 3.7 Hz, ÍH), 5.27-5.32 (m, ÍH), 7.08 (dd, J = 1-8, 8.1 Hz , ÍH), 7.32 (t, J = 7.2 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.69-7.78 (m, 4H), 7.88 (d, J = 7.5 Hz, 2H), 9.42 (s, ÍH), IR (KBr) 3360, 3010, 2950, 1755, 1590, 1535, 1440, 1420, 1370, 1230, 1050 and 755 cm "1; mass [(+) ESI], m / z 1069.2 (M + H) +, 1086.2 / 1088.2 (M + NH4) + Analysis calculated for CS1H57C1N • 3.5 H20: C, 54.09; H, 5.70: N, 2.47. Found: C, 53.67; H, "5.11; N, 2.34.
stage 2
N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl] - (9H-fluoren-9-ylmethoxycarbonyl) -L-alaninamide
To a stirred solution of KCN (0.032 g, 0.491 mmole) in 10 ml of MeOH at 0 ° C is added the 9H-fluoren-9-methyl ester of the acid (1- (5- (4 ', 6'-O) -benzylidene-ß-D-maltosyl) -oxi-methyl] -2-chloro-phenyl-carbamoyl.} ethyl) -carbamic acid (1.05 g, 0.982 mmol). The reaction mixture is stirred at this temperature for 24 h and then concentrated. The resulting residue is diluted with THF: saturated aqueous NaHCO3 (1: 1, 20 ml) followed by addition of Fmoc-Cl (0.170 g, 0.658 mmol). This solution is stirred at rt for 0.5 h and the resulting mixture is filtered to remove the solid that forms. The filtrate is concentrated and the residue is purified by flash chromatography (80: 2: 1 to 4: 2: 1 EtOAc: EtOH: H20) to give the product (0.600 g, 79%) which is used in the next step without additional purification.
stage 3
9H-Fluoren-9-methylmethyl (l- {5 - [(4 ', 6' -0-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl-carbamoyl} ester. ethyl) -carbamic
The title compound is prepared as an off-white solid (0.295 g, 41%) from N- [2-chloro-5- (β-D-maltosyl-oxymethyl) -phenyl- (9H-fluoren-9-ylmethoxycarbonyl -L-alaninamide using a procedure similar to that of Example 24. pf > 190 ° C (decomposition); 1 H NMR, (DMSO-d 6) d 1.34 (d, J = 7.0 Hz, 3H), 3.06-3.14 (m, HH), 3.28-3.42 (m, 3H), 3.41 (td, J = 2.2, 9.2 Hz, 1H), 3.51-3.60 (m, 2H), 3.64-3.76 (m, 4H), 4.11 (dd, J = 2.4, 7.7 Hz, ÍH), 4.22 (t J = 6.6 Hz, ÍH), 4.26-4.35 ( m, 4H), 4.67 (t J = 5.7 Hz, ÍH), 4.69 (ABc, J = 12.5 Hz,? d = 0.22, 2H), 5.14 (d, J = 3.7 Hz, ÍH), 5.26 (d, J = 4.8 Hz, ÍH), 5.31 (d, J = 5.1Hz, 1H), 5.52 (d, J = 2.6 Hz, ÍH), 5.57 (s, ÍH), 5.64 (d, J = 6.2 Hz, ÍH) , 7.24 (d, J = 7.7 Hz, ÍH), 7.28-7.48 (m, IOH), 7.69-7.79 (m, 4H), 7.88 (d, J = 7.5 Hz, 2H), 9.46 (s, ÍH); IR (KBr) 3390, 3080, 2920, 1870, 2350, 1705, 1590, 1525, 1445, 1420, 1375, 1340, 1310, 1255, 1140, 1070, 1030 and 740 cm "1, - mass spectrum [(+ ) ESI], m / z 880 (M + NH,) +; Analysis calculated for
C ^ H ^ CIN- 1.0 H20; C, 59.96; H, 5.60; N, 3.18, Found;
C, 60.23; H, 5.53; N, 3.45
Example 76
N- (9H-Fluoren-9-ylmethoxycarbonyl) -N '- (5- [(6-Q-benzoyl-4', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro- phenyl.}. -L-alaninamide
The title compound is prepared as a white solid (0.083 g, 62%) from the 9H-f luoren-9-methyl-1-methyl ester of the acid (1- {5- [(4 '), 6'-O-benzylidene-β-D-maltosyl) -oxi-methyl] -2-chloro-f-enylcarbonyl} ethyl) -carbamic using a procedure similar to that of Example 2, p.f. 224-226 ° C, 1H NMR (DMSO-d6) d 1.32 (d, J = 7.2 Hz, 3H), 3.19 (t, J = 8.3 Hz, IN), 3.26-3.37 (m, 4H), 3.48-3.63 (m, 3H), 3.70 (dd, J = 5.1, 9.9 Hz, ÍH), 3.73-3.78 (m, ÍH), 4.05 (dd, J = 4.8, 9.9 Fiz, ÍH), 4.21 (t, J = 6.8 Hz, ÍH), 4.24-4.38 (m, 3H), 4.40 (d, J = 7.7 Hz, ÍH), 4.56-4.63 (m, ÍH), 4.65 (ABc, J = 12.5 Hz,? D 0.15, 2H) , 5.13 (d, J = 3.7 Hz, HH), 5.27-5.41 (s broad 1H), 5.52 (s, HH), 5.54-5.61 (s broad ÍH), 5.75-5.84 (s broad ÍH), 7.21 (d) , J = 8.6 Hz- 1H), 7.18-7.37 (m, 5H), 7.37-7.45 (m, 5H), 7.51 (t, J = 7.9 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H) , 7.69-7.77 (m, .4H), 7.88 (d, J = 7.7 HZ, 2H), 7.98 (d, J = 7.1 Hz, 2H), 9.43 (s, 1H); IR (KBr) 3400, 3080, 2920, 2850, 1725, 1590, 1530, 1440, 1420, 1375, 1320, 1275, 1070, 1025, 745, and 715 cm "1; mass spectrum [(+) FAB] m / z 989/991 (M + Na) +, Analysis calculated for C51H51C1N2015 • 1.0 H20; C, 62.16; H, 5.42; N, 2.84, Found; C, 61.99; H, 5.23; N, 3.06.
Example 77
N '- (5- [(6-O-benzoyl] -4', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl}. -L-alaninamide
To a stirred solution of 20% piperidine (2.00 ml, 20.2 mmol) in 10 ml of DMF at rt is added N- (9H-fluoren-9-ylmethoxycarbonyl) -N1-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -L-alaninamide (0.300 g, 0.256 mmol). After 2 h at this temperature, the solution is concentrated under high vacuum. The residue is purified by preparative flash chromatography (10: 2: 1 EtOAc: EtOH: H20) to give the product (0.018 g, 78%) as an off-white solid, m.p. 131-133 ° C;; H NMR (DMSO-d6) d 1.26 (d, J = 7.0
Hz, 3H), 3.15-3.22 (m, ÍH), 3.26-3.42 (.m, 5H), 3.47-3.64 (m,
4H), 3.70 (dd, J = 4.6, 9.7 Hz, ÍH), 3.73-3.79 (m, ÍH), 4.05
(dd, J = 4.8, 9.9 Hz, ÍH), 4.35 (dd, J = 5.1, 12.1 Hz, ÍH),
4. 40 (d, J = 7.7 Hz, ÍH), 4.60 (d, J = 12.7 Hz, ÍH), 4.66 (ABc, J 12.3 Hz,? D = 0. 14. 2H,), 5.13 (d, J = 3.7 Hz, ÍH), 5.34 (dd, J = 0.9, 5.3 Hz, 2H), 5.5-1 (s, 1H), 5.57 (d, J = 2.9 Hz, ÍH), 5.80 (d, J = 6.2 Hz, ÍH) ), 7.15 (dd, J = 2.0, 8.1 Hz, ÍH), 7.33-7.38 (m, 3H), 7.38-7.45 (m, 3H), 7.53 (t, J - = 7.7 Hz, 2H), 7.63-7.68 (m, 2H), 7.98 (d, J = 1.3 Hz, ÍH), 8.00 (5, ÍH), 8.20 (s, ÍH); IR (KBr) 3410, 2920, 2850, 1720, 1625. 1590, 1525, 1445, 1420, 1375, 1275, 1070, 1025, and 715 cm "1; mass spectrum [(+) FAB], m / z 745 (M + H) +, 767 (M + Na) + Analysis calculated for C35H41CIN2013 • 2.0H20; C, 55.35; H, 5.8.1; N, 3.59. Found: C, 55.63; H, 5.77; N, 3.23.
Example 78
N-. { 5 - [(4 ', 6', O -benzyl iden-β-D-maltosyl) -oxymethyl 1-2-chloro-phenyl} -N-methyl-acetamide
stage 1
N- [5- (2,2 ', 3,3", 4', 6,6'-hepta-O-acetyl-β-D-maltosyl) -oxi-methyl-2-chlorophenyl] -N-methyl- acetamide
To a stirred solution of N- [2-chloro-5- (hepta-0-acetyl-β-D-maltosyl-oxymethyl) -phenyl] -acetamide (0.100 g, 0.122 mmol) in 2.0 ml of THF at -78 ° C NaHMSA (0.183 ml, 1.0 M in THF) is added. After 0.5 at this temperature, methyl iodide (0.0152 ml, 0.244 mmol) is added and the reaction is heated to rt for 2 h. At this point, the reaction is diluted in 100 ml of EtOAc, washed with 10 ml of 1N HCl, 10 ml of saturated aqueous NaHCO 3, and 10 ml of brine and then dried with MgSO 4. After concentration, the resulting oily residue is purified by preparative plate chromatography using 50:50 EtOAc: petroleum ether as the eluent to give the product (0.0408 g, 40%) as a white foam, m.p. > 252 ° C (decomposition); 1 H NMR (CDC13) d 1.81 (s, 3 H), 2.00 (s, 3 H), 2.01 (s, 6 H), 2.02 (s, 3 H), 2.04
(s, 3H), 2.10 (s, 3H), 2.15 (s, 3H), 3.19 (d, J = 2.9 Hz, 3H),
3. 67-3.72 (m, ÍH), 3.94-3.99 (m, ÍH), 4.03 (t, J = 9.4Hz, ÍH),
4. 07 (d, J = 2.2 Hz, ÍH), 4.21-4.28 (m, 2H), 4.54 (dd, J = 2.9.
