JP2000212191A - Phosphoric acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having high cell membrane permeability and high intracellular calcium ion concentration raising activity. SOLUTION: This new compound is a compound of formula I R1 is H or the like; R2 and R3 are each H or an ester-forming group; R4 to R6 are each a group of formula II (R9 and R10 are each OH, mercapto, a 1-4C alkoxy, or the like; X is O or S); R7 is H or a (ester-formed) OH; wherein excepting such compounds that R1 is not H; R2, R3, etc., are each H; R4 to R6 are each a phosphoric acid residue [P(=O) (OH)2]; and R7 is OH), e.g. 3'-O-[α-D-(3,4-bis-O- diethylphosphoryl)glucosyl]-2'-O-(diethylphosphoryl)adenosine. The compound of formula I is obtained, for example, by reaction between a compound of formula III (Bn is benzyl; R1a is H or the like; R2a and R3a are each 4- methoxytrityl or the like) and a compound of formula IV followed by addition of an oxidizing agent to afford a compound of formula V as one of the objective compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel phosphate derivative having excellent cell membrane permeability and excellent activity for increasing intracellular calcium ion concentration.

[0002]

2. Description of the Related Art It is widely known that calcium ions are important as intracellular signaling substances for nerve transmission, muscle contraction, cell growth and differentiation, establishment of fertilization, and the like.

Inositol 1,4,5-trisphosphate (InsP ₃ ) is said to play an important role in mobilizing calcium ions into cells (Nature, 341).
197-205 (1989)). That, InsP ₃ is produced from cell membrane phospholipids (Nature, 312, pp. 315-321 (1
984 years)), binds to InsP ₃ receptors located on the endoplasmic reticulum (Nat
As a result, calcium ions stored in the endoplasmic reticulum are released and the intracellular calcium ion concentration increases (Nature, 342, 87-89).
P. (1989)).

[0004] InsP ₃ and bonded to the same manner InsP ₃ receptors, as a compound having a calcium ion concentration increasing activity, Adenohosuchin (adenophostin) such that the following, Penicillium br
evicompactum found in cultures of SANK 11991 and SANK 12177 strains (JP-A-5-19580, J. Antibio
t., 47, 95-100 (1994)).

[0005]

Embedded image (Where R is a hydrogen atom is adenophosphin A and R is an acetyl group is adenophosphin B.) When the adenophosphin B is injected into an oocyte, calcium oscillation (Ca ²⁺ oscillations) occurs. Happens,
It is known that the activation of oocytes improves the efficiency of artificial fertilization (Biology of Reproduction 5
8, 867-873 (1998)).

However, these compounds have not been sufficiently satisfactory in terms of cell membrane permeability.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel phosphoric acid derivative having excellent cell membrane permeability and excellent activity for increasing intracellular calcium ion concentration.

[0008]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, a novel phosphoric acid derivative has excellent cell membrane permeability and excellent cell membrane permeability. The present inventors have found that they have an activity to increase the internal calcium ion concentration, and completed the present invention.

The novel phosphoric acid derivative of the present invention comprises: 1) a compound represented by the general formula (I):

[0010]

Embedded image [Wherein, R ¹ is a hydrogen atom or a formula (II)

[0011]

Embedded image (Wherein, R ⁸ represents a hydrogen atom or a group forming an amide), R ² and R ³ are the same or different and represent a hydrogen atom or a group forming an ester, R ⁴ ,
R ⁵ and R ⁶ are the same or different and have the formula (III)

[0012]

Embedded image (Wherein R ⁹ and R ¹⁰ are the same or different and each is a hydroxyl group, a mercapto group, a C ₁ -C ₄ alkoxy group, a (C ₁ -C ₅ aliphatic acyl) oxy- (C ₁ -C ₃ alkyl) oxy Group or (C ₁ -C ₅
X represents an aliphatic acyl) thio- (C ₁ -C ₃ alkyl) oxy group, and X represents an oxygen atom or a sulfur atom. ), And R ⁷ represents a hydrogen atom or a hydroxyl group which may form an ester.

However, R ¹ is not a hydrogen atom, but R ² , R ³ and
A compound wherein R ⁸ is all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphate residues (P ((O) (OH) ₂ ) and R ⁷ is a hydroxyl group, and R ¹ is A compound in which R ² and R ⁸ are hydrogen atoms, R ³ is an acetyl group, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues, and R ⁷ is a hydroxyl group, not a hydrogen atom, and ,
Except for compounds in which R ¹ , R ² and R ³ are all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues and R ⁷ is a hydroxyl group. Or a pharmacologically acceptable salt thereof, preferably 2) a compound of the general formula (IV)

[0014]

Embedded image [Wherein, R ¹ is a hydrogen atom or a formula (II)

[0015]

Embedded image (Wherein, R ⁸ represents a hydrogen atom or a group forming an amide), R ² and R ³ are the same or different and represent a hydrogen atom or a group forming an ester, R ⁴ ,
R ⁵ and R ⁶ are the same or different and have the formula (III)

[0016]

Embedded image (Wherein R ⁹ and R ¹⁰ are the same or different and each is a hydroxyl group, a mercapto group, a C ₁ -C ₄ alkoxy group, a (C ₁ -C ₅ aliphatic acyl) oxy- (C ₁ -C ₃ alkyl) oxy Group or (C ₁ -C ₅
X represents an aliphatic acyl) thio- (C ₁ -C ₃ alkyl) oxy group, and X represents an oxygen atom or a sulfur atom. ), And R ⁷ represents a hydrogen atom or a hydroxyl group which may form an ester.

