EP0339842A2
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Novel oligoribonucleotide derivatives and application thereof to antiviral agents
Assignee: Ionis Pharmaceuticals Inc
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Filing: 1989-04-13
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Granted: —
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Expires: 2009-04-13
Abstract
Abstract The invention provides oligoribonucleotide derivatives represented by the general formula: <CHEM> wherein m, B, Q, X, R, Y1, Y2 and X are as defined in the specification. These derivatives inhibit the proliferation of the AIDS virus.
Inventors
- 👤 Susumu Central Research Laboratories Shibahara
- 👤 Hirokazu Central Research Laboratories Morisawa
- 👤 Hideki Nakajima
- 👤 Naoki Yamamoto
- 👤 Sachiko C/O Central Research Laboratories Mukai
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-04 22:50
CPC Classifications
C; C07; C07H; C07H21/00; C07H19/00; C07H19/02; C07H19/04; C07H19/06; C07H19/10; C07H19/16; C07H19/20
Claims Analysis
Total Claims: 40
Claim 1
Independent Claim
356 words
An oligoribonucleotide derivative represented by the general formula: wherein: m is an integer of 1 to 100 (provided that when X, and X are all substituted at the 2 -position and represent a hydrogen atom, m represents an integer of 4 to 50); B represents B 2 , B 3 , ..... B (m+1) , and B 1 to B (m+2) ' which may be the same or different, each represents any one of hypoxanthine-9-yl, guanine-9-yi, adenine-9-yi, cytosine-1-yl, uracil-1-yl and thymine-1-yl (provided that when X, and all of X are substituted at the 3 -position and represent a hydrogen atom, all of them do not represent adenine-9-yl; Q represents Q 2 , Q 3 , ...... Q (m+1) , and Q 1 to Q (m+1) ' independently represents any one of a thioanion, an oxoanion, an alkyl group, an aryloxy group, an alkylamino group, an arylamino group, an alkylthio group and an arylthio group (provided that at least one of Qi to Q (m+1) represents a thioanion); X represents X 2 , X 3 , ..... X (m+1) , and X 1 to X (m+1) ' which may be the same or different, each represents any one of a hydrogen atom, a methyl group or an acyl group having 1 to 20 carbon atoms; R represents a hydrogen atom, an acyl group having 1 to 20 carbon atoms, a phosphoryl group which may optionally have a substituent, a thiophosphoryl group which may optionally have a substituent or an alkylaminophosphoryl group which may optionally have a substituent; Y 1 and Y 2 independently represent a methoxy group, a carboxyl group having 1 to 20 carbon atoms, a hydrogen atom, a hydroxyl group, an alkyloxy group which may optionally have a substituent, a phosphoryloxy group which may optionally have a substituent, a thiophosphoryloxy group which may optionally have a substituent and an alkylaminophosphoryloxy group which may optionally have a substituent; and X is capable of binding to an oxygen atom either at 2 -position or at the 3 -position in the sugar moiety of nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 2
Dependent Claim
356 words
An oligoribonucleotide derivative represented by the general formula: wherein: m is an integer of 1 to 100 (provided that when X, and X are all substituted at the 2 -position and represent a hydrogen atom, m represents an integer of 4 to 50); B represents B 2 , B 3 , ..... B (m+1) , and B 1 to B (m+2) ' which may be the same or different, each represents any one of hypoxanthine-9-yl, guanine-9-yi, adenine-9-yi, cytosine-1-yl, uracil-1-yl and thymine-1-yl (provided that when X, and all of X are substituted at the 3 -position and represent a hydrogen atom, all of them do not represent adenine-9-yl; Q represents Q 2 , Q 3 , ...... Q (m+1) , and Q 1 to Q (m+1) ' independently represents any one of a thioanion, an oxoanion, an alkyl group, an aryloxy group, an alkylamino group, an arylamino group, an alkylthio group and an arylthio group (provided that at least one of Qi to Q (m+1) represents a thioanion); X represents X 2 , X 3 , ..... X (m+1) , and X 1 to X (m+1) ' which may be the same or different, each represents any one of a hydrogen atom, a methyl group or an acyl group having 1 to 20 carbon atoms; R represents a hydrogen atom, an acyl group having 1 to 20 carbon atoms, a phosphoryl group which may optionally have a substituent, a thiophosphoryl group which may optionally have a substituent or an alkylaminophosphoryl group which may optionally have a substituent; Y 1 and Y 2 independently represent a methoxy group, a carboxyl group having 1 to 20 carbon atoms, a hydrogen atom, a hydroxyl group, an alkyloxy group which may optionally have a substituent, a phosphoryloxy group which may optionally have a substituent, a thiophosphoryloxy group which may optionally have a substituent and an alkylaminophosphoryloxy group which may optionally have a substituent; and X is capable of binding to an oxygen atom either at 2 -position or at the 3 -position in the sugar moiety of nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 3
Dependent Claim
141 words
A derivative as claimed in claim 1, wherein said substituent on R, Y 1 and Y 2 , which may be the same or different, each represents any one of a cyanoethyl group, a chlorophenyl group, a monophosphoryl group, a pyrophosphoryl group, a hydrocarbon residue having 1 to 20 carbon atoms, a cholesteryl group and a group having the formula J-(K-0-L) E wherein J represents: a hydroxyl group or any one of the oligoribonucleotidyl groups defined for the structural formula of said derivative according to claim 1, from which any one of RO, Y 1 and Y 2 is removed; K represents any one of a phosphoryl group, a thiophosphoryl group and an alkylaminophosphoryl group having 1 to 10 carbon atoms; L represents a hydrocarbon residue having 1 to 20 carbon atoms; and E represents an integer of 1 to 10.