12. 3 Hz, ÍH), 4.59 (d, J = 11.6 Hz, 1H), 4.64 (d, J = 7.5 Hz, ÍH), 4.83-4.93 (m, 3H), 5.06 (t, J = 10.1Hz, ÍH) , 5.26 (td, J = 3.3, 9.0 Hz, 1H), 5.36 (t J = 9.7 Hz, ÍH), 5.42 (d, J = 4.0Hz, ÍH), 7.20 (d, J = 2.0 Hz, ÍH) , 7.24 (dt, J = 2.0, 8.1Hz, ÍH), 7.47 (dd, J = 1.1, 8.1Hz, ÍH); IR (KBr) 3470, 2950, 1755, 1620, 1480, 1420, 1380, 1230, 1140 and 1045 cm "1; mass spectrum [(+) ESI], m / z 832 (M + H) +. for C35H46CIN019 • 1.5 H20; C, 50.32; H, 5.75; N, 1.63, Found; C, 50.17.H, 5.38.N, 1.67.
Stage 2 - Ißl -N-. { 2-Chloro-5- [(ß-D-maltosyl) -oxymethyl] -phenyl} -N-methyl-acetamide
The title compound is prepared as a white solid (0.475 g, 99%) from N- [5- (2, 2 ', 3, 3', 4 ', 6,6' -hepta-O-acetyl- β-D-maltosyl) -oxi-methyl-2-chloro-phenyl] -N-methyl-acetamide using a procedure similar to that of step 4 of Example 1, mp > 96 ° C (decomposition): XH NMR (DMSO-d6) d 1.67 (s, 3H), 3.05 (d, J = 1. 1Hz, 3H), 3.06-3.14 (m, ÍH), (m, 2H), 3.18-3.38 (m, 2H), 3.38-3.49 (m, 4H), 3.53-3.63 (m, 2H), 3.68-3.75 (m, 11-1), 4.28 (dd, J = 7 4.48-4.53 (m , 2H), 4.62
(dd, J = 3.3, 13.2 Hz, ÍH), 4.84 (d, J 13.0 Hz, 5.5, 7.7 Hz, 2H), 5.01 (d, J = 3.7 Hz, 1H), 5.30 (dd, J = 4.8, 7.7 Hz, 1H), 2.4. 6.2 Hz, HH), 5.52 (d, J = 3.1Hz IR), 7.43 (d, J = 1.8, 8.1Hz, HH), 7.60 (d, 8.3 Hz, HH); IR (KBr) 3400, 3000, 1910, 1645, 1580, 1480, 1420, 1385 1320, 1255, 1195, 1145, 1120, 1075, 1035, and 755 cm "1; mass spectrum [(+) FAB], m / z 538
(M + H) +, 560 (M + Na) +, Analysis calculated for C22H32C1N012 • 1.0 H20; C, 47.53: H, 6.16; N, 2.52, Found; C, 47.18; H, 6.01; N, 2.39.
stage 3
N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl-oxymethyl chlorophenyl-N-methyl-acetamide) The title compound is prepared as a white foam (0.315 g, 63%) from N- {.2-Chloro-5- [(ß-D-maltosyl) -oxymethyl] -phenyl} - N-methyl-acetamide using a procedure similar to that of Example 24, mp> 125 ° C (decomposition); t NMR (DMSO-d6) d 1.68 (d, J = 1.3Hz, 3H), 3.06 (d, J = 1.3 Hz, 3H), 3.09-3.16 (m, HH), 3.28-3.42 (m, 4H), 3.42-3.50 (m, ÍH), 3.50-3.60 (m, 2H), 3.64-3.75 (m, 3H), 4.09-4.14 (m, ÍH), 4.30
(dd, J = 7.7, 10.3 Hz, 1H), 4.60-4.69 (m, 2H), 4.85 (d, J = 13.2 Hz, ÍH), 5.14 (d, J = 4.0 Hz, 1H @), 5.30 (d , J = 5.1Hz, ÍH), 5.33 (dd, J = 5.1, 7.9 Hz, ÍH), 5.53 (d, J = 3.3 Hz, ÍH), 5.57 (s, ÍH), 5.63 (dd, J = 2.9, 6.8 Hz, ÍH), 7.34-7.38
(m, 3H), 7.41-7.46 (M, 3H), 7.58 (s, ÍH), 7.60 (d, J = 8.3 Hz-1H); IR (KBr) 3410, 2920, 2860, 1640, 1610, 1580, 1480, 1440, 1410, 1380, 1320, 1185, 1150, 1070, 1030, 955, and 755 cm "1; mass spectrum [(-) FAB ], m / z 624 (M-H) +, Analysis calculated for C29H36CIN012 • 2.5H20, C, 51.90, H, 6.16, N, 2.09, Found, C, 5 1.92, H, 5.48, N, 2.09.
D-mal tosyl) -oxymethyl-2-chloro-phenyl} -N-methyl-acetamide using a procedure similar to that of Example 2, p.f. 180-183 ° C; XH NMR (DMSO-d6) d 1.64 (d, J = 4.0 Hz, 3H), 3.02 (s, 3H), 3.17-3.25 (m, ÍH), 3.35 (d, J = 9.4 Hz, ÍH), 3.37- 3.43 (m, 1H), 3.49-3.65 (m, 4H) 3.70 (dd, J = 4.6, 9.9 Hz, ÍH), 3.73-3.79 (m, ÍH), 4.04 (d, J = 5.1, 9.9 Hz, 1H ), 4.34 (ddd, J = 2.4 4.8, 12.1Hz, ÍH), 4.41 (dd, J = 7.9, 10.1 Hz, ÍH), 4.58 (d, J = 11.4 Hz, 1H), 4.72 (ABc, J = 12.5 Hz,? D = 0.12, 2H), 5.14
(d, J = 3.7 Hz, ÍH), 5.34 (d, J = 4.8 Hz, 1H), 5.43 (dd, J = 5.3, 7.2 Hz, ÍH), 5.52 (s, ÍH), 5.59 (d, J = 2.6 Hz, ÍH), 5.79
(dd, J = 2.0, 5.7 Hz, 1H), 7.33-7.37 (m, 3H), 7.38-7.43 (m, 3H), 7.50-7.55 (m, 3H), 7.56 (d, J = 8.3 Hz, ÍH ), 7.63-7.68 (m, ÍH), 7.96-8.00 (m, 2H); IR (KBr) 3495, 3400, 3090.2930, 2890, 1730, 1645, 1600, 1575, 1480, 1445, 1420, 1385, 1360, 1320, 1270, 1200, 1160, 1110, 1070, 1050, 1020, 985, and 715 cm "1; mass spectrum [(+) FAB], m / z 730 (M + H) *, 752 (M + Na) +; Analysis calculated for C36H40CINO13 • H20: C, 59.22; H, 5.52: N, 1.92, Found, C. 59.02; H, 5.50; N, 1.79.
Example 80
Methyl ester of N-5 - [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl acid} -carbamic
Stage 1 Methyl ester of N- acid. { 5- [(2, 2 ', 3, 3', 4 ', 6, 6 • -hepta-O-acetyl-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -carbamic
To a stirred solution of 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine (1.40 g, 1.80 mmol) in 18 ml of THF at 0 ° C is added NaH (0.108 g) , 2.70 mmoles). After
minutes. at this temperature, methyl chloroformate is added
(0.167 ml, 2.16 mmol), and then the reaction is heated to rt for 3 h. At this point, the reaction is concentrated and the residue is diluted with 300 ml of EtOAc. This solution is washed with 30 ml of 1N HCl, 30 ml of saturated aqueous NaHCO 3 and 30 ml of brine, and then dried with MgSO 4. After concentration, the resulting oily residue is purified by flash chromatography (2:98 to 10:90 gradient of acetone: CHC13) to give the product (1.33 g, 88%) as a white foam, m.p. > 79 ° C (decomposition); 1 H NMR (DMS0-d 6) d 1.93 (s, 3 H), 1.94 (s, 6 H), 1,970 (s, 3 H), 1,973 (s, 3 H), 2.01 (s, 3 H), 1.08 (s, 3 H), 3.64 (s, 3H), 3.91-4.03 (m, 4H), 4.12-4.23 (m, 2H), 4.38 (dd, J = 1.8, 11.9 Hz, ÍH), 4.54 (d, J = 12.7 Hz, ÍH), 4.69-4.75 (m, 2H), 4.83-4.88 (m,
2H), 4.97 (t, J = 9-7 Hz, ÍH), 5.21 (dd, J = 9.7, 10.3 Hz, ÍH),
. 27 (d, J = 3.7 Hz, ÍH), 5.30 (dd, J = 8.6, 9.2 Hz, ÍH), 7.07
(dd, J = 2.0, 8.3 Hz, ÍH), 7.44 (d, J = 8.1 Hz. ÍH), 7.48 (d,
J = 1.8 Hz, ÍH), 9.08 (s, ÍH); IR (KBr) 3420, 2950, 1755, 1590, 1530, 1450, 1420, 1375, 1230, 1130 and 1040 cm "1; mass spectrum [(+ FAB], m / z 834 (M + H) +, 856 (M + Na) +, Analysis calculated for C35H44ClNO20 • 0.5 H20; C, 49.86; H, 5.38; N, 1.66. Found; C, 49.68; H, 5, 14. N, 1.58.
