US2011201794A1PendingUtilityA1
Disaccharides for drug discovery
Est. expiryMay 3, 2022(expired)· nominal 20-yr term from priority
Inventors:Wim MeutermansMichael L. WestGeorge AdamsonGiang Thanh LeNicholas B. DrinnanGiovani AbbenanteBernd BeckerMatthias GrathwohlPremraj RajaratnamGerald Tometzki
C40B 40/12C07H 3/02C40B 50/14C07H 3/04
45
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Claims
Abstract
Methods are described for the preparation of combinatorial libraries of potentially biologically active disaccharide compounds. These compounds are variously functionalized, with a view to varying lipid solubility size, function an other properties, with the particular aim of discovering novel drug or drug-like compounds, or compounds with useful properties. The invention provides intermediates, processes and synthetic strategies for the solution or solid phase synthesis of disaccharides, variously functionalized about the sugar ring, including the addition of aromaticity and charge, and the placement of pharmaceutically useful groups and isosteres.
Claims
exact text as granted — not AI-modified1 . A disaccharide compound of formula I
A-d-L-e-B formula I
wherein A and B are independently chosen from
T is O or CH 2 ;
R6 and R7 are hydrogen, or together form a carbonyl oxygen;
R1 is hydrogen, —N(Z)Y, C(Z)Y, OZ or SZ wherein;
when R1 is N(Z)Y
Y is selected from the group consisting of hydrogen or the following;
wherein;
Z is selected from hydrogen or X1,
Q is selected from hydrogen or W,
W is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms,
X1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms,
where R1 is C(Z)Y;
Y, is absent or is selected from hydrogen, double bond oxygen (═O) to form a carbonyl, or triple bond nitrogen to form a nitrile,
Z is absent or is selected from hydrogen or X2,
wherein X2 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, aminoalkyl, aminoaryl, aryloxy, alkoxy, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms,
where R1 is OZ or SZ,
Z is selected from hydrogen or X3,
wherein X3 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms,
The groups R2, R3, R4 and R5 are selected from the group consisting of hydrogen, N 3 , OH, OX4, N(Z)Y, wherein N(Z)Y is as defined above or Y is
where Q and W are as defined above,
and X4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, aminoalkyl, aminoaryl, aryloxy, alkoxy, heteroaryloxy, aminoaryl, aminoheteroaryl, alkylcarbamoyl, arylcarbamoyl or heteroarylcarbamoyl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms,
d and e represent the connection points for A and B and replace one of the groups R1, R2, R3, R4, or R5 in each of the groups A and B and form the connection point for the linker L,
d and e form a covalent bond or are selected from the group consisting of:
L is absent, or is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 12 atoms.
2 . The compound of claim 1 , wherein
when R1 is N(Z)Y, W is substituted with at least one moiety selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, and hydroxamic acid.
3 . The compound of claim 1 , wherein
when R1 is N(Z)Y,
Z and Y are combined to form a monocyclic or bicyclic ring structure of 4 to 10 atoms.
4 . The compound of claim 1 , wherein X1 is substituted with at least one moiety selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, and hydroxamic acid.
5 . The compound of claim 1 , wherein;
when R1 is C(Z)Y;
X2 is substituted with at least one moiety selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl.
6 . The compound of claim 1 , wherein;
when R1 is C(Z)Y;
Z and Y form a ring structure of 4 to 10 atoms.
7 . The compound of claim 6 , wherein the ring structure is substituted by X1 groups.
8 . The compound of claim 1 , wherein;
when R1 is OZ or SZ;
X3 is substituted with at least one moiety selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminodialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl.
9 . The compound of claim 1 , wherein;
when R1 is OZ or SZ;
X4 is substituted with at least one moiety selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, and hydroxamic acid.
10 . The compound of claim 1 , wherein Z and Y are combined to form a ring structure of 4 to 10 atoms.
11 . The compound of claim 10 , wherein the ring structure is substituted with X1 groups.
12 . The compound of claim 1 , wherein L is substituted with at least one moiety selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl.
13 . The compound of claim 1 , wherein in group A, T is oxygen, group A is a pyranose ring, and the linker, d-L-e, is a glycosidic linkage formed between the anomeric position R1 of group A, and any position R1 to R5 of group B, such that the d is (—O—), L is absent, and e is a covalent bond.
14 . The compound of claim 13 , wherein the structure of formula 1 is
15 . The compound of claim 13 , wherein the structure of formula 1 is
16 . The compound of claim 13 , wherein the structure of formula 1 is
17 . The compound of claim 13 , wherein the structure of formula 1 is
18 . The compound of claim 13 , wherein the structure of formula 1 is
19 . The compound of claim 13 , wherein the structure of formula 1 is
20 . The compound of claim 13 , wherein the structure of formula 1 is
21 . The compound of claim 13 , wherein the structure of formula 1 is
22 . The compound of claim 13 , wherein the structure of formula 1 is
23 . The compound of claim 1 , wherein in group A, T is oxygen, group A is a pyranose ring, the linker, d-L-e, forms an amide linkage in which R6 and R7 of A is a C═O, R5 is d which is a covalent bond, L is absent, and any of R1, R2, R3, R4, R5 on B is e which is
24 . The compound of claim 23 , wherein the structure of formula 1 is
25 . The compound of claim 23 , wherein the structure of formula 1 is
26 . The compound of claim 23 , wherein the structure of formula 1 is
27 . The compound of claim 23 , wherein the structure of formula 1 is
28 . The compound of claim 23 , wherein the structure of formula 1 is
29 . The compound of claim 23 , wherein the structure of formula 1 is
30 . The compound of claim 23 , wherein the structure of formula 1 is
31 . The compound of claim 23 , wherein the structure of formula 1 is
32 . The compound of claim 23 , wherein the structure of formula 1 is
33 . The compound of claim 1 , wherein in group A, T is oxygen, both groups A and B are pyranose rings, the linkage, d-L-e, is an ether type linkage in which any of R1 to R5 in group A and group B is d and e respectively and is
and L is present.