Claim 4
Dependent Claim
72 words
A derivative as claimed in claim 1, wherein m represents 25, B 1 to B 27 represents, in sequence, U, U, C, C, C, U, U, U, C, G, C, U, U, U, C, A, A, G, U, C, C, C, U, G, U, U, C and G; Q 1 to Q 26 each represent a thioanion; Y, and Y 2 represent OCH 3 ; and Y 3 and R represents H.
Claim 5
Dependent Claim
73 words
A derivative as claimed in claim 1, wherein m represents 28, B 1 to B 30 represent, in sequence U, C, C, U, U, C, U, A, G, C, U, C, C, G, C, U, A, G, U, C, A, A, A, A, U, U, U and U; Q 1 to Q 29 each represent a thioanion; Y 1 and Y 2 represent OCH 3 ; and Y 3 and R represents H.
Claim 6
Dependent Claim
73 words
A derivative as claimed in claim 1, wherein m represents 26, B 1 to B 28 represent, in sequence, U, U, U, U, A, A, U, U, U, A, U, A, U, U, U, U, U, U, C, U, U, U, C, C, C, C, C and U; Q 1 to Q 27 each represent a thioanion; Y 1 and Y 2 represent OCH 3 ; and Y 3 and R represents H.
Claim 7
Dependent Claim
54 words
A derivative as claimed in claim 1, having the structural formula: wherein .a hydrogen atom (H) is capable of binding to the oxygen atom either at the 2 -position or at the 3'- position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 8
Dependent Claim
53 words
A derivative as claimed in claim 1, having the structural formula: wherein a hydrogen atom (H) is capable of binding to the oxygen atom either at the 2'-position or at the 3'- position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 9
Dependent Claim
54 words
A derivative as claimed in claim 1, having the structural formula: wherein an acetyl group is capable of binding to the oxygen atom either at the 2 -position or at the 3 - position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to a phosphorous atom (P).
Claim 10
Dependent Claim
54 words
A derivative as claimed in claim 1, having the structural formula: wherein a hydrogen atom (H) is capable of binding to the oxygen atom either at the 2 -position or at the 3'- position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 11
Dependent Claim
53 words
A derivative as claimed in claim 1, having the structural formula: wherein a hydrogen atom (H) is capable of binding to the oxygen atom either at the 2'-position or at the 3'- position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 12
Dependent Claim
55 words
A derivative as claimed in claim 1, having the structural formula: wherein a hydrogen atom (H) is capable of binding to the oxygen atom either at the 2 -position or at the 3 - position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 13
Dependent Claim
53 words
A derivative as claimed in claim 1, having the structural formula: wherein a hydrogen atom (H) is capable of binding to the oxygen atom either at the 2'-position or at the 3'- position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to a phosphorus atom (P).
Claim 14
Dependent Claim
23 words
13 An anti-AIDS viral agent comprising as an effective ingredient at least oligoribonucleolide derivative as claimed in any of claims 1 to 12.
