WO1999019474A1 - Modified oligodeoxyribonucleotides having tggg sequence - Google Patents

Abstract

Novel modified oligodeoxyribonucleotides having an excellent activity against human immunodeficiency virus (HIV-1). They are compounds represented by general formula (1) or pharmacologically acceptable salts thereof, wherein Q is a group represented by R1R2R3Z (wherein R1, R2, and R3 each represents H, C1-4 alkyl, optionally substituted aryl, or optionally substituted anthraquinonyl and Z represents C or Si, or R2, R3 and Z in combination represent fluorenyl or xanthenyl); R4 is H, optionally substituted C1-4 alkyl, optionally substituted aryl, or optionally substituted aralkyl; Y1, Y3, and Y4 each is O, S, or NH; Y2 is O, S, NH, C1-4 alkylene, or phenylene; Z is C or Si; X is C1-10 alkylene optionally substituted by OH; m and n each is an integer of 0 to 10; and B is an oligodeoxyribonucleotide having a sequence represented by TGGGGT, TGGGGTT, TGGGGGT, TGGGCG, TGGGTG, TGGGG, TGGGGG, or TGGGAG.

Description

 Specification

TECHNICAL FIELD The present invention relates to a novel oligodeoxyribonucleotide having an excellent anti-AIDS virus action. BACKGROUND ART Oligodeoxyribonucleotides having a sequence complementary to a certain gene (hereinafter referred to as antisense oligodeoxyribonucleotide) are known to inhibit the functional expression of the gene. It has also been reported that antisense oligodeoxyribonucleotides of the viral gene or oncogene can inhibit viral replication or cell growth, respectively, by inhibiting the function of that gene. Natl. Acad. Sci. USA, Vol. 75, No. 1, page 280 (1977), and P. Zamecnik, J. Goodchild, Y. Taguchi, Sarin, Proc (PC Zamecnik, ML Stephenson, Proc. Natl. Natl. Acad. Sci. USA, Vol. 83, No. 6, 4143 (1986)).

In order for the antisense oligodeoxyribonucleotide to exhibit the above-mentioned inhibitory action, it must form a stable hybrid with the target RNA or DNA in vivo. In order to form this hybrid, it is said that the antisense oligodeoxyribonucleotide needs to have a length of at least about 15 nucleotides or more. Had been.

 However, in general, those having a length of about 15 nucleotides or more are difficult to put into practical use due to a problem of synthesis cost. Also, if the length is 1

It is considered that the activity of inhibiting the replication of a virus or the growth of cells by antisense oligodeoxyribonucleotides of about 5 nucleotides is not sufficiently satisfactory.

 The present inventors have proposed various nucleotide sequences and 5′-terminal and 3′-terminal oligo-nucleotide ribonucleotides, which have been considered to have no specific inhibitory activity. As a result of intensive studies on oligodeoxynucleotides having various modifying groups on the terminal side, it has been found that modified oligodeoxyribonucleotides having a constant nucleotide sequence have a remarkably high anti-AIDS virus activity, and Found that the compound has low toxicity to normal cells, was relatively easy to synthesize, and was practically useful, and disclosed the compound described in Japanese Patent Laid-Open Publication No. 7-87982.

 Furthermore, as a result of continuous synthesis and activity evaluation of oligodeoxyribonucleotide derivatives, a group of compounds not specifically disclosed in the patent publication (JP-A-7-87982) was found. The present inventors have found that the compound exhibits remarkably excellent anti-AIDS virus activity as compared with the compound specifically described in the publication, and completed the present invention. The novel oligodeoxyribonucleotide of the present invention is

(1) を有し、 また、 本発明は、 その薬理上許容しうる塩も包含する。 General formula

(1) The present invention also includes a pharmacologically acceptable salt thereof.

In the above formula (1), Q represents a RiRsRsZ group (wherein, R, R ₂ and R ₃ may be the same or different and may have a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a substituent. Z represents C or Si; or R ₂ , R ₃ and Z together form a fluorenyl group or a xanthyl group. R ₄ has a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which may have a substituent, an aryl group or a substituent which may have a substituent. even shows good Ararukiru group,丫丄, Y ₃ and Y ₄ are the same or different and Omicron, S or ΝΗ, Υ ₂ is 0, S, NH, C 1乃optimum 4 alkylene group having a carbon Or X represents a phenylene group, and X represents a linear or branched alkylene having 1 to 10 carbon atoms which may be substituted with a hydroxyl group. Represents a group, m and n are the same or different and represent an integer of 0 to 10, and B is selected from the sequence TGGGGT, TGGGGTT, TGGGGGT, TGGGCG, TGGGGGTG, TGGGGG, TGGGGG or TGGGAG. Indicates the selected oligodeoxyribonucleotide (hereinafter referred to as ODN). However, in B, the hydroxyl groups at the 5 'end and 3' end of each oligodeoxyribonucleotide are not included. The left end of each sequence is the 5 'end, and the right end is the 3' end. Further, when B is TGGGG or TGGGGG, is a 3,4- (dibenzyloxy) phenyl group, R ₂ , R ₃ and R ₄ are each a hydrogen atom, and X is an ethylene group. And Y or Υ ₂ , Υ ₃ and Υ ₄ are each an oxygen atom, Ζ is a carbon atom, m is 1 to 3, and n is 1. When B is TGGGAG, is a 3,41- (dibenzyloxy) phenyl group, R ₂ , R ₃ and R ₄ are each a hydrogen atom, X is an ethylene group, and Υ _2, Upsilon ₃ and Upsilon ₄ are each an oxygen atom, Zeta Is a carbon atom, m is 2 to 3, and n is 1.

 The present invention also relates to a drug, particularly an anti-AIDS agent, comprising the compound (1) or a pharmacologically acceptable salt thereof as an active ingredient.

Furthermore, the present invention relates to the use of the above compound (1) or a pharmacologically acceptable salt thereof for producing a medicament, particularly an anti-AIDS agent. In the above formula (1), examples of the alkyl group having 1 to 4 carbon atoms of R ₂ and R ₃ in the Q group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Examples thereof include an s-butyl and t-butyl group, preferably an tert-butyl group.

In the above formula (1), examples of the aryl group which may have a substituent for R i, R ₂ and R ₃ in the Q group include, for example, phenyl group; 4-methylphenyl, 41 t Alkylene substituted phenyl group having 1 to 4 carbon atoms, such as monobutyl fuel; 2 — phenylyl phenyl, aryl substituted phenyl group such as 4 phenyl phenol, 4 monofluorophenyl, 2 — Mono- or dihalogen-substituted phenyl groups such as black mouth phenyl, 4 — black mouth phenyl, 4- phenyl, lomophenyl, 4 — phenyl, 2,4-difluorophenyl; 4 2-nitro-substituted phenyl groups such as 12-trophenyl; alkoxy substituted phenyl groups having 1 to 4 carbon atoms such as 4-t-butoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl; 3-phenyloxy ^^, 4-phenyloxy-substituted phenyl groups such as 4-phenoxyphenyl; 2-benzyloxyphenyl, 4-benzyloxyphenyl, 3,4- (dibenzyloxy) phenyl, 3,5- ( Mono- or di-aralkyloxy-substituted fuel groups, such as dibenzyloxy) phenyl; mono- or di-aralkyloxy-substituted, such as 3,5-bis [3,5- (dibenzyloxy) benzyloxy] phenyl, Aralkyloxymono- or di-substituted phenyl groups; naphthylene groups such as naphthalene-1-yl and naphthalene-12-yl; phenanthryl groups such as phenanthrene-14-yl; anthracene Anthracel groups and pyreyl groups such as 1-9-yl and anthracene-12-yl are preferable, and an unsubstituted phenyl group and an alkoxy-substituted phenyl group are preferred.

(Especially 4-methoxyphenyl), diaralkyloxy-substituted phenyl groups (especially 3,4- (dibenzyloxy) phenyl, 3,5- (dibenzyloxy) phenyl) and mono- or diphenyl. Alkenyl-substituted mono- or di-aralkyloxy-substituted phenyl groups (especially 3,5-bis

[3,5-((dibenzyloxy) benzyloxy] phenyl), and more preferably 3,4- (dibenzyloxy) phenyl and 3,51- (dibenzyloxy) phenyl (particularly, 3,4- (dibenzyloxy) phenyl). C) a phenyl group).

In the above formula (1), examples of the anthraquinonyl group which may have a substituent of R ₂ and R ₃ in the Q group include, for example, 9,10-anthraquinone-11-yl, 9, Unsubstituted anthraquinonyl groups such as 10-anthraquinone-2-yl; such as 9,10-anthraquinone-1-4-methyl-1-yl, 9,10-anthraquinone-1-6-ethyl-2-yl An alkyl-substituted anthraquinonyl group having 1 to 4 carbon atoms; 1 to 4 carbon atoms such as 9,10-anthraquinone-5-methoxy-11-yl, 9,10-anthraquinone-18-ethoxy-2-yl 9 alkoxy-substituted anthraquinol groups; 9,10-anthraquinone-7-chloro-1-yl, 9,10-anthraquinone-18-fluoro-2-yl-substituted halogen-substituted anthraquinol groups; 9 , 10- Anthraquinone 1 — Hydroxy One 1 - good Unahi de proxy replacement Anne Torakinoniru group I Lumpur, and the like, preferably of the non-substituted, and the like. In the above formula (1), the fluorenyl group or xanthyl group formed together by R ₂ , R ₃ and Z of the Q group is preferably fluorene-19-yl, xanthene-19-yl Group.

In the formula (1), examples of the alkyl group having 1 to 4 carbon atoms which may have a substituent of R ₄ include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, Unsubstituted alkyl groups such as isobutyl, s-butyl, and t-butyl; amino-substituted alkyl groups such as 2-aminoethyl and 3-aminopropyl; carbons such as 2-methoxyethoxy and 3-methoxypropyl Examples thereof include an alkoxy-substituted alkyl group having 1 to 4 alkoxy groups, preferably, methyl, ethyl, n-propyl, 2-aminoethyl, and 2-methoxethyl groups.

In the above formula (1), examples of the aryl group which may have a substituent of R ₄ include, for example, phenyl group; alkyl having 1 to 4 carbon atoms such as 2-methylphenyl and 3-ethylphenyl. Substituted phenyl group; 2-phenylphenol, 2-phenylphenyl, 4-chlorophenyl, 2-bromophenyl, 2-phenylphenyl, etc. Gen-substituted phenyl group A 2-substituted phenyl group such as 2-nitrophenyl, 4-nitrophenol; an alkoxy-substituted phenyl group such as 4-methoxyphenyl or 4-ethoxyphenyl; An alkylthio-substituted phenyl group having 1 to 4 carbon atoms such as 4-methylthiophene and 4-ethylthiophenyl; a naphthyl group; a phenanthrenyl group; an anthracenyl group; and a pyrenyl group. Examples include phenyl, halogen-substituted phenyl, and nitrogen-substituted phenyl groups.

In the above formula (1), examples of the aralkyl group which may have a substituent for R ₄ include, for example, a benzyl group; an alkyl-substituted benzyl group having 1 to 4 carbon atoms such as methylbenzyl and ethylbenzyl; Methoxyben Alkoxy-substituted benzinole groups having 1 to 4 carbon atoms, such as ethoxybenzyl; halogen-substituted benzinole groups, such as phenoleno benzone, chlorobenzenole, and bulomobenzinole; chloronaphthylmethyl Halogen-substituted naphthylmethyl group such as phenol; indulmethyl group; phenanthrenylmethyl group; anthracenylmethyl group; diphenylmethyl group; triphenylmethyl group; 1-phenylene, 2-phenethyl, 2,2-diphenylethylenol, Mono-, di- or triphenyl-substituted ethyl groups such as 2,2-triphenylethyl and 3,3,3, -triphenylpropyl; naphthyl such as tronaphthylethyl and 2-naphthylethyl Substituted ethyl group; 1-phenylpropyl, 2-phenylphenol, 3-phenylpropyl, 1- Aryl-substituted propynole groups such as phthylpropyl, 2-naphthylpropyl, and 3-naphthylpropyl; 1-phenylbutynole, 2-phenylbutinole, 3-phenylbutynole, 4-phenylbutinole, 1-napthinolebutyl, 2 Phenyl or naphthyl-substituted butyl groups such as -naphthinoleptinole, 3-naphthynolebutyl, and 4-naphthylbutyl; 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentinole, 4_phenylpentyl, Fe- or naphthyl-substituted pentyl groups such as 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl; 1-phenylenoxyl, 2- Phenyl hexyl, 3-phenyl hexyl, 4-phenyl hexyl, 5-phenyl hexyl, 6-phenyl Phenyl or naphthyl such as 1-naphthyl hexinole, 1-naphthyl hexinole, 2-naphthinole hexinole, 3-naphthinole hexinole, 4-naphthinole hexinole, 5-naphthyl hexinole, 6-naphthylhexyl Examples thereof include a substituted hexyl group, preferably an unsubstituted benzyl group or a 2-phenethyl group.

In the above formula (1), examples of the alkylene having 1 to 4 carbon atoms of Y ₂ include methylene, ethylene, propylene, tetramethylene, and pentamethylene. And methylene, preferably methylene.

In the above formula (1), each of Y, Y ₃ and Y ₄ is preferably an oxygen atom.

In the above formula (1), Υ ₂ is preferably an oxygen or sulfur atom. In the above formula (1), の in the Q group is preferably a carbon atom. In the formula (1), examples of the linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a hydroxyl group of X include, for example, methylene, methylmethylene, ethylene, Propylene, tetramethylene, methinoleethylene, 丄 -methinoletrimethylene, 2-methinoletrimethylene, 2-methyltetramethylene, 3-methyltrimethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, Examples thereof include nonamethylene, decamethylene, 2-hydroxytrimethylene, and 2-hydroxytramethylene, and preferably methylene, methylmethylene, ethylene, propylene, and methylethylene.

 In the above formula (1), m is preferably 0 to 6, and more preferably 0 to 4. However, when B is TGGGGG or TGGGGG, m is preferably 1 to 3, and when B is TGGGAG, m is preferably 2 to 3.

 In the above formula (1), n is preferably 0 to 6, and more preferably 1.

In the above formula (1), the sequence of B TG GG GT, TGG GGTT, TG GG GGT, TGG G CG, T GG GT G, T GG GG, TG GG GG or TG GGAG is selected from the group consisting of oligodeoxyribonucleotides. Preferred among them are the sequences TGGGGT, TGGGGGTT, TGGGGGT, TGGGGG, TGGGGG or TGGGGG. In the sequence of B, A is adenine deoxyribonucleotide, G is guanine deoxyribonucleotide, C is cytosine deoxyribonucleotide, and T is thymine deoxyribonucleotide. Shows Reotide. The left end is the 5 'end and the right end is the 3' end. However, the hydroxyl groups at the 5 'end and 3' end of each oligodeoxylyl nucleotide are not included.

In the formula (1), preferred groups at the 5 ′ end (Ri Rs Rs Z—Yi) obtained by combining R ₂ , R ₃ , and Z include triphenylmethyloxy, 3, 4- (dibenzinoleoxy) benzoyloxy, 3, 5- (dibenzyloxy) benzyloxy, t-butylinolethiophenolenosilyloxy, phenylenoleoleoni / reoxy, and phenylxanthenyloxy, More preferably, they are triphenylmethinoleoxy, 3,4- (dibenzyloxy) benzyloxy, 3,5- (dibenzyloxy) benzyloxy group or 3,5-bis [3,5- (dibenzyloxy) benzyloxy] benzyloxy group. Is a 3,4- (dibenzyloxy) benzyloxy group.

In the above formula (1), a suitable group at the 3 ′ terminal obtained by a combination of R ₄ , X, Y ₂ , Υ ₃ , Υ ₄ , m and η ([P (O) (Y ₂ R ₄ ) I Y ₃ — (X-Υ ₄ ) _n ] _m Η) includes hydrogen (Η), methyl phosphoryl [P (0) (0CH ₃ ) 0 H], 2 — phenylphosphoryl [ P (0) (0-2-C1- Ph) 0H], (O- methyl) Chiohosuhoriru _{[P (0) (0CH 3} ) SH], Mechiruhosu Honiru _{[P (0) (CH 3} ) 0H], main switch Luthiophosphonyl [P (0) (CH ₃ ) SH], Phenylphosphonyl [P (0) (Ph) OH], 2 — Hydroxicetyl phosphoryl [P (0) (0H) 0CH ₂ CH ₂ 0H] , [O— (2-hydroxystyl)] thiophosphoryl [P (0) (SH) 0CH ₂ CH ₂ 0H], phenylphosphoryl [P (0) (OPh) OH], Lil [P (0) (0-4- CI- Ph) 0H], 2- two filtrated off Eniruhosuho Lil [P (0) (0-2- N0 2 -Ph) OH] N 4 twelve Toro Fueniruhosuho Lyl [P (0) (0- 2-N0 ₂ -Ph) 0H], ethyl phosphoryl [P (0) (0CH ₂ CH ₃ ) 0H], (、 -ethyl) thiophosphoryl [P (0) ( 0CH ₂ CH ₃ ) SH], 2 — (2—Hydroxy)

{[P (0) (0H) 0CH ₂ CH ₂ 0] ₂ H}, 2— [2— (2—hydroxylethylphosphoryloxy)) {[P (0) (0H ) 0CH 2 CH 2 0] 3 H} group, and more preferably, hydrogen, main Chinorehosuho Rinore, 2 - click b port phenylene Norehosuho Rinore, (O-Mechinore) Chi Phospholinole, methinolephosphoninole, methinolethiophosphoninole, feninole phospho-nole, 2 — hydroxishetinole phosphorinole, [O-(2 —hydroxicetyl)] thiophosphoryl, 2 — (2 — 2- (2- (2-hydroxy-2-ethyl) -phosphoryloxy) ethylphosphoryloxy) ethylphosphoryl, and most preferably 2—hydroxyl-phosphoryl, 2 -— (2-hydroxy (2-hydroxyethyl) phosphinyloxy) ethylphosphoryl. 2— (Hydroxyshetinolephosphorinoleoxy) ethynolephosphorinole, 2— [2— (2— (Hydroxyshetylphosphoryloxy) ethylphosphorinoleoxy]] ethylphosphoryl group.