However, R ¹ is not a hydrogen atom, but R ² , R ³ and
A compound wherein R ⁸ is all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphate residues (P ((O) (OH) ₂ ) and R ⁷ is a hydroxyl group, and R ¹ is A compound in which R ² and R ⁸ are hydrogen atoms, R ³ is an acetyl group, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues, and R ⁷ is a hydroxyl group, not a hydrogen atom, and ,
Except for compounds in which R ¹ , R ² and R ³ are all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues and R ⁷ is a hydroxyl group. Or a pharmacologically acceptable salt thereof.

Among the compounds of the present invention, more preferred are: 3) In any one selected from claim 1 or 2, R ¹ is a group represented by the formula (II)

[0019]

Embedded image (Wherein, R ⁸ represents a hydrogen atom or a group forming an amide). 4) R ² and R ³ are the same or different and have a hydrogen atom or a substituent. A compound which is a C ₁ -C ₁₂ aliphatic acyl group or a C ₆ -C ₁₄ aromatic acyl group which may have a substituent, 5) wherein R ² and R ³ are the same or different and are each a hydrogen atom Or a compound which is a C ₁ -C ₁₂ aliphatic acyl group which may have a substituent, 6) R ² and R ³ are the same or different and are each a hydrogen atom, a C ₁ -C ₆
Aliphatic acyl group, or, (C ₁ -C ₄ alkyl) oxycarbonyl amino - (C ₃ -C ₈ aliphatic acyl) compounds is a group, 7) R ² and R ^3, represent hydrogen atom, 8) A compound wherein R ⁷ is a hydrogen atom or a hydroxyl group; 9) a compound wherein R ⁷ is a hydroxyl group; 10) a compound wherein R ⁸ is a hydrogen atom or a C _1- which may have a substituent;
C ₁₂ aliphatic acyl group or C ₆ -C optionally having a substituent
₁₄ a compound which is an aromatic acyl group, 11) R ⁸ is a hydrogen atom or a C ₁ which may have a substituent
-C ₁₂ compound is an aliphatic acyl group, 12) R ⁸ is a hydrogen atom or a C ₁ -C ₆ compound is an aliphatic acyl group, 13) a compound wherein R ⁸ is a hydrogen atom, 14) R ⁹ and R ¹⁰ is the same or different and represents a C ₁ -C ₄ alkoxy group, a (C ₁ -C ₅ aliphatic acyl) oxy- (C ₁ -C ₃ alkyl) oxy group or a (C ₁ -C ₅ aliphatic acyl) Thio- (C ₁
-C ₃ alkyl) group, Compound, 15) R ⁹ and R ¹⁰ are the same or different, C ₁ -C ₄ alkoxy groups, (C ₁ -C ₅ aliphatic acyl) oxy - methyl group or ( A compound which is a C ₁ -C ₅ aliphatic acyl) thio-ethyloxy group, 16) R ⁹ and R ¹⁰ are the same and are an ethoxy group, an acetoxymethyloxy group, a pivaloyloxy-methyloxy group or an acetylthio-ethyloxy group 17) A compound wherein X is an oxygen atom, or a pharmacologically acceptable salt thereof.

Among these, particularly preferred compounds are: 18) 3'-O- {α-D- (3,4-bis-O-diethylphosphoryl) glucosyl} -2'-O- (diethylphosphoryl) adenosine , 3'-O- [α-D- ｛3,4-bis-O-di (2-acetoxyethyl)
Phosphoryl｝ glucosyl] -2'-O- ｛di (2-acetoxyethyl) phosphoryl｝ adenosine, 3'-O- ｛α-D- (3,4-bis-O
-Di-n-butylphosphoryl) glucosyl｝ -2′-O- (di-n-butylphosphoryl) adenosine or 3′-O- ｛α-D- (3,4-
Bis-O-di-n-butylphosphoryl) -2-deoxyglucosyl {-2'-O- (di-n-butylphosphoryl) adenosine or a pharmaceutically acceptable salt thereof.

R^TwoAnd R^ThreeForming an ester in the definition of
Examples of the `` group to do '' include an ester of a hydroxyl group
The group is not particularly limited as long as it is an alkylcarbonyl group.
Group, carboxylated alkylcarbonyl group, halogeno lower
Alkylcarbonyl group, lower alkoxy lower alkyl group
Rubonyl group, lower alkoxycarbonylamino lower alkyl
Such as a killcarbonyl group and an unsaturated alkylcarbonyl group.
"Aliphatic acyl group optionally having substituent (s)";
Carbonyl group, halogenoarylcarbonyl group, lower
Alkylated arylcarbonyl group, lower alkoxylated
Reel carbonyl group, carboxylated aryl carbonyl
Group, nitrated arylcarbonyl group, lower alkoxyca
Rubonylated arylcarbonyl group, arylated aryl
An aromatic group which may have a substituent such as a carbonyl group
"Sil group"; "Alkoxycarbonyl group"; "Alkenyl"
Oxycarbonyl group ";" aralkyloxycarbonyl
Group '', and preferably, `` may have a substituent
Aliphatic acyl group "and" optionally substituted
Aromatic acyl group '', and more preferably, `` having a substituent
May be C<sub>1</sub>−C<sub>12</sub>An aliphatic acyl group '' and a `` substituent
C that you may have₆−C ₁₄Aromatic acyl group ".