Claim 15
Dependent Claim
164 words
A 2'-O-methylribooligonucleotide phosphorothiate derivative containing a sequence complementary to genomic RNA of AIDS virus or to DNA integrated into a chromosome and represented by the general formula: wherein: m' is an integer of 1 to 50; B to B (m'+2) ' which may be the same or different, each represents any one of adenine-9-yl, guanine-9-yl, cytosine-1-yl, uracil-1-yl, thymine-1-yl and hypoxanthine-9-yl; Q' 1 , represents any one of a thioanion, an oxoanion, an alkyl group, an alkyloxy group, an aryloxy group, an alkylamino group, an alkyloxy group, an alkylthio group and an arylthio group; at least one of Q' 2 to Q' (m' +1) , represents a thioanion and the other(s) is(are) either a thioanion or an oxoanion; Y' 1 , to Y independently represents a methoxy group, an alkyloxy group which may optionally have a substituent, a hydroxyl group, an alkylsilyl group or a hydrogen atom; R represents a hydrogen atom, a phosphoryl group or a thiophosphoryl group which may optionally have a substituent.
Claim 16
Dependent Claim
164 words
A 2'-O-methylribooligonucleotide phosphorothiate derivative containing a sequence complementary to genomic RNA of AIDS virus or to DNA integrated into a chromosome and represented by the general formula: wherein: m' is an integer of 1 to 50; B to B (m'+2) ' which may be the same or different, each represents any one of adenine-9-yl, guanine-9-yl, cytosine-1-yl, uracil-1-yl, thymine-1-yl and hypoxanthine-9-yl; Q' 1 , represents any one of a thioanion, an oxoanion, an alkyl group, an alkyloxy group, an aryloxy group, an alkylamino group, an alkyloxy group, an alkylthio group and an arylthio group; at least one of Q' 2 to Q' (m' +1) , represents a thioanion and the other(s) is(are) either a thioanion or an oxoanion; Y' 1 , to Y independently represents a methoxy group, an alkyloxy group which may optionally have a substituent, a hydroxyl group, an alkylsilyl group or a hydrogen atom; R represents a hydrogen atom, a phosphoryl group or a thiophosphoryl group which may optionally have a substituent.
Claim 17
Dependent Claim
69 words
A derivative as claimed in claim 14, wherein m represents 18; B' 1 , to B' 20 represent, in sequence, A, C, A, C, C, C, A, A, U, U, C, U, G, A, A, A, A, U, G and G; Q' 1 , to Q' 19 represent a thioanion; Y' 1 , and Y 2 represent OCH 3 ; Y' represents OH; and R represents a hydrogen atom.
Claim 18
Dependent Claim
64 words
A derivative as claimed in claim 14, wherein m represents 15; B' 1 to B' 17 represent, in sequence, C, C, C, A, A, U, U, C, U, G, A, A, A, A, U, G and G; Q' 1 to Q' 16 represent a thioanion; Y' 1 and Y' 2 represent OCH 3 ; Y 3 represents OH; and R represents a hydrogen atom.
Claim 19
Dependent Claim
72 words
A derivative as claimed in claim 14, wherein m represents 23; B' 1 to B' 25 represent, in sequence, A, C, A, C, C, C, A, A, U, U, C, U, G, A, A, A, A, U, G, G, A, U, A, A and A; Q' 1 to Q' 24 represent a thioanion; Y' 1 and Y 2 represent OCH 3 ; Y' 3 represents OH; and R' represents a hydrogen atom.
Claim 20
Dependent Claim
57 words
A derivative as claimed in claim 14, wherein m' represents 8; B' 1 to B' 10 represent, in sequence, C, A, A, U, U, C, U, G, A and A; Q' 1 to Q 9 represent a thioanion; Y' 1 and Y' 2 represent OCH 3 ; Y' 3 represents OH; and R represents a hydrogen atom.
Claim 21
Dependent Claim
69 words
A derivative as claimed in claim 14, wherein m' represents 19; B' 1 , to B' 21 represent, in sequence, G, U, C, C, C, U, G, U, U, C, G, G, G, C, G, C, C, A, C, U and G; Q' 1 to Q' 20 represent a thioanion; Y' 1 and Y' 2 represent OCH 3 ; Y 3 represents OH; and R represents a hydrogen atom.
Claim 22
Dependent Claim
66 words
A derivative as claimed in claim 14, wherein m represents 19; B to B' 21 represent, in sequence, G, A, G, C, U, C, C, C, A, G, G, C, U, C, A, G, A, U, C, U and G; Q' 1 to Q' 20 represent a thioanion; Y' 1 and Y' 2 represent OCH 3 ; Y represents OH; and R represents a hydrogen atom.
Claim 23
Dependent Claim
96 words
A derivative as claimed in claim 14, wherein m represents 18; B' 1 to B' 20 represent, in sequence, A, C, A, C, C, C, A, A, U, U, C, U, G, A, A, A, A, U, G, and G; Q' 1 to Q' 5 represent a thioanion; Q' 6 to Q' 1 , represent an oxoanion; at least two of Q' 15 to Q' 19 represent a thioanion and the other three each represent an oxoanion; Y' 1 and Y 2 represent OCH 3 ; Y 3 represents OH; and R represents a hydrogen atom.