 In the compound of the present invention, preferred compounds include

 1) a compound, wherein B is an oligodeoxyribonucleotide selected from the sequence TGGGGT, TGGGGGTT, TGGGGGT, TGGGGG, TGGGGG or TGGGGG;

2) R _{1 得} obtained by the combination of R ₂ , R ₃ , Y i and Z

5 ′ terminal group (R i Rs Rs Z —, triphenylmethyloxy, 3,4- (dibenzyloxy) benzyloxy, 3,51- (dibenzyloxy) benzyloxy, 3,5-bis [3,51- (dibenzyloxy) benzyl) / Reoxy] pendinoleoxy, t-butyldiphenylsilyl / reoxy, phenylfluoroxy, A phenylalanine hexane Saturation Ruo alkoxy _{group, R 4, X, Y 2} , Υ 3, Υ 4, 3 is obtained by a combination of m and eta 'end of the group ([[rho

_{(O) (Y 2 R 4} ) one _{Υ 3 - (X- Y 4)} n] m H), hydrogen, Mechiruhosuhoriru, 2-click throat Hue - Ruhosuhorinore, (O-methylcarbamoyl Honoré) Chiohosuhoriru, Mechiruhosuhoniru , Methylthiophosphonyl, pheninolephosphoninole, 2-hydroxyschinolephosphorinole, [O-

(2-Hydroxyshetyl)] Thiophosphoryl, Ferulphosphorinole, 41-Mouth Feninolephosphorinole, 2-Ethrophenolene Phosphorinole, 4-Nitrofeninolephosphorinole, Ethinole Phosphorinole, (O —Ethinole) Thiophosphorinole, 2— (2-Hydroxyshetinolephosphoryloxy) ethylphosphoryl, 2 -— [2- (2-Hydroxyshetinolephosphoryloxy) Ethinolephosphorinole] Ethinolephosphoryl group A compound wherein B is the oligodeoxyribonucleotide selected from the sequence TGGGGT, TGGGGTT, TGGG GGT, TGGG CG or TG GGTG,

Obtained by a combination of R _x , R ₂ , R ₃ ^ Y and Z

The 5 ′ terminal group (R i Rs Rg Z—Y i) is a triphenylmethyloxy, 3,4- (dibenzyloxy) benzyloxy, 3,5- (dibenzyloxy) benzyloxy group, and R ₄ , X, Y ₂ 3 ′ terminal group ([P (0) (Y ₂ R ₄ ) — — ₃ — (X—Y ₄ ) _n ] _m H) force 'hydrogen obtained by the combination of, Y ₃ , Y ₄ , m and η , Methinole phosphoryl, 2-black mouth phenole phosphorinole,

(O-methyl) thiophosphoryl, methylphosphoninole, methinorethiophosphoninole, feninolephosphoninole, 2-hydroxyhexynolephosphorinole, [O- (2-hydroxoxethyl)] thiophosphoryl, 2-

(2-Hydroxitytyl phosphoryloxy) ethyl phosphoryl, 2— [2- (2-hydroxyloxyphosphoryloxy) ethylphosphoryloxy] ethylphosphoryl group, and B is an oligodoxyribonucleotide selected from the sequence TGGG GT, TG GGGTT or TGG GGGT Compound,

4) R, R _2, R _3, obtained Ri by the combination of Y and Z 5 'end of the group (R ₁ R ₂ R ₃ Z- force 3, 4- (Jibenji Ruokishi) a Benjiruokishi group, R ₄ , X, Y ₂ , Υ ₃ , Υ 4, m and η, the 3 ′ terminal group ([Ρ

(O) (Y ₂ R ₄ ) -Y _3- (X—Υ ₄ ) _η ] _m Η), 2-hydroxydecynolephosphorinole, 2- (2-hydroxydecinolephosphoryloxy) Tylphosphorinole, 2- [2- (2-hydroxyphenylphosphorinoleoxy) ethynolephosphorinoleoxy] ethynolephosphoryl group, wherein Β is selected from the sequence TGGGG Τ, TGGGG Τ Τ or GGGGGGGG T A compound that is a nucleotide. Further, the compounds of the present invention listed in the following 5) and 6) are also suitable.

5) — General formula

[Wherein B represents oligodeoxyribonucleotide represented by the sequence TGGGG or TGGGGG, and _m represents 1, 2 or 3. However, in B, G is guanine deoxyribonucleotide, T represents thymine deoxyribonucleotide. Also, the hydroxyl groups at the 5 'end and 3' end of each oligodeoxyribonucleotide are not included. The left end of each sequence is the 5 'end, and the right end is the 3' end. A compound represented by the formula:

 6) General formula

[Wherein, B represents oligodeoxyribonucleotide represented by the sequence TGGGGAG, and m represents 2 or 3. However, in B, A indicates adenine deoxyribonucleotide, G indicates guaendeoxy ribonucleotide, and T indicates thymine deoxyribonucleotide. Also, the hydroxyl groups at the 5 'end and the 3' end of the oligodeoxyribonucleotide are not included. The left end of the sequence is the 5 'end and the right end is the 3' end. ] The compound represented by these.

 The compound having the general formula (1) of the present invention can be used in the form of a “pharmaceutically acceptable salt”. Examples of such a salt include sodium and potassium salts. Inorganic or organic salts such as alkaline metals such as calcium; alkaline earth metals such as calcium; ammonia; basic amino acids such as lysine and arginine; alkylamines such as triethylamine; Preferably, it is an alkali metal salt such as sodium or potassium.

In addition, the compound having the general formula (1) and a pharmacologically acceptable salt thereof may form a solvate in the production process or a hydrate during storage. The present invention also includes hydrates and hydrates. 99/19474

 14 As typical compounds of the present invention, for example, the compounds described in Table 1 can be mentioned, but the present invention is not limited to these compounds.

 In the table, Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl, tBu is t-butyl, 3,4-DBP is 3,4-mono (dibenzyloxy) fuel, 3, 5-BDBBP is 3,5-bis {3,5- (dibenzyloxy) benzyloxy} phenyl, 3,5-DBP is 3,5- (dibenzyloxy) phenyl, 1-PYR is pyrene-1-yl 2-NAP is naphthalene-1-yl, 4-PhPh is 4- (phenyl) phenyl, 2-PhPh is 2- (phenyl) phenyl, and 9-ANT is anthracene-9-yl 2-ANT is anthracene-1-yl, 1-NAP is naphthalene-1-yl, 2-ANQ is anthraquinone-12-yl, and 4-PHE is phenanthrene-14-yl. , PhE is 1,4-phenylene, 2-NH2Et is 2-aminoethyl, 2-MeOEt is 2-methoxethyl, and 1-Me-PrE is 1-methylpropyl. Pyrene, 2-Me-BuE is 2-methylbutylene, 2-0H-PrE is 2-hydroxypropylene, ① is TGGGGT, ② is TGGG GTT, (1 ^ ¾TGGGGGT, ④ is TGGGCG, ⑤ is TGGGTG , ⑥ indicates TGGGG, ⑦ indicates TGGGGG, ⑧ indicates TGGG AG.

 (table 1 )

Number Rl R2 R3 Z Yl Y2 R4 Y3 X Y4 n m

1 3, 4-DBP HCOO 0 CH2CH2 Oil 1 2 3, 4- DBP HCOS 0 CH2CH2 Oil 1 Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ

〇

o 〇 o

o o o o

ΐ. £ , 5-DBP HHCO CH2 H 0--0 ①, 5 DBP HHCO CH2 HS--0 ①, 5-DBP HHCO PhE H 0--0 ①, 5-DBP HHC 0 NH Pr 0 CH2CH2 0 1 ①, 5- DBP HHC 0 0 Me NH (CH2) 3 1 1 ①-MeOPh 4-MeOPh Ph COOH 0 CH2CH2 0 1 ①- MeOPh 4- MeOPh Ph COSH 0 CH2CH2 0 1 ①- MeOPh 4- MeOPh Ph CO-----0 ①-MeOPh 4-MeOPh Ph COO Me 0--0 ①-MeOPh 4-MeOPIi Ph COO Me S--0 ① MeOPh 4-MeOPh Ph COO 2 ClPh 0--0 ①- MeOPh 4- MeOPh Ph CO CH2 H 0 --0 ①- MeOPh 4- MeOPh Ph CO CH2 HS--0 ①- MeOPh 4- MeOPh Ph CO PhE H 0--0 ① MeOPh 4- MeOPh Ph CO NH Pr 0 CH2CH2 0 1 ①- MeOPh 4- MeOPh PCOO Me NH (CH2) 3 1 1 ①-MeOPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ①-MeOPh Ph Ph COSH 0 CH2CH2 0 1 ①--MeOPh Ph Ph CO-----0 ①- MeOPh Ph Ph C 0 0 Me 0--0 ①- MeOPh Ph Ph C 0 0 Me S--0 ①-MeOPh Ph Ph COO 2-ClPh 0--0 ①- MeOPh Ph Ph CO CH2 H 0--0 ①-MeOPh Ph Ph CO CH2 HS--0 ①-MeOPh Ph Ph CO PhE H 0--0 ①-MeOPh Ph Ph CO NH Pr 0 CH2CH2 0 1 ① oo

o o 〇

 〇 o o

Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ

81 4- BnOPh H H C O O Me 0--0 ①

82 4-BnOPh H H C O O Me S--0 ①

83 4-BnOPh H H C O O 2-ClPh 0--0 ①

84 4--BnOPh H II C 0 CH2 H 0--0 ①

85 4 BnOPh H H C 0 CH2 H S--0 ①

86 4-BnOPh H H C O PhE H 0--0 ①

87 4- BnOPh H H C 0 NH Pr 0 CH2CH2 0 1 ①

88 4 BnOPh H H C 0 0 Me NH (CH2) 3-1 ①

89 Ph Xan then-9-yl 0 0 H 0 CH2CH2 0 1 ①

90 Ph Xanthen-9-yl 0 S H 0 CH2CH2 0 1 ① 91 Ph Xanthen-9-yl 0-----0 ①

92 Ph Xanthen-9-yl 0 0 Me 0--0 ①

93 Ph Xanthen-9-y l 0 0 Me S--0 ①

94 Ph Xanthen-9-yl 0 0 2-ClPh 0--0 ①

95 Ph Xanthen-9-yl 0 CH2 H 0--0 ①

96 Ph Xanthen-9-yl 0 CH2 H S--0 ①

97 Ph Xanthen-9-yl 0 PhE H ■ 0--0 ①

98 Ph Xanthen-9-yl 0 NH Pr 0 CH2CH2 0 1 ①

99 Ph Xanthen-9-yl 0 0 Me NH (CH2) 3-1 ① 100 Ph Fluoren 9-yl 0 0 H 0 CH2CH2 0 1 ① 101 Ph Fluoren-9-yl 0 S H 0 CH2CH2 0 1 ①

102 Ph Fluoren-9-yl 0----0 ①

103 Ph Fluoren-9-yl 0 0 Me 0-0 ①

104 Ph Fluoren-9- yl 0 0 Me S--0 ①

105 Ph Fluoren-9-yl 0 0 2-ClPh 0--0 ①

106 Ph Fluoren-9-yl 0 CH2 H 0-one 0 ① 99/19474

 19

107 Ph Fluoren-9-y 10 CH2 II S-①

108 Ph Fluoren-9-y 1 0 PhE H 0 ①

109 Ph Fluoren-9-yl 0 NH Pr 0 CH2CH2 ①

110 Ph Fluoren-9-yl 0 0 Me NH (CH2) 3 ①

111 1-PYR HHC 0 0 H 0 CH2CH2 0 1 ① 112 1-PYR HHC 0 SH 0 CH2CH2 0 1 ① 113 1-PYR HHC 0--0 ① 114 1-PYR HH c 0 0 Me 0--0 ① 115 1-PYR HH c 0 0 Me S--0 ①

116 2-NAP H H c 0 0 H 0 CH2CH2 0 1 ①

117 2-NAP H H c 0 S H 0 CH2CH2 0 1 ①

118 2-NAP H H c 0--0 ①

119 2-NAP H H c 0 0 Me 0--0 ①

120 2-NAP H H c 0 0 Me S--0 ① 121 Ph Ph H c 0 0 H 0 CH2CH2 0 1 ①

122 Ph Ph H c 0 S H 0 CH2CH2 0 1 ①

123 Ph Ph H c 0--0 ①

124 Ph Ph H c 0 0 Me 0--0 ①

125 Ph Ph H c 0 0 Me S--0 ①

126 4-PhPh H H c 0 0 H 0 CH2CH2 0 1 ①

127 4-PhPh H H c 0 s H 0 CH2CH2 0 1 ①

128 4-PhPh H H c 0--0 ①

129 4-PhPh H H c 0 0 Me 0--0 ①

130 -PhPh HH c 0 0 Me S--0 ① 131 2-PhPh HH c 0 0 H 0 CH2CH2 0 1 ① 132 2-PhPh HH c 0 s H 0 CH2CH2 0 1 ① Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ Θ

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159 3, 4- DBP H H C O O H 0 CH2CH2 0 6 2 ①

160 3, 4- DBP H H c o o H 0 CH2CH2 0 6 3 ① 161 3, 4- DBP II H c o o H 0 CH2CH2 0 6 4 ①

162 3, 4- DBP H H c o o H 0 2-OH-PrE NH 1 ①

163 Ph Ph Ph C 0 NH Me 0 CH2CH2 0 1 ①

164 Ph Ph Ph C O O Ph 0-0 ①

165 Ph Ph Ph C O O 4-ClPh 0-0 ①

166 Ph Ph Ph C 0 NH 2-NH2Et 0 CH2CH2 0 1 ①

167 Ph Ph Ph C 0 NH 2-MeOEt 0 CH2CH2 0 1 ①

168 Ph Ph Ph C O S Me 0-0 ①

169 Ph Ph Ph C O S H 0-0 ①

170 Ph Ph Ph C O O H S CH2CH2 0 1 ① 171 Ph Ph Ph C CO O Et 0-0 ①

172 Ph Ph Ph C O O Et s-0 ①

173 Ph Ph Ph c o o Bu 0-0 ①

174 Ph Ph Ph c o o Bu s-0 ①

175 Ph Ph Ph c o o H 0 CH2CH2 0 6 ①

176 Ph Ph Ph c o o H 0 CH2CH2 0 6 2 ①

177 Ph Ph Ph c o o H 0 CH2CH2 0 6 3 ①

178 Ph Ph Ph c oo H 0 CH2CH2 0 6 4 ①

179 Ph Ph Ph c o o H 0 2-OH-PrE NH 1 1 ①

180 3, 5- DBP H H C 0 NH Me 0 CH2CH2 0 1 1 ① 181 3, 5- DBP H H c o o Ph 0-0 1 ①

182 3, 5-DBP H H coo 4-ClPh 0-0 1 ①

183 3, 5- DBP H H C 0 NH 2-NH2Et 0 CH2CH2 0 1 1 ①

184 3, 5-DBP HHC 0 NH 2-MeOEt 0 CH2CH2 0 1 1 ① idf., 3d6l〇Λν "

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289 3, 4-DBP H H C S CH2 H 0--0 ①

290 3, 4-DBP H H c s CH2 H S--0 ① 291 3, 4 -DBP H H c s Ph E H 0--0 ①

292 3, 4-DBP H H cs NH Pr 0 CH2CH2 0 1 ①

293 3, 4-DBP H Hcs 0 Me NH (CH2) 3-1 ①

294 9- ANT H H cs 0 H 0 CH2CH2 0 1 ①

295 9- ANT H H c s S H 0 CH2CH2 0 1 ①

296 9- ANT H H c s-0 ①

297 9- ANT H H cs 0 Me 0--0 ①

298 9- ANT H H cs 0 Me S--0 ①

299 9- ANT H H cs 0 2-C l Ph 0--0 ①

300 9- ANT H H c s CH2 H 0-0 ① 301 9- ANT H H c s CH2 H S--0 ①

302 9- ANT H H c s PhE H 0--0 ①

303 9- ANT I I H cs NH Pr 0 CH2CH2 0 1 ①

304 9 ANT H H cs 0 Me NH (CH2) 3-1 ①

305 2- NAP H H c s 0 H 0 CH2CH2 0 1 ①

306 2- NAP H H c s S H 0 CH2CH2 0 1 ①

307 2- NAP H H c s-0 ①

308 2- NAP H H c s 0 Me 0--0 ①

309 2- NAP H H c s 0 Me S--0 ①

310 2- NAP H H cs 0 2-C lPh 0--0 ① 31 1 2-NAP H H c s CH2 H 0--0 ①

312 2- NAP H H c s CH2 H S--0 ①

313 2- NAP H H c s PhE H 0--0 ①

314 2- NAP HH cs NH Pr 0 CH2CH2 0 1 ① 315 2-NAP II HCS 0 Me NH (CH2) 3-1 ①

316 BDBBP H H C S 0 H 0 CH2CH2 0 1 ①

317 BDBBP H H C S S H 0 CH2CH2 0 1 ①

318 BDBBP H H C S----0 ①

319 BDBBP H H C S O Me 0--0 ①

320 BDBBP H H C S O Me S--0 ① 321 BDBBP H H C S 0 2-ClPh 0--0 ①

322 BDBBP H H C S CH2 H 0--0 ①

323 BDBBP H H C S CH2 H S--0 ①

324 BDBBP H H C S PhE H 0--0 ①

325 BDBBP H H C S NH Pr 0 CH2CH2 0 1 ①

326 BDBBP H H C S 0 Me NH (CH2) 3-1 ①

327 3, 4-DBP H H C O O H 0 CH2CH2 0 1 ②

328 3, 4-DBP H H C O S H 0 CH2CH2 0 1 ②

329 3, 4-DBP H H C O-----0 ②

330 3, 4-DBP H H C O O Me 0--0 ② 331 3, 4-DBP H H C O O Me S--0 ②

332 3,4-DBP H H C O O 2-ClPh 0--0 ②

333 3, 4-DBP H H C 0 CH2 H 0--0 ②

334 3, 4-DBP H H C 0 CH2 H S —-0 ②

335 3,4-DBP H H C O PhE H 0--0 ②

336 3, 4-DBP H H C 0 NH Pr 0 CH2CH2 0 1 ②

337 3, 4-DBP H H C 0 0 Me NH (CH2) 3-1 ②

338 Ph Ph Ph C 0 0 H 0 CH2CH2 0 1

339 Ph Ph Ph C O S H 0 CH2CH2 0 1 ②

340 Ph Ph Ph C 0---0 0 ② ® Θ ® ® Θ ® (§} @) (§) Θ ί§) (§) @) © (§) ® (§) (§) (§) @) ® (§) (§) (§) © (§)

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367 4-MeOPh 4-MeOPh Ph C 0 CH2 H S--0

368 4-MeOPh 4-MeOPh Ph C O PhE H 0--0 ②

369 4 MeOPh 4-MeOPh Ph C 0 NH Pr 0 CH2CH2 0 1 ②

370 4-MeOPh 4-MeOPh Ph C 0 0 Me NH (CH2) 3-1 ② 371 4 MeOPh Ph Ph C O 0 H 0 CH2CH2 0 1 ②

372 4 -MeOPh Ph Ph C O S H 0 CH2CH2 0 1

373 4 MeOPh Ph Ph C 0-0

374 4-MeOPh Ph Ph C 0 0 Me 0--0 ②

375 4-MeOPh Ph Ph C O 0 Me S--0 ②

376 4 MeOPh Ph Ph C O 0 2-ClPh 0--0 ②

377 4- MeOPh Ph Ph C 0 CH2 H 0--0 ②

378 4- MeOPh Ph Ph C O CH2 H S--0 ②

379 4-MeOPh Ph Ph C 0 PhE H 0--0 ②

380 4- MeOPh Ph Ph C O H Pr 0 CH2CH2 0 1 381 4-MeOPh Ph P C 0 0 Me NH (CH2) 3-1

382 tBu Ph Ph Si 0 0 H 0 CH2CH2 0 1

383 tBu Ph Ph Si 0 S H 0 CH2CH2 0 1

384 tBu Ph Ph Si 0-0 ②

385 tBu Ph Ph Si 0 0 Me 0--0 ②

386 tBu Ph Ph Si 0 0 Me S--0 ②

387 tBu Ph Ph Si 0 0 2-ClPh 0--0 ②

388 tBu Ph Ph Si 0 CH2 H 0--0 ②

389 tBu Ph Ph Si 0 CH2 HS--0 ② 390 -tBu Ph Ph Si 0 PhE H 0--0 391 tBu Ph Ph Si 0 NH Pr 0 CH2CH2 0 1 392 tBu Ph Ph Si 0 0 Me NH (CH2) 3 One one ② ΐ 0-0 0 .Md 81 ② 0 0-0-② ΐ 0 0 HS 0-Md 9 ⑤ I 0 0 Η 0 0-.6-USI ^ UBX Md 9 \ f

② ΐ 0 2HD2H3 0 d HN 0 0 H dO'JO-i 'ε ② 0--0 H 3Md 0 0 H ^L idoug- zif ② 0--SH ZHO 03 H qdo ^u oi? Π ② 0--0 H ZHD 0 3 H MdOUO-i '0 ② 0--0 ^ ά \ ^-Z 0 0 3 H doug-ef ⑧ 0--S 9W 0 0 3 H Lidoug-sof ⑤ 0--0 9W 0 0 0 H MdO'JO-t 'LOf ② 0-0 0 H MdOUQ- ^ 90

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② ΐ 0 ZHDZUD 0 HS 0 3 H MdOU8-i ', ② ΐ 0 0 H 0 0 3 H MdO u Ot- ② 1 - (. ΖΗ) ε ΗΝ S W 0 S 3 Md Md εο ⑧ ΐ 0 ZHDZH3 0 Jd HN S 3 Md ZO

0--0 H 3Md S 3 ηό Md Ϊ0

② 0--SH 2H3 S 3 Md Md 00 ^ ② 0--0 H ZH3 SD d 66G 0--0 MdID-2 0 SD Md Md 86 £ 0--S ^a W 0 S 3 qd Md L6