The “hydroxyl group which may form an ester” in the definition of R ⁷ is the above “group that forms an ester”
And a hydroxyl group, preferably an "optionally substituted aliphatic acyl-oxy group", "optionally substituted aromatic acyl-oxy group". Group "and a hydroxyl group, and more preferably a hydroxyl group.

"Amide-forming group" in the definition of R ⁸
Is not particularly limited as long as it is a group exemplified as an amide, and examples thereof include an “optionally substituted aliphatic acyl group” such as an alkylcarbonyl group, a lower alkoxy lower alkylcarbonyl group, and an unsaturated alkylcarbonyl group. ;
Having a substituent such as an arylcarbonyl group, a halogenoarylcarbonyl group, a lower alkylated arylcarbonyl group, a lower alkoxylated arylcarbonyl group, a nitrated arylcarbonyl group, a lower alkoxycarbonylated arylcarbonyl group, or an arylated arylcarbonyl group; An "optionally substituted aromatic acyl group"; an "alkoxycarbonyl group"; an "alkenyloxycarbonyl group"; an "aralkyloxycarbonyl group"; preferably an "optionally substituted aliphatic group". Acyl group '' and `` aromatic acyl group which may have a substituent ''
More preferably, `` optionally substituted C ₁ -C ₁₂ aliphatic acyl group '' and `` optionally substituted C ₆ -C
₁₄ aromatic acyl groups ”.

The "lower alkyl" group in the definition of the "group forming an ester" and the "group forming an amide" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- Butyl, tert
-Butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl,
Isohexyl, 4-methylpentyl, 3-methylpentyl,
2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl.

The "lower alkoxy" group in the definition of the "group forming an ester" and the "group forming an amide" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s
-Butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-
Straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, and 2,3-dimethylbutoxy; Can be

The “C ₁ -C ₁₂ aliphatic acyl” group in the definition of the “group forming an ester” and the “group forming an amide” includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, A linear or branched alkylcarbonyl group having 1 to 12 carbon atoms such as isovaleryl, pivaloyl, octanoyl, nonanoyl, decanoyl, undecanoyl, 8-methyldecanoyl, 3-ethylnonanoyl, 3,7-dimethylnonanoyl, dodecanoyl. can give.

The “C ₆ -C ₁₄ aromatic acyl” group in the definition of the “group forming an ester” and the “group forming an amide” includes, for example, benzoyl, α-naphthoyl, β-naphthoyl, An aromatic acyl group having 1 to 14 carbon atoms such as phenylbenzoyl is exemplified.

The “C ₁ -C ₄ alkoxy group” in the definition of R ⁹ and R ¹⁰ is, for example, a straight or branched chain having 1 to 4 carbon atoms among the groups exemplified as the above “lower alkoxy” group. An alkoxy group is mentioned, and ethoxy, n-propoxy and n-butoxy groups are preferred.

The "(C ₁ -C ₅ aliphatic acyl) oxy- (C ₁ -C ₃ alkyl) oxy group" and "(C ₁ -C ₅ aliphatic acyl) thio- () in the definition of R ⁹ and R ¹⁰ The “C ₁ -C ₅ aliphatic acyl” group in the “C ₁ -C ₃ alkyl) oxy group” includes
For example, among the groups exemplified as the above-mentioned “C ₁ -C ₁₂ aliphatic acyl” group, a straight-chain or branched-chain alkylcarbonyl group having 1 to 5 carbon atoms can be mentioned. As the “C ₁ -C ₃ alkyl” group, Is
For example, among the groups exemplified as the above “lower alkyl” group,
Examples thereof include an alkyl group having 1 to 3 carbon atoms.

The “(C ₁ -C ₅ aliphatic acyl) oxy- (C ₁ -C ₃ alkyl) oxy group” in the definition of R ⁹ and R ¹⁰ is, for example, acetoxymethyloxy, pivaloyloxymethyl Oxy and acetoxyethyloxy groups are exemplified, and preferred are acetoxymethyloxy and pivaloyloxymethyloxy groups.

The “(C ₁ -C ₅ aliphatic acyl) thio- (C ₁ -C ₃ alkyl) oxy group” in the definition of R ⁹ and R ¹⁰ is, for example, acetylthioethyloxy, pivaloylthiopropyl An oxy group is mentioned, preferably an acetylthioethyloxy group.

The "pharmacologically acceptable salt" means the compound (I) of the present invention, which can be converted into a salt, and the salt is preferred. Alkali metal salts such as potassium salts, lithium salts,
Calcium salts, alkaline earth metal salts such as magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, metal salts such as cobalt salts; inorganic salts such as ammonium salts, t-octylamine salts, Dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, Amine salts such as chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, organic salts such as tetramethylammonium salts, tris (hydroxymethyl) aminomethane salts; hydrofluoric acid salts, hydrochloric acid Salt, hydrobromide, hydrogen iodide Hydrohalide such as salts,
Inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; methanesulfonate, trifluoromethanesulfonate,
Lower alkane sulfonates such as ethane sulfonate, benzene sulfonates, aryl sulfonates such as p-toluene sulfonate, acetic acid, malic acid, fumaric acid
Oxalate, succinate, citrate, tartrate, oxalate,
Organic acid salts such as maleic acid salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates.