stage 2
Methyl ester of acid. { 2-Chloro-5- [(ß-D-maltosyl) -oxy-methyl] -phenyl} -carbamic
The title compound is prepared as a white foam (0.753 g 99%) from the methyl ester of the acid
[(2, 2 ', 3, 3', 4 ', 6, 6' -hepta-O-acetyl-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -carbamic using a procedure similar to that of step 2 of Example 63, p.f. > 109 ° C (decomposition); 1 H NMR (DMSO-d 6) d 3.01-3.11 (m, 2H), 3.19-3.27 (m, 2H), 3.28-3.38
(m, 2H), 3.38-3.50 (m, 3H), 3.52-3.64 (m, 2H), 3.64 (s, 3H),
3. 72 (d, J = 11.2 Hz, ÍH), 4.28 (d, J = 7.9 Hz, ÍH), 4.44--4.57
(m, 2H), 4.67 (ABc, J = 12.5 Hz,? d = 0.22, 2H), 4.83-4.96 (s broad 2H), 5.01 (d, J = 4.0 Hz, ÍH), 5.16-5.32 (s broad ÍH), 5.34-5.58 (s broad 2H), 7.21 (dd, J = 2.0, 8.1 Hz, ÍH), 7.43
(d, J = 8.1 Hz, ÍH), 7.53 (d, J = 1.8 Hz, ÍH), 9.07 (s, ÍH);
IR (KBr) 3420, 2920, 1725, 1590, 1530, 1450, 1425. 1370, 1310,
1255, 1230, 1140, 1070, and 1030 cm "1; mass spectrum [(+) FAB] m / z 562/564 (M + Na) *, Analysis calculated for C21H30ClNO13 • 0.5 H20; C, 45.95; H, 5.69; N, 2.55, Found; C, 45.81; H, 5.82; N, 2.39.
stage 3
Methyl ester of N- acid. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -carbamic
The title compound is prepared as a white solid (0.552 g, 71%) from the methyl ester of the acid. { 2-Chloro-5- [(ß-D-maltosyl) -oxi-methyl-phenyl} -carbamic using a procedure similar to that of Example 24, p.f. 142- 145 ° C; 1 H NMR (DMS0-d6) d 3.06-3.13 (m, HH), 3.28-3.41 (m, 4H), 3-46 (td, J = 2.4, 8.8 Hz, 1H), 3.50-3.61 (m, 2H) , 3.65 (s, 3H), 3.65-3.75 (m, 3H), 4.11 (dd, J = 3.1, 8.1 Hz, ÍH), 4.30 (d, J = 7.7
Hz, ÍH), 4.64-4.69 (m, ÍH), 4.68 (ABc, J = 12.5 Hz,? D = 0.22.
2H), 5.14 (d, J = 3.7 Hz, ÍH), 5.26 (d, J = 5.1 Hz, ÍH), 5.30
(d, J = 4.8 Hz, ÍH), 5.51 (d, J = 2.9 Hz, 1H), 5.57 (s, ÍH),
. 63 (d, J = 6.4 Hz, ÍH), 7.22 (dd, J = 2.0, 8.1 Hz, ÍH), 7.34-7.38 (m, 3H), 7.41-7.46 (m, 3H), 7.54 (d, J = 1.8 Hz, ÍH), 9.07 (s, 1H): IR (KBr) 3530, 3410, 2920, 2850, 1730, 1590, 1535, 1450, 1420, 1375, 1310, 1250, 1230, 1145, 1075, 1030, and 1000 cm "1; mass spectrum [(+) FAB, m / z 650/652 (M + Na) +; Analysis calculated for C28H34C1N013 • 0.5 H20; C, 52.79; H, 5.54; N, 2.20.; C, 52.85; H, 5.77; N, 211.
157 Example 81
Methyl ester of N- acid. { 5- [(6-0-Benzoyl-4 ', 6'-Q-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl) -carbamic
The title compound is prepared as a white solid (0.407 g, 71%) from the N- methyl ester. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -carbamic using a procedure similar to that of Example 2, p.f. > 103 ° C (decomposition); XH NMR (DMSO-d6) d 3.16-3.22 (m, HH), 3.27-3.42 (m, 2H), 3.48-3.63 (m, 4H), 3.63
(s, 3H), 3.70 (dd, J = 5.1, 10.1 Hz, ÍH), 3.73-3.79 (m, ÍH), 4.05 (dd, J = 4.8, 9.9 Hz, ÍH), 4.35 (dd, J = 5.1 , 12.1 Hz, ÍH), 4.40 (d, J = 7.7 Hz, ÍH), 4.58-4.63 (m, ÍH), 4.66 (ABc, J = 12.5 Hz,? D = 0.14, 2H), 5.14 (d, J = 4.0 Hz, ÍH), 5.35
(dd, J = 5.3, 8.3 Hz, 2H), 5.52 (s, 1H), 5.57 (d, J = 3.1 Hz, ÍH), 5.80 (d, J = 6.2 Hz, ÍH), 7.19 (dd, J = 2.0, 8.1 Hz, 1H), 7.33-7.43 (m, 6H), 7.50-7.55 (m, 3H), 7.63-7.68 (m, ÍH), 8.00
(dd, J = 1.1, 8.1 1Hz, 2H), 9.05 (s, ÍH); IR (KBr) 3420, 3080, 2920, 2860, 1725, 1640, 1590, 1530, 1445, 1425, 1370, 1320, 1275, 1220, 1140, 1070, 1025, and 720 c "1; Mass spectrum [(+ ESI), m / z 732/734 (M + H) + 754/756 (M + Na) +, Analysis calculated for C35H28C1N014; C, 57.42; H, 5.23; N, 1.91, Found; C, 57.17 H, 5.26; N, 1.81.
Example 82
N- (5- [(6-0-3-benzyl-l-oxo-propyl) 4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl-2-chloro-methyl acid methyl ester phenyl)
The title compound is prepared as a white solid (0.152 g, 42%) from N- methyl ester. { 5 - [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -carbamic using hydrocinnoyl chloride and a procedure similar to that of Example 2, p.f. > 93 ° C (decomposition); t NMR (DMS0-d6) d 2.66 (t J = 7.7 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 3.08-3.16 (m, 1H), 3.27-3.49 (m, 4H), 3.53-3.60 (m, 2H), 3.62-3.72 (m, 2H), 3.63 (s, 3H), 4.05-4.13 (m, 2H), 4.31-4.37 (m, 2H), 4.63 (ABc, J = 12.5 Hz,? D = 0.15, 2H), 5.09 (d, J = 3.7 Hz, ÍH), 5.34 (t J = 5.5 Hz, 2H), 5.55-5.58 (m, 2H), 5.82 (d, J = 6.2 Hz, ÍH), 7.12-7.18 (m, ÍH), 7.18-7.27 (m ', 5H), 7.34-7.39 (m, 3H), 7.41-7.46 (m, 3H), 7.54 (d, J = 1.8 Hz , ÍH), 9.07 (s, ÍH); IR (KBr) 3410, 3080, 3030, 2920, 2850, 1735, 1590, 1530, 1450, 1425, 1375, 1310, 1250, 1220, 1145, 1070, 1030, 750 and 500 cm "1; mass spectrum F ( -) ESI], m / z 758 (M - H) +, Analysis calculated for C37H42C1N014 • 1.0 H20; C, 57.11; H, 5.70, N, 1.80, Found; C, 57.30; H, 5.52; N, 1.77.
83
N-. { 5- r (4 ', 6' -O-benzylidene-β-D-maltosyl) -oxi-methi-11-chloro-phenyl} -methanesulfonamide
stage 1
N-. { 5 - [(2, 2 l, 3, 3,, 4,, 6, 6 > -hepta-O-acetyl-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -methanesulfonamide
To a stirred solution of NaH (0.0467 g, 1.17 mmol) and 10 mL of CH2C12 at rt is added 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl-oxymethyl) -phenylamine (0.755 mg, 0.973 mmoles). After 10 min. MsCl (0.0906 ml, 1.17 mmol) is added dropwise to this solution, and the reaction is stirred at rt for 18 h. Another 2.4 equivalents of MsCl are added and stirring is continued at rt for 144 h. Since the reaction is only about 25% complete, it is refluxed for 24 h. Then add another 2.4 equivalents of MsCl and continue under reflux for 120 h. The resulting solution is concentrated and then diluted with 200 ml of EtOAc. This layer is washed with 20 ml of 1 H HCl, 20 ml of saturated NaHCO 3 and 20 ml of brine, and then dried (MgSO 4). After concentration, the oily residue is purified by flash chromatography (gradient from 10:90 to 60:40 acetone: hexanes) to give the product (0.23 g, 51%) as a white foam, m.p. > 73 ° C (decomposition): 1 H NMR (DMSO-d 6) d 1.93
(d, J = 1.8 Hz, 3H), 1.94 (d, J = 1.8 Hz, 3H), 1.95 (d, J = 1.5 Hz, 3H), 1.97 (d, J = 0.9 Hz, 6H), 2.01 (d , J = 1.5 Hz, 3H), 2.08 (d, J = 1.5 Hz, 3H), 3.02 (d, J = 1.3 Hz, 3H), 3.90-4.04 (m, 4H), 4.11-4.23 (m, 2H) , 4.38 (d, J = 11.6 Hz, ÍH), 4.56 (d, J = 12.7 Hz, 1H), 4.68-4.77 (m, 2H), 4.82-4.89 (m, 2H), 4.97 (t, J = 9.7 Hz, ÍH), 5.20 (t, J = 9.4 Hz,. ÍH), 5.27
(d, J = 3.1 Hz, HH), 5.27-5.34 (m, HH), 7.15 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 7.50, (dd, J = 1.5, 8.3 Hz , ÍH), 9.47 (s, ÍH); IR (KBr) 3480, 3260, 3010, 2950, 1755, 1590, 1495, 1420, 1375, 1355, 1230, 1140, 1045, 975, 900, and 755 cm; Mass spectrum [(+) FAB], m / z 854 (M + H) \ 876 (M + Na) *. Analysis calculated for CH34C44ClNO20S • 1.25 H20: C, 46.58; H, 5.35; N, 1.60, Found; C, 46.22. H, 4.93; N, 1.49.