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② ΐ 0 ZHDZHD 0 S 3 ^l ld Md (-6C ΐ 0 ZHDZ D 0 H 0 S 3 Md οε

SZ9tO / 86df / IDd 419 Ph Xan then-9- y 丄 0 0 Me S--0 ②

420 Ph Xanthen-9-yl 0 0 2-ClPh 0--0 ② 421 Ph Xanthen 9-yl 0 h 12 H 0--0 ②

422 Ph Xant en-9-y 1 0 CH2 H S--0 ②

423 Ph Xanthen-9-y 10 PhE H 0--0 ②

424 Ph Xanthen-9- y l 0 NH Pr 0 CH2CH2 0 1 ②

425 Ph Xanthen-9-yl 0 0 Me NH (CH2) 3-1 ②

426 Ph Fluoren- 9-yl 0 0 H 0 CH2CH2 0 1 ②

427 Ph Fluoren- 9-y l 0 S H 0 CH2CH2 0 1 ②

428 Ph Fluoren- 9-yl 0--0 ②

429 Ph Fluoren-9-yl 0 0 Me 0--0 ②

430 Ph Fluoren-9-yl 0 0 Me S--0 431 Ph Fluoren-9-yl 0 0 2-ClPh 0--0 ②

432 Ph Fluoren-9-yl 0 CH2 H 0--0

433 Ph Fluoren-9-yl 0 CH2 H S--0

434 Ph Fluoren-9-y l 0 PhE H 0--0 ②

435 Ph Fluoren-9-yl 0 NH Pr 0 CH2CH2 0 1 ②

436 Ph Fluoren-9-yl 0 0 Me NH (CH2) 3-1 ② 437 1-PYR HHC 0 0 H 0 CH2CH2 0 1 ② 438 1-PYR HC 0 s H 0 CH2CH2 0 1 ② 439 1-PYR HC 0 --0 ② 440 1-PYR H c 0 0 Me 0--0 441 1-PYR H c 0 0 Me S--0

442 2-NAP H c 0 0 H 0 CH2CH2 0 1

443 2- NAP H c 0 s H 0 CH2CH2 0 1 ②

444 2--NAP H c 0 1-0 0 445 2- NAP HHC 0 0 Me 0--0 1 ②

446 2- NAP H H C 0 0 Me S--0 1

447 Ph Ph H C 0 0 H 0 CH2CH2 0 1 1 ②

448 Ph Ph H C 0 S H 0 CH2CH2 0 1 1

449 Ph Ph H C 0-0 0

450 Ph Ph H C 0 0 Me 0--0 1 451 Ph Ph H C 0 0 Me S--0 1

452 4-PhPh H H C 0 0 H 0 CH2CH2 0 1 1 ②

453 4- PhPh H H C 0 S H 0 CH2CH2 0 1 1 ②

454 4- PhPh H H C 0-0 0 ②

455 4-PhPh H H C 0 0 Me 0--0 1 ②

456 4-PhPh H H C 0 0 Me S--0 1 ②

457 2- PhPh H H C 0 0 H 0 CH2CH2 0 1 1 ②

458 2- Ph Ph H H C 0 S H 0 CH2CH2 0 1 1 ②

459 2-Ph Ph H H C 0-0 0 ②

460 2- PhPh H H C 0 0 Me 0--0 1 ② 461 2-PhPh H H C 0 0 Me S--0 1 ②

462 Ph Ph H cs 0 H 0 CH2CH2 0 1 1 ②

463 Ph Ph H c s S H 0 CH2CH2 0 1 1 ②

464 Ph Ph H c s-0 0

465 Ph Ph H c s 0 Me 0--0 1

466 Ph Ph H c s 0 Me S--0 1 ②

467 Ph Ph Ph C NH 0 H 0 CH2CH2 0 1 1 ②

468 Ph Ph Ph C NH S H 0 CH2CH2 0 1 1 ②

469 Ph Ph Ph C NH-0 0 ②

470 Ph Ph Ph C NH 0 Me 0 0 1 ② Δ 6/66 OAV

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Ζ 9 0 0 H 0 0 3 H daa- '6I S ΐ 9 0 ZH3ZHD 0 H 0 0 D H H doa-' C 8Ϊ 9 ΐ 0-S ng 0 0 0 H H daa- 'ε ΐ 9

② ΐ 0-0 "a 0 3 H H daa- 'ε 919 ② 2 Τ 0-S ^ 3 0 3 H H d9a' ε s i 9 I 0-0 13 0 0 3 H H doa- 'e

② ΐ ΐ 0 Z OZHD SH 0 0 3 HH dea- 'ε ε τ ο ⑤ 1 0-0 HS 0 3 HH daa-' ε ζ ΐ ② ΐ 0-0 9W S 0 3 HH doa- 'e ns ② ΐ ΐ 0 2H3ZH3 0 HN 0 DHH doa- 'ε 01 ② ΐ ΐ 0 0 HN 0 3 HH daa-' ε 609 ② ΐ 0-0 MdTD-i '0 0 3 HH d8a-' ε 809 ② ΐ 0-0 Md 0 0 0 HH daa- 'ε ο ⑧ ΐ ΐ 0 0 aw HN 0 3 HH daa-' ε 90S ② ΐ ΐ ΗΝ 0 H 0 0 3 Md Hd Md 90S ② f 9 0 0 H 0 0 0 Md Md Md ίΌ9 ε 9 ο 0 H 0 0 3 Md d Md SOS

2 9 0 0 H 0 0 D ^ ό Md

② ΐ 9 0 ZtiDZWD 0 H 0 0 3 Md ^ ό ^l ld 109 ② I 0-S no 0 3 Md i | d OOS ⑤ ΐ 0-0 "9 0 0 3 ^l Id ^ d 66f ΐ 0-S 13 0 0 3 Md Md Md 86 ^

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SCTtO / 86 <U7 丄 :) d 1 ^^ 61/66 O 523 4-MePh Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

524 4-MePh 4-MePh Ph C O O H 0 CH2CH2 0 1 ②

525 4-MePh 4-MePh 4-MePh C O O H 0 CH2CH2 0 1 ②

526 4-tBuPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

527 4-tBuPh 4- tBuPh Ph C 0 0 H 0 CH2CH2 0 1 ②

528 4- t'BuPli 4 tBuPh 4-tBuPh C O O H 0 CH2CH2 0 1 ②

529 4-N02P Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

530 4 -Hide Ph 4-N02Ph Ph C O O H 0 CH2CH2 0 1 ② 531 4-FPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

532 4-FPh 4-FPh Ph C 0 0 H 0 CH2CH2 0 1 ②

533 2, 4-F2Ph Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

534 2-ClPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

535 4- ClPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

536 4-ClPh 4-ClPh Ph C O O H 0 CH2CH2 0 1 ②

537 4-BrPh P Ph C 0 0 H 0 CH2CH2 0 1 ②

538 4-BrPh 4-BrPh Ph C O O H 0 CH2CH2 0 1 ②

539 4-IPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

540 4-tBuOPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ② 541 -EtOPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ②

542 4-EtOPh 4-EtOPh Ph C 0 0 H 0 CH2CH2 0 1

543 2-BnOPh H H C O O H 0 CH2CH2 0 1 ②

544 4-BnOPh Ph Ph C 0 0 H 0 CH2CH2 0 1

545 4-BnOPh 4-BnOPh Ph C O O H 0 CH2CH2 0 1

546 4-MeOPh 4-MeOPh 4-MeOPh C O O H 0 CH2CH2 0.1 ②

547 9-ANT H H C O O H 0 CH2CH2 0 1 ②

548 2— ANT HHC 0 0 H 0 CH2CH2 0 1 ② ② ΐ 0 6 (ΖΗ) 0 Η 0 0 3 HH dea-fr '£ ② t 0 8 (ΖΗ0) 0 Η 0 0 3 HH daa-t-' e ② ΐ 0 Ζ (2Η3) 0 Η 0 0 0 HH daa-fr 'ε gzg ΐ 0 9 (ΖΗ0) 0 Η 0 0 0 HH d -f' £ TZQ

⑤ ΐ 0 9 (2Η3) 0 Η 0 0 0 HH Class-'ε ο ② ΐ 0 ί- (2Η3) 0 Η 0 0 0 H Η dQQ-f' ε 69g ② 1 0 0 Η 0 0 3 H Η daa -t- 'ε 89 ⑤ 0-0 dOia-fr 0 0 3 H Η dea-t' ε 9s 0-0 0 0 3 H Η doa-fr 'ε 999 0-0 Md09W-i- 0 0 3 H- dM '' £ 99S

③ 0-0 I-Z 0 0 0 H Η daa- ^ 'ε t-99 0-o 0 0 3 H Η dOa-i' 'C S99 0-0 άά-Ζ 0 0 D H Η 删-' ε Z9S

⑤ 0-0 MdZON-i '0 0 3 H Η doa-fr' ε ΐ99 ② 0-o zon-z 0 0 3 H Η dOa-t '' C 099 ② Ζ 0 0 HSODH Η dOa- ^ 'C 659 ② Ζ 0 0 H 0 0 3 H Η daa-t '' ε 8 S ② 9 0 0 ^ ring-2 HN 0 3 H Η dQQ-f 'ε Z.9S

9 0 0 Jd HN 0 0 H Η daa-t- 'ε 939

9 0 ΖΗΟΖΗΟ 0 ¾3 HN 0 3 H Η dea -i '' ε ggg

② 9 0 0 HS 0 3 H Η dsa-t- 'ε i-gg ② ΐ 0 0 H 0 0 〇 H Η 3Hd-fr £ 99 ② ΐ 0 2HDZH3 0 H 0 0 3 H Η DNV-Z 299 ΐ 0 0 H 0 0 3 H Η dOMd-i '199

⑤ ΐ 0 ZViOZWd 0 H 0 0 3 H Η MdOMd-e 0S9 ② ΐ 0 0 H 0 0 3 H Η dVN-I 6 S

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601 3, 4-DBP H H C 0 NH Pr 0 (CH2) 7 0 1 ②

602 3, 4-DBP H H C O Nil Pr 0 (CH2) 8 0 1 ②

603 3, 4-DBP H H C 0 NH Pr 0 (CH2) 9 0 1

604 3, 4-DBP H H C 0 NH Pr 0 (CH2) 10 0 1 ②

605 3, 4-DBP H H C 0 NH Pr 0 CH2CH (CH3) 0 1 ②

606 3, 4-DBP H H C 0 NH Pr 0 1-Me-PrE 0 1

607 3, 4-DBP H H C 0 NH Pr 0 2-Me-BuE 0 1

608 Ph Ph P C NH 0 H 0 CH2CH2 0 6

609 3, 4-DBP H H C S 0 H 0 CH2CH2 0 1 ②

610 3, 4-DBP H H C S S H 0 CH2CH2 0 1 ② 611 3, 4-DBP H H C S---0

612 3, 4-DBP H H C S 0 Me 0--0 ②

613 3, 4-DBP H H C S 0 Me S-0

614 3, 4-DBP H H C S 0 2-ClPh 0--0

615 3, 4-DBP H H C S CH2 H 0--0

616 3, 4-DBP H H C S CH2 H S--0 ②

617 3, 4-DBP H H C S P E H 0--0

618 3, 4-DBP H H C S NH Pr 0 CH2CH2 0 1

619 3, 4-DBP H H C S 0 Me NH (CH2) 3-1 ②

620 9-ANT H H C S 0 H 0 CH2CH2 0 1 ② 621 9-ANT H H C S S H 0 CH2CH2 0 1 ②

622 9-ANT H H C S---0

623 9-ANT H H C S 0 Me 0--0

624 9-ANT H H C S 0 Me S--0 ②

625 9- ANT H H C S 0 2-ClPh 0--0 ②

626 9 1 ANT HHCS CH2 H 0 1 1 0 ② 627 9-ANT HHCS CH2 HS--0

628 9 ANT H H c s PhE H 0-0 ②

629 9-ANT H H cs NH Pr 0 CH2CH2 0 1 ②

630 9-ANT H H cs 0 Me NH (CH2) 3 ② 631 2-NAP H H cs 0 H 0 CH2CH2 0 1 ②

632 2- NAP H H c s S H 0 CH2CH2 0 1 ②

633 2- NAP H H c s-0 ②

634 2-NAP H Hcs 0 Me 0--0 ②

635 2- NAP H H c s 0 Me S--0 ②

636 2- NAP H H c s 0 2-C l Ph 0--0 ②

637 2- NAP H H c s CH2 H 0--0 ②

638 2-NAP H H c s CH2 H S--0 ②

639 2-NAP H H c s PhE H 0--0 ②

640 2-NAP H H cs NH Pr 0 CH2CH2 0 1 ② 641 2-NAP H H cs 0 Me NH (CH2) 3 1 ②

642 BDBBP H H c s 0 H 0 CH2CH2 0 1

643 BDBBP H H c s S H 0 CH2CH2 0 1

644 BDBBP H H c s-0

645 BDBBP H H c s 0 Me 0--0

646 BDBBP H H c s 0 Me S--0 ②

647 BDBBP H H c ss 0 2-Cl Ph 0--0 ②

648 BDBBP H H c s CH2 H 0--0 ②

649 BDBBP H H c s CH2 H S--0 ②

650 BDBBP HH cs PhE H 0--0 ② 651 BDBBP HH cs NH Pr 0 CH2CH2 0 1 652 BDBBP HH cs 0 Me NH (CH2) 3 1 1

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i 679 3, 5-DBP HHCOO Me S--0

680 3, 5-DBP H H C O O 2- ClPh 0--0 ③ 681 3,5-DBP H H C 0 CH2 H 0--0 ③

682 3, 5-DBP H H C O CH2 H S--0 ③

683 3,5-DBP H H C O PhE H 0 —-0 ③

684 3, 5-DBP H H C 0 NH Pr 0 CH2CH2 0 1 ③

685 3, 5-DBP H H C 0 0 Me NH (CH2) 3 ― 1 ③

686 4 MeOPh 4-MeOPh Ph C O O H 0 CH2CH2 0 1 ③

687 4-MeOPh 4-MeOPh Ph C O S H 0 CH2CH2 0 1 ③

688 4-MeOPh 4-MeOPh Ph C O-----0 ③

689 4-MeOPh 4-MeOPh Ph C 0 0 Me 0--0 ③

690 4- MeOPh 4- MeOPh Ph C 0 0 Me S--0 ③ 691 4- MeOPh 4- MeOPh Ph C O O 2- ClPh 0--0 ③

692 4-MeOPh 4- MeOPh Ph C O CH2 H 0--0 ③

693 4-MeOPh 4- MeOPh Ph C O CH2 H S--0 ③

694 4- MeOPh 4- MeOPh Ph C O PhE H 0--0 ③

695 4-MeOPh 4-MeOPh Ph C 0 NH Pr 0 CH2CH2 0 1 ③

696 4-MeOPh 4-MeOPh Ph C O O Me NH (CH2) 3-1 ③

697 4-MeOPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ③

698 4- MeOPh Ph Ph C O S H 0 CH2CH2 0 1 ③

699 4-MeOPh Ph Ph C O-----0 ③

700 4-MeOPh Ph Ph C 0 0 Me 0--0 ③ 701 4-MeOPh Ph Ph C 0 0 Me S--0 ③

702 4- MeOPh Ph Ph C O O 2-ClPh 0--0 ③

703 4-MeOPh Ph Ph C 0 CH2 H 0--0 ③

704 4— MeOPh Ph Ph CO CH2 HS-1 0 ③ ooo a-

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Stupid 731 4-BnOPh HHC 0 s H 0 CH2CH2 0 1 1 ③

732 4-Bn oOPh H H C 0--one--0 0 ③

733 H H c 0 0 Me 0--0 1 ③

734 4-BnOPh H H c 0 0 Me S-― 0 1 ③

735 4-BnOPh H H c 0 0 2-ClPh 0--0 1 ③

736 4-BnOPh H H c 0 CH2 H 0 one ― 0 1 ③

737 4- BnOPh H H c 0 CH2 H s-― 0 1 ③

738 4-BnOPh H H c 0 PhE H 0 one-0 1 ③

739 4-BnOPh H H c 0 NH Pr 0 CH2CH2 0 1 1 ③

740 4-BnOPh H H c 0 0 Me NH (CH2) 3 ― 1 1 ③

741 Ph Xanthen-9-yl 0 0 H 0 CH2CH2 0 1 1 ③

742 Ph Xanthen-9 yl 0 S H 0 CH2CH2 0 1 1 ③

743 Ph Xanthen-9-yl 0-----0 0 ③

744 Ph Xanthen-9-yl 0 0 Me 0--0 1 ③

745 Ph Xanthen-9-y l 0 0 Me s--0 1 ③

746 Ph Xanthen-9-yl 0 0 2-ClPh 0--0 1 ③

747 Ph Xanthen-9 yl 0 CH2 H 0--0 1 ③

748 Ph Xanthen-9-yl 0 CH2 H s-― 0 1 ③

749 Ph Xanthen-9- yl 0 PhE H 0--0 1 ③

750 Ph Xanthen-9 yl 0 NH Pr 0 CH2CH2 0 1 1 ③

751 Ph Xanthen-9-yl 0 0 Me NH (CH2) 3 ― 1 1 ③

752 Ph Fluoren-9-yl 0 0 H 0 CH2CH2 0 1 1 ③

753 Ph Fluoren-9-yl 0 S H 0 CH2CH2 0 1 1 ③

754 Ph Fluoren- 9-yl 0 0 0 ③

755 Ph Fluoren-9-yl 0 0 Me 0 0 1 ③

756 Ph Fluoren-9 yl 0 0 Me S 0 1 ③ 757 Ph Fluoren-9- -yl 0 0 2-ClPh 0 0 1 ③-

758 P F 丄 uoren— 9- -yl 0 CH2 H 0 one 0 1 ③

759 Ph Fl uoren-9- -y l 0 CH2 H S-0 1 ③

760 Ph Fluoren-9- -y l 0 PhE H 0 1 0 1 ③

761 Ph Fluoren-9- -yl 0 NH Pr 0 CH2CH2 0 1 1 ③

762 Ph Fluoren-9- -y l 0 0 Me NH (CH2) 3 ― 1 1 ③

763 H II c 0 0 H 0 CH2CH2 0 1 1 ③

764 H H c 0 S H 0 CH2CH2 0 1 1 ③

765 H H c 0---― 0 0 ③

766 H H c 0 0 Me 0-― 0 1 ③

767 H H c 0 0 Me s-― 0 1 ③

768 2-NAP H H c 0 0 H 0 CH2CH2 0 1 1 ③

769 2-NAP H H c 0 s H 0 CH2CH2 0 1 1 ③

770 2-NAP H H c 0-----0 0 ③

771 2-NAP H H c 0 0 Me 0-― 0 1 ③

772 2-NAP H H c 0 0 Me s--0 1 ③

773 Ph Ph H c 0 0 H 0 CH2CH2 0 1 1 ③

774 Ph Ph H c 0 s H 0 CH2CH2 0 1 1 ③

775 Ph Ph H c 0-----0 0 ③

776 Ph Ph H c 0 0 Me 0 ― ― 0 1 ③

777 Ph Ph H c 0 0 Me s ― 0 1 ③

778 4-PhPh H H c 0 0 H 0 CH2CH2 0 1 1 ③

779 4-PhPh H H c 0 s H 0 CH2CH2 0 1 1 ③

780 4-PhPh H H c 0 0 0 ③

781 4 ~ PhPh H H c 0 0 Me 0 0 1 ③

782 4-PhPh HH c 0 0 Me s 0 1 ③ 3ϋ; 3d

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0- U Q- CU C

⑥ ΐ 0 0 0 0 0 H H doa--s' c s

⑤ ΐ 0 _ 0 Hd 0 0 0 H H doa- -s' ε

⑧ ΐ ΐ 0 0 s _W HN 0 3 HH dea- -g 'ε Z £ 8

⑧ Τ τ ΗΝ 3 d- HO-Z 0 H 0 0 D d Md IC8

⑥ 9 0 SHOZHD 0 H 0 0 3 Md lid 0C8

⑧ ε 9 0 0 H 0 0 3 Md Md Md 6Z8

⑧ ζ 9 0 0 H 0 0 0 Hd Md SZ8

⑥ ΐ 9 0 0 H 0 0 D Md Md ^ d LZS

⑥ τ 0 1 1 S 19 0 0 0 Md Md Md 928

Τ τ 0 1 1 0 "8 0 0 0 Md ^ ά Md ZS

⑧ τ 0 ― _ S 13 0 0 D Md d qd U

Τ τ 0 ― 0 53 0 0 0 ^l ! D Md Z8

⑧ ΐ ΐ 0 SH 0 0 3 4d Md ^l id ZZ8

⑧ τ 0 0 H S 0 0 Md Md IZ8

⑧ I 0 0 S 0 D Md Md Md 0Z8

Τ τ ΐ 0 0 HN 0 D Md Md Md 618

⑥ ΐ ΐ 0 0 HN 0 d Md 4d Md 818

⑧ ι 0 0 0 0 D ild Md Md LIS

⑧ ΐ 0 0 Md 0 0 D Md Md Md 918

Τ τ I 0 ZHDSHD 0 a _W H 0 D Hd [ld t | d gi8

Id ΐ ι ΗΝ 3-id-HO-Z 0 H 0 0 3 H II doa--i, 'H8

V 9 u (JHJOHJ u H 0 J H H dHQ- -V ί CI8

⑧ ε 9 0 0 H 0 0 3 H H doa- -f 'ε ZIS

⑧ ζ 9 0 0 H 0 0 3 H H daa--'ε Π8

⑧ I 9 0 0 H 0 0 3 H H daa- -y 'z 0Ϊ8

⑧ ι 0 s ng 0 0 3 H H daa 'ε 608

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SZ9tO / 86df / 13d f .f6l / 66 O 835 3,5-DBP HHC 0 H 2-NH2 Et 0 CH2CH2 0 1 1 ③

