PHARMACEUTICAL DOPAMINE GLYCOCONJUGATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
申请人:Christian Samuel T.
公开号:US20080194802A1
公开(公告)日:2008-08-14
Hydrophilic transportable N-linked glycosyl dopaminergic prodrug compounds according to FORMULA V and methods of their use,
wherein,
Ring 1 comprises an aryl or heteroaryl ring having 4 to 8 carbon atoms, among which atoms are counted “X” and “Y”;
each of X and Y is optional; X, when present is either —C(R
1
)
2
— or —C(R)
2
—; Y, when present, is either —CH
2
— or —CH
2
—CH
2
—;
z, R
5
and R
5′
are optional, and when present z, R
5
and R
5′
together form a lower alkyl or a substituted lower alkyl moiety;
N is part of either an amine or an amide linkage;
E is a saccharide which forms a linkage with N through a single bond from a carbon or oxygen atom thereof;
R
1
and R
4
are selected form the group consisting of hydrogen, hydroxyl, halogen, halo-lower alkyl, alkoxyl, alkoxyl-lower alkyl, halo-alkoxy, thioamido, amidosulfonyl, alkoxylcarbonyl, carboxamide, aminocarbonyl, and alkylamino-carbonyl;
R
2
and R
3
are hydroxyl;
R
5
and R
6
, when present, are selected from the group consisting of hydrogen, hydroxyl, alkoxyl, carbonyl, alkoxylcarbonyl, aminocarbonyl, alkylamino-carbonyl and dialkylamino-carbonyl; and,
R
6
and R
6′
are selected from the group consisting of hydrogen, hydroxyl, alkoxyl, carboxyl, alkoxylcarbonyl, aminocarbonyl, alkylamino-carbonyl and dialylamino-carbonyl,
with the proviso that Ring 1 is capable of binding to any of:
a dopaminergic receptor selected from the group consisting of a D1 receptor and a D5 receptor; a DAT transporter; a VMAT transporter; and,
with the proviso that E is capable of binding to a GLUT transporter selected from the group consisting of a GLUT1 receptor and a GLUT3 receptor.
根据公式V及其使用方法,
水亲和性可转运的N-连接糖基
多巴胺前药化合物,其中,环1包括4至8个碳原子的芳基或杂芳基环,其中原子计算为“X”和“Y”;X和Y各自是可选的;当存在X时,它是—C(R1)2—或—C(R)2—;当存在Y时,它是—
CH2—或— — —;z,R5和R5'是可选的,当存在时,z,R5和R5'共同形成较低的烷基或取代较低的烷基基团;N是胺或酰胺连接的一部分;E是一种糖,通过其碳或氧原子中的单键与N形成连接;R1和R4从氢、羟基、卤素、卤素较低烷基、烷氧基、烷氧基较低烷基、卤素烷氧基、
硫酰胺、
氨基磺酰、烷氧基羰基、羧酰胺、
氨基羰基和烷基
氨基羰基中选择;R2和R3是羟基;当存在R5和R6时,它们从氢、羟基、烷氧基、羰基、烷氧基羰基、
氨基羰基、烷基
氨基羰基和二烷基
氨基羰基中选择;R6和R6'从氢、羟基、烷氧基、羧基、烷氧基羰基、
氨基羰基、烷基
氨基羰基和二烷基
氨基羰基中选择,但环1能够与以下任意一种结合:D1受体和D5受体中选择的
多巴胺能受体;
DAT转运体;VMAT转运体;并且,E能够与GLUT1受体和GLUT3受体中选择的GLUT转运体结合。