When the compound (I) of the present invention is left in the air, it may absorb water and may absorb adsorbed water or form hydrates. Included in the invention.

Specific examples of the compound (I) of the present invention include:
For example, compounds as shown in Table 1 below can be mentioned.

[0035]

Embedded image

[0036]

Table 1 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Compound No.R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 1 HHHP ¹ P ¹ P ¹ OH − 2 H Byr Byr P ¹ P ¹ P ¹ OH − 3 HHHP ⁵ P ⁵ P ⁵ OH − 4 HHHP ⁷ P ⁷ P ⁷ OH − 5 H Byr Byr P ⁷ P ⁷ P ⁷ OH − 6 HHHP ¹³ P ¹³ P ¹³ OH − 7 H Byr Byr P ¹³ P ¹³ P ¹³ OH − 8 HHHP ¹⁷ P ¹⁷ P ¹⁷ OH − 9 HHHP ²² P ²² P ²² OH − 10 HHHP ²³ P ²³ P ²³ OH − 11 HHHP ²⁵ P ²⁵ P ²⁵ OH − 12 H Byr Byr P ²⁷ P ²⁷ P ²⁷ OH-13 base II HHP ¹ P ¹ P ¹ OH H 14 base II Byr Byr P ¹ P ¹ P ¹ OH Byr 15 base II HHP ² P ² P ² OH H 16 base II HHP ³ P ³ P ³ OH H 17 group ^{II HHP 4 P 4 P 4 OH} H 18 group ^{II HHP 5 P 5 P 5 OH} H 19 group ^{II Byr Byr P 5 P 5 P} 5 OH Byr 20 group II HHP ⁶ P ⁶ P ⁶ OH H 21 base II HHP ⁷ P ⁷ P ⁷ OH H 22 base II Byr Byr P ⁷ P ⁷ P ⁷ OH Byr 23 base II HHP ⁸ P ⁸ P ⁸ OH H 24 base II HHP ⁹ P ⁹ P ⁹ OH H 25 Group II HHP ¹⁰ P ¹⁰ P ¹⁰ OH H 26 base II HHP ¹¹ P ¹¹ P ¹¹ OH H 27 base II HHP ¹² P ¹² P ¹² OH H 28 base II HHP ¹³ P ¹³ P ¹³ OH H 29 base II Byr Byr P ¹³ P ¹³ P ¹³ OH Byr 30 base II HHP ¹⁴ P ¹⁴ P ¹⁴ OH H 31 base II HHP ¹⁵ P ¹⁵ P ¹⁵ OH H 32 base II HHP ¹⁶ P ¹⁶ P ¹⁶ OH H 33 base II HHP ¹⁷ P ¹⁷ P ¹⁷ OH H 34 base II Byr Byr P ¹⁷ P ¹⁷ P ¹⁷ OH Byr 35 base II HHP ¹⁸ P ¹⁸ P ¹⁸ OH H 36 base II HHP ¹⁹ P ¹⁹ P ¹⁹ OH H 37 base II HHP ²⁰ P ²⁰ P ²⁰ OH H 38 base II HHP ²¹ P ²¹ P ²¹ OH H 39 base II HHP ²² P ²² P ²² OH H 40 base II Byr Byr P ²² P ²² P ²² OH Byr 41 base II HHP ²³ P ²³ P ²³ OH H 42 base II Byr Byr P ²³ P ²³ P ²³ OH Byr 43 base II HHP ²³ P ²³ P ²³ HH 44 base II HHP ²⁴ P ²⁴ P ²⁴ OH H 45 base II HHP ²⁵ P ²⁵ P ²⁵ OH H 46 base II HHP ²⁶ P ²⁶ P ²⁶ OH H 47 base II HHP ²⁶ P ²⁶ P ²⁶ HH 48 base II HHP ²⁷ P ²⁷ P ²⁷ OH Octo 49 base II Ac Ac P ²⁷ P ²⁷ P ²⁷ OH Ac 50 base II Prn Prn P ²⁷ P ²⁷ P ²⁷ OH Prn 51 base II Byr Byr P ²⁷ P ²⁷ P ²⁷ OH Byr 52 base II iByr iByr P ²⁷ P ²⁷ P ²⁷ OH iByr 53 base II Va Va P ²⁷ P ²⁷ P ²⁷ OH Va 54 base II Piv Piv P ²⁷ P ²⁷ P ²⁷ OH Piv 55 base II Hxo Hxo P ²⁷ P ^{2 7} P ²⁷ OH Hxo 56 base II Octo Octo P ²⁷ P ²⁷ P ²⁷ OH Octo 57 base II Dco Dco P ²⁷ P ²⁷ P ²⁷ OH Dco 58 base II Ddco Ddco P ²⁷ P ²⁷ P ²⁷ OH Ddco 59 base II MeO-CONH -Prn MeO-CONH-Prn P ²⁷ P ²⁷ P ²⁷ OH MeO-CONH-Prn 60 base II Bz Bz P ²⁷ P ²⁷ P ²⁷ OH Bz 61 base II 4-Me-Bz 4-Me-Bz P ²⁷ P ²⁷ P ²⁷ OH 4-Me-Bz 62 base II 4-Ph-Bz 4-Ph-Bz P ²⁷ P ²⁷ P ²⁷ OH 4-Ph-Bz 63 base II Npo Npo P ²⁷ P ²⁷ P ²⁷ OH Npo 64 base II tBuO- CONH-Hxo tBuO-CONH-Hxo P ²⁷ P ²⁷ P ²⁷ OH H 65 base II HHP ²⁷ P ²⁷ P ²⁷ HH 66 base II HHP ²⁸ P ²⁸ P ²⁸ OH H 67 base II HHP ²⁹ P ²⁹ P ²⁹ OH H 68 base II HHP ³⁰ P ³⁰ P ³⁰ OH H 69 group II HHP ¹ P ¹ P ²⁷ OH H 70 group II HHP ¹ P ¹ P ²⁷ HH −−−−−−−−−−−−−−−−−−−−−− -------------- in table 1, "group II" is the same as "group (II)" described above, the group "P ^1" to "P ^30", the These are the groups shown in Table 2 below.