836 3, 5-DBP H H C 0 NH 2-MeOEt 0 CH2CH2 0 1 1 ③

837 3, 5-DBP H H C 0 S Me 0-0 1

838 3, 5-DBP H H C 0 S H 0-0 1 ③

839 3, 5-DBP H H C 0 0 H S CH2CH2 0 1 1 ③

840 3,5-DBP H H C 0 0 Et 0-0 1 ③ 841 3,5-DBP H H C 0 0 Et S-0 1 ③

842 3, 5-DBP H H C 0 0 Bu 0-0 1 ③

843 3, 5-DBP H H C 0 0 Bu S-0 1 ③

844 3,5-DBP H H C 0 0 H 0 CH2CH2 0 6 1 ③

845 3, 5-DBP H H C 0 0 H 0 CH2CH2 0 6 2 ③

846 3, 5-DBP H H C 0 0 H 0 CH2CH2 0 6 3 ③

847 3,5-DBP H H C 0 0 H 0 CH2CH2 0 6 4 ③

848 3,5-DBP H H C 0 0 H 0 2-OH-PrE NH 1 ③

849 4-MePh Ph Ph C 0 0 H 0 CH2CH2 0 1 ③

850 4-MePh 4-MePh Ph C 0 0 H0 CH2CH2 0 1 ③ 85 1 4-MePh 4-MePh 4-MePh C 0 0 H0 CH2CH2 0 1 ③

852 4- tBuPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ③

853 4-t Bu Ph 4-tBuPh Ph C 0 0 H 0 CH2CH2 0 1 ③

854 4- t Bu Ph 4-tBuPh 4-tBuPh C 0 0 H 0 CH2CH2 0 1 ③

855 4-N02 PH Ph Ph C 0 0 H 0 CH2CH2 0 1 ③

856 4-N02Ph 4- N02Pli Ph C 0 0 H 0 CH2CH2 0 1 ③

857 4-FPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ③

858 4-FPh 4-FPh Ph C 0 0 H 0 CH2CH2 0 1 ③

859 2, 4- F2Ph Ph Ph C 0 0 H 0 CH2CH2 0 1

860 2-ClPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ③ O

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wo ZW z 887 3, 4-DBP 11 HCOO 4-Free Ph 0-0 ③

888 3, 4-DBP H H c o o 2-FP 0-0 ③

889 3, 4-DBP H H c o o 2-BrPh 0-0 ③

890 3, 4-DBP H H coo 2-IPh 0-0 ③ 891 3, 4-DBP H H coo 4 MeOPh 0-0 ③

892 3, 4-DBP H H coo 4- eSPh 0-0 ③

893 3, 4-DBP H H coo 4-EtOPh 0-0 ③

894 3, 4-DBP H H c o o H 0 CH2) 3 0 1 ③

895 3, 4-DBP H H c o o H 0 CH2) 4 0 1

896 3, 4-DBP H H c o o H 0 CH2) 5 0 1 ③

897 3, 4-DBP H H c o o H 0 CH2) 6 0 1 ③

898 3, 4-DBP H H c o o H 0 CH2) 7 0 1 ③

899 3, 4-DBP H H c o o H 0 CH2) 8 0 1 ③

900 3, 4-DBP H H c o o H 0 CH 2) 9 0 1 ③ 901 3, 4-DBP H H c o o H 0 CH 2) 10 0 1 ③

902 3, 4-DBP H H c o o H 0 CH2CH (CH3) 0 1 ③

903 3 '4-DBP H H c o o H 0 -Me-PrE 0 1 ③

904 3, 4-DBP H H c o o H 0 -Me-BuE 0 1 ③

905 3, 4-DBP H H C O S H 0 CH2) 3 0 1 ③

906 3, 4-DBP H H C O S H 0 CH2) 4 0 1 ③

907 3, 4-DBP H H C O S H 0 CH2) 5 0 1 ③

908 3, 4-DBP H H C O S H 0 CH2) 6 0 1 ③

909 3, -DBP H H C O S H 0 CH2) 7 0 1 ③

910 3 '4-DBP HHCOSH 0 CH2) 8 0 1 ③ 911 3, 4-DBP HHCOSH 0 CH2) 9 0 1 ③ 912 3, 4-DBP HHCOSH 0 C 2) 10 0 1 ③ ⑤ T 0 0 0 S 3 HH dea-f '' ε 8S6

⑧ 0 0---_ one S 3 H H daa-i '' e ZC6

⑧ ΐ ΐ 0 0 H S S 3 H H d -f 'ε 9S6

⑧ ΐ ΐ 0 ΖΗΟΖΗΟ 0 H 0 S 3 H H daa-i '' ε 9 £ 6

⑧ ΐ 9 0 0 H 0 HN 3 Md Md Md H6

⑧ I ΐ 0 0 d HN 0 3 H H daa-t '' c Z6

⑤ I ΐ 0 I 0 HN 0 d H H daa-i '' G ZZ6

⑧ ΐ ΐ 0 (SHD) HOZHO 0 HN 0 D H H daa-i- 'ε IC6

⑧ ί τ 0 0Τ (2Η3) 0 Jd HN 0 3 H H daa-i '' z 0C6

⑧ ΐ ΐ 0 6 (2Η3) 0 Jd HN 0 3 H H doa-t '' e 626

⑧ ΐ ΐ 0 8 (2Η3) 0 -td HN 0 0 H H daa- ^ 'z SZ6

⑧ ΐ ΐ 0 Ζ (ΖΗΟ) 0id HN 0 3 H H daa-i '' G LZ6

⑥ I ΐ 0 9 (2Η3) 0id HN 0 D H H 926

⑧ I I 05 (2Η3) 0 d HN 0 3 H H daa-fr 'ε 9Z6

⑧ I I 0 (ZUD) 0id id 0 D H H daa '' c fZ6

⑧ I ΐ 0 £ (ΖΗΟ) 0 HN 0 D H H dm-f '£ G26

⑥ I ΐ 0 ε (Η) 0 Md HN 0 3 H H dga- 'ε ZZ6

⑥ ΐ ΐ 0 ε (2Η3) 0 HN 0 3 H H dm-f 'IZ6

⑧ ΐ ΐ 0 ζ (ζηο) 0 HN 0 0 H H daa-f- 'ε 026

⑧ ΐ ΐ 0 0 d HN 0 3 H II daa-i- 'c 616

⑧ 1 I 0 C (2HO) 0 HN 0 3 H H 816 τ τ o;

⑧ I ΐ 0 0 Md HN 0 D H H daa-i '' e 9Ϊ6

⑧ ΐ ΐ 0 0 H S 0 D H H daa-i '' ε 916

⑧ ΐ ΐ 0 0 H S 0 D H H dga-t '' z H6

⑧ ΐ ΐ 0 (εΗ3) Η02Η3 0 H S 0 D H H daa-i '' ε £ 16

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SWtO / 86df / X3d ^ 6l / 66 O 939 3 4-DBP HHCS 0 Me S-0 ③

940 3 4-DBP H H c s 0 2-C l Ph 0-0 ③ 941 3 4-DBP H H c s CH2 H 0-0 ③

942 3 4-DBP H G I cs CH2 H S--0 ③

943 3 4-DBP H H c s PhE H 0--0 ③

944 3 4-DBP H H cs NH Pr 0 CH2CH2 0 1 ③

945 3 _; 4-DBP HH cs 0 Me NH (CH2) 3-1 ③

946 9- ANT H H cs 0 H 0 CH2CH2 0 1 ③

947 9 ANT H H c s S H 0 CH2CH2 0 1 ③

948 9- ANT H H c s-0 ③

949 9-ANT H H cs 0 Me 0-0 ③

950 9- ANT H H cs 0 Me S-0 ③ 951 9- ANT H H cs 0 2-Cl Ph 0-0 ③

952 9- ANT H H c s CH2 H 0-0 ③

953 9- ANT H H cs CH2 H S--0 ③

954 9- ANT H H c s PhE H 0--0 ③

955 9- ANT II H cs NH Pr 0 CH2CH2 0 1 ③

956 9-ANT H H cs 0 Me NH (CH2) 3-1 ③

957 2-NAP H H c s 0 H 0 CH2CH2 0 1 ③

958 2- NAP H H c s S H 0 CH2CH2 0 1 ③

959 2- NAP H H c s-0 ③

960 2- NAP H H cs 0 Me 0--0 ③ 961 2- NAP H H cs 0 Me S--0 ③

962 2- NAP H H c ss 0 2-C l Ph 0--0 ③

963 2- NAP H H c s CH2 H 0--0 ③

964 2- NAP HH cs CH2 HS-1 0 ③ ® ΐ ΐ 0 ZUDZHD 0 H 0 0 0 Md Md Md 066

® ΐ ΐ-£ (ZWO) HN 0 3 H H aaa-t '' ε 686

® ΐ τ 0 ZHdZtiD 0 HN 0 0 H H dSa-t '' £ 886

® ΐ 0--0 H 3Md 0 0 H H daa-ε 86

® ΐ 0--S H Z O 0 D H H daa-fr 'e 986

® ΐ 0 ― ― 0 H ZH3 0 3 H H daa-t '' ε 986

© I 0--0 0 0 3 H H doa-t '' ε

® I 0-― s 0 0 D H H doa-t 'ε S86

® ΐ 0-― 0 0 0 0 H H doa-f '' ε Z86

® 0 0--1 1-0 D H H daa- ■ ε ΐ 86

® I ΐ 0 0 H S 0 3 H H doa-t '' ε 086

® ΐ 1 0 Z DZtiD 0 H 0 0 3 H H dQQ-f 'ε 616

⑥ ΐ I-(Z 3) HN a 0 s 0 H H d98a0 8Ζ6

⑧ ΐ ΐ 0 0 HN s D H H da 园 ιι <

⑧ ΐ 0 ― 1 0 H 3Md s 0 H H dg leak 9 6

⑧ ΐ 0-one S H ZWd s D H H daaao S 6

⑧ ΐ 0 ―-0 H Ζ \ Ώ s 3 H 11 dtiaaa i- e

⑧ ΐ 0--0 0 s 3 H H d Sub 8 CA6

⑧ ΐ 0 ―-S 0 s 0 H H d8 drawing ZL6

⑥ ΐ 0-― 0 0 s 3 H H daaao 6

⑧ 0 0--― ― ― s 3 H H deoao 0A6

I ι 0 ZHDZUD o o u, ιααπα «α«

S ΐ ΐ 0 SHOZHD 0 H 0 s 3 H H daaao see

⑥ ΐ ΐ C (ZHD) 1 HN 0 s 3 H H dVN-2 Z96

⑧ Τ ΐ 0 ZUDZUD 0 d 1-1 s 3 H H dVN-2 996

⑥ ΐ 0 0 H: Twist d s 0 H H dVN ~ Z 996

twenty five

SZ9tO / 86dT / 13 I ^ 6l / 66 OW 991 Ph Ph Ph C 0 s H 0 CH2CH2 0 1 1 ④

992 Ph Ph Ph c 0 ―-― ― 1 0 0 ④

993 Ph Ph Ph c 0 0 Me 0--0 1 ④

994 Ph Ph Ph c 0 0 Me S 1 ― 0 1 ④

995 Ph Ph Ph c 0 0 2-ClPh 0--0 1 ④

996 Ph Ph Ph c 0 CH2 H 0--0 1 ④

997 Ph Ph Ph c 0 CH2 Hs-― 0 1 ④

998 Ph Ph Ph c 0 PhE H 0 1-0 1 ④

999 Ph Ph P c 0 NH Pr 0 CH2CH2 0 1 1 ④

1000 Ph Ph Ph c 0 0 Me NH (CH2) 3-1 1 ④

1001 3, 5-DBP H II c 0 0 H 0 CH2CH2 0 1 1 ④

1002 3, 5- DBP H H c 0 S H 0 CH2CH2 0 1 1 ④

1003 3, 5-DBP H H c 0-----0 0 ④

1004 3, 5-DBP H H c 0 0 Me 0--0 1 ④

1005 3, 5-DBP H H c 0 0 Me s ―-0 1 ④

1006 3, 5-DBP H H c 0 0 2-ClPh 0 1-0 1 ④

1007 3, 5-DBP H H c 0 CH2 H 0--0 1 ④

1008 3, 5-DBP H H c 0 CH2 H s ― 1 0 1 ④

1009 3, 5-DBP H H c 0 PhE H 0-― 0 1 ④

1010 3, 5-DBP H H c 0 NH Pr 0 CH2CH2 0 1 1 ④

101 1 3, 5-DBP H H c 0 0 Me NH (CH2) 3-1 1 ④

1012 4-MeOPh 4- MeOPh Ph c 0 0 H 0 CH2CH2 0 1 1 ④

1013 4- MeOPh 4-MeOPh Ph c 0 S H 0 CH2CH2 0 1 1 ④

1014 4-MeOPh 4-MeOPh Ph c 0 0 0 ④

1015 4-MeOPh 4-MeOPh Ph c 0 0 Me 0 0 1 ④

1016 4— MeOPh 4-MeOPh Ph c 0 0 Me S 0 1 ④ 1017 4- MeOPh 4-MeOPh Ph C 0 0 2 ClPh 0-0 ④

1018 4-MeOPh 4-MeOPh Ph C 0 CH2 H 0-0 ④

1019 4-MeOPh 4- MeOPh Ph C 0 CH2 H S-0 ④

1020 4 MeOPh 4- MeOPh Ph C 0 PhE H 0--0 ④ 1021 4-MeOPh 4-MeOPh Ph C 0 NH Pr 0 CH2CH2 0 1 ④