34 . The compound of claim 33 , wherein the structure of formula 1 is
35 . The compound of claim 33 , wherein the structure of formula 1 is
36 . The compound of claim 33 , wherein the structure of formula 1 is
37 . The compound of claim 33 , wherein the structure of formula 1 is
38 . The compound of claim 33 , wherein the structure of formula 1 is
39 . The compound of claim 33 , wherein the structure of formula 1 is
40 . The compound of claim 33 , wherein the structure of formula 1 is
41 . The compound of claim 33 , wherein the structure of formula 1 is
42 . The compound of claim 33 , wherein the structure of formula 1 is
43 . The compound of claim 33 , wherein the structure of formula 1 is
44 . The compound of claim 33 , wherein the structure of formula 1 is
45 . The compound of claim 33 , wherein the structure of formula 1 is
46 . The compound of claim 33 , wherein the structure of formula 1 is
47 . The compound of claim 33 , wherein the structure of formula 1 is
48 . The compound of claim 33 , wherein the structure of formula 1 is
49 . The compound of claim 33 , wherein the structure of formula 1 is
50 . The compound of claim 33 , wherein the structure of formula 1 is
51 . The compound of claim 33 , wherein the structure of formula 1 is
52 . The compound of claim 33 , wherein the structure of formula 1 is
53 . The compound of claim 33 , wherein the structure of formula 1 is
54 . The compound of claim 33 , wherein the structure of formula 1 is
55 . The compound of claim 33 , wherein the structure of formula 1 is
56 . The compound of claim 33 , wherein the structure of formula 1 is
57 . The compound of claim 33 , wherein the structure of formula 1 is
58 . The compound of claim 33 , wherein the structure of formula 1 is
59 . The compound of claim 1 , wherein in group A, T is oxygen, the linkage, d-L-e, is a linkage in which R1 in group A is d, is selected from the group consisting of a covalent bond,
L is present;
and e is selected from the group consisting of
and the connection to the B ring is at any of R1-R5.
60 . The compound of claim 59 , wherein the structure of formula 1 is
61 . The compound of claim 59 , wherein the structure of formula 1 is
62 . The compound of claim 59 , wherein the structure of formula 1 is
63 . The compound of claim 59 , wherein the structure of formula 1 is
64 . The compound of claim 1 , wherein in group A, T is oxygen, the linkage, d-L-e, is a linkage in which R1 in group A is d, R1 in group B is e, and both d and e are independently chosen from the group consisting of: a covalent bond;
and L is present.
65 . The compound of claim 64 , wherein the structure of formula 1 is
66 . The compound of claim 64 , wherein the structure of formula 1 is
67 . The compound of claim 1 , wherein in group A, T is oxygen, the linker, d-L-e, is a linkage in which at least one R group R1 to R5 in group A is d and is selected from the group consisting of
and any one of R1 to R5 in group B is e and e is
L is present.
68 . The compound of claim 67 , wherein the structure of formula 1 is
69 . The compound of claim 67 , wherein the structure of formula 1 is
70 . The compound of claim 67 , wherein the structure of formula 1 is
71 . The compound of claim 67 , wherein the structure of formula 1 is
72 . The compound of claim 1 , wherein in group A, T is oxygen, the linkage, d-L-e, is a linkage in which at least one R group R1 to R5 in groups A and B is d and e and d and e are independently selected from the group consisting of
and L is present.
73 . The compound of claim 72 , wherein the structure of formula 1 is
74 . The compound of claim 72 , wherein the structure of formula 1 is
75 . The compound of claim 72 , wherein the structure of formula 1 is
76 . The compound of claim 72 , wherein the structure of formula 1 is
77 . The compound of claim 72 , wherein the structure of formula 1 is
78 . A method of synthesizing a disaccharide compound of claim 1 comprising reacting compound A and compound B in solution.
79 . A method of combinatorial synthesis of compounds of claim 1 comprising the step of immobilizing a compound of group B onto a support through at least one of the functionalized positions R1 to R5.
80 . The method of claim 79 , wherein the support is selected from the group consisting of derivatised polystyrene, tentagel, wang resin, MBHA resin, aminomethylpolystyrene, rink amide resin DOX-mpeg, and polyethylene glycol.
81 . A method of synthesising a compound of formula I in solution, comprising the step of reacting compound A with a linker group L to form a compound A-d-L and further reacting the compound A-d-L with compound B to form a compound of formula I.
82 . A method of synthesising a compound of formula I in solution, comprising the step of reacting compound B with a linker group L to form a compound B-e-L and further reacting the compound B-e-L with compound A to form a compound of formula I.Join the waitlist — get patent alerts
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