[0037]

Embedded image

[0038]

Table 2 Names of groups R ⁹ R ¹⁰ X --- --- ---------------------------- −−−−−−−−−−−−−−−−−−−−−−−− P ¹ AcOCH ₂ O AcOCH ₂ OOP ² PrnOCH ₂ O PrnOCH ₂ OOP ³ ByrOCH ₂ O ByrOCH ₂ OOP ⁴ iByrOCH ₂ O iByrOCH ₂ OOP ⁵ PivOCH ₂ O PivOCH ₂ OOP ⁶ VaOCH ₂ O VaOCH ₂ OOP ⁷ AcO (CH ₂ ) ₂ O AcO (CH ₂ ) ₂ OOP ⁸ PivO (CH ₂ ) ₂ O PivO (CH ₂ ) ₂ OOP ⁹ AcO (CH ₂ ) ₃ O AcO (CH ₂ ) ₃ OOP ¹⁰ AcOCH ₂ O OH OP ¹¹ AcSCH ₂ O AcSCH ₂ OOP ¹² PivSCH ₂ O PivSCH ₂ OOP ¹³ AcS (CH ₂ ) ₂ O AcS (CH ₂ ) ₂ OOP ¹⁴ PrnS (CH ₂ ) ₂ O PrnS (CH ₂ ) ₂ OOP ¹⁵ ByrS (CH ₂ ) ₂ O ByrS (CH ₂ ) ₂ OOP ¹⁶ iByrS (CH ₂ ) ₂ O iByrS (CH ₂ ) ₂ OOP ¹⁷ PivS (CH ₂ ) ₂ O PivS ( CH ₂ ) ₂ OOP ¹⁸ VaS (CH ₂ ) ₂ O VaS (CH ₂ ) ₂ OOP ¹⁹ AcS (CH ₂ ) ₃ O AcS (CH ₂ ) ₃ OOP ²⁰ AcS (CH ₂ ) ₂ O OH OP ²¹ MeO MeO OP ^{22 EtO EtO OP 23 BuO BuO OP 24} tBuO tBuO OP 25 EtO OH OP 26 SH OH OP 27 OH OH OP 28 EtO EtO SP 29 BuO BuO SP 30 EtO tBuO S ----------- In the above table and thereafter, "Ac" is an acetyl group, "Bu" is a butyl group, and "tBu" is t -Butyl group,
"Byr" is a butyryl group, "iByr" is an isobutyryl group, "Bz" is a benzoyl group, "Dco" is a decanoyl group, "Ddco" is a dodecanoyl group, "Et" is an ethyl group, and "Hxo '' Is a hexanoyl group, `` Me '' is a methyl group, `` Npo '' is a naphthoyl group, `` Octo '' is an octanoyl group, `` Piv '' is a pivaloyl group, `` Prn '' is a propionyl group, and `` Va '' is And a valeryl group.

In Table 1 above, preferred compounds include the compounds of Compound Nos. 13, 18, 21, 28, 33, 39, 41 and 43, and more preferred compounds are Compound No. 213'-O- [α-D- ｛3,4-bis-O-di (2-acetoxyethyl) phosphoryl｝ glucosyl] -2′-O- ｛di (2-acetoxyethyl) phosphoryl｝ adenosine, Compound No. 39 3'-O -｛Α-D- (3,4-bis-O-diethylphosphoryl) glucosyl｝ -2'-O- (diethylphosphoryl) adenosine, Compound No. 41 3'-O- ｛α-D- (3,4- Bis-O-di-n-butylphosphoryl) glucosyl｝ -2'-O- (di-n-butylphosphoryl) adenosine and Compound No. 43 3'-O- ｛α-D- (3,4-bis-O -Di-n-butylphosphoryl) -2-deoxyglucosyl｝ -2'-O- (di-n-butylphosphoryl) adenosine.

[0040]

BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of the present invention can be produced by the following methods A to C.

[0041]

Embedded image

[0042]

Embedded image

[0043]

Embedded image In the above process chart, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ and X are as defined above.

Further, in the above process chart and thereafter, "Bn" indicates a benzyl group.

R ^1a is a hydrogen atom or a compound of the formula (IIa)

[0046]

Embedded image (Wherein, R ^8a represents a 4,4′-dimethoxytrityl group or a 4-methoxytrityl group), and is preferably represented by the formula (IIa).

R ^2a and R ^3a are the same or different and each represents 4,4′-
It is a dimethoxytrityl group or a 4-methoxytrityl group.