1022 4-MeOPh 4-MeOPh Ph C 0 0 Me NH (CH2) 3-1 ④

1023 4- MeOPh Ph Ph C 0 0 H 0 CH2CH2 0 1 ④

1024 4- MeOPh Ph Ph C 0 S H 0 CH2CH2 0 1 ④

1025 4-MeOPh Ph Ph C 0-0 ④

1026 4- MeOPh Ph Ph C 0 0 Me 0--0 ④

1027 4- MeOPh Ph Ph C 0 0 Me S--0 ④

1028 4-MeOPh Ph Ph C 0 0 2 Cl Ph 0--0 ④

1029 4- MeOPh Ph Ph C 0 CH2 H 0--0 ④

1030 4-MeOPh Ph Ph C 0 CH2 Hs--0 ④ 1031 4- MeOPh Ph Ph C 0 PhE H 0--0 ④

1032 4-MeOPh Ph Ph C 0 NH Pr 0 CH2CH2 0 1 ④

1033 4 MeOPh Ph Ph C 0 0 Me NH (CW2) 3-1 ④

1034 tBu Ph Ph S i 0 0 H 0 CH2CH2 0 1 ④

1035 tBu Ph Ph S i 0 S H 0 CH2CH2 0 1 ④

1036 tBu Ph Ph S i 0-0 ④

1037 t Bu Ph Ph S i 0 0 Me 0--0 ④

1038 tBu Ph Ph S i 0 0 Me S--0 ④

1039 tBu Ph Ph S i 0 0 2-ClPh 0--0 ④

1040 tBu Ph Ph S i 0 CH2 H 0--0 ④

1041 tBu Ph Ph S i 0 CH2 H S--0 ④

1042 tBu Ph Ph S i 0 PhE H 0 one-0 ④ O 99/19474

 55

1043 tBu Ph S i 0 Nil Pr 0 CH2CH2 0 1 1 ④

1044 tBu Ph S i 0 0 Me NH (CH2) 3-1 1 ④

 HHHHHHHHHHHPPPPPPPPPPPP P

 1045 Ph hhhhhhhhhhhh h Ph C S 0 H 0 CH2CH2 0 1 1 ④

1046 Ph Ph C S S H 0 CH2CH2 0 1 1 ④

1047 Ph Ph C S-0 0 ④

1048 Ph Ph C S 0 Me 0--0 1 ④

1049 Ph Ph C S 0 Me S--0 1 ④

1050 Ph Ph C S 0 2-CIPh 0-0 1 ④

1051 P Ph C S CH2 H 0--0 1 ④

1052 Ph Ph C S CH2 H S--0 1 ④

1053 Ph Ph C S PhE H 0--0 1 ④

1054 Ph Ph C S NH Pr 0 CH2CH2 0 1 1 ④

1055 Ph Ph C S 0 Me NH (CH2) 3-1 1 ④

1056 4-BnOPh H C 0 0 H 0 CH2CH2 0 1 1 ④

1057 4-BnOPh H C 0 S H 0 CH2CH2 0 1 1 ④

1058 4-BnOPh H C 0-0 0 ④

1059 4-BnOPh H C 0 0 Me 0--0 1 ④

1060 4-BnOPh H C 0 0 Me S--0 1 ④

1061 4-BnOPh H C 0 0 2-CIPh 0--0 1 ④

1062 4-BnOPh H C 0 CH2 H 0--0 1 ④

1063 4-BnOPh H C 0 CH2 H S--0 1 ④

1064 4-BnOPh H C 0 PhE H 0--0 1 ④

1065 4-BnOPh H C 0 NH Pr 0 CH2CH2 0 1 1 ④

1066 4-BnOPh H C 0 0 Me NH (CH2) 3-1 1 ④

1067 Ph Xanthen-9-yl 0 0 H 0 CH2CH2 0 1 1 ④

1068 Ph Xanthen-9— yl 0 SH 0 CH2CH2 0 1 1 ④ 1069 Ph Xanthen— 9-yl 0 0 0 ④

1070 Ph Xanthen- 9- yl 0 0 Me 0--0 1 ④

1071 Ph Xanthen-9-yl 0 0 Me S--0 1 ④

1072 Ph Xanthen-9-yl 0 0 2-ClPh 0--0 1 ④

1073 Ph Xanthen- 9-yl 0 CH2 H 0--0 1 ④

1074 Ph Xanthen-9-yl 0 CH2 H S ― ― 0 1 ④

1075 Ph Xanthen-9-y 丄 0 PhE H 0 ― 1 0 1 ④

1076 Ph Xanthen-9-yl 0 NH Pr 0 CH2CH2 0 1 1 ④

1077 Ph Xanthen- 9-yl 0 0 Me NH (CH2) 3 ― 1 1 ④

1078 Ph Fluoren-9-yl 0 0 H 0 CH2CH2 0 1 1 ④

1079 Ph Fluoren-9-yl 0 S H 0 CH2CH2 0 1 1 ④

1080 Ph Fluoren-9-yl 0 ―--― ― 0 0 ④

1081 Ph Fluoren-9-yl 0 0 Me 0-one 0 1 ④

1082 Ph Fluoren-9 yl 0 0 Me s 1-0 1 ④

1083 Ph Fluoren-9-yl 0 0 2-ClPh 0 ―-0 1 ④

1084 Ph Fluoren-9-yl 0 CH2 H 0-one 0 1 ④

1085 Ph Fluoren-9-y 丄 0 CH2 H s one-0 1 ④

1086 Ph Fluoren-9-yl 0 PhE H 0-― 0 1 ④

1087 Ph Fluoren-9-yl 0 NH Pr 0 CH2CH2 0 1 1 ④

1088 Ph Fluoren-9-yl 0 0 Me NH (CH2) 3-1 1 ④

1089 3, 4-DBP H H C 0 0 H 0 CH2CH2 0 1 1 ⑤

1090 3, 4-DBP H H C 0 S H 0 CH2CH2 0 1 1 ⑤

1091 3, 4--DBP H H C 0 0 0 ⑤

1092 3, 4- -DBP H H C 0 0 Me 0 0 1 ⑤

1093 3, 4-DBP H H C 0 0 Me S 0 1 ⑤

1094 3, 4-DBP HHC 0 0 2-ClPh 0 0 1 ⑤ 1095 3, 4-DBP HHC 0 CH2 H 0 0 1 ⑤

1096 3, 4-DBP H H C 0 HI 12 H S-0 1 ⑤

1097 3, 4-DBP H H c 0 PhE H 0 0 1 ⑤

1098 3, 4-DBP H H c 0 NH Pr 0 CH2CH2 0 1 1 ⑤

1099 3, 4-DBP H H c 0 0 Me NH (CH2) 3 ― 1 1 ⑤

1 100 Ph Ph Ph c 0 0 H 0 CH2CH2 0 1 1 ⑤

1 101 Ph Ph Ph c 0 S H 0 CH2CH2 0 1 1 ⑤

1 102 Ph Ph Ph c 0 1 ― 0 0 ⑤

1103 Ph Ph Ph c 0 0 Me 0--0 1 ⑤

1 104 Ph Ph Ph c 0 0 Me s one 0 1 ⑤

1 105 Ph Ph Ph c 0 0 2-ClPh 0-― 0 1 ⑤

1 106 Ph Ph Ph c 0 CH2 H 0 0 1 ⑤

1107 Ph Ph Ph c 0 CH2 Hs 1 1 0 1 ⑤

1108 Ph Ph Ph c 0 PhE H 0 1 0 1 ⑤

1109 Ph Ph Ph c 0 NH Pr 0 CH2CH2 0 1 1 ⑤

1 1 10 Ph Ph Ph c 0 0 Me NH (CH2) 3 1 1 ⑤

11 11 3, 5-DBP H H c 0 0 H 0 CH2CH2 0 1 1 ⑤

1112 3, 5-DBP H H c 0 S H 0 CH2CH2 0 1 1 ⑤

1113 3, 5-DBP H H c 0-----0 0 ⑤

1114 3, 5-DBP H H c 0 0 Me 0-― 0 1 ⑤

1 1 15 3, 5-DBP H H c 0 0 Me s-― 0 1 ⑤

1116 3, 5-DBP H H c 0 0 2-ClPh 0 0 1 ⑤

1 117 3, 5-DBP H H c 0 CH2 H 0 0 1 ⑤

1118 3, 5-DBP H H c 0 CH2 Hs 0 1 ⑤

11 19 3, 5-DBP H H c 0 PhE H 0 0 1 ⑤

1120 3,5-DBP HH c 0 NH Pr 0 CH2CH2 0 1 1 ⑤ 1121 3, 5-DBP HHCOO Me NH (CH2) 3-1 1 ⑤

1122 4-MeOPh 4- MeOPh Ph C 0 0 H 0 CH2CH2 0 1 1 ⑤

1123 4-MeOPh 4- MeOPh Ph C O S H 0 CH2CH2 0 1 1 ⑤

1124 4- MeOPh 4- MeOPh Ph C O-0 0 ⑤

1125 4-MeOPh 4-MeOPh Ph C 0 0 Me 0--0 1 ⑤

1126 4- MeOPh 4- MeOPh Ph C 0 0 Me S--0 1

1127 4-MeOPh 4- MeOPh Ph C O O 2-ClPh 0--0 1 ⑤

1128 4- MeOPh 4- MeOPh Ph C 0 CH2 H 0--0 1 ⑤

1129 4-MeOPh 4-MeOPh Ph C 0 CH2 H S--0 1 ⑤

1130 4- MeOPh 4- MeOPh Ph C 0 PhE H 0--0 1 ⑤ 1131 4- MeOPh 4- MeOPh Ph C 0 NH Pr 0 CH2CH2 0 1 1 ⑤

1132 4-MeOPh 4- MeOPh Ph C 0 0 Me NH (CH2) 3-1 1 ⑤

1133 4- MeOPh Ph Ph C O O H 0 CH2CH2 0 1 1 ⑤

1134 4-MeOPh Ph Ph C O S H 0 CH2CH2 0 1 1 ⑤

1135 4- MeOPh Ph Ph C O--0 0 ⑤

1136 4- MeOPh Ph Ph C O O Me 0--0 1 ⑤

1137 4- MeOPh Ph Ph C O O Me S--0 1 ⑤

1138 4- MeOPh Ph Ph C O O 2-ClPh 0--0 1 ⑤

1139 4- MeOPh Ph Ph C 0 CH2 H 0--0 1 ⑤

1140 4- MeOPh Ph Ph C 0 CH2 H S--0 1 ⑤ 1141 4- MeOPh Ph Ph C 0 PhE H 0--0 1 ⑤

1142 4- MeOPh Ph P C 0 H Pr 0 CH2CH2 0 1 1 ⑤

1143 4-MeOPh P Ph C O O Me NH (CH2) 3-1 1 ⑤

1144 tBu Ph Ph Si 0 0 H 0 CH2CH2 0 1 1 ⑤

1145 tBu Ph Ph Si 0 S H 0 CH2CH2 0 1 1 ⑤

1146 tBu Ph Ph Si 0 1 1 0 0 ⑤ 0--0 HZD oo HH MdOua-t ZLll

⑤ 0--0 dio-z 0 oo HH dOUO-t 'ILU ⑤ 0-S 0 0 3 HH ^L ldO "8-t' ⑤ ⑤ 0--0 0 0 DHH WOug-69Π ⑨ 0-0 0 HH 4dOug 89ΐΐ ⑨ I 0 0 HS 0 DHH MdO "8- ^ Ζ9Π ⑤ ΐ 0 SH3ZH3 0 H 0 0 3 HH MdOua-t '99Π ΐ ΐ-S (ZH) ΗΝ 0 S 3 Md Md Md 59ΐΐ ⑤ ΐ 0 ZWZHD 0 Jd HN S 0 Md ^ d Md t9II ⑤ 0--0 H 3Md S 3 d Md C9U ⑨ 0--SH ZWD SD Md Md Md Ζ9Π ⑤ 0--0 H ZUD S 3 Md Md Md Ϊ9Π ⑤ 0--0 ^ άlD-z o SD Md Md 09Π ⑤ 0--S 0 S 3 t | d 6SU

⑤ 0-S 0 Md ^l ld ^ d Ζ9Π ΐ ΐ 0 ZHOZHO 0 HSS 3 Md Md Md 99 Π ⑨ Τ 0 zmztiD 0 H 0 S 3 Md Md dl 99ΐΐ ⑤ ΐ-S (ZH) ΗΝ 8HI 0 0 TS Md Md

⑤ 1 0 ztiozm o -td HN 0 TS 4d Md S9IT ⑤ 0--0 H 3Md 0 TS Md Lid 'Ζ9ΐΐ ⑨ 0--SH zm 0 TS Md Md'"W Ι9Π ⑤ 0--0 H ZHD 0 TS Md Md nei 0911 ⑤ 0--0 dT3-2 0 0 Md ^ d ngi 6ΗΪ ⑤ 0--S o 0 TS Hd ^L ld> 8Ηΐ ⑤ 0--0 0 TS ngi ΖΙΊΙ

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One § 1225 3, 5-DBP HHC 0 0 H 0 CH2CH2 0 1.2 ⑤

1226 3, 4-DBP H H C 0 0 H 0 CH2CH2 0 1 3 ⑤

1227 Ph Ph Ph C 0 0 H 0 CH2CH2 0 1 3 ⑤

1228 3, 5-DBP H H c 0 0 H 0 CH2CH2 0 1 3 ⑤

1229 3, 4-DBP H H c 0 0 H 0 CH2CH2 0 1 1 ⑦

1230 3, 4-DBP H H c 0 0 G 1 0 CH2CH2 0 1 1 ⑥

1231 3, 4-DBP H H c 0 0 H 0 CH2CH2 0 1 2 ⑥

1232 3, 4-DBP H H c 0 0 H 0 CH2CH2 0 1 3 ⑥

1233 3, 4-DBP H H c 0 0 H 0 CH2CH2 0 1 2 ⑧

1234 3, 4-DBP H H c 0 0 H 0 CH2CH2 0 1 3 ⑧

1235 3, 4-DBP H H c 0 0 H 0 CH2CH2 0 1 2 ⑦

1236 3, 4-DBP H H c 0 0 H 0 CH2CH2 0 1 3 ⑦

Among the above-exemplified compounds, preferred compounds include 1 to 33, 32 27 to 39, 65 3 to 68, 979 to 1011, and 1089 to The compounds of 121, 119, 1205, 121 and 122 to 123 can be cited.

 Further, preferred compounds include 1 to 11, 1, 327 to 337, 653 to 663, 979 to 989, 1089 to 1099, 1 Compounds of 199, 125, 1221, 122, and 123 to 123 can be mentioned.

Most preferred compounds include 1,327,653,979,109,122,122,123 and 1322 compounds. . The compound of the general formula (1) according to the present invention comprises the following compound (2) produced by the following methods A-1 and A_2

And the following compounds (3), (4-a), (4-b), (5), (6a) produced by the following B-1, B_2, B-3, B-4, and B-5 ), (6b), (6c), (6d), (7a) or (7b)

DMT -one O--F -w, (3) DMT-O-F one w _4b (6 b)

DMT--o-F -w _2a (4-a) DMT-o-F -w _4c (6 c)

DMT-〇 one F--w _2b (4-b) DMT-o one F one w _4d (6 d)

DMT-o-F- -w ₃ (5) DMT-o-F-w _5a (7a)

DMT-o-F-i w _4a (6a) DMT-o-F-w _5b (7b) de-DMT (4,4'-dimethoxytrityl) is used as a raw material, and the following C-1, It can be manufactured by the methods shown in C1-2 and C-3.

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第 2工程

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Sr9fO / 86df / IDd ^ 61/66 OAV Compounds (2) to (7b) in the above process chart, A-1, A-2, B-1, B-2, B-3, B-4, B-5, C-1, C-2 And in the C-3 method, R, R ₂ , R ₃ , R ₄ , Z, Y or Y ₂ , Y ₃ , Y ₄ , X, n, m and B have the same meanings as described above;

 A, is a trityl group (T r), which is generally used to specifically protect the primary hydroxyl group of a nucleoside, a 4-monomethoxytrityl (MMT) group, and a 4,4′-dimethoxytrityl (DMT) group. ) Represents a group;

A ₂ is tert-butyldimethylsilyl (TB DMS) groups and triisopropylate Rushiriru (TIPS) good UNA trisubstituted silyl group group, Application Benefits Kuroroe Toki Shikaruboeru (T roc) Application Benefits Nono Rogenoe Tokishikarubo two Le groups such as An aralkyloxycarbonyl group such as a benzyloxycarbonyl (Z) group;

 D 'represents a thymine base or a protected thymine base,

 D ″ represents the base moiety of the nucleotide at the 3′-terminal where the amino group is protected with the acryl group;

 D "" indicates the base of any nucleotides used in DNA synthesis, and indicates a base selected from adene, guanine, cytosine and thymine or a corresponding protected base;

 F is the oligonucleotide moiety excluding the nucleotide at the 5 'end of the desired nucleotide sequence, which is commonly used in DNA synthesis, and is protected by a protecting group on the phosphoric acid moiety. Indicates the oligonucleotide (including the 5'-terminal hydroxyl group of the 5'-terminal nucleoside and the 3'-position hydroxyl group of the 3'-terminal nucleoside);

V is a protecting group for the phosphoric acid moiety (particularly, a lower alkyloxy group such as a methoxy group, a cyanoalkyloxy group such as a cyanoethyloxy group, and in Step 39, particularly, an orthochlorophenoxy group). Group); U is an amino group in the amidite portion (particularly a complex having one or two oxygen atoms and / or nitrogen atoms in the ring, such as a dialkylamino group such as a dimethylamino group or a diisopropylamino group, and a morpholino group). A cyclic group);

Wi, W _2a , W ₂ , W ₃ , W, W ₄ , W _{5 a} or W _{5 b} are obtained by converting the oligonucleotide F from the CPG of the final target compound in the method shown in B-1 to B-5. '3' of the terminal part up to the oxygen atom of the hydroxyl group;

 1 (L) is! Represents an integer of ~ .9;

 E represents a hydrogen atom or an optionally protected hydroxyl or amino group;

 K represents an oxygen or sulfur atom;

 DMT represents 4, 4'-dimethoxytrityl group;

H a 1 is (preferably, a chlorine or bromine atom) a halogen atom indicates; R ₅ is methyl, Echiru, propyl, butyl, phenyl, main butoxy, E butoxy, Purobokishi, butoxy, is Xia Roh ethyl O alkoxy or substituted Phenyloxy group (preferably unsubstituted).

 Methods A-1 and A-2 are methods for producing compound (2), which is an important intermediate, for producing compound (1).

 Method B-1 is based on a nucleotide having a protecting group at the 5 'terminal

The 3 'terminal nucleoside) is linked to a controlled' pore glass' (CPG) via a linker as a starting material, and is a commercially available nucleoside reagent for DNA synthesis on a DNA synthesizer. A method for producing a compound (3) in which nucleotides are successively elongated using a conventional method (hereinafter referred to as "nucleotide units"), and bound to the oligonucleotide before the oligonucleotide by one less than the desired oligonucleotide. It is.

 In the B-2 method, one of the hydroxyl groups of the alkylene diol (4-1) is

4 'Protect with a trimethyl group (hereinafter referred to as DMT group) One of the hydroxyl groups is condensed with a dicarboxylic anhydride to give succinic acid half ester (indicated by succinic acid as a representative of dicarboxylic acid in the scheme), and the carboxyl group of the ester and CPG The CPG carrier (416) obtained by binding the amino group and removing the terminal DMT group is used to produce nucleotides on a DNA synthesizer using a nucleotide unit in the usual manner. This is a method for producing a compound (4-a) that has been extended to the position before the oligonucleotide, which is one less than the desired oligonucleotide, and also uses a CPG carrier (4-6), which is the same raw material, on a DNA synthesizer. First, a nucleotide reagent capable of forming a phosphorothioate bond is reacted, and the nucleotide is then sequentially extended using a nucleotide unit in the usual manner. It is also the desired Origonuku Reochido Yori one less O Li Gonuku Reochido compound bound before (4 one b) Method of manufacturing.

In the B-3 method, a commercially available compound (5-2) is obtained from a CPG carrier (5-1) (that is, (4-1-6)) in which an alkylene diol and CPG are bonded via a dicarboxylic acid as a raw material. using, DNA synthesizer to produce a compound (5-3), then reacting with a substituted a Min 1¾ ₄ NH _2, compound - to produce (5 4) further, using the quinuclidine Reochidoyuni' bets This is a method for producing a compound (5) in which nucleotides are sequentially extended by an ordinary method and bound up to one oligonucleotide less than a desired oligonucleotide.

In the B-4 method, one hydroxyl group of the diol compound (6-1) is converted to a compound (6-2) obtained by DMT, and then the other hydroxyl group is mixed with an amidating reagent (6-3 '). Reacting the compound (6-3) to obtain the compound (6-3). In the same manner as in the method B-3, the compound (6-2) is bound to CPG via dicarboxylic acid, and the CPG carrier is obtained. (6-6), and using the CPG carrier (6-7) obtained by removing the DMT group as a raw material. Then, using a nucleotide unit on a DNA synthesizer, the nucleotides are sequentially extended in a usual manner, and the compound is bound to a position before the desired oligonucleotide, which is one less than the desired oligonucleotide ( _{6). a} ) is produced by reacting the compound (6-3) with the CPG carrier (6-7) once, twice or three times on a DNA synthesizer. Using the product (6-9), (6-10) or (6-11) as a raw material, the nucleotide is sequentially extended by a usual method using a nucleotide unit to obtain a desired product. This is a method for producing a compound (6b), (6c) or (6d), which is bound to one oligonucleotide less than the oligonucleotide.

 The B-5 method is based on the removal of the DMT group of a commercially available protected 2'-deoxynucleoside-linked CPG (hereinafter referred to as D '' '-CPG) by the linker (7- (Tetrahedron Letters, 27, 475 (19986))) (2-cyanoethoxy) one [2— (2'—O one) 4,4'-Dimethoxytrityloxetylsulfonyl) ethoxy]-(N, N-diisopropylamino) phosphine (7-1) to produce compound (7-3) Then, a compound obtained by removing the DMT group of the compound (7-3) and a compound separately synthesized by a conventional method

To produce a compound (7-5) obtained by condensing (7-4) with (7-5), and using the compound (7-5) as a raw material and a nucleotide unit in the usual manner, using a nucleotide unit. This is a method for producing a compound (7a) in which a nucleotide is extended and bound to one less than the desired oligonucleotide before the oligonucleotide, and the DMT group of the aforementioned compound (7-3) is removed. The compound (7-7) obtained by condensing the compound (7-7) synthesized separately with the compound (7-6) synthesized by a conventional method, and further using the compound (7-7) as a raw material Using a unit This is a method for producing a compound (7b) in which nucleotides are sequentially extended by a method and bound to one less oligonucleotide than the desired oligonucleotide.

 In the C-11 method, the compound (2) is reacted with a phosphating agent to prepare a 3′-phosphorous acid derivative (8), and the compound (3) synthesized by the methods B-1 to B-5 is used. ), (4—a), (4—b), (5), (6a), (6b),

The corresponding compound of (6c), (6d), (7a) or (7b), from which the DMT group has been removed, is condensed on a DNA synthesizer, and then oxidized. This is a method for producing the compound (1) of the present invention by cleaving the bond with and finally removing the protecting group.

 The C-12 method is based on the compound (2), which is prepared by reacting a phosphorylating agent with a 3, monophosphate derivative (9), and the compounds (3), (4) synthesized by the methods B-1 to B-5. — Corresponding to a), (4-1b), (5), (6a), (6b), (6c), (6d), (7a), or (7b) with the DMT group removed This is a method for producing the compound (1) of the present invention by condensing the compound and on a DNA synthesizer, cleaving the bond with CPG, and finally removing the protecting group.

 The C-13 method comprises a compound (10) in which a phosphonic acid group is introduced at the 3′-position of the compound (2), and a compound (3), (4—a) synthesized by the methods B-1 to B-5. ), (4-b), (5), (6a), (6b), (6c), (6d), (7a), and the corresponding compound from which the DMT group has been removed. Are condensed and then oxidized to form a phosphodiester bond, further cleave the bond with CPG, and finally, remove the protecting group to obtain the compound (1) of the present invention. Is the way.

Hereinafter, each step in the methods A_1 to C-13 will be described in detail. Note that steps that can be performed in the same manner will be described with the earliest step as a representative. (Steps 1, 8, and 18)

 This step includes, in an inert solvent, the step of protecting compound (2-1) <wherein the base moiety is A, G or C in the presence of A, G or C, for protecting an existing amino group from acylation.

 The protection step can be easily performed by a known method (J. Am. Chetn. Soc., 104, 1316, (1982)).

 As the protecting group for the amino group, a lower aliphatic acyl or an aromatic acyl is generally used.