stage 2
Sodium salt of N-. { 5- [(ß-D-maltosyl) -oxi-methyl) -2-chloro-phenyl} -methanesulfonamide
The title compound is prepared as a white solid (0.310 g, 71%) from N-. { 5- [(2, 2 ', 3, 3', 4 ', 6, 6' -hepa-O-acetyl-β-D-maltosyl) -oxi-methyl] -2-chloro-phenyl} -methanesulfonamide using 1.3 equivalents 25% by weight of NaOMe in MeOH (due to the acidity of the sulfonamide) and a procedure similar to stage 4 of Example 1, p.f. > 189 ° C (decomposition); lK NMR (DMS0-d6) d 2.54 (s, 3H), 3.05 (t, J «= 8.1 Hz, 2H), 3.16 (s, ÍH), 3.18-3.24 (m, 2H), 3.27-3.42 (m, 2H), 3.42-3.51 (m, 2H), 3.53-3.63 (m, 2H,), 3.72 (d, J = 11.2 Hz, 1H), 4.24 (d, J = 7.7 Hz, ÍH), 4.44-4.54 ( s broad H), 4.50 (ABc, J = 11.6 Hz,? d = 0.24, 2H), 4.54-4.60 (s broad H), 4.80-4.93 (s broad 2H), 5.01 (d, J = 3.7 Hz, 1H ), 5.09-5.18 (s broad H), 5.27-5.55 (s broad 2H), 6.47 (dd, J = 2.0, 7.9 Hz, ÍH), 7.05 (d, J = 7.9 Hz, ÍH), 7.19 (d, J = 2.0 Hz, ÍH); IR (KBr) 3410, 2920, 1630, 1590, 1475, 1420, 1375. 1310, 1215, 1140, 1110, 1075, and 1020 cm "1; Mass spectrum [(+) FAB, m / z 582 (M + Na) * 7 Analysis calculated for C20H29ClNO13S Na
3. 5 H20; C, 37.24; H, 5.63; N, 2.17. Found; C, 37.00; H, 5.10; N, 2.13.
stage 3
N-. { 5 - [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -methanesulfonamide
The title compound is prepared as a white solid (0.198 g, 55%) from the N- sodium salt. { 5 - [(ß-D-maltosyl) -oxy-methyl) -2-chloro-phenyl} -methanesulfonamide using a procedure similar to that of Example 24, p.f.
> 93 ° C (decomposition); ? E NMR (DMSO-d6) d 3.05 (s, 3H), 3.07-3.14 (m, ÍH), 32.6-3.42 (m, 4H), 3.42-3.48 (m, ÍH), 3.50-3.59
(m, 2H), 3.63-3.75 (m, 3H), 4.11 (d, J = 5.4 Hz, ÍH), 4.30 (d, J = 7.7 Hz, ÍH), 4.66 (t, J = 6.6 Hz, ÍH) , 4.71 (ABc, J = 12.7 Hz,? D = 0.19, 2H), 5.14 (d, J = 3.7 Hz), 5.29 (t, J = 4.2 Hz, 2H), 5.51 (d, J = 3.1 Hz, ÍH), 5.57 (s, ÍH), 5.63 (d, J = 6.6 Hz, 1H), 7.30 (dd, J = 1.8, 8.1 Hz, ÍH), 7.34-7.39 (m, 3H), 7.42-7.47 (m , 3H), 7.49 (d, J = 8.1 Hz, ÍH), 9.44 (s, ÍH); GO
(KBr) 3410, 2910, 1840, 1630, 1590, 1495, 1445, 1385, 1345, 1235, 1160, 1070, 1015, 990 and 755 cm "1, mass spectrum FAB], m / z 646 (M-H ) +; Analysis calculated for C27H34C1N023S • 2.0 H20; C, 47.40, H, 5.60; N, 2.05, Found; C, 47.09; H, 4.99; N, 1.98.
Example 84
N-. { 5- F (6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxi-methyl 2-cyan-phenyl} -acetamide
stage 1
a-bromo-2-nitro-p-tolunitrile
A stirred mixture containing 4-methyl-2-nitrobenzonitrile (2.04 g, 12.6 mmol), N-bromosuccinimide (2.24 g, 12.6 mmol) and azobisisobutyronitrile (0.103 g, 0.630 mmol) in 50 mL of CC14 is irradiated with flat light of 300 watts for 2 h. The reaction is diluted with 50 ml of CH2C12, filtered and concentrated. Purification by flash chromatography (gradient of 35 and 40% ether / petroleum ether) gives 1.44 g (47%) of the title compound as a yellow oil. ? NMR (DMS0-d6) d 4.90 (s, 2 H), 8.05 (dd, J 8.0, 1.5 Hz, ÍH), 8.18 (d, J = 8.0, ÍH), 8.52 (s, ÍH).
stage 2
a-hydroxy-2-nitro-p-tolunitrile
A stirred solution containing a-bromo-2-nitro-p-tolunitrile (1228 g, 5095 mmol) and sodium formate (0.8664 g, 12.74 mmol) in ethanol: water (4: 1, 25 ml) is refluxed for 2 h. The reaction is cooled to room temperature, diluted with 20% CH2C12 / EtOAc, washed with H20 (3x), dried (MgSO4) and concentrated. Purification by flash chromatography (gradient of 1.2 and 3% MeOH / CHCl 3) gives 0.695 g (77%) of the title compound as a white solid. XH NMR (DMSO-d6) d 4.71 (d, 2H), 5.75 (t, ÍH), 7.89 '(dd, J = 7.9 Hz, ÍH), 8.14 (d, J = 7.9 Hz, ÍH), 8.32 (s) , ÍH).
stage 3
- . 5 - [(hepta-O-acetyl-β-D-maltosyl) -oxy-methyl] 2-cyano-1-nitrobenzene
At room temperature, to a stirred solution of acetobromomaltose (2.39 g, 3.41 mmol), a-hydroxy-2-nitro-p-tolunitrile (0.789 g 4.43 mmol) and HgBr2 (1.60 g, 4.43 mmol) in 34 ml of fresh CH3CN The distillate is added in one portion Hg (CN) 2 (1.12 g, 4.43 g, mmoles). After 16 h. 50 ml of brine are added and the mixture is extracted with 10% CH2C12 / EtOAc. The combined organic extracts are washed with brine (3x), dried with MgSO 4 and concentrated. Purification by flash chromatography (gradient of 1.2 and 3% MeOH / CHCl3) provides 1.941 g (71%) of the title compound as a foam. An analytical sample is obtained by crystallization from EtOAc / hexane followed by recrystallization from EtOH to provide a colorless solid, m.p. 155-157 ° C, SE NMR (DMS0-d6) d 1.93 (s, 3 H), 1.94 (s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H), 3.93-4.01 (m, 4H), 4.36 (d, J = 11.0 Hz, ÍH), 4.77 (dd, J = 9.6, 8.0 Hz, 1H), 483-4.88 (m, 2H) , 4.93-5.00 (m, 3H), 5.21 (dd, J = 10.3.9.7 Hz, ÍH), 5.27 (d, J = 3.7 Hz, ÍH), 5.30-5.34 (m, ÍH), 7.84 (dd, J = 7.9, 1.5 Hz, ÍH), 8.18 (d, J = 7.9 Hz, ÍH), 8.27 (s, ÍH), IR (KBr) 3450, 2950, 2225, 1750, 1225 and 1050 cm "1. [(+) FAB] m / z 797 (M + H) + Analysis calculated for C34H4QN2O20: C, 51.26, H, 5.06; N, 3.52. Found; C, 51.06; H, 5.02; N, 3.3 1.
stage 4
- [(hepta-O-acetyl-β-maltosyl) -oxi-methyl-2-cyano-phenylamine
A stirred mixture containing 5- [(hepta-O-acetyl-β-D-maltosyl) -oxy-methyl] -2-cyano-l-nitrobenzene (1491 g, 1872 mmol) iron powder (0.3658 g, 6.550 mmol) ) and 7 ml of glacial acetic acid in 7 ml of 2-propanol is heated at 75 ° C for 2 h. Activated carbon is added to the reaction and the hot solution is filtered through a sulka ploc pad rinsed with EtOAc. The filtrate is washed with H20 (3x), saturated aqueous NaHCO3 (3x), dried with Na2SO4 and concentrated. Purification by flash chromatography (gradient of 1.2 and 3% MeOH / CHCl 3) gives 1.04 g (72%) of the title compound. X H NMR (DMSO-d 6) d 1.94 (s, 3 H), 1.95 (s, 3 H), 1.96 (s, 3 H), 1.99 (s, 6 H), 2.02 (s, 3 H), 2.09 (s, 3 H) ), 3.95-4.02 (m, 4H), 4.14-4.22 (m, ÍH), 4-36-4.40 (m, ÍH), 4.56 (ABc J = 13.2 Hz,? D = 0.09, 2H), 4- 72 (dd, J = 9.4, 8.2 Hz, ÍH) 4.98 (t J = 9.7 Hz, ÍH), 5.19-5.37 (m, 3H), 6.06 (s, ÍH), 6.49 (dd, J = 8.1, 1.0 Hz , ÍH), 6.66 (s, ÍH), 7.36 (d, J = 8.1 Hz, ÍH), mass spectrum [(+) FAB], m / z 767 (M + H) +.