R ¹¹ and R ¹² may be the same or different, or
¹¹ and R ¹² may form a ring together, at least one of which represents a group which is β-eliminated or hydrogenolyzed. The group to be β-eliminated or hydrogenolyzed is not particularly limited,
Preferably, a 2-cyanoethoxy group, a benzyloxy group or
Represents a 3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl group. The group that is not hydrogenolyzed includes a C ₁ -C ₄ alkoxy group and (C ₁ -C ₅ aliphatic acyl)
It represents an oxy- (C ₁ -C ₃ alkyl) oxy group or a (C ₁ -C ₅ aliphatic acyl) thio- (C ₁ -C ₃ alkyl) oxy group.

R ¹³ represents a group capable of leaving together with an oxygen atom, and is preferably phenoxy (thiocarbonyl)
Group.

Method A is a method for obtaining target compounds (Ia) and (Ib) in which the hydroxyl group of phosphoric acid is substituted from compound (V).

In the method B, the compound (V) is obtained by converting the target compound (I
This is the method to get c).

Method C is a method for obtaining the target compound (Id) wherein R ⁷ is a hydrogen atom from the compound (XII). Less than,
Each of the steps A to C will be described in detail.

Method A (Step A-1) This step is a step of preparing compound (VII) by phosphorylating compound (V).

This step is composed of two steps. First,
1) The compound (VI) is reacted in an inert solvent in the presence of 1H-tetrazole, and 2) an oxidizing agent is added to the resulting reaction mixture to produce a compound (VII).

1) The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but acetonitrile and methylene chloride are preferred. The reaction temperature is from 10 ° C to 40 ° C, and the reaction time is from 10 minutes to 2 hours.

2) After completion of the reaction of 1), -50 to -30
Cool to ° C. and add an oxidizing agent such as meta-chloroperbenzoic acid or sulfur. The reaction temperature is preferably set to room temperature by allowing it to stand naturally from -50 to -30 ° C.
Although it depends on the type of the oxidizing agent, it is 10 minutes to 3 days.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, dilute with a water-immiscible organic solvent such as ethyl acetate, add an aqueous solution of sodium metabisulfite to decompose the remaining oxidizing agent, wash with water or the like, and separate the organic layer containing the target compound,
After drying over anhydrous sodium sulfate or the like, it is obtained by distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method,
For example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, and magnesium-silica gel type florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm and Haas),
A method using a synthetic adsorbent such as distribution column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Kasei), a method using ion exchange chromatography, or a normal phase using silica gel or alkylated silica gel. Separation and purification can be performed by appropriately combining reverse phase column chromatography and eluting with a suitable eluent.

(Step A-2) This step is composed of two steps. First, 1) reacting the compound (VII) with an acid to remove the protecting group for the primary hydroxyl group and the adenine base, if any, and then reacting the resulting compound with 2) a deprotecting agent. In this step, the benzyl group which is a protecting group for the hydroxyl group of the sugar moiety is removed to produce the target compound (Ia).

1) As the solvent used in this reaction, halogenated hydrocarbons such as chloroform and methylene chloride are preferred. Moreover, it may be directly dissolved in an acid without using a solvent.

As the acid used, acetic acid (especially 80%
Acetic acid) and trifluoroacetic acid.

The reaction temperature is usually from 0 to 40 ° C., and the reaction time is usually from 5 minutes to 3 minutes, depending on the starting material, the reaction temperature and the like.
Days.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, and a water-immiscible organic solvent such as ethyl acetate is added to appropriately neutralize the reaction mixture, and if unnecessary substances are present, they are removed by filtration and then washed with water or the like. Thereafter, it is obtained by distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method.
For example, it can be purified by a method commonly used for recrystallization, reprecipitation, or separation and purification of an organic compound, for example, the method described in the above-mentioned step A-1.

2) As the solvent used in this reaction, alcohols such as methanol and ethanol; acetic acid; water, and a mixed solvent thereof are suitable.

The deprotecting agent to be used is not particularly limited as long as it is usually used, but a combination of palladium-black and hydrogen gas is preferred.

The reaction temperature is usually from 0 to 40 ° C., preferably room temperature.

The reaction time depends on the raw materials, the reaction temperature and the like.
Usually 5 hours to 7 days, preferably 10 hours to 3 hours
Days.

After completion of the reaction, the reduction catalyst is removed by filtration, washed with a solvent such as ethanol, the filtrate and the washing liquid are combined, and the solvent is distilled off under reduced pressure to obtain the desired compound.

If necessary, the obtained target compound can be obtained by a conventional method,
For example, it can be purified by a method commonly used for recrystallization, reprecipitation, or separation and purification of an organic compound, for example, the method described in the above-mentioned step A-1.

(Step A-3) This step comprises the steps of: 1) reacting compound (Ia) with an acid anhydride or an acid halide in an inert solvent in the presence of a base; The compound (Ia) is reacted with an acid in the presence or absence of a base and a condensing agent to acylate the primary hydroxyl group of the compound (Ia) and, when an adenine base is present, the amino group thereof. This is the manufacturing process.

1) When reacting an acid anhydride or an acid halide: Specific examples of the acid anhydride include aliphatic carboxylic acids such as acetic anhydride, propionic anhydride, valeric anhydride, hexanoic anhydride, and lauric anhydride. Acid anhydrides can be mentioned, and mixed acid anhydrides such as formic acid and acetic acid can also be used.