 The lower aliphatic acyl used includes, for example, formyl, acetinole, propiole, butyryl, isobutylinole, pentanoyl, pivaloyl, valeryl, isovaleryl, and the like. Examples of the benzyl include benzoyl, 4-acetoxybenzoyl, 4-methoxybenzoyl, 4-methylbenzoyl, and 11-naphthyl. Preferably, when the base moiety is A or C, It is a benzoyl group, and in the case of G, it is an isoptyryl group. In this step, a compound (2-2) in which only the hydroxyl group at the 5′-position is selectively protected is produced by reacting a hydroxyl-protecting reagent. '

The solvent used is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, or cyclobenzene. And halogenated hydrocarbons such as dichlorobenzene; esters such as engineered formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl propylether, tetrahydrofuran, dioxane, and the like. Ethers such as dimethoxetane and diethylene glycol dimethyl ether; ketones such as acetone, methylethylketone, methylisobutylketone, isofolone and cyclohexanone; nitrotroethane, nitrite Nitro compounds such as benzene; acetonitrile, a Buchiroyu Tritoles such as trinole; amides such as formamide, dimethylformamide (DMF), dimethylacetamide, hexamethylphosphorotriamide; dimethylsulfoxide Sulfolane, sulfolane; aliphatic tertiary amines such as trimethylamine, triethylamine, N-methylmorpholine; aromatic amines, such as pyridine and picolin. More preferred are halogenated hydrocarbons (particularly methylene chloride) and amides (particularly DMF).

 The protecting reagent used is not particularly limited as long as it can selectively protect only at the 5'-position and can be removed under acidic and neutral conditions. Trimethyl chlorides such as lithichloride, monomethoxytrityl chloride, and dimethoxytrityl chloride. When a triarylmethyl halide is used as a protecting reagent, a base is usually used.

 In this case, the base to be used may be a heterocyclic amine such as pyridine, dimethylaminopyridine, pyrrolidinopyridine, or an aliphatic tertiary amine such as trimethylamine or triethylamine. Amines are preferred, and pyridine, dimethylaminopyridine and pyrrolidinopyridine are preferred.

 When a liquid base is used as the solvent, the base itself acts as a deoxidizing agent, so that it is not necessary to add a base again.

 The reaction temperature is usually from 0 to 150 ° C, preferably from 20 to 100 ° C, depending on the starting materials, reagents, solvents and the like used. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 to 100 hours, preferably 2 to 24 hours.

After completion of the reaction, the reaction solution is poured into water, extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, and the like, and the solvent is distilled off from the extract to obtain the desired product (2-2). And usually the next Used in the step. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

 (2nd step)

 In this step, compound (2-2) is reacted with a hydroxyl-protecting reagent in an inert solvent to produce compound (2-3).

 The solvent used is preferably an aromatic hydrocarbon such as benzene, toluene, or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, or dichloromethane. Halogenated hydrocarbons such as chlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxetane Ethenes such as diethylene glycol dimethinoleone; ketones such as acetone, methylethylketone, methylisobutylketone, isofolone and cyclohexanone; nitroethane, nitrobenzene Nitro compounds such as: acetonitrile, Butyramides such as soptilonitrile; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; and sulfoxides such as dimethylsulfoxide and sulfolane. More preferably, ethers (especially tetrahydrofuran), halogenated hydrocarbons (especially methylene chloride), aromatic hydrocarbons (especially toluene), amides (especially toluene) Dimethylformamide).

The protecting reagent to be used is not particularly limited as long as it can be deprotected in distinction from the protecting group at the 5'-position. Preferably, t-butyldimethylsilyl chloride is used. Certain compounds include silyl halides such as triisoprovir silyl chloride, haloalkoxycarbon halides such as triethoxy ethoxycarbonyl chloride, and benzyloxy canoleles. Examples include aralkyloxycarbonyl halides such as bojyl chloride.

 When a silyl halide, a haloalkoxycarbonyl halide or a dialkyloxycarbonyl halide is used as a protecting reagent, a base is usually used.

 In this case, the base used is preferably an organic base (particularly, triethylamine, pyridine, N-methylmorpholine, DBU, imidazole, etc.).

 The reaction temperature is usually from 120 to 150 ° C, preferably from −10 to 50 ° C, depending on the reagents, raw materials, solvents and the like used. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 to 100 hours, preferably 1 to 24 hours.

 After completion of the reaction, for example, the reaction solution is poured into water, extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, or the like. 3) is obtained and usually used as it is in the next step. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

 (Steps 3, 11, 22, and 25)

 In this step, the compounds (2-3), (4-5), (6-

6) or (6-8) is reacted with a deprotection reagent to selectively remove the 5'-hydroxyl protecting group, and the compounds (2-4), (4-6), (6-6)

7) or (6-9).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction. Preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform and tetrachloride Halogenated hydrocarbons such as carbon, dichloroethane, cyclobenzene, and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and ethyl carbonate Esters such as tyl; ethers such as getyl ether, disopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and methyl dimethyl ether; methanol, ethanol, n -Prono. Alcohols such as ethanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methinolace Ketones such as acetone, methylethylketone, methylisobutylketone, isophorone and cyclohexanone; two-mouth compounds such as nitroethane and nitrobenzene; acetonitrile, isobutyroni Ditolyls, such as tolyl; amides, such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphotriamide; sulfoxides, such as dimethylsulfoxide and sulfolane; More preferably, alcohols ( Methanol, ethanol) or if you methylene chloride and deprotection reagent using acetic acid is a mixture of acetic acid and water are listed.

 The deprotecting reagent to be used is not particularly limited as long as it is a commonly used deprotecting reagent.If the protecting group is a triarylmethyl group, for example, acetic acid, dichloroacetic acid, trifluoroacetic acid, hydrochloric acid And Lewis acids such as zinc bromide, preferably acetic acid, dichloroacetic acid and trifluoroacetic acid.

 The reaction temperature varies depending on the used reagents, raw materials, solvents and the like, but is usually from 10 to 100 ° C, preferably from 0 to 50 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like used, but is usually 1 minute to 50 hours, preferably 1 minute to 24 hours.

After the reaction is completed, for example, the reaction solution is neutralized with a base such as pyridine, poured into water, extracted with a water-immiscible solvent such as benzene, ether, ethyl acetate, etc., and the solvent is distilled off from the extract. By doing The product (2-4) is obtained and usually used as it is in the next step. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

 In the first, first, second and second steps, the desired compounds (4_6), (6-7) and (6-9) can be collected by filtration, and an organic solvent such as methylene chloride can be used. After washing with, use it as it is in the next step.

 (Steps 4 and 6)

 In this step, compound (2-5) is reacted with compound (2-1) or (2-4) in an inert solvent in the presence of a base to produce compound (2) or (216) This is the step of performing

The solvent used is preferably an aromatic hydrocarbon such as benzene, toluene, or xylene; a halogen such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, or dichlorobenzene. Esters such as ethyl ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl oxetane, diethylene glycol dimethynoate ether Ethers; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone; nitro compounds such as nitroethane, nitrobenzene; acetonitrile; Issobutyroni Tril Nitriles; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; and sulfoxides such as dimethylsulfoxide and sulfolane. Ethers (especially tetrahydrofuran), ketones (especially acetone), halogenated hydrocarbons (especially methylene chloride), amides (especially dimethylformamide), and aromatic amines (especially , Pyridine). The base used is preferably an organic base (particularly, triethylamine, pyridine, N-methylmorpholine, DBU, etc.), an alkali metal hydride (particularly, sodium hydride), and an alkali metal carbonate. Salts (particularly sodium carbonate and lithium carbonate) are preferred. When Z in the compound (2-5) is a silicon atom, an organic base such as imidazole is most preferred.

 Although the reaction temperature is not particularly limited, it is generally 0 to 100 ° C, preferably 20 to 60 ° C. The reaction time is usually from 5 minutes to 30 hours, but when the reaction is carried out at 50 ° C, the reaction is completed in 10 hours.

 For example, after completion of the reaction, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. The organic layer containing the compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired product (2) or (2-6).

 The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

 (Fifth step)

 This step is a step of producing compound (2) by reacting compound (2-6) with a deprotecting agent in an inert solvent.

 The method of this step differs depending on the type of the protecting group of compound (2-6).

 1) When a group having a silyl atom is used as the 3′-protecting group, it is usually removed by treating with a compound that generates fluoride ions such as tetratraptyl ammonium fluoride. Is done.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred. Suitable.

 The reaction temperature is not particularly limited, but is usually from 130 ° C to 100 ° C, and preferably from 0 ° C to 30 ° C.

 The reaction time is usually 5 minutes to 30 hours, but when the reaction is carried out at 20 ° C., the reaction is completed in 10 hours.

 For example, after completion of the reaction, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. After separating the organic layer containing, the organic layer is dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired product (2).

 If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

 2) When a haloalkoxycarbonyl group is used as the 3′-protecting group, zinc powder is usually used.

 The solvent used is not particularly limited as long as it does not inhibit the reaction, but acetic acid, alcohol, or a mixed solvent of these and water is preferred.

 The reaction temperature is not particularly limited, but is usually 0 to 100 ° C., and preferably is carried out at room temperature. The reaction time is usually 5 minutes to 30 hours, but when the reaction is carried out at room temperature, the reaction is completed in 10 hours.

 For example, after completion of the reaction, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. The organic layer containing the compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired product (2).

The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. 3) When an aralkyloxycarbonyl group is used as the 3′-position deprotection, the reaction can be carried out by catalytic reduction or oxidation.

 The reduction catalyst used in the catalytic reduction is not particularly limited as long as it is usually used in the catalytic reduction reaction, but is preferably palladium carbon, Raney nickel, platinum oxide, platinum black. , Rhodium aluminum monoxide, triphenylphosphine-rhodium chloride, and palladium monosulfate.

 The pressure is not particularly limited, but it is usually 1 to 10 atm. The reaction temperature and reaction time vary depending on the type of the starting material, the solvent and the catalyst, and the like. The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent. As the organic solvent, preferably, ketones such as acetone, halogenated hydrocarbons such as methylene-based lid, chloroform-based form, carbon tetrachloride, and acetonitrile are preferred. Nitriles, ethers such as Jethyl ether, tetrahydrofuran, dioxane, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, and dimethylsulfoxide Sulphoxides.

 The oxidizing agent to be used is not particularly limited as long as it is a compound used for the oxidation, but preferably, potassium persulfate, sodium persulfate, ammonium permite nitrate (CAN), 2, 3-Zikuguchi-5, 6-Diciano-p-Venzoquinone (DDQ) is used.

The reaction temperature and the reaction time vary depending on the starting material, the solvent, the type of the catalyst, and the like, but are usually carried out at 0 to 150 ° C for 10 minutes to 24 hours. In liquid ammonia or in alcohols such as methanol and ethanol, -78 to -20 It can also be removed by the action of alkali metals such as tritium.

 Furthermore, it can also be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide in an inert solvent.

 In this case, the solvent to be used is not particularly limited as long as it does not participate in this reaction, but preferably, -tolyls such as acetonitrile, methylene chloride, and chloroform Halogenated hydrocarbons such as form or a mixed solvent thereof are used.

 The reaction temperature and reaction time vary depending on the starting materials, the solvent, and the like, but are usually 0 to 50 ° C. for 5 minutes to 3B.

 In the case where the reaction substrate has a sulfur atom, sodium aluminum chloride and iodide are preferably used.

 After completion of the reaction, for example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added. The organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired product (2).

 If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

 (7th, 12th, 14th, 17th, 23rd, 26th, 28th, 30th, 33th, and 35th steps)

In this step, CPG (3-1) carrying a nucleoside, which is the nucleotide at the 3 'end of the target oligonucleotide, is used as a raw material and is usually used for a DNA chain elongation reaction on a DNA synthesizer. This procedure is repeated to extend the oligonucleotide to the oligonucleotide excluding the nucleotide other than the 5 'end of the desired oligonucleotide, and the oligonucleotide is supported on cPG. This is the step of obtaining oxyribonucleotide (3) and the like.

 Hereinafter, the phosphoramidite method is described with respect to the DNA chain elongation reaction on the DNA synthesizer, but is not particularly limited to this method. In the seventh step, a CPG (3-1) carrying a nucleoside, which is a nucleotide on the 3 ′ end side of the target oligonucleotide, which is commercially available or obtained by the method described above or below, is added to D. After removing DMT using a reagent to remove DMT on the NA synthesizer, the phosphite-triester bond formed by condensing the nucleotide unit is converted to phosphoric acid-triester using an oxidizing agent. Oxidize.

 The above operation was repeated to extend the oligonucleotide except for the nucleotide other than the 5 'end of the target oligonucleotide to the oligonucleotide, and to carry the DMT group at the 5' end. 3) (hereinafter, oligodeoxynucleotide is abbreviated as ODN).

 A CPG carrying the ODN of the desired nucleotide sequence protected at the 5 ′ end with a DMT group can be synthesized using a DNA synthesizer (for example, Applied Biosystems' phosphoramidite model 380B, The compound can be synthesized by the method in Nucleic Acids Res, 124539 (1994) or a modified method thereof using a cycloamidite method by the phosphoramidite method of Z Biosearch.

 As the nucleotide unit of the nucleotide unit used for the synthesis of an oligonucleotide, a nucleotide unit protected with an aliphatic or aromatic acyl group is used. When the base is A or C, a benzoyl group is used, and when the base is G, an isobutyryl group is suitably used.

The solvent used in the condensation reaction in this step is not particularly limited as long as it does not inhibit the reaction. Hydrofuran is preferred, and tetrazole is preferred as the acidic substance used as the catalyst.

 The reaction temperature may be anywhere from 130 to 50 ° C., but is usually carried out at room temperature. The reaction time varies depending on the reaction temperature from 1 minute to 20 hours. When the reaction is carried out at room temperature, the reaction is completed in 10 minutes. The solvent used in the oxidation reaction of this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, the heterocyclic amines (particularly, pyridine ), Nitriles (especially, acetonitrile), ethers (especially, tetrahydrofuran), and nitrogenated hydrocarbons (especially, methylene chloride). There is no particular limitation as long as it is usually used in an oxidation reaction, but preferably, a peracid such as m_chloroperbenzoic acid; and a peracid such as t-butyl hydrobaroxide. Oxides: iodine-pyridine-water.

 The reaction is carried out at a temperature of from 150 to 100 ° C, and the reaction time is usually from 30 minutes to 15 hours, although it depends mainly on the reaction temperature, the type of the starting compound or the type of the solvent used.

 In the above oxidation reaction, the reaction is accelerated by adding an interlayer transfer catalyst such as tributylbenzylammonium mouthride or tributylbenzylammonium bromide.

 After completion of the reaction, the desired product (3) is collected by filtration, washed with an organic solvent such as methylene chloride, and used as it is in the next step.

 The 12th, 14th, 15th, 15th, 17th, 23rd, 26th, 28th, 30th, 33th, and 35th steps can be performed in the same manner as described above.

(Steps 9 and 20) In this step, the compound (4-2) or (6-2) is reacted with an anhydride of a dicarboxylic acid in the presence of a basic catalyst to form a dicarboxylic acid half ester (4-3) or (6-4). This is the step of obtaining.

 In the process scheme, succinic acid is described as a representative, but the same can be performed for other dicarboxylic acids. The dicarboxylic acid used is not particularly limited, but is preferably one having 2 to 10 carbon atoms, and most preferably succinic acid or glutaric acid.

 Examples of the basic catalyst used include aminopyridines such as dimethylaminopyridine and pyrrolidinoviridine, tertiary amines such as trimethylaminetriethylamine, and hydrogencarbonate. Alkali metal carbonates such as lithium and lithium carbonate are preferred, but dimethylaminopyridine and pyrrolidinopyridine are most preferred.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; methylene chloride Halogenated hydrocarbons such as lids and chloroform; ethers such as ether, tetrahydrofuran, dioxane, and dimethoxetane; dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Amides such as amides; sulfoxides such as dimethyl sulfoxide; methanol, ethanol, n-propanol, and isoprono II. Alcohols such as ethanol, n-butanol, isobutanol, and isoamino alcohol; dilute acids such as sulfuric acid water; dilute bases such as sodium hydroxide water; water; acetate; methylethylketone; Ketones; heterocyclic amides such as pyridine or nitriles such as acetonitrile Preferably, they are nitriles (especially acetonitrile), ethers (especially tetrahydrofuran), and halogenated hydrocarbons (especially methylene chloride).

 The reaction is carried out at a temperature of 150 to 100 ° C., and the reaction time is usually 30 minutes to 15 hours, although it depends mainly on the reaction temperature, the type of the starting compound or the type of the solvent used.

 After the completion of the reaction, for example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, a water-immiscible organic solvent such as water and ethyl acetate is added, and the mixture is washed with water. Thereafter, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off, whereby the target product (4-1-3) or (6-4) can be obtained.

(Steps 10 and 21)

 In this step, in the presence of a condensing agent, a half ester of dicarboxylic acid (4-3) or (6-4) obtained in the ninth or 20th step is reacted with a phenol such as pentachlorophenol, The active ester is then reacted with the amino CPG (4-4) or (6-5) in the presence of a base to give the desired product (4-15) or (6-5). — 6).

 The phenol used is not particularly limited as long as it reacts with a carboxylic acid to form an active ester, but pentachlorophenol 412 trophenol is preferred.

 The base to be used is not particularly limited as long as it is used as a base in a usual reaction, and is preferably triethylamine, tributylamine, or diisopropylamine.

The solvent used does not hinder the reaction and dissolves the starting materials to some extent. There is no particular limitation so long as it is understood, but amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; acetate; Ketones such as luethyl ketone; heterocyclic amides such as pyridine or nitriles such as acetonitrile; preferably, amides such as dimethylformamide. It is a kind.

 The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably triethylamine, tributylamine, diisopropylamineethyl. , N-methylmorpholinepyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-getinoleaniline, 1,5-diazabicyclo [4,3,0] ] Nona 1-5, 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,8 diazabicyclo [5,4,0] Ndeku 7-Den (DBU) Examples thereof include organic bases, preferably, triethylamine, pyridine, N-methylmorpholine, and DBU.

 The reaction is carried out at a temperature of 150 to 100 ° C, and the reaction time varies depending mainly on the reaction temperature, the type of the starting compound or the solvent used. 30 to 50 hours.

 After completion of the reaction, the target substance is collected by filtration, washed with an organic solvent such as methylene chloride, and used as it is in the next step.

(Steps 13 and 32)

In the 13th step, the compound (416) obtained in the 1st step is reacted with a commercially available 5'-O-DMT-nucleoside-13'-phosphoramidite reagent on a DNA synthesizer. Then, the chelating reagent is reacted, This is a step of obtaining the desired product (4.7) which is a CPG carrier having a C bond. The reagent for the formation of a cholate is not particularly limited as long as it can react with trivalent phosphorus to form a cholate. Tetraethylthiuram disulfide (TETD) or Beaucage reagent, which can be obtained from Miragen Z Bioresearch, is suitable. After the reaction is completed, in the case of the former, Tetrahedron Letters 3 2.3.05 In accordance with the method described in (1991) or a modification thereof, in the case of the latter, it is described in J, Am. Chem. Soc. 1_1 2_1253 (1990) The desired product (4-7) can be obtained by processing according to the method or a modification thereof. In the third step, the compound (7-3) is reacted with a 5'-O-DMT-nucleotide 3'-phosphoramidite reagent, and a phosphoric acid triester bond is formed by a usual treatment. The desired product (7-7) can be obtained by reacting the thioating reagent with a thioating reagent having a certain force.

 After completion of the reaction, the desired product is collected by filtration, washed with an organic solvent such as methylene chloride, and used as it is in the next step.

(Step 15)

 In this step, the compound (5-1) obtained in the same manner as the compound (416) in an inert solvent in the presence of a condensing agent and a deoxidizing agent, and a commercially available phosphonic acid monoester (5-2) (For example, available from Mirigen / Biosearch) to obtain the desired product (5-3).

The condensing agent to be used is not particularly limited as long as it forms a mixed acid anhydride with the phosphonic acid monoester, but is preferably adamanta. 1-Carbonyl chloride and pivaloyl chloride are used. The deoxidizing agent used is not particularly limited as long as it is a deoxidizing agent used for acylation using a fatty acid halide, but usually pyridin is used.