stage 5
N-. { 5- [(hepta-O-acetyl-β-D-maltosi) -oxi-methyl-2-siane-phenyl) -acetamide
At room temperature, a solution of 5 - [(hepta-O-acetyl-β-maltosi) -oxi-methyl] -2-cyano-phenylamine (0.280 g, 0.365 mmole) in 3.6 ml of CH2C12 is added with 60% NaH / mineral oil (14.6 mg, 0.365 mmole) and the reaction is stirred for 0.5 h. Acetyl chloride (31.3 μl, 0.438 mmol) is added to the reaction and the reaction is stirred for 16 h. The reaction is suspended with 25 mL of saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts are dried with Na 2 SO 4 and concentrated. Purification by flash chromatography (gradient of 1.2 and 3% MeOH / CHCl 3) gives 0.249 g (84%) of the title compound. An analytical sample is obtained by crystallization from EtOAc / hexane to give a colorless solid, m.p. 85-95 ° C; JH NMR (DMS0-d6) d 1.93 (s, 3H), 1.94 (s, 3H), 1.95 (s, 3H), 1.97 (s, 6H), 2.01 (s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 3.92 - 4.01 (m, 4H), 4.13 - 4.21 (m, 2H), 4.37 (dd, J = 12.0, 2.1 Hz, ÍH), 4.73 (ABc, J = 13.8 Hz,? D = 0.07, 2 H), 4.73 (dd, J = 9.5, 8.0 Hz, 1 H), 4.84-4.89 (m, 2H), 4.97 (t, J = 9.8 Hz, ÍH), 5.21 (dd, J = 10.3 , 9.7 Hz, 1 H), 5.27 - 5.33 (m, 2H), 7.21 (dd, J = 8.0, 1.4 Hz, ÍH), 7.48 (s, ÍH), 7.78 (d, J = 8.0 Hz, 1H), 10.15 (s, ÍH), IR (KBr), 3400, 2950, 2225, 1750, 1240 and 1050 cm "1. Mass spectrum [(+) ESI], m / z 809 (M + H) +. for C36H44N2019: C, 53.47; H, 5.84; N, 3.46, Found: C, 53.55; H, 5.41; N, 3.40.
stage 6
N-. { 5- [(ß-D-maltosyl) -oxi-methyl] -2-cyano-phenyl} -acetamide
A solution of N- is stirred at room temperature. { 2-cyano- [5- (2,2 ', 3,3', 4 ', 6,6'-hepta-O-acetyl-β-D-maltosyl) -oxymethyl] -phenyl} -acetamide (2.31 g, 2.86 mmol) in 70 ml of MeOH is added a portion of potassium cyanide (92.9 mg, 1.43 mmol). After 3 hours the reaction mixture is concentrated in vacuo. Purification by preparative CLAP (C18, 20% CH3CN: H20) and provides 1.18 g, (80%) of the title compound; XH NMR (DMS0-d6) d 2.08 (s, 3H), 3.03-3.17 (m, 2H), 3.20-3.49 (m, 7H), 3.50-3.64 (m, 2H), 3.71-3.75 (m, ÍH) , 4.31 (d, J = 7.6 Hz, ÍH), 4.51-4.55 (m, 2H), 4.64-4.78 (m, 3H), 4.88-5.00 (m, 2H), 5.02 (d, J = 3.7 Hz, ÍH ), 5.29-5.53 (m, 3H), 7.38 (dd, J = 8.1, 1.1 Hz, ÍH), 7.56 (s, ÍH), '7.77 (d, J = 8.1 Hz, ÍH), 7.80 (s, ÍH) ).
stage 7
N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxi-methyl] -2-cyano-phenyl} -acetamide
The title compound is prepared as a solid (0.682 g, 57%) from N-. { 5- [(B-D-maltosyl) oxy-methyl] -2-cyano-phenyl} acetamide using a procedure similar to that of Example 24; XH NMR (DMSO-d6) 2.09 (s, 3H), 3.13-3.16 (m, 2H), 3.35-3.73 (m, 9H), 4.12-4.13 (m, ÍH), 4.34 (d, J = 7.8 Hz, 1H) 4.65-4.70 (m, 2H), 4.91 (d, J = 13.6 Hz, ÍH), 5.15 (d, J = 3.8 Hz, ÍH), 5.32 (m, 2H), 5.55-5.58 (m, 3H) , 7.36-7.47 6H), 7.56 (s, ÍH), 7.78 (d, J = 8.2 Hz, ÍH), 10.17 (s, ÍH).
stage 8
N-. { 5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-cyanophenyl} -acetamide
The title compound is prepared as a white solid (0.173 g, 49%) from N-. { 5- [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-cyano-phenyl} -acetamide using a procedure similar to that of Example 2, p.f. 122-129 ° C; 2 H NMR (DMSO-d 6) d 2.05 (s, 3 H), 3.21 (t, H), 3.34- 3.41 (m, 2 H), 3.53-3.64 (m, 4 H), 3.71-3.77 (m, 2 H), 4.03 (dd, ÍH), 4.34 (dd, J = 12.2, 4.9 Hz, 1H), 4.42 (d, J = 7.7 Hz, ÍH), 4.59 (d,
1H), 4.75 (ABc, J = 13.7 Hz,? D = 0.06, 2H), 5.14 (d, J = 4.0
Hz, ÍH), 5.35 (s broad, ÍH), 5.41 (s broad, ÍH), 5.52 (s,
1H), 5.58 (s broad, ÍH), 5.82 (s broad, ÍH), 7.34-7.37 (m,
4H), 7.40-7.42 (m, 2H), 7.51-7.54 (m, 3H), 7.65 (t. ÍH), 7.73
(d, J = 7.9 Hz, ÍH), 7.97-8.00 (m, 2H), 10.13 (s, ÍH); GO
(KBr) 3400, 2900, 2200, 1710, 1275 and 1065 cm "1; mass spectrum
[(+) ESI], m / z 724 (M + NH4) +; Analysis calculated for
C36H38N2013 0.5 H20; C, 60.42, H, 5.49 N, 3.91. Found; C,
60. 36; H, 5.22. N, 3.91.
Example 85
N-. { 5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] 2-methyl-phenyl} -acetamide
The title compound is prepared as a colorless solid (1.30 g, 60%) from N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-methyl-phenyl} -acetamide using a procedure similar to that of Example 2, p.f. 193-198 ° C, E NMR (DMSO-d6) d 2.00 (s, 3H), 2.15 (s, 3H), 3.17 (t, J = 8.4 Hz, ÍH), 3.34-3.40 (m, 2H), 3.48 -3.62 (m, 4H), 3.69-3.77 (m, 2H), 4.06 (dd, ÍH), 4.33-4.38 (m, 2H), 4.60 (ABc, J = 11.9 Hz,? D = 0.08, 2H), 4.61 (d, J = 10.5 Hz, ÍH), .5.14 (d, J = 4.0 Hz, 1H), 5.33 (s broad, 2H), 5.32 (s, ÍH), 5.56 (s broad, ÍH), 5.79 ( s broad, ÍH), 7.06 (dd, ÍH), 7.11 (d, J = 7.9 Hz- -ÍH), 7.34-7.37 (m, 4H), 7.40-7.43 (m, 2H), 7.51-7.55 (m, 2H), 7.63-7.68 (m, ÍH), 7.99. 8.01 (m, 2H), 9.26 (s, ÍH); IR (KBr) 3250, 2900, 1725, 1650, 1275 and 1070 mass spectrum [(+) ESI], m / z 696 (M + H) +; Analysis calculated for C36H41N013; C, 62.15; H 5.94. N, 2.01, Found, - C, 62.20; H, 6.02. N, 2.04.
Example 86
6- [6- (4-chloro-3-n-tro-benzyl sulf indigo) -4,5-dihydroxy-2-hydroxymethyl-tetrahydro-pyran-3-yloxy-2-phenyl-hexahydropyran [3,2-d] [1,31 dioxin- 7,8-diol
stage 1
(4-chloro-3-nitro-benzyl) -hepta-O-acetyl-l-thio-β-D-maltoside
A solution of hepta-O-acetyl-l-thio-β-maltose (2.0 g, 3065 mmol) in 20 ml of acetone is stirred, 4-chloro-3-nitrobenzyl bromide (0.844 mg, 3.37 mmol) is added and a mixture of potassium carbonate (0.423 mg, 3.06 mmol) in 10 ml of water. The mixture is heated under reflux for 30 minutes, cooled and concentrated. The residue is extracted with dichloromethane and the combined extract is washed with water and brine, dried with MgSO 4 and concentrated. Purification by flash chromatography (gradient of EtOAc 40% -60% / petroleum ether) provides 1588 g (63%) of the title compound as a white solid, m.p. 73-75 ° C, tE NMR (CDC13) d 1.99 (s, 3 H), 2.00 (s, 3 H), 2.02 (s, 3 H), 2.03 (s, 6 H), 2.11 (s, 3 H) ), 2.15 (s, 3 H), 3.61 - 3.64 (m, ÍH), 3.80 (d, J = 13.6 Hz, ÍH), 3.94 - 4.00 (m, 3 H), 4.08 (dd, J = 12.3, 2.4 Hz, 1 H), 4.18 - 4.27 (m, 2 H), 4.36 (d, J = 9.9 Hz, ÍH), 4.50 (dd, J = 12.1, 2.6 Hz, ÍH), 4.85 (dd, J = 10.5. 4.0 Hz, ÍH), 4.90
(apparent t, J = 9.9 Hz, ÍH), 5.05 (apparent t, J = 9.9 Hz, 1H), 5.23 (apparent t, J = 9.2 Hz, ÍH), 5.34 (apparent t, J = 9.7 Hz, ÍH) , 5.40 (d, J = 4.0 Hz, HH), 7.47 (d, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, HH), 7.87 (d, J = 2.0 Hz, ÍH ) , GO
(KBr) 3500, 2950, 1750, 1250 and 1050 cm "1 mass spectrum [(+) FAB] m / z 822 (M + H) +, 844 (M + Na) +, analysis calculated for C ^ H ^ CI O ^: C, 48.2 1; H, 4.90; N, 1.70, Found; C, 47.75; H, 4.86; N, 1.65.