Claim 24
Dependent Claim
29 words
A 2'-O-methylribonucleotide derivative having the general formula: wherein W represents a monomethoxytrityl group or a dimethoxytrityl group; Z represents a substituent represented by any one of the general formulae:
Claim 25
Dependent Claim
29 words
A 2'-O-methylribonucleotide derivative having the general formula: wherein W represents a monomethoxytrityl group or a dimethoxytrityl group; Z represents a substituent represented by any one of the general formulae:
Claim 26
Dependent Claim
86 words
A nucleoside derivative represented by the general formula: wherein W represents a monomethoxytrityl group or a dimethoxytrityl group; Y 4 represents a methoxy group, an alkyloxy group which may optionally have a substituent or a hydrogen atom; n and t, which may be the same or different, each represents an integer of 1 to 30; IP represents any one of a controlled pore glass derivative, a polystyrene derivative or a silica gel derivative; and Z represents a substituent represented by any one of the general formulae:
Claim 27
Dependent Claim
86 words
A nucleoside derivative represented by the general formula: wherein W represents a monomethoxytrityl group or a dimethoxytrityl group; Y 4 represents a methoxy group, an alkyloxy group which may optionally have a substituent or a hydrogen atom; n and t, which may be the same or different, each represents an integer of 1 to 30; IP represents any one of a controlled pore glass derivative, a polystyrene derivative or a silica gel derivative; and Z represents a substituent represented by any one of the general formulae:
Claim 28
Dependent Claim
117 words
A 2'-O-methylribooligonucleotide phosphorothioate derivative represented by the general formula: wherein: m" is an integer of 1 to 50; B and B" (m"+2) , which may be the same or different, each represents any one of adenine-9-yl, guanine-9-yl, cytosine-1-yl, uracil-1-yl, thymine-1-yl and hypoxanthine-9-yl; Q contains at least one thioanion and represents any one of a thioanion, an oxoanion, an aryloxy group, an alkylamino group, an arylamino group, an alkylthio group and an arylthio group; Y" 1 to Y" 3 independently represents a methoxy group, an alkyloxy group which may optionally have a substituent, a hydroxyl group, an alkylsilyl group and a hydrogen atom; R represents a hydrogen atom or a phosphoryl group which may optionally have a substituent.
Claim 29
Dependent Claim
117 words
A 2'-O-methylribooligonucleotide phosphorothioate derivative represented by the general formula: wherein: m" is an integer of 1 to 50; B and B" (m"+2) , which may be the same or different, each represents any one of adenine-9-yl, guanine-9-yl, cytosine-1-yl, uracil-1-yl, thymine-1-yl and hypoxanthine-9-yl; Q contains at least one thioanion and represents any one of a thioanion, an oxoanion, an aryloxy group, an alkylamino group, an arylamino group, an alkylthio group and an arylthio group; Y" 1 to Y" 3 independently represents a methoxy group, an alkyloxy group which may optionally have a substituent, a hydroxyl group, an alkylsilyl group and a hydrogen atom; R represents a hydrogen atom or a phosphoryl group which may optionally have a substituent.
Claim 30
Dependent Claim
41 words
A derivative as claimed in claim 24, wherein m" represents 18; B" 1 to B" 20 represents adenine-9-yi; Q" represents a thioanion; Y" 1 and Y" 2 represent OCH 3 ; Y" 3 represents OH; and R represents a hydrogen atom.
Claim 31
Dependent Claim
41 words
A derivative as claimed in claim 24, wherein m represents 18; B" 1 to B" 20 represent hypoxanthine-9-yl; Q represents a thioanion; Y" 1 and Y" 2 represent OCH 3 ; Y 3 represents OH; and R represents a hydrogen atom.
Claim 32
Dependent Claim
41 words
A derivative as claimed in claim 24, wherein m represents 18; B" 1 to B" 20 represent uracil-1-yi; Q represents a thioanion; Y" 1 and Y" 2 represent OCH 3 ; Y" 3 represents OH; and R represents a hydrogen atom.
Claim 33
Dependent Claim
41 words
A derivative as claimed in claim 24, wherein m represents 18; B" 1 to B" 20 represent cytosine-1-yl; Q" represents a thioanion; Y" 1 and Y" 2 represent OCH 3 ; Y" 3 represents OH; and R represents a hydrogen atom.
