[EN] GalNAc CLUSTER PHOSPHORAMIDITE<br/>[FR] AGRÉGAT DE GALNAC-PHOSPHORAMIDITE
申请人:HOFFMANN LA ROCHE
公开号:WO2017084987A1
公开(公告)日:2017-05-26
The invention comprises Gal NAc phosphoramidite derivatives of the formula (I), wherein R1 is a hydroxy protecting group, n is an integer from 0 to 10 and m is an integer from 0 to 20 and its corresponding enantiomers and/ or optical isomers thereof. The invention further comprises a process for the preparation of the Gal NAc phosphoramidite derivatives of the formula (I) and its use in the preparation of therapeutically valuable GalNAc-cluster oligonucleotide conjugates.
The present invention relates to the use of end groups Y, where Y stands for CF
3
(CH
2
)
a
S— or CF
3
CF
2
S— or [CF
3
—(CH
2
)
a
]
2
N—, where a stands for an integer selected from the range from 0 to 5, as end group in surface-active compounds, to corresponding novel compounds, and to processes for the preparation of these compounds.
The invention comprises GalNAc phosphoramidite derivatives of the formula I
wherein R1 is a hydroxy protecting group, n is an integer from 0 to 10 and m is an integer from 0 to 20 and its corresponding enantiomers and/or optical isomers thereof. The invention further comprises a process for the preparation of the GalNAc phosphoramidite derivatives of the formula I and its use in the preparation of therapeutically valuable GalNAc-cluster oligonucleotide conjugates.
The synthesis and irreversible alpha-blocking activity in the rat vas deferens of a series of tetra- and diamine disulfides 2-38, structural analogues of benextramine (BHC), are described. All compounds containing a central cystamine moiety displayed an irreversible alpha-adrenergic blockade at concentrations ranging from 10(-4) to 6 X 10(-6)M. Potency was increased in cystamines N,N'-disubstituted with 6-aminohexyl groups, especially when the outer nitrogen atoms bear arylalkyl substituents or are enclosed in a ring. However, N,N,N',N'-tetrasubstituted cystamines were poor blockers. Structural specificity in the outer portion of the tetramine disulfide is low, since many types of substituents gave rise to potent alpha-blockers. Even replacement of the outer amines with nonbasic ethers or amides was observed to maintain irreversible alpha-blockade.
ALVAREZ, M.;MAULEON, D.;PUJOL, M. D.;ROSELL, G.;SALAS, M. L., AN. QUIM. REAL. SOC. ESP. QUIM., 83,(1987) N 2, 155-161
作者:ALVAREZ, M.、MAULEON, D.、PUJOL, M. D.、ROSELL, G.、SALAS, M. L.