stage 2
(4-chloro-3-ni ro-benzyl) -1-deoxy-l-thio-β-D-maltoside
The title compound is prepared as a white solid (0.513 g, 99%) from (4-chloro-3-nitro-benzyl) -hepta-O-acetyl-l-thio-β-D-maltoside using a procedure similar to that of stage 4 of Example 1, mp 90-93 ° C; t NMR (DMS0-d6) d 3.03-3.74 (m, 11H), 3.80 (d, J = 6.2 Hz, ÍH), 3.86 (d, J = 13.4 Hz, ÍH), 4.01-4.08 (m, 2H), 4.58 (broad d, 2H), 4.98 (broad d, 3H), 5.20-5.67 (broad s, 3 H), 7.65-7.72 (m, 2H), 8.03 (d, J = 1.76 Hz, 1H), IR ( KBr) 3400, 2930, 1550, 1300 and 1075 cm "1, mass spectrum [(-) FAB)], m / z 526 (M - H) \ Analysis calculated for C19H26C1N012S • H20: C, 41.80; H, 5.13; N, 2.56, Found: C, 41.35; H, 4.89; N, 2.40.
stage 3
6- [6- (4-chloro-3-nitro-benzylsulfane) -4,5-dihydroxy-2-hydroxymethyl-tetrahydro-pyran-3-yloxy] -2-phenyl-hexahydro-pyran [3, 2-d] [1, 3] dioxin-7, 8-diol
The title compound is prepared as a white solid from (4-chloro-3-nitro-benzyl) -1-deoxy-l-thio-β-D-maltoside using a procedure similar to that of Example 24, p.p. 120-122 ° C; H NMR (DMS0-d6) d3.07-3.24 (m, 2H), 3.24-3.43 (m, 3H), 3.47-3.58 (m, 3H), 3.64-3.75 (m, 3H), 3.95 (ABc, J = 13.4 Hz,? D = 0.12, 2H), 4.08-4.13 (m, 2H), 4.77 (t,
J = 5.5 Hz, ÍH), 5.12 (d, J = 3.95 Hz, 1H), 5.28 (d, J = 5.3
Hz, ÍH), 5.31 (d, J = 5.3 Hz, ÍH), 5.56 (m, 2H), 5.65 (d, J =
6. 4 Hz, ÍH), 7.35-7.40 (m, 3H), 7.42-7.46 (m, 2H), 7.66-7.71
(m, 2H), 8.04 (d, J = 1.76 Hz, ÍH): IR (KBr) 3450, 2930, 1550, 1300 and 1075 c "1; mass spectrum [(-) BAR], m / z 614 ( M-H);
IR (KBr) 3450, 2930, 1550, 1300 and 1075 cm "1; mass spectrum
[(-) BAR], m / z 614 (M-H) characterized in that Analysis calculated for C ^ H ^ ClNO- ^ S: C, 49.96; H, 5.1; N, 2.24,
Found: C, 49.42; H, 4.78; N, 2.26.
Example 87
(4-chloro-3-nitro-benzyl) -6-0-benzoyl-4 ', 6'-O-benzylidene-1-thio-β-D-maltoside
The title compound is prepared as a white solid from 6- [6- (4-chloro-3-nitro-benzylsulfanyl) -4,5-dihydroxy-2-hydroxymethyl-tetrahydro-pyran-3-yloxy] -2 -pheny1-hexahydro-pyran [3,2-d] [1.3] dioxin-7,8-diol using a procedure similar to Example 2, mp. 105-107 ° C; 1H NMR
(DMSO) d 3.17-3.23 (m, ÍH), 3.27-3.42 (m, 2H), 3.46-3.51 (m, 1H), 3.53-3.62 (m, 3H), 3.69-3.76 (m, 2H), 3.91 (c, J = 14.1 Hz, 2H), 4.06 (dd, J = 10.3, 4.8 Hz, 1H), 4.28-4.34 (m, 2H), 4.62 (d, J = 10.5 Hz, ÍH), 5.13 (d, J = 3.7 Hz, ÍH), 5.34 (d, J = 5.3 Hz, ÍH), 5.41 (d, J = 6.2 Hz, ÍH), 5.53 (s, ÍH), 5.64
(d, J = 2.9 Hz, HH), 5.80 (d, J = 6.1 Hz, HH), 7.31 (m, 3H), 7.40-7.43 (m, 2H), 7.47 (t, J = 5.7 Hz, 2H) , 7.59-7.65 (m, 3H), 7.95-7.98 (m, 3H); IR (KBr) 3400, 2930, 1745, 1550, 1255 and 1075 cm "1; mass spectrum [(+) FAB], m / z 720 (M + H) +, 742 (M + Na) +; for C33H34C1N013S: C, 55.04; H, 4.76; N, 1.95, Found: C, 55.36; H, 4.89; N, 1.91.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (24)
1. A compound of formula I, which has the structure characterized in that X is O or S; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono -, di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, pyridyl substituted with R8, furyl substituted with R8, thienyl substituted with R8 and thiazolyl substituted with R8, -s hydrogen, acyl of 2 to 6 carbon atoms, haloacyl of 2 to 6 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 atoms of carbon, carboalkoxyacyl of 4 to 12 carbon atoms, R3, R4, R5 and R6 are each independently hydrogen, acyl of 2 to 7 carbon atoms, benzoyl wherein the phenyl portion is mono-, di- or trisubstituted with R8, haloacyl of 2 to 7 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 carbon atoms; R7 is hydrogen, methyl or phenyl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN. -N02, halogen 0 -. 0 -CF3; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, -NHR3, -NR3R3, -NR3R14, -NHC02R14, -NHS02R14, R10, R11 and R12 are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen, -CF3 or -O9- a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halogen; R14 is alkyl of 1 to 6 carbon atoms: R15 is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or -C02R16; R16 is alkyl of 1 to 6 carbon atoms, benzyl, phenyl or fluorenyl; n = 0-3; p = 0-6; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, characterized in that R 2 is hydrogen, acyl of 2 to 6 carbon atoms, carboalkoxyacyl of 4 to 12 carbon atoms, R3, R4, RB and R6 are each independently hydrogen or acyl of 2 to 7 carbon atoms; R9 is hydrogen, -N02, halogen, -CF3, -NHR3, -NR3R3, -NR3R14, -NHC02R14, -NHS02R14, or a pharmaceutically acceptable salt thereof,
3. The compound according to claim 2, characterized in that X is O; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, or pyridyl substituted with R8; R2 is hydrogen, acyl of 2 to 6 carbon atoms, carboalkoxyacyl of 4 to 12 carbon atoms, ^ "V p R3, R4, R5 and R6 are each independently hydrogen or acyl of 2 to 7 carbon atoms; R7 is hydrogen; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, -CN or halogen; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms carbon or halogen; R16 is alkyl of 1 to 6 carbon atoms or fluorenyl; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, characterized in that it is N-. { 5- [(6-O-benzoyl-4 ', 6'-O-propylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1, characterized in that it is N-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1, characterized in that it is N-. { 5- [(6-O-benzoyl-4 ', 6' -O- (4-nitro) -benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, characterized in that it is N-. { 5- [(6-O-benzoyl-4 ', 6' -O-isobutylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1, characterized in that it is N-. { 5- [(6-O-benzoyl-4 ', 6' -0- ((IR) -2-phenyl-ethylidene) -β-D-maltosyloxy-methyl] -2-chloro-phenyl] -acetamide or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, characterized in that it is N-. { 5- [(6-O-benzoyl-4 ', 6' -O- ((IR) -3-cyanopropylidene) -β-D-maltosyloxy] -methyl] -2-chloro-phenyl] -acetamide or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1, characterized in that it is 6- (3-acetylamino-4-chloro-benzoyloxy) -3- (7,8-dihydroxy-2-pyridin-4-yl-hexahydro-pyran [3.2-] ester. d] [1,3] -dioxin-6-yloxy) -4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl benzoic acid or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, characterized in that it is N-. { 5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl-oxy-methyl] -2-chloro-phenyl] -acetamide or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, characterized in that it is (R) -N- [2-chloro-5- [[[6-0- (3-trifluoromethylbenzoyl) -4-0- [4, 60- (phenyl- methylene) -aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] -methyl] -phenyl] acetamide or. a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1, characterized in that it is N-. { 5- [(4 ', 6' -0-benzylidene-6-0- (2-iodo) -benzoyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1, characterized in that it is (R) -N- [2-chloro-5- [[[6-0- (phenylacetyl) -4-0- [4,6-0- (phenylmethylene)] α-D-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1, characterized in that it is N-. { 5- [(4 ', 6'-O-benzylidene-6-0-phenyl-ethyl-carboxy] -β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1, characterized in that it is 4-benzoyl-N-. { 5- [(4 ', 6' -0-benzylidene-6-0- (2-iodo) -benzoyl-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1, characterized in that it is the methyl ester of N- acid. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -carbamic or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1, characterized in that it is 4-chloro-3-nitro-benzyl) 6-0-benzoyl-4 ', 6' -0-benzoyl-4 ', 6'-O-benzylidene-1- thio-β-D-maltoside or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1, characterized in that it is: N-. { 2-Chloro-5- [(4 ', 6'-ethylidene) -β-D-maltosyloxymethyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; (R) -N- [5- [[[6-0-benzoyl-4-0- (4,6-O-ethylidene-aD-glucopyranosyl) -β-D-glucopyranosyl] oxy] methyl] -2-chlorophenyl ] acetamide or a pharmaceutically acceptable salt thereof; C) (R) -N- [2-chloro-5- [[[2, 3-di-0-acetyl-6-0-benzoyl-4-0- (2,3-di-0-acetyl-4 , 6-O-ethylidene-aD-glucopyranosyl) - ß-D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; d) N-. { 2-Chloro-5- [(4 ', 6' -O-propylidene-β-D-maltosyl) -oxymethyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; e) N- (5- { [4 ', 6' -O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyl] -oxy-methyl.} -2-chloro-phenyl ) -acetamide or a pharmaceutically acceptable salt thereof; f) N- (5- { [2,3,2 ', 3'-tetra-O-acetyl-4', 6'-benzylidene-6 O- (4-toluenesulfonyl) -β-D-maltosyl ] -oxi-methyl.