Claim 34
Dependent Claim
317 words
An oligoribonucleotide derivative represented by the general formula: wherein: m'" is an integer of 1 to 100 (provided that when X' 1 and X' are all substituted at the 2'-position and represent a hydrogen atom, m''' represents an integer of 4 to 50); B" represents B''' 2 , B" 3 , ..... B''' (m'''+1) , and B''' 1 to B''' (m'''+2') which may be the same or different, each represents any one of hypoxanthine-9-yl, guanine-9-yl, adenine-9-yl, cytosine-1-yi, uracil-1-yl and thymine-1-yl (provided that all of them do not represent adenine-9-yi); Q" represents Q'"2, Q"' 3 , ..... Q"' (m'''+1) , and Q''' 1 to Q''' (m+1) , independently represents any one of a thioanion, an oxoanion, an aryloxy group, an alkylamino group, an arylamino group, an alkylthio group and an arylthio group (provided that at least one of Q''' 1 to Q''' (m'''+1) , represents a thioanion); X represents X' 2 , X' 3 ,..... X' (m'''+1) , and X to X' (m'''+1), which may be the same or different, each represents a hydrogen atom or methyl group (provided that when all of X to X' (m'''+1) are substituted at the 2 -position, all of them do not represent a methyl group); R''' represents any on of a hydrogen atom, an acyl group having 1 to 20 carbon atoms and a phosphoryl group which may optionally have a substituent; Y''' 1 and Y'" 2 independently represents any one of a methoxy group, a carboxyl group having 1 to 20 carbon atoms, an alkyloxy group which may optionally have a substituent, a hydroxyl group, an alkylsilyl group, a hydrogen atom and a phosphoryl group which may optionally have a substituent; and X is capable of binding to an oxygen atom either at the 2 -position or at the 3 -position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to phosphorus atom (P).
Claim 35
Dependent Claim
317 words
An oligoribonucleotide derivative represented by the general formula: wherein: m'" is an integer of 1 to 100 (provided that when X' 1 and X' are all substituted at the 2'-position and represent a hydrogen atom, m''' represents an integer of 4 to 50); B" represents B''' 2 , B" 3 , ..... B''' (m'''+1) , and B''' 1 to B''' (m'''+2') which may be the same or different, each represents any one of hypoxanthine-9-yl, guanine-9-yl, adenine-9-yl, cytosine-1-yi, uracil-1-yl and thymine-1-yl (provided that all of them do not represent adenine-9-yi); Q" represents Q'"2, Q"' 3 , ..... Q"' (m'''+1) , and Q''' 1 to Q''' (m+1) , independently represents any one of a thioanion, an oxoanion, an aryloxy group, an alkylamino group, an arylamino group, an alkylthio group and an arylthio group (provided that at least one of Q''' 1 to Q''' (m'''+1) , represents a thioanion); X represents X' 2 , X' 3 ,..... X' (m'''+1) , and X to X' (m'''+1), which may be the same or different, each represents a hydrogen atom or methyl group (provided that when all of X to X' (m'''+1) are substituted at the 2 -position, all of them do not represent a methyl group); R''' represents any on of a hydrogen atom, an acyl group having 1 to 20 carbon atoms and a phosphoryl group which may optionally have a substituent; Y''' 1 and Y'" 2 independently represents any one of a methoxy group, a carboxyl group having 1 to 20 carbon atoms, an alkyloxy group which may optionally have a substituent, a hydroxyl group, an alkylsilyl group, a hydrogen atom and a phosphoryl group which may optionally have a substituent; and X is capable of binding to an oxygen atom either at the 2 -position or at the 3 -position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to phosphorus atom (P).
Claim 36
Dependent Claim
30 words
A derivative as claimed in claim 29, wherein said substituent is any one of a cyanoethyl group, a chlorophenyl group and a hydrocarbon residue having 1 to 20 carbon atoms.
Claim 37
Dependent Claim
11 words
31 A derivative as claimed in claim 29, having structural formula:
Claim 38
Dependent Claim
11 words
A derivative as claimed in claim 29, having the structural formula:
Claim 39
Dependent Claim
52 words
A derivative as claimed in claim 29, having the structural formula: wherein a hydrogen atom (H) is capable of binding to an oxygen atom either at the 2'-position or at the 3'- position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to phosphorus atom (P).
Claim 40
Dependent Claim
56 words
A derivative as claimed in claim 29, having the structural formula: wherein a methyl group (CH 3 ) is capable of binding to an oxygen atom either at the 2 -position or at the 3 - position in the sugar moiety of the nucleoside monomer and, in this case, another is bound to phosphorus atom (P).
References Cited (Backward Citations)
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