 The solvent to be used is not particularly limited as long as it does not inhibit the reaction, but nitriles such as anhydrous acetonitrile are preferably used. The reaction time is 5 to 60 minutes when the reaction is carried out at room temperature.

 After completion of the reaction, the target substance is collected by filtration, washed with an organic solvent such as methylene chloride, and used as it is in the next step.

(Step 16)

 This step is a step of reacting the compound (5-3) with a desired alkylamine and carbon tetrachloride to form a phosphoramidate bond.

 As a solvent to be used, usually, a reagent, carbon tetrachloride, is used. The reaction temperature is from 150 ° C. to 100 ° C., and is not particularly limited. In the case of room temperature, the reaction time is from 1 hour to 10 hours.

 After completion of the reaction, the target substance is collected by filtration, washed with an organic solvent such as methylene chloride, and used as it is in the next step.

(Steps 19 and 36)

 In this step, a compound (2) or (6-2) is reacted with a phosphating agent (6-3 ') in an inert solvent in the presence of a deoxidizing agent to form a 3' phosphite derivative ( 3) or (6-3).

Phosphorylating agents (6-3 ′) include black-mouth morpholino methoxyphosphine, black-mouth morpholino cyanoethoxy phosphine, black mouth dimethylamino methoxy phosphine, and chlorodimethylamino methoxy phosphine. Phosphines such as phosphine, chlorinated isopropylamino methoxyphosphine, and chlorinated isopropylamino ethoxyphosphine are preferred. Nos. Ethoxyphosphine, chlorodisopropinolemino methoxyphosphine and chlorodiisopirua minosinoethoxy phosphine.

 The solvent to be used is not particularly limited as long as it does not affect the reaction, and is preferably an ether such as tetrahydrofuran, getylether, or dioxane.

Examples of the deoxidizing agent used include heterocyclic amines such as pyridine and dimethylaminopyridine, and aliphatic amines such as trimethylamine, triethylamine and diisopropylethylamine. Among them, preferred are aliphatic amines (particularly, diisopropylethylamine). The reaction temperature is not particularly limited, is usually one 5 0 to 5 0 ^D C, preferably a room temperature. The reaction time varies depending on the starting materials, reagents, temperature and the like to be used, but is usually 5 minutes to 30 hours, and preferably 30 minutes when reacted at room temperature.

 After completion of the reaction, the target compound is neutralized, for example, by appropriately neutralizing the reaction mixture.If any insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, followed by washing with water. Thereafter, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.

(Step 24)

In this step, in the seventh step, the nucleotide In this step, a CPG carrier (6-8) having a phosphate triester bond is obtained in the same manner except that the compound (6-3) is used in place of the compound (6-3).

(Steps 27 and 29)

 In this step, the CPG carrier (6-9) obtained in the 25th step was converted in the same manner as in the 24th and 25th steps (in the 29th step, these steps were repeated twice). A step of obtaining a CPG carrier (6-10) or (6-11) having two or three phosphoric acid ester bonds.

(Step 3)

 In this step, the compound (7—

2) and commercially available (2-cyanoethoxy)-[2- [2, -O- (4,4'dimethoxytrityloxoxetylsulfonyl] ethoxy)

(N, N-diisopropylpropylamino) phosphine (7-1) [Towns as Porn et al., Tetrahedron Letters 27, 4750 (19986)] and the 24th step In this step, a CPG carrier (7-3) having a 4,4'-dimethoxytrityloxhexylsulfo-lethoxy group is obtained.

(Step 34)

 In this step, the CPG carrier obtained in the 31st step (7-

This is a step of reacting the compound obtained by removing the DMT group in 3) with the compound (7-4) in the presence of a condensing agent to obtain the compound (7-5).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction, but an aromatic amine such as pyridine is preferably used. Examples of the condensing agent used include dicyclohexylcarpoimide (DCC), mesitylenesulfonic acid chloride (Ms—C1), triisopropylpropylbenzenesnorefonyl chloride, and mesitylene. Trisulfonic acid (MST), mesitylenesulfonic acid-3-ethoxytriazolide (MSNT), triisopropylpropyl benzene sulfonic acid tetrazolid (TPS-Te), triisopropyl benzene Examples thereof include sulfonic acid-troymidazolide (TPS-NI), and triisopropylbenzenesulfonic acid pyridyltetrazolide, and the like, and preferably, MSNT, TPS-Te, and TPS-NI.

The reaction temperature is one 1-0 to 1 0 0 ^D C, is not particularly limited, is typically carried out at a room temperature. The reaction time varies depending on the solvent used and the reaction temperature, but is 30 minutes when pyridine is used as the reaction solvent and the reaction is carried out at room temperature.

 After completion of the reaction, the target substance is collected by filtration, washed with an organic solvent such as methylene chloride, and used as it is in the next step.

(Step 37)

 In this step, compound (8) obtained in step 36, compound (3), compound (4-1a), compound (4-1b), compound (5), compound (6a), compound (6) b), the compound (6c), the compound (6d), the compound (7a) or the compound obtained by removing the DMT group at the 5′-terminal of the compound (7b), in the presence of an acid catalyst This is a step of condensing, then oxidizing, further cleaving CPG, and finally removing the protecting group, and purifying to obtain the target compound (1) of the present invention.

In the condensation reaction, the acid catalyst used is preferably tetrazol. The oxidizing agent used in the oxidation reaction is not particularly limited as long as it is usually used in the oxidation reaction, but is preferably a peracid such as m-chloroperbenzoic acid; Peroxides such as t-butyl hydroperoxide; iodine-pyridine-water.

 The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably a heterocyclic amide (particularly, pyridine). Tolyls (especially acetonitril), ethers

(Especially tetrahydrofuran) and halogenated hydrocarbons (especially methylene chloride).

 The reaction temperature is from −50 to 100 ° C. The reaction time varies depending on the reaction temperature, the starting compound and the type of solvent used, but is usually from 30 minutes to 15 hours. It is.

 In the above oxidation reaction, the reaction is accelerated by adding an interlayer transfer catalyst such as triethylbenzylammonium chloride or tributylbenzylammonium bromide.

 CPG cleavage and removal of the protecting group in the final step can be performed by a known method (J. Am. Chem. Soc., 103, 3185, (1981)). The reaction mixture thus obtained containing the compound of the general formula (1) is subjected to various chromatographies such as reversed-phase and ion-exchange chromatography (including high-performance liquid chromatography). However, the target compound can be obtained by performing purification using an operation usually performed in oligonucleotide purification.

(Step 38)

In this step, compound (2) is added to a phosphorylating reagent (for example, a V-substituted phosphorophosphoriazolide (V is a 2-cyclo phenyl group) in an inert solvent. In this case, this is a step of reacting 2-cyclopropane; r-nylphosphorobistriazolide) to obtain an intermediate mononucleotide (9).

 The solvent to be used is not particularly limited as long as it does not inhibit the reaction. Usually, an aromatic amine such as pyridine is used.

 The reaction temperature is not particularly limited to 120 to 10 ° C., but is usually carried out at room temperature. The reaction time varies depending on the solvent and the reaction temperature, but is 1 hour when pyridine is used as the reaction solvent at room temperature. After completion of the reaction, the desired compound is neutralized, for example, by appropriately neutralizing the reaction mixture, and removing any insoluble matter by filtration, and then adding an immiscible organic solvent such as water and ethyl acetate. After washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

 The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.

(Step 9)

 In this step, compound (9) obtained in step 38, compound (3), compound (4-a), (4-1b), (5), (6a), (6b ), (6c), (6d), (7a) and (7b) are condensed with those from which only the DMT group at the 5 'end has been removed, then the CPG is cleaved and finally the protecting group To obtain the compound (1) of the present invention.

 The solvent to be used is not particularly limited as long as it does not inhibit the reaction. Preferably, an aromatic amine such as pyridine is used.

Examples of the condensing agent used for the condensation include dicyclopropiamide (DCC), mesitylenesulfonic acid chloride (Ms—Cl), triisopropylpropylbenzenesulfonic acid chloride, medicament, and the like. Trisene azotylene citrate (MST), mesitylenesulfonic acid 1-3-2 trifluorotriazolide (MS NT), triisopropylpropylbenzenesulfonic acid tetrazolid (TPS—Te), triisopropylpropylbenzenesulfonic acid nitrite Loimidazolide (TPS-NI), triisopropylpropylbenzenesulfonate pyridylte tolazolide and the like can be mentioned, and MSNT, TPS-Te and TPS-NI are preferably used.

 The reaction temperature is not particularly limited and ranges from −10 to 100 ° C., but is usually carried out at room temperature. The reaction time varies depending on the solvent used and the reaction temperature, but is 30 minutes when pyridine is used as the reaction solvent and the reaction is carried out at room temperature.

 The cleavage of CPG and the removal of the protecting group in the final step can be performed by a known method (J. Am. Chem. Soc., 103, 3185, (1981)). The reaction mixture containing the compound of the general formula (1) thus obtained is subjected to various chromatographies such as reversed-phase and ion-exchange chromatography (including high-performance liquid chromatography). Then, the desired compound can be obtained by purifying it using a procedure generally used for oligonucleotide purification.

(Step 40)

 In this step, compound (2) is added to the compound (2) in an inert solvent, for example, according to the literature (B.C.

Tris- (1,2,4-triazolyl) phosphite prepared from phosphorus trichloride and 1,2,4-triazole according to Freohler, PG Ng and MD. Matteucci, Nucleic Acids Res., 145399 (1986)). To obtain nucleoside 3′H-phosphonate (10).

The solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride. You.

 The reaction temperature is from −20 to 100 ° C., although there is no particular limitation. Usually, the reaction is carried out at room temperature.

 The reaction time varies depending on the solvent and the reaction time, but is 30 minutes when the reaction is carried out at room temperature in methylene chloride.

 After completion of the reaction, the desired compound is neutralized, for example, by appropriately neutralizing the reaction mixture, and removing insolubles by filtration, adding an immiscible organic solvent such as water and ethyl acetate, and washing with water. The organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

 The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step 41)

 In this step, compound (10) obtained in step 40, compound (3), compound (4-1a), compound (414b), compound (5), compound (6a), compound (6a) 6b), compound (6c), compound (6d), compound (7a) or compound (7b) from which the DMT group at the 5 terminal has been removed is condensed in the presence of a condensing agent and a deoxidizing agent. And then oxidizing, and finally, the step of cleaving CPG under basic conditions and simultaneously removing the protecting group to obtain the compound (1) of the present invention.

 The solvent used is not particularly limited as long as it does not inhibit the reaction, but anhydrous acetonitril is preferably used.

 As the condensing agent to be used, carboxylic acid or acid chloride of phosphoric acid is used, and pivaloyl chloride is preferably used.

The oxidizing agents used are usually those used in oxidation reactions. Although it is not particularly limited, preferred are peracids such as m-chloroperbenzoic acid; peroxides such as t-butylhydroperoxide; iodine pyridine monohydrate.

 Examples of the deoxidizing agent used include heterocyclic amines such as pyridine and dimethylaminopyridine, and aliphatic amines such as trimethylamine, triethylamine and disopropylethylamine. Preferred are aliphatic amines (particularly diisopropyl eramine). Although the reaction temperature is not particularly limited, it is generally −50 to 50, and preferably room temperature.

 The reaction time varies depending on the starting materials, reagents, temperature and the like to be used, but is usually 5 minutes to 30 hours, and preferably 30 minutes when reacted at room temperature.

CPG cleavage and removal of protecting groups in the final step can be performed by a known method (J. Am. Chem. Soc., 103, 3185, (1981)). The reaction mixture containing the compound of the general formula (1) thus obtained is subjected to various chromatographies such as reverse phase and ion exchange chromatography (including high-performance liquid chromatography). The compound having the above general formula (1) can be obtained by purification using an ordinary procedure for nucleic acid purification such as chromatography. The compound (1) of the present invention and a pharmaceutically acceptable salt thereof exhibit excellent anti-HIV-1 activity, and the compound (1) and a pharmaceutically acceptable salt thereof can be used as a pharmaceutical (particularly, an anti-AIDS When used as tablets, tablets, capsules, granules, powders, or tablets, capsules, granules, powders or syrups, by themselves or mixed with appropriate pharmacologically acceptable excipients, diluents, etc. Orally by injection or parenterally by injection, etc. can do. These preparations may contain excipients (e.g., lactose, sucrose, glucose, sugar derivatives such as mannite, sorbitol; corn starch, potato starch, Hi-starch, dextrin, Starch derivatives such as carboxymethyl starch; microcrystalline cellulose, low-substituted hydroxypropyl propylcellulose, hydroxypropyl propylcellulose, canoleboxime phenolic cellulose, internal cross-linked carboxy carboxylate Cellulose derivatives such as methylcellulose sodium; arabia rubber; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, and magnesium metasilicate. Silicates, such as calcium phosphate Carbonates such as calcium carbonate; sulfates such as calcium sulfate; binders (eg, the above-mentioned excipients; gelatin; polybutylpyrrolidone; (Eg, the excipients mentioned above; chemically modified starches, celluloses, such as cross-carmello- sodium, carboxymethyl starch sodium, cross-linked polyvinyl pyrrolidone). Derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloid silica; veegum, Waxes such as gay mouth; boric acid; glycochol; fumaric acid; carboxylic acids such as adipic acid: sodium benzoate Sodium sulfate; sodium sulfate, such as sodium sulfate; oral isocyanate; sodium laurel, sodium laurate, magnesium, such as magnesium laurel sulfate Sulphate; silicic acid such as silicic anhydride and silicic acid hydrate , Such as starch derivatives in the above-mentioned excipients), stabilizers (for example, methylparapene, propylparapene, etc., elastenoyl laoxybenzoate), chlorobutanol, benzylol Alcohols such as anolecol and phenylethyl alcohol; benzalcoium chloride; phenol; phenols such as cresol; thimerosal; Acetic anhydride; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, sour agents, flavors, etc.), suspending agents (eg, polysorbate 80, phorenoruboximetylcell) It is manufactured by a well-known method using additives such as rose sodium, a diluent, and a formulation solvent (eg, water, ethanol, glycerin, etc.).

 The dosage varies depending on symptoms, age, etc., but for oral administration to adults, 0.1 to 2000 mg / day (preferably 1 to 100 mg / day). mg) per day in the case of intravenous administration, 0.1 to 2000 mg (preferably 1 to 100 mg) 1 to 6 times per day depending on the symptoms It is desirable to do it. It can also be administered continuously to maintain the concentration of compound (1) required for effective treatment. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Formulation Examples.

The nucleotide sequence (for example, TGGGGT) in the chemical formula shown below represents a triethylamine salt of oligodoxyribonucleotide having a nucleotide sequence corresponding to each of the 5 ′ ends, unless otherwise specified. , 5 'end It shall not contain hydroxyl groups at the terminal and 3 'terminal.

 In addition, a chemical name or a structural formula is appropriately used to indicate a target compound.

(Example 1)

パーキンエルマ一社製の 3 9 2 DNA/RNA シンセサイザ一に、 付属す る合成用試薬類を接続し、 プログラムと して ΙΟ /z molDNA 合成を使用し た。 但し、 このとき、 #5 のボトルに、 約 0. 1 M に調製した 5 ' — 0—

The attached synthesis reagents were connected to a 392 DNA / RNA synthesizer manufactured by PerkinElmer, Inc., and ΙΟ / z molDNA synthesis was used as a program. However, at this time, the 5 'bottle was adjusted to about 0.1 M in the # 5 bottle.

[(3,4-Dibenzyloxy) benzyl] thymidine-1 3 '— 0 — [(2—cyanoethyl) (N, N-diisopropyl) phosphoramidite]

Using an acetonitrile solution (described in Example 7b of JP-A-7-87982), a modified controlled-pore glass (CPG) was used as a solid phase carrier.

DMT-OCH ₂ CH ₂ OCCH ₂ CH ₂ CNHCH ₂ CH ₂ CH ₂ -<^^>

 0 0

7.5 μmol (as described in Example 12b of JP-A-7-87982) was weighed and used in an empty column for 10 // mol. By inputting the base sequence 5GGGGTT and running the program that does not perform acid treatment after binding the reagent of the last # 5 bottle, the oligonucleotide protected on CPG was constructed. The derivative was obtained. After drying under reduced pressure, remove it from the column and add about 10 mL of 29% ammonia The reaction was added to water, sealed, and reacted at room temperature for about 2 days. CPG was removed by filtration and washed twice with 1 Om of water. The filtrate and the washing solution were combined, and the aqueous solution was concentrated to about 4 mL under reduced pressure. The concentrated solution was heated at 90 ° C for 5 minutes, cooled on ice, and then reversed-phase silica gel column chromatography (Cosmosil 75C18-0PN, Nacalai Tesque, 1.5 × 15 cm; A: 50 mM bicarbonate) Lithium amine aqueous solution (TEAB), pH 7.5, B: acetonitrile; 10-50% B / lineargradient; 254 nm). The fractions eluted with about 30% acetonitrile are collected, the solvent is distilled off under reduced pressure, dissolved in about 1 O mL of water, and the solvent is distilled off again. The compound was obtained as 16.6 OD (260 ηm).

 This compound was analyzed by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetonitrile, 0.1 M triethylamine acetate aqueous solution (TE AA), pH 7.0, B: acetonitrile; 10-60% B / 20 min; 1 ineargradient; lml / min; 260 nm) eluted at 14.06 min.

_{UVmax (H 2 0): 256} nm

 (Example 2)

Synthesis was performed in the same manner as in Example 1 except that the nucleotide sequence 5GGGGTTT was input instead of 5GGGGTT. In the purification, reverse-phase silica gel column chromatography (Cosmosil 75C18-0PN, Nacalai Tesque, 1.5 × 15 cm; A: 50 mM TEAB, pH 7.5, B: acetonitril; 5-40% B; 1 ineargradient; 254 nm) was used. The same post-treatment as in Example 1 was carried out to obtain the desired compound in the form of ammonium in 230 OD (260 nm).

 This compound was analyzed by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetone nitrile, 0.1 MT E AA, pH 7.0, B: acetone nitrile) When analyzed by 10-60% BZ20 min; 1 ineargradient; 1 ml / min; 260 nm), it was eluted at 13.82 min.

UVmax (H ₂ 0): 258nm

 (Example 3)

Synthesis was performed in the same manner as in Example 1 except that the nucleotide sequence 5GGGGGTT was input instead of 5GGGGTT. In the purification, reverse phase silica gel column chromatography (Cosmosil 75C18-0PN, Nacalai Tesque, 1.515 cm; A: 50 mM TEAB, pH 7.5, B: acetonitrile Ril; 5-40% B; 1 ineargradient; 254 nm). The same post-treatment as in Example 1 was carried out to obtain a target compound in the form of amorphous (151 nm, 260 nm). This compound was obtained by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetate nitrile, 0.1 MT EAA, pH 7.0, B: acetate nitrite) When analyzed by 10% to 60% BZ for 20 minutes; 1 ineargradient; 1 ml / min; 260 nm), it was eluted at 13.76 minutes.

UVmax (H ₂ 0): 256nm (Example 4)

A nucleotide sequence of 5GGGCGT was input in place of 5GGGGTT, and synthesis was performed in the same manner as in Example 1 using 10 // mol of modified CPG. In the purification, reverse phase silica gel column chromatography (Cosmosil 75C18-0PN, Nacalai Tesque, 1.5 × 15 cm; A: 50 mM TEAB, pH 7.5, 8: acetonitrile; 1 0—40% 8; 11 neargradient; 25 4 nm) was used. The same post-treatment as in Example 1 was performed to obtain an amorphous target compound (270 nm, 260 nm).

 This compound was obtained by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetonitrile, 0.1 MT EAA, pH 7.0, B: acetonitrile; It was eluted at 15.39 minutes when analyzed by 10-60% BZ for 20 minutes; lineargradient; 1 ml; minute; 260 nm).

_{UVmax (H 2 0): 256} nm

 (Example 5)

A nucleotide sequence of 5GGGTGT was input in place of 5GGGGTT, and synthesis was performed in the same manner as in Example 1 using 10 μmol of modified CPG. Purification smell _{wo 99 1}

 109, reverse-phase silica gel column chromatography (Cosmosil 75C18-0PN, Nacalai Tesque, 1.515 cm; A: 50 mM TEAB, pH 7.5, B: acetonitrile; 1 0—40% B; 1 ineargradient; 254 nm) was used. The same post-treatment as in Example 1 was performed to obtain 310 O D (260 nm) of the target compound in an amorphous state.