Specific examples of acid halides include, for example, aliphatic acyl halides such as acetyl chloride, propionyl chloride, butyryl bromide, valeryl chloride, and hexanoyl chloride; and aromatic acyl halides such as benzoyl chloride, benzoyl bromide and naphthoyl chloride. Acyl halides include lower alkoxycarbonyl halides such as methoxycarbonyl chloride, methoxycarbonyl bromide, ethoxycarbonyl chloride, propoxycarbonyl chloride, butoxycarbonyl chloride and hexyloxycarbonyl chloride.

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Preferably, aliphatic solvents such as hexane and heptane; Aromatic hydrocarbons such as toluene and xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide;
Examples include amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. Preferably, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,
Pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
N-dimethylamino) pyridine, 2,6-di (tert-butyl)-
Organic bases such as 4-methylpyridine, quinoline, N, N-dimethylaniline and N, N-diethylaniline can be mentioned.

It should be noted that 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine may be used in combination with other bases in a catalytic amount, and may be used in order to carry out the reaction effectively. And quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, and crown ethers such as dibenzo-18-crown-6.

The reaction temperature is usually from -20 ° C to the reflux temperature of the solvent used, preferably from 0 ° C to the reflux temperature of the solvent used.

The reaction time mainly depends on the reaction temperature, the starting compound,
The time is usually from 10 minutes to 3 days, depending on the type of the base or the solvent used.

2) In the case of reacting an acid The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
-3 The same solvent as described in Step 1) can be used.

As the base to be used, the same base as described in the above A-3, step 1) can be used.

The condensing agent used is preferably 1,1,
And carbodiimides such as 3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.

The reaction is carried out at a temperature of from -20 ° C to 80 ° C, preferably from 0 ° C to room temperature.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 10 minutes to 3 days, preferably 30 minutes to 1 day.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, and a water-immiscible organic solvent such as ethyl acetate is added to appropriately neutralize the reaction mixture, and if unnecessary substances are present, they are removed by filtration and then washed with water or the like. Thereafter, it is obtained by distilling off the solvent.

If necessary, the obtained target compound may be prepared by a conventional method,
For example, it can be purified by a method commonly used for recrystallization, reprecipitation, or separation and purification of an organic compound, for example, the method described in the above-mentioned step A-1.

Method B (Step B-1) In this step, compound (V) is reacted with compound (VII)
This is a step of producing compound (IX) by phosphorylation according to I), and can be carried out in the same manner as in the above-mentioned step A-1.

(Step B-2) In this step, a compound (IX) is reacted with an acid to remove a primary hydroxyl group and an adenine base when the amino group is present, thereby producing a compound (X). Step A-2) can be performed in the same manner as in step A-2 1).

(Step B-3) This step is a step of preparing the compound (XI) by acylating the amino group of the primary hydroxyl group and adenine base of the compound (X) when the compound is present. It can be performed in the same manner as the process.

Further, after protection with a t-butyldimethylsilyl group is carried out by a well-known method, this reaction is carried out, and
By deprotecting the butyldimethylsilyl group, a compound in which only the amino group of the adenine base is acylated can be obtained.

(Step B-4) In this step, the compound (XI) is reacted with a deprotecting agent to remove 1) a protecting group for phosphoric acid and 2) a benzyl group which is a protecting group for a hydroxyl group of a sugar moiety. This is a step of producing the target compound (Ic).

1) The protecting group of phosphoric acid is removed by treating with a base in an inert solvent.

The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction. Water; alcohols such as methanol, ethanol and n-propanol; ethers such as tetrahydrofuran and dioxane. Or an organic solvent such as an organic base such as pyridine, or a mixed solvent of water and the above organic solvent.

The base used is preferably one which does not affect the other parts of the compound, such as triethylammonium acetate, N, O-bis (trimethylsilyl)
Acetamides such as acetamide or aqueous ammonia, ammonia such as concentrated ammonia-methanol are preferred.

The reaction temperature and reaction time vary depending on the solvent and the base used, but are preferably at room temperature for 5 minutes to 1 hour.

2) The removal of the benzyl group, which is a protecting group for the hydroxyl group of the sugar moiety, can be carried out in the same manner as in the above step A-2 2).

Method C (Step C-1) This step was carried out by reacting compound (XII) in pyridine.
This is a step of producing a compound (XIII) by reacting phenylchlorothionoformate with the hydroxyl group of the sugar moiety of the above.

The reaction temperature is usually from -20 ° C to 100 ° C.
The temperature is preferably 50 ° C.

The reaction time mainly depends on the reaction temperature, starting compound,
The time is usually from 10 minutes to 3 days, depending on the type of the base or the solvent used.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, and a water-immiscible organic solvent such as ethyl acetate is added to appropriately neutralize the reaction mixture, and if unnecessary substances are present, they are removed by filtration and then washed with water or the like. Thereafter, it is obtained by distilling off the solvent.

If necessary, the obtained target compound may be prepared by a conventional method.
For example, it can be purified by a method commonly used for recrystallization, reprecipitation, or separation and purification of an organic compound, for example, the method described in the above-mentioned step A-1.

(Step C-2) In this step, the compound (XIV) is reacted with tributyltin hydride and α, α'-azobisisobutyronitrile in an inert solvent such as benzene. This is the manufacturing process.

The reaction temperature is preferably 80.degree.