} -2-chloro-phenyl) acetamide or a pharmaceutically acceptable salt thereof. g) N-. { 5- [(6-O-Benzyl-4 ', 6'-O-ethylidene-β-D-maltosyl] -oxy-methyl] -2-chloro-phenyl] acetamide or a pharmaceutically acceptable salt thereof; h) N- (2-chloro-5- { [4 ', 6' -0- (4-nitro) -benzylidene-β-D-maltosyl] -oxy-methyl] -phenyl) -acetamide or a pharmaceutically acceptable salt thereof; N- [2-chloro-5- [(4 ', 6' -O- (4-chloro) -benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; j) N-. { 5- [6-0-benzoyl- ', 6' -O- (4-chloro) -benzylidene-β-D-maltosyl) -oxi-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; k) N-. { 2-Chloro-5- [(4 ', 6' -O-isobutylene-β-D-maltosyl) -oxymethyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; 1) N-. { 5- [(4 ', 6' -O- ((IR) -2-phenyl-ethylidene) -β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; m) N-. { 2-Chloro-5- [(4 ', 6' -0- (IR) -3-cyano-propylidene) -β-D-maltosiloxy) -methyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; n N-. { 2-Chloro-5- [(4 ', 6' -O- ((IR) -3-ethoxy-propylidene) -β-D-maltosyloxy) -methyl] -phenyl} -acetamide or a pharmaceutically acceptable salt thereof; N-. { 5-. { [6-0-benzoyl-4 ', 6' -O- ((IR) -3-ethoxypropylidene) -β-D-maltosyloxy] -methyl} -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; P) N- (2-chloro-5- { [4 ', 6' -O- (4-pyridinmethylidene) -β-D-maltosyl] -oxy-methyl] -phenyl) -acetamide or a salt pharmaceutically acceptable thereof; q) N-. { 5- [(4,6'-O-benzylidene-β-D-maltosiloxy) -methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof, - r) N-. { 5- [(4 ', 6'-O-benzylidene-2, 2', 3, 3 ', 6-penta-O-acetyl-β-D-maltosyl-oxy) -methyl] -2-chloro-phenyl} acetamide or a pharmaceutically acceptable salt thereof; s) (R) -N- (2-chloro-5- [[[2, 3-di-0-acetyl-6-0-benzoyl-4-0- [2,3-di-0-acetyl-4] , 6-0- (phenylmethylene) -aD-glucopyranosyl] - ß -glucopyranosyl-oxy] met yl] -phenyl] acetamide or a pharmaceutically acceptable salt thereof, - t) (R) -N- [2-chloro-5 - [[[6-0- (5-methoxy-l, 5-dioxopentyl) -4-0- [4,6-0- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof, -u) 4-chloro-3-nitro-benzyl-4 ', 6'-O-benzylidene-β-D-maltoside or a pharmaceutically acceptable salt thereof; v) 4-chloro-3-nitro-benzyl-6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltoside or a pharmaceutically acceptable salt thereof; w) (R) - (4-chloro-3-nitrophenyl) methyl-2,3-di-0-acetyl-6-0-benzoyl-4-O- [2,3-di-O-acetyl-4, 6-0- (phenylmethylene) -a- D-glucopyranosyl] -β-D-glucopyranoside or a pharmaceutically acceptable salt thereof; x) 6- (4-chloro-3-nor-tro-benzylloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3.2-d] [1,3] dioxin- 6 - ester iloxy) -4,5-dihydroxy-tetrahydropyran-2-ylmethyl nicotinic acid acid or a pharmaceutically acceptable salt thereof; y) 4- [2,3-di-0-acetyl-4,6-0- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranoside 2,3-diacetate 6- (3-pyridinecarboxylate) of (R) - (4-chloro-3-nitrofenyl) methyl or a pharmaceutically acceptable salt thereof; z) 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3.2-d] [1,3] dioxin-6-yloxy) -4 ester; 5-dihydroxy-tetrahydropyran-2-ylmethyl 4-methoxybenzoic acid or a pharmaceutically acceptable salt thereof; aa) 4,5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-d] [1,3] dioxin ester -6-yloxy) -tetrahydro-pyran-2-ylmethyl of 4-methoxy-benzoic acid or a pharmaceutically acceptable salt thereof; bb) 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3.2-d] [1, 3] dioxin-6-yloxy) ester 4, 5-dihydroxy-tetrahydropyran-2-ylmethyl 4-chlorobenzoic acid or a pharmaceutically acceptable salt thereof; ce) 4-5-diacetoxy -6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-d] [1.3] dioxin-6-ester. -loxy) -tetrahydro-pyran-2-ylmethyl of 4-chloro-benzoic acid or a pharmaceutically acceptable salt thereof; dd) (R) -N- [2-chloro-5- [[[6-0- (4-chloro-3-nitrobenzoyl) -4- O- [4,6-0- (phenylmethylene) -aD-glucopyranosyl ] -β-D-glucopyranosyl] oxy] methyl] -phenylacetamide or a pharmaceutically acceptable salt thereof; N-. { 5- [(2,2 ', 3, -tri-O-acetyl-6-0- (4-chloro-3-nitro-benzoyl) -4', 6'-0- (benzyl iden) -β -D-maltoside) oxymethyl] -2-chloro-f-enyl) -acetamide or a pharmaceutically acceptable salt thereof; ff: (R) -N- [2-chloro-5- [[[6-0- (4-cyanobenzoyl) -4-0- [4,6-0- (phenylmethylene) -aD-glucopyranosyl] -β- D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; gg) (R) -N- [2-chloro-5- [[[6-0- (4-nitrobenzoyl) -4-0- [4,6-0- (phenylmethylene) -aD-glucopyranosyl] -β- D-glucopyranosyl] oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; hh) N-. { 5- [(4 ', 6' -0-benzylidene-6-0- (3-iodo) -benzoyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl) -acetamide or a salt pharmaceutically acceptable thereof; 11 N-. { 5- [(4 ', 6'-O-benzylidene-6- (4-iodobenzoyl) oxy-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; 33 (R) -N- [2-chloro-5- [[[2, 3-di-O-acetyl-4-O- [2,3-di-O-acetyl-4, 6, 0- (phenylmethylene ) -aD-glucopyranosyl] -6-0- (f-enylacet-yl) -β-D-glucopyranosyl] -oxy] methyl] phenyl] acetamide or a pharmaceutically acceptable salt thereof; kk) N-. { 5- [(4 ', 6'-O-benzylidene-6-O-f-enyl-propyl-carboxyl-β-D-maltosyl) -oxy-methyl] -2-chloro-f-enyl} -acetamide or a pharmaceutically acceptable salt thereof; 11) 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyranol [3,2-d] [1,3] dioxin-6-yloxy) ester 4, 5-dihydroxyethyl-2-hydroxy-2-ylmethyl of diphenylacetic acid or a pharmaceutically acceptable salt thereof; mm) 4,5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-d] [1,3] dioxin ester 6-yloxy) tetrahydro-pyran-2-ylmethyl of the dif-enyl-acetic acid or a pharmaceutically acceptable salt thereof; nn) 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenyl-hexahydro-pyran [3,2-d] [1,3] dioxin-6-yloxy) ester 4,4-dihydroxy-tetrahydro-pyran-2-methyl (3,4-dimethoxy-f-enyl) -acetic acid or a pharmaceutically acceptable salt thereof; oo) 4,5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3, 2-d] [1,3 dioxin-6-yloxy) -tetrahydro-pyran-2-ylmethyl (3,4-dimethoxy-f-enyl) -acetic acid or a pharmaceutically acceptable salt thereof; PP) 6- (3-Acetylamino-4-chloro-benzyloxy) -3- (7,8-dihydroxy-2-phenylhexahydro-pyran [3, 2-d] [1,3] dioxin-6-yloxy) ester 4, 5-dihydroxy-tetrahydro-pyran-2-ylmethyl of nicotinic acid or a pharmaceutically acceptable salt thereof; qq) 4-5-diacetoxy-6- (3-acetylamino-4-chloro-benzyloxy) -3- (7,8-diacetoxy-2-phenyl-hexahydro-pyran [3.2-d] [1,3] dioxin ester -6-yloxy) -tetrahydro-pyran-2-ylmethyl of nicotinic acid or a pharmaceutically acceptable salt thereof; rr (R) -N- [5- [[[6-0- (4-benzoylbenzoyl) -4-0- [4,6-0- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] -2-chlorofenyl] acetamide or a pharmaceutically acceptable salt thereof; ss) N-. { 5- [(4 ', 6' -O-benzylidene-β-maltosyl) -oxy-methyl] -2-methyl-phenyl] -acetamide or a pharmaceutically acceptable salt thereof; tt) N- acetyl-. { 5- [(2,2 ', 3,3', 6-penta-0-acetyl-4 ', 6'-0-benzylidene-β-D-maltosyl) -oxy-methyl] -2-methyl-f-enyl } acetamide or a pharmaceutically acceptable salt thereof; uu) N- (5- { [4 ', 6' -0-benzylidene-6-0- (4-toluenesulfonyl) -β-D-maltosyl] -oxy-methyl.} -2-methyl-phenyl ) -acetamide or a pharmaceutically acceptable salt thereof; w) N-. { 5- [(4 ', 6'-O-benzylidene-6-O-phenyl-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; ww) (R) -N- [2-chloro-5- [[[4-0- [4 ', 6' -O- (phenylmethylene) -aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] phenyl] -3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof; xx) (R) -N- [5- [[[6-0-benzoyl-4-0- [4 •, 6 • -O- (phenylmethylene)-aD-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] -2- chlorophenyl] -3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof; yy). { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} furan-2-carboxylic acid amide or a pharmaceutically acceptable salt thereof; zz). { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} furan-2-carboxylic acid amide or a pharmaceutically acceptable salt thereof; aaa) N-. { 2-Chloro-5- [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxymethyl] -phenyl} -pent-4 -enamide or a pharmaceutically acceptable salt thereof; bbb) N-. { 2-Chloro-5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -phenyl} -pent-4-enamide or a pharmaceutically acceptable salt thereof; ccc) 5- (6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxymethyl-1'-2'-chloro-f-enylamine or a pharmaceutically acceptable salt thereof; ddd) (4-chloro) -benzyl-4 ', 6'-O-benzylidene-β-D-maltoside or a pharmaceutically acceptable salt thereof; eee) 1-0- (4-chloro) -benzyl-4 ', 6'-O-benzylidene-6-deoxy-β-D-malto-6-yl ester of benzoic acid; fff) 4-benzoyl-N-. { 5- [(4 ', 6' -O-benzylidene-β-D-maltosyl) -oxi-methyl] -2-chloro-phenyl} benzamide or a pharmaceutically acceptable salt thereof, - ggg) 4-benzoyl-N- amide. { 5- [(6-Benzoyl-oxy-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzoic acid or a pharmaceutically acceptable salt thereof; hhh) 4-benzoyl-N-. { 5- [(4 ', 6'-O-benzylidene-6-O- (3-iodo-benzoyl) -β-D-maltosyl) -oxy-methyl]' - 2-chloro-phenyl} - benzamide or a pharmaceutically acceptable salt thereof; iii) 4-benzoyl-N- amide. { 5- [(4 ', 6'-O-benzylidene-6- (4-iodo-benzoyl) -oxy-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -benzoic acid or a pharmaceutically acceptable salt thereof; jjj) 9H-Fluoren-9-ylmethyl ester of (l-. {5 - [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl- carbamoyl.