 This compound was analyzed by reversed-phase HPLC (Wakosil WS-DNA, 4.6x150 mm; A: 5% acetonitrile, 0.1 MT E AA, pH 7.0, B: acetonitrine). Analysis was performed at 10-60% BZ for 20 minutes; lineargradient; 1 ml / min; 260 nm) and eluted at 15.42 minutes.

UVmax (H ₂ 0): 255nm

 (Example 6) Compound of compound number 1 229 in Table 1

A nucleotide sequence of 5GGGGGT was input in place of 5GGGGTT, and synthesis was performed in the same manner as in Example 1 using 10 μπιι of modified CPG. In the purification, reverse-phase silica gel column chromatography (Cosmosil 75C18-0PN, Narai Lightesque, 1.5 × 15 cm; A: 50 mM aqueous triethylamine bicarbonate (TEAB), pH 7. 5, B: donated to acetonitrile; 10-50% B 1 ineargradient (254 nm). The fractions eluted with about 30% acetonitrile are collected, evaporated under reduced pressure, dissolved in about 1 OmL of water, and the solvent is distilled off again to obtain an amorphous target compound. Was obtained at 167 OD (260 nm). The compound was analyzed by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pII 7.0, II When analyzed with 10 to 60% (acetonitrile; 20 minutes; 1 ineargradient; 1 ml, minute; 260 nm), it was eluted at 13.83 minutes.

_{UVmax (H 2 0): 254} nm

(Example 7) Compound of compound number 1 230 in Table 1

Synthesis was performed in the same manner as in Example 6, except that the nucleotide sequence was changed to 5GGGGGT instead of 5GGGGGT and then input. In the purification, reversed-phase silica gel column chromatography (Cosmosil 75C18-0PN, 1.5 x 15 cm; A: 50 m TEAB, pH 7.5, B: acetonitrile; 10-4 0% B; lineargradient; 254 nm). The same post-treatment as in Example 6 was performed to obtain 227 OD (260 nm) of an amorphous target compound.

 This compound was obtained by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetate nitrile, 0.1 MTE AA, pH 7.0, B: acetate nitrile; When analyzed by 10-60% BZ 20 min; linear gradient; 1 m 1 min; 260 nm), it was eluted at 15.28 min.

_{UVmax (H 2 0): 255nm} Q (Example 8) Compound of compound number 1 2 3 1 in Table 1

(8a) 0- (4,4'-Dimethoxytrityl) Ethylene glycol-0- (2-Cyanoethyl N, N-diisopropyl) Phosphoroamidite

 0-(4,4'-Dimethyloxytrityl) ethylene glycol (Japanese Unexamined Patent Publication No. 7-8

317 mg (0.84 mmol) was dissolved in pyridine, distilled off, and dried. To this, methylene chloride (3 ml) was added and dissolved, and diisopropyrethylamine 0.61 ml (3.48 mm o)

1) was added and the atmosphere was replaced with nitrogen. There, 2-cyanoethyl N, N diisopropyl chloro mouth phosphoramidite 0.23 ml (1.04 mmo

1) was added dropwise over 2 minutes. After stirring at room temperature for 60 minutes, the disappearance of the starting materials was confirmed by TLC, and ethyl acetate (30 ml) was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was filtered using IPS filter paper (trade name, manufactured by Wattman), the solvent was distilled off, and the residue was subjected to silica gel column chromatography (70-230 mesh, 16 g, eluent). Hexane: ethyl acetate = 3: 1) and purification gave 270 _mg (55%) of the desired compound as an oil.

1 H-NMR (270MHz, CDC1 3, TMS) δ ppm: 7.48-7.19 (9Η, m, Ph), 6.84- 6.80 (4H, m, Ph), 3 · 87- 3.58 (12H, m, - 0CH 3 _{, P0CH 2 and PNCH), 3.26-} 3.21 (2H, m, DMTr- 0- CH 2), 2.62-2.58 (2H, m, CH 2 CN), 1.26-1.17 (12H, m, CH 3).

 (8 b)

In the # 6 bottle, use the acetonitrile solution (8a) adjusted to about 0.1 M and change the base sequence to 5GGGG6T instead of 5GGGGGT and input. Then, it was synthesized in the same manner as in Example 1 using 10 μmol of the modified CPG. For purification, reverse-phase silica gel column chromatography (Cosmosil 75C18-OPN, 1.5 xl 5 cm; A: 50 mM TEAB, pII7.5, B: acetonitrile; 10 — 40 % B; 1 ineargradient; 254 nm). The same post-treatment as in Example 6 was performed to obtain 89 OD (260 nm) of the target compound in an amorphous state. This compound was analyzed by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetate nitrile, 0.1 MTE AA, pH 7.0, B: acetate nitrile; 10 — 60% B / 20 min; lineargradient; 1 m 1 / min; 260 nm) eluted at 15.19 min.

_{UVmax (H 2 0): 255} nm.

(Example 9) Compound of compound number 1 2 32 in Table 1

In the bottle of # 6, use the acetate solution of (8a) adjusted to approximately 0.1 M, change the nucleotide sequence to 5GGGG66T instead of 5GGGGGT, and enter the modified CPG 10 μιηοΐ. And synthesized in the same manner as in Example 1. However, in the purification, reverse phase silica gel column chromatography (Cosmosil 75C18-0PN, 1.5 x 15 cm; A: 50 mM TEAB, pH 7.5, B: acetonitrile; 1 0 — 40% B; lineargradient; 254 nm) was used. The same post-treatment as in Example 6 was carried out to obtain an amorphous target compound at 1966 OD (260 nm). This compound was obtained by reversed-phase HPLC (Wakosil WS-DNA, 4.6 x 150 mm; A: 5% acetate nitrile, 0.1 MTE AA, pH 7.0, B: acetone nitrile; 10 — 60% B / 20 min; lineargradient; 1 m1 / min; 260 nm) eluted at 15.4 min.

_{UVmax (11 2 0): 25½m} .

(Example 10) Compound of compound number 1 2 3 3 in Table 1

The nucleotide sequence was changed to 5GGGAG6T in place of 5GGGGGT, and the sequence was input and synthesized in the same manner as in Example 6. The same post-treatment as in Example 1 was carried out to obtain 150 OD (260 nm) of the target compound in the form of amorphous.

 This compound was analyzed by reversed-phase HPLC (Symmetry, 3.9 x 150 mm; A: 5% acetonitril, 0.05 MTE AA, pH 7.0, B: acetonitril; 10—40% B / 4 5 min; lineargradient; 1 m 1 Z min; 260 nm) eluted at 31.64 min.

Was eluted.

_{UVmax (H 2 0): 254nm} G

 (宾 Example 11) Compound No. 1 2 3 4 in Table 1

ο ο ο

CH ₂ 0 "-CH _2- " 0-TGGGAG-0-P.OCH ₂ CH ₂ 0-P-OCH, CH, 0-P-OCH, CH ₂ OH

 OH OH OH

Change the base sequence to 5GGGAG66T instead of 5GGGGGT and enter it. O 99/19474

 114 Synthesized in the same manner as in Example 6. The same post-treatment as in Example 1 was carried out to obtain 16.5 OD (260 nm) of the target compound in an amorphous state.

 This compound was analyzed by reversed-phase HPLC (Symmetry, 3.9 x 150 mm; A: 5% acetonitrile, 0.05 MTE AA, pH 7.0, B: acetonitrile; 10—40% When analyzed by B / 4 5 min; linear gradient, 1 Z min; 260 nm), it was eluted at 31.20 min.

Was eluted.

 UV max (11,0): 254 nm.

(Reference example 1)

0

CH ₂ -0-TGGGAG-0-P-OCH ₂ CH ₂ OH

 OH It was synthesized according to the method described in Example 94 of JP-A-7-87982.

(Formulation Example 1) Injection

Prepare 1.5% by weight of the compound of Example 1 in 10% by volume of propylene glycol, make up to volume with water for injection, and sterilize.

(Formulation Example 2) Tablet 1

 1) Compound 200 of Example 1

 2) Sodium pyrophosphate 5

3) Aerosil 2 0 0 5 4) Magnesium stearate 5

 9 9 7 mg

 Of the above, 5) to 8) were mixed and granulated, and 1) to 4) were mixed and pulverized, and the mixture was pulverized using a tableting machine. Tablets.

(Formulation Example 3) Capsule

 1) Compound of Example 1 200

2) Calcium hydrogen phosphate 200 0

 3) Aluminum silicate 3 4 5

 4) Microcrystalline cellulose 250

5) Magnesium stearate 2

 9 9 7 mg in total

Mix and pulverize the above 1) to 5), pass through a sieve, mix well, and make 200 mg capsules according to the usual method.

(Formulation example 4) Hard capsule

Fill each of the standard bipartite hard gelatin capsules with 100 mg of the powdered Example 1 compound, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. A unit capsule is manufactured, washed and dried. (Formulation Example 5) Soft capsule

 A mixture of the compound of Example 1 in a digestible oil, for example soybean oil, cottonseed oil or olive oil, is prepared and poured into gelatin with a positive displacement pump to give 100 mg of the active ingredient. The resulting soft capsules are obtained, washed and dried.

(Formulation Example 6) Tablet 2

 In a conventional manner, 100 mg of the compound of Example 1, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose Manufacture using. Hereinafter, the effects of the present invention will be specifically described with reference to test examples. (Test Example 1) Measurement of anti-HIV-1 activity of modified oligodeoxyribonucleotide

Anti-HIV-1 activity was measured by the method of Pawell et al. (R. Pauel et al., J. Virological Methods 20, 309-321 (1988)). That is, MT-4 cells in the logarithmic growth phase are centrifuged at 150 × g for 5 minutes, and the resulting cell pellet is suspended in a medium, and HIV-1 (type IIIB) is suspended in 10 CCID ₅ . At 37 ° C for 1 hour. Then, the cells were centrifuged and washed with RPMI-1640 medium containing 10% fetal bovine serum (hereinafter referred to as "serum medium") to obtain HIV-1 infected MT-4 cells.

HIV-1 infected MT-4 cells and HIV-1 uninfected MT-4 cells were each suspended in serum medium at 4 × 10 ⁵ cells / ml. A sample compound solution (dissolved in serum medium) serially diluted in advance was placed in a 96-well plastic microtiter plate at 100 μl / well. 100 μl of the above cell suspension was added to each well, and the cells were incubated for 6 days in the presence of 5% carbon dioxide.

 Similarly, HIV-1 infected ΜΤ-4 cells with the test compound and HIV-1 non-infected ΜΤ-4 cells without the test compound were cultured.

 After completion of the culture, the number of viable cells was measured based on the ΜΤΤ (3- (4,5-dimethylthiazole-2-yl) -2,5-dipheny ltet razolium bromide) method (M. Green et al., J. Immunol.

Methods, 70, 257-268 (1984)), and cytotoxicity by HIV-1 was determined. The cytotoxic activity of HIV-1 infected MT-4 cells without the addition of the test compound is defined as 100%, and the cytotoxic activity of HIV-1 (IIIB) uninfected MT-4 cells without the test compound is defined as 0%. Then, the concentration (IC ₅₀ ) of a sample capable of suppressing the cytotoxic activity of HIV-1 infected MT-4 cells by ₅₀ % was determined. As the cytotoxic activity of the test compound, a concentration (CC ₅₀ ) at which proliferation of HIV-1 non-infected MT-4 cells was inhibited by ₅₀ % was determined. Table 2 shows the measurement results.

It should be noted that, in this study, IC _5. And CC ₅ . Since the value may vary from test to test depending on the state of the cells, the compound of Reference Example 1 was used as a comparative compound. Compound IC ₅ of Reference Example 1. With a value of 1. 0, IC ₅ an IC ₅₀ value of the compound of Reference Example 1 of the compound of each Example. IC ₅ by dividing the value in value. Relative values were used.

The compound of Reference Example 1 is the compound disclosed in Example 94 in JP-A-7-87982. (Table 2) Compound I c 5 OIC _so relative value CC ₅ .

 (μg / ml) (μg / ml) Example 10 0.2 0.4> 50

 2 0.2 0.4〉 5 0

 3 0.6 0. 3 2〉 5 0

 6 0 .2 0 .4〉 50

 8 0.2 0.2 4〉 5 0

 9 0.8 0.8 0.3 6〉 50

 1 0 1.2 0 0.75〉 50

Reference Example 10.5 1.0> 50 As a result, it was revealed that all of the modified oligodeoxyribonucleotides shown in Table 2 have excellent anti-HIV-1 activity.

 Here, the compounds of Examples 1, 2 and 3 are 2.5 times or more the compound of Reference Example 1 [the compound disclosed in Example 94 in JP-A-7-87982]. Demonstrated excellent anti-HIV-1 activity. INDUSTRIAL APPLICABILITY The compound of the present invention has a specific damaging activity against AIDS virus (HIV-1), and can specifically inhibit the growth of the virus in infected cells. Therefore, the compounds of the present invention are useful as therapeutic and prophylactic agents for AIDS diseases.

Claims

The scope of the claims 1. General formula (1)

[Q is an R RsRsZ group (wherein, R i, R ₂ and R ₃ are each independently the same or different and are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and an aryl which may have a substituent. Z represents C or Si; or R ₂ , R ₃ and Z together form a fluorenyl group or a xanthyl group. And R ₄ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which may have a substituent, an aryl group which may have a substituent or a substituent.示 し 1, Y ₃ and Y ₄ are the same or different and represent 0, S or 、; Υ ₂ is 0, S, ΝΗ, an alkylene group having 1 to 4 carbon atoms or And X represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a hydroxyl group. , M and η are the same or different and each represent an integer of 0 to 10, and Β represents the sequence オ リ ゴ an oligodeoxyribonucleotide selected from the group consisting of GGGGT, TGGGGTT, TGGGGGT, TGGGCG, TGGGTG, TGGGG, TGGGGG or TGGGAG. , ODN). However, in B, the hydroxyl groups at the 5 'end and 3' end of each oligodeoxyribonucleotide are not included. The left end of each sequence is the 5 'end, and the right end is the 3' end. Further, B is TGGGG or TGGGG In the case of G, the length 尺 is a 3,4- (dibenzyloxy) phenyl group, R ₂ , R ₃ and R ₄ are each a hydrogen atom, X is an ethylene group, and Y ₂ , Upsilon ₃ and Upsilon ₄ are each an oxygen atom, Zeta is carbon atom, m is 1 to 3, n is 1. Also, if B is TGGG AG is Ri but 3, 4 one (Jibenjiruokishi) phenyl group der is R _2, R ₃ and R ₄ are each a hydrogen atom, X is an ethylene group, Upsilon _{1 [lambda} Upsilon _2, Upsilon ₃ and Upsilon ₄ are each an oxygen atom, Zeta is carbon atom, m is 2 to 3, n is 1. Or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, wherein B is an oligodeoxyribonucleotide selected from the sequence TGGGGT, TGGGGTT, TGGGGT, TGGGG, TGGGG, or TGGGAG. 3. The 5′-end group (RiRsRgZ- 丫) obtained by the combination of shaku, R ₂ , R ₃ , 丫 and Z according to claim 1, triphenylmethyloxy, 3,4- (Dibenzyloxy) benzinoleoxy, 3, 5- (dibenzyloxy) benzyloxy, 3,5-bis [3,5- (dibenzyloxy) benzyloxy] benzyloxy, t-butyl diphenylenoloxy, phenylenoloxy lanthanoxy, phenylenoxy group, R ₄ , Χ, γ ₂ , γ ₃ , γ ₄ , _m and _η , 3, the terminal group ([P (0) (Y ₂ R ₄ ) -Υ 3-(X—Υ ₄ ) _η ] _m Η) Force, hydrogen, methylphosphoryl, 2-chloro phenolephosphorinole, (ο-methinole) thi phosphorinole, methinolephosphonyl, methylthiophosphonyl, phenylphosphonyl, 2-hydroxyethylphosphoryl, [ Ο— (2-hydroxyschityl)] Nore, phoenorephosphorinol, 41-cloth phoenorephosphorinol, .2-ethnophine phoenorephosphorinole, 412 trofeninolephosphorinole, ethinolefoshol, (O —Echinole) Thiophosphorinole, 2— (2-Hydroxyshetchylphosphoryloxy) ethynolephosphoryl, 2- [2- (2-Hydroxyshettinolephosphorinoxy) ethynolephosphorinoxy] Etinolephosphoryl group, and B is the sequence T A compound which is an oligodeoxyribonucleotide selected from GG GGT, TG GG TT, TGG GG GT, TG GGCG or TG GG TG. 4. The 5 ′ terminal group (Ri Rs Rg Z—Yi) obtained by the combination of R i, R ₂ , R ₃ , and Z according to claim 1, triphenylmethyloxy, 3,4- (dibenzyloxy) pendinoleoxy , 3, 5 - (Jibenjiruokishi) a Benjiruokishi _{group, R 4, X, Y 2} , Υ 3, Υ 4, obtained by a combination of m and eta 3 'end of the group ([Ρ (O) (Y 2 R ₄ )-Y _3- (X-Υ ₄ ) _η ] _m Η) is hydrogen, methylphosphorinole, 2-cyclohexylphosphinolene, (Ο-methinole) thiophos phosphorinole, methinolephosphoninole, methinoletin Phosphorinole, Phenoinole Phosphoegre, 2-Hydroxyshetinolephosphorinole, [Ο— (2-Hydroxyshetyl)] Thiophosphoryl, 2- (2-Hydroxyshetylphosphoryloxy) ethylphosphoryl, 2- [2 — (2— ヒLoki Chez a chill phosphodiester Riruokishi) Echiruhosuho Riruokishi] Echiruhosuhoriru group, beta is arranged T GG GGT, TGG GGTT or TG GG GG T compounds oligo de O carboxymethyl ribonucleotides selected from. 5. The 5 ′ terminal group (R i Rs RZ—force S, 3, 4—) obtained by the combination of R ₁ R ₂ , R ₃ , and Z according to claim 1. (Dibenzyloxy) is a benzyloxy group, a group at the 3 ′ terminal obtained by a combination of R ₄ , X, Y ₂ , Υ ₃ , Υ ₄ , m and η ([Ρ (Ο) (Y ₂ R ₄ )-Y _3- (X-Υ ₄ ) _η ] _ιη Η) mosquito, 2-hydroxy-2-hydroxyphosphoryl, 2- (2-hydroxyoxyl phosphoryloxy) ethyl phosphoryl, 2- [2- (2-hydroxyhexyl phosphoryloxy) ethyl phosphoryloxy] is an ethyl phosphoryl group, and Β is selected from the sequence TG GGGT, TG GGG TT or TGG G GG T A compound that is a nucleotide. 6-General formula

[Wherein, B represents oligodeoxyribonucleotide represented by the sequence TGGGG or TGGGGG, and m represents 1, 2 or 3. In B, G represents guanine deoxyribonucleotide and T represents thymine deoxyribonucleotide. It does not include hydroxyl groups at the 5 'end and 3' end of each oligodeoxyribonucleotide. The left end of each sequence is the 5 'end, and the right end is the 3' end. ] The compound represented by these. 7. General formula

O 99/19474  one two Three [Wherein, B represents oligodeoxyribonucleotide represented by the sequence TGGG AG, and m represents 2 or 3. However, in B, A represents adene deoxyribonucleotide, G represents guanine deoxyribonucleotide, and T represents thymine deoxyribonucleotide. Also, the hydroxyl groups at the 5 'end and the 3' end of the oligodeoxyribonucleotide are not included. The left end of the sequence is the 5 'end and the right end is the 3' end. ] The compound represented by this. 8. A compound selected from the above-mentioned compounds or a pharmacologically acceptable salt thereof;

H0 ² H0 ² HO

9 strokes 6dfAL3 <I 9. A medicament comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.  10. An anti-AIDS agent comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.  11. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for producing a medicament.  12. Use of the compound according to claim 1 or a pharmacologically acceptable salt thereof for producing an anti-AIDS agent.