} ethyl) -carbamic or a pharmaceutically acceptable salt thereof; kkk) N- (9H-fluoren-9-ylmethoxycarbonyl) -N '-. { 5- [(6-0-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -L-alaninamide or a pharmaceutically acceptable salt thereof; 111) N '-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -L-alaninamide or a pharmaceutically acceptable salt thereof; Mmm n- . { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -N-methyl-acetamide or a pharmaceutically acceptable salt thereof, -nnn) N-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -N-methylacetamide or a pharmaceutically acceptable salt thereof; ooo) N- methyl ester. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl] -carbamic acid or a pharmaceutically acceptable salt thereof; PPPJ methyl ester of N- acid. { 5- [(6-0- (3-benzyl) -1-oxo-propyl) -4 ', 6'-O-benzylidene-β-D-maltosyl) -oxymethyl] -2-chloro-phenyl} -carbamic or a pharmaceutically acceptable salt thereof; qqq) N-. { 5- [(4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-chloro-phenyl} -metanesulfonamide or a pharmaceutically acceptable salt thereof; rrr) N-. { 5- [(6-O-benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxi-methyl] -2-cyano-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; sss) N-. { 5- [(6-0-Benzoyl-4 ', 6'-O-benzylidene-β-D-maltosyl) -oxy-methyl] -2-methyl-phenyl} -acetamide or a pharmaceutically acceptable salt thereof; ttt) 6- [6- (4-chloro-3-nitro-benzylsulfonyl) -4,5-dihydroxy-2-hydroxymethyl-tetrahydropyran-3-yloxy] -2-f-enyl-hexahydro-pyran [3 .2- d] [1, 3] dioxin-7,8-diol or a pharmaceutically acceptable salt thereof.
20. A method for treating or inhibiting hyperproliferative vascular disorders in a mammal in need thereof, characterized in that it comprises administering to the mammal an effective amount of a compound of formula I having the structure: where X is O or S; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, pyridyl substituted with R8, furyl substituted with R8, thienyl substituted with R8 and substituted thiazolyl with R8; s hydrogen, acyl of 2 to 6 carbon atoms, haloacyl of 2 to 6 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or fluoromethylacil of 3 to 8 carbon atoms, carboalkoxyacyl of 4 to 12 carbon atoms, 10 R3, R4, R5 and R6 are each independently hydrogen, acyl of 2 to 7 carbon atoms, benzoyl wherein the phenyl portion is mono-, di- or trisubstituted with R8, haloacyl of 2 to 7 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 carbon atoms; R7 is hydrogen, methyl or phenyl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN. -N02, halogen 0 -. 0 -CF3; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, -NHR3, -NR3R -NR3R14, -NHC02R14, -NHS02R14, R10, R11 and R12 are each independently hydrogen, alkoyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen, -CF3 or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halogen; R14 is alkyl of 1 to 6 carbon atoms: R15 is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or -C02R16; R16 is alkyl of 1 to 6 carbon atoms, benzyl, phenyl or fluorenyl; n = 0-3; p = 0-6; or a pharmaceutically acceptable salt thereof.
21. A method for treating or inhibiting restenosis in a mammal in need thereof, characterized in that it comprises administering to the mammal an effective amount of a compound of formula I having the structure where X is O or S; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, pyridyl substituted with R8, furyl substituted with R8, thienyl substituted with R8 and substituted thiazolyl with R8; R2 is hydrogen, acyl of 2 to 6 carbon atoms, haloacyl of 2 to 6 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 carbon atoms, carboalkoxyacyl from 4 to 12 carbon atoms, R3, R4, R5 and R6 are each independently hydrogen, acyl of 2 to 7 carbon atoms, benzoyl wherein the phenyl portion is mono-, di- or trisubstituted with R8, haloacyl of 2 to 7 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 carbon atoms; R7 is hydrogen, methyl or phenyl; R8 is hydrogen, alkoyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen 0 -. 0 -. 0 -CF3; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3 / -NHR3, '-NR3R3, -NR3R14, -NHC02R14, -NHS02R14, R10, R11 and R12 are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen, -CF3 or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halogen; - II 9 -R 14 is alkyl of 1 to 6 carbon atoms: R 15 is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or -C02R16; R16 is alkyl of 1 to 6 carbon atoms, benzyl, phenyl or fluorenyl; n = 0-3; p = 0-6; or a pharmaceutically acceptable salt thereof.
22. The method in accordance with the claim 21, characterized in that the restenosis results from a vascular angioplasty procedure, vascular reconstructive surgery or organ or tissue transplantation.
23. A method for inhibiting angiogenesis in a malignant tumor, sarcoma or neoplastic tissue in a mammal in need thereof, characterized in that it comprises administering to the mammal an effective amount of a compound of formula I having the structure in which X is O or S; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, pyridyl substituted with R8, furyl substituted with R8, thienyl substituted with R8 and substituted thiazolyl with R8; R2 is hydrogen, acyl of 2 to 6 carbon atoms, haloacyl of 2 to 6 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or fluoromethylcyl of 3 to 8 carbon atoms, carboalkoxyacyl from 4 to 12 carbon atoms, R3, R4, R5 and R6 are each independently hydrogen, acyl of 2 to 7 carbon atoms, benzoyl wherein the phenyl portion is mono-, di- or trisubstituted with R8, haloacyl of 2 to 7 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 carbon atoms; R7 is hydrogen, methyl or phenyl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen 0 -CF3; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, -NHR3, -NR3R3, -NR3R14, -NHC02R14, -NHS02R14, R10, R11 and R12 are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen, -CF3 or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halogen; R14 is alkyl of 1 to 6 carbon atoms: R15 is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or -C02R16, -R1S is alkyl of 1 to 6 carbon atoms, benzyl, phenyl or fluorenyl; n = 0-3; p = 0.6; or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition, characterized in that it comprises a compound of formula I having the structure where X is O or S; R1 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, nitroalkyl of 1 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, phenyl mono- , di- or trisubstituted with R8, phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is mono-, di- or trisubstituted with R8, pyridyl substituted with R8, furyl substituted with R8, thienyl substituted with R8 and substituted thiazolyl with R8; hydrogen, acyl of 2 to 6 carbon atoms, haloacyl of 2 to 6 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoaccyl of 2 to 7 carbon atoms or fluoromethylacil of 3 to 8 carbon atoms, carboalkoxyacyl of 4 to 12 carbon atoms, R3, R4, R5 and Re are each independently hydrogen, acyl of 2 to 7 carbon atoms, benzoyl wherein the phenyl portion is mono-, di- or trisubstituted with R8, haloacyl of 2 to 7 carbon atoms, nitroacyl of 2 to 7 carbon atoms, cyanoacyl of 2 to 7 carbon atoms or trifluoromethylacil of 3 to 8 carbon atoms; R7 is hydrogen, methyl or phenyl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN. -N02, halogen 0 -. 0 -CF3; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, -NHR3, -NR3R3, -NR3R14, -NHC02R14, -NHS02R14, R10, R11 and R12 are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, -CN, -N02, halogen, -CF3, acyl of 2 to 7 carbon atoms , or benzoyl, wherein the phenyl group or the phenyl portion of the benzoyl group is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen or -CF3; R13 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -N02, halogen, -CF3 or a phenyl group, wherein the phenyl portion is optionally mono-, di- or trisubstituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halogen; R14 is alkyl of 1 to 6 carbon atoms: R1S is hydrogen, acyl of 2 to 7 carbon atoms, benzoyl or -C02R16; R16 is alkyl of 1 to 6 carbon atoms, benzyl, phenyl or fluorenyl; n = 0-3; p = 0-6; or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/198,803 | 1998-11-24 |
Publications (1)
Publication Number | Publication Date |
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MXPA01005176A true MXPA01005176A (en) | 2001-12-04 |
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