The reaction time depends mainly on the reaction temperature or the type of the solvent used, but is usually from 10 minutes to 3 days.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, and a water-immiscible organic solvent such as ethyl acetate is added to appropriately neutralize the reaction mixture, and if unnecessary substances are present, they are removed by filtration and then washed with water or the like. Thereafter, it is obtained by distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method,
For example, it can be purified by a method commonly used for recrystallization, reprecipitation, or separation and purification of an organic compound, for example, the method described in the above-mentioned step A-1.

(Step C-3) In this step, compound (XIV)
In the case where a primary hydroxyl group and an adenine base are present by reacting with an acid, the protecting group for the amino group is removed to produce the desired compound (Id), which can be carried out in the same manner as the above-mentioned step A-2.

The starting compound (V) was prepared according to the method described in JP-A-8-127590.
And the compound described in JP-A-9-316093, and the starting compound (XII) can be easily synthesized from the compound (VII).

The starting compounds (VI) and (VIII) are
Is a known compound or is described in the literature (C. Sund et a
l., Tetrahedron 48, 695-718 (1992); W. Bannwarth et
al., Helv. Chim. Acta. 70, 175-186 (1987)).

The novel phosphoric acid derivative of the present invention has an excellent activity of increasing the intracellular calcium ion concentration and has low toxicity, so that brain diseases such as senile dementia, Alzheimer's disease and Huntington's chorea are available. Useful for the treatment of It is also useful as a vasopressor, an immunopotentiator that activates immunocompetent cells, a pressure sore, a therapeutic agent for upper skin ulcer, or a therapeutic agent for type I diabetes by promoting insulin secretion.

Further, the novel phosphate derivative of the present invention has excellent cell membrane permeability, so that when it is added to an extracellular solution, it permeates into cells, and the phosphate derivative itself of the present invention or a metabolite thereof There reaches the InsP ₃ receptors, it is possible to increase the intracellular calcium ion concentration. Therefore, the efficiency of artificial fertilization can be improved, and for example, it can be used for animal cloning technology.

Examples of the dosage form of the phosphoric acid derivative of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections or suppositories. These formulations may contain excipients (e.g., lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, alpha starch, dextrin, starch derivatives such as carboxymethyl starch; crystalline cellulose; Cellulose derivatives such as low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; organic excipients such as pullulan Silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate and magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. Excipients), lubricants (eg, stearic acid, metal salts of stearic acid such as calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; Adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; Silicic acids; and the above-mentioned starch derivatives.) Binders (for example, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, the same compounds as the above-mentioned excipients,
And chemically modified starch celluloses such as croscarmellose sodium, carboxymethyl starch sodium, cross-linked polyvinyl pyrrolidone. ), Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride;
Phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. ), Flavoring agents (eg, commonly used,
Sweeteners, acidulants, flavors and the like can be mentioned. ), And manufactured by a known method using additives such as a diluent.

The amount used depends on the condition, age, administration method and the like. For example, in the case of oral administration,
The lower limit is 0.1 mg / kg body weight (preferably 1 mg / kg body weight), and the upper limit is 1000 mg / kg body weight (preferably 500 m
g / kg body weight) in the case of intravenous administration, 0.01 mg / kg body weight (preferably 0.1 mg / kg body weight) as a lower limit and 100 mg / kg body weight (preferably 50 mg / k
g body weight) one to several times a day depending on the condition.

Hereinafter, the present invention will be described in more detail with reference to Examples and Preparation Examples, but the scope of the present invention is not limited thereto.

"TBS" is a t-butyldimethylsilyl group, "MMTr" is a 4-methoxytrityl group, "DMTr"
Represents a 4,4′-dimethoxytrityl group, and “Boc” represents a t-butoxycarbonyl group.

[0115]

Example 1 3′-O- ｛α-D- (3,4-bis-O-diethylphospho
Ryl) glucosyl｝ -2'-O- (diethylphosphoryl) adeno
Syn (Exemplary Compound No. 39)

[0116]

Embedded image (1-1)

[0117]

Embedded image 3'-O- [α-D- {2-O-benzyl-6-O- (4,4'-dimethoxytrityl) glucosyl}]-6-N, 5'-O-bis- (4,4 ' -Dimethoxytrityl) adenosine (described in JP-A-8-127590) 28.5m
g (0.02 mmol) and 1H-tetrazole 9.8 mg (0.14 mmol) were dissolved in anhydrous acetonitrile 200 μL, and N, N-diisopropyldiethylphosphoramidite (N, N-Diisopropyldiethy
lphosphoramidite) (K. Afarinkia et al., J. Chem. So
c. Chem. Commun., 285-287 (1992).) 20 mg (0.09 mmol)
Was dissolved in 300 μL of anhydrous acetonitrile,
The mixture was stirred at room temperature under a nitrogen atmosphere. After 15 minutes, the mixture was cooled to -40 ° C, 31 mg (0.18 mmol) of metachloroperbenzoic acid (> 70%) was added, and the mixture was stirred while returning to room temperature. After 20 minutes ethyl acetate 1
The mixture was diluted with 00 mL, washed successively with 100 mL each of 10% aqueous Na ₂ S ₂ O ₅ , 0.01 N aqueous hydrochloric acid, and 5% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (methylene chloride: methanol = 15: 1) to obtain 21.5 mg (58%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 7.95 (s, 1H),
7.82 (s, 1H), 7.50-6.64 (m, 44H), 6.25 (d, J = 7.
2 Hz, 1H), 5.88 (m, 1H), 5.14 (d, J = 3.7 Hz, 1H),
4.72 (q, J = 10 Hz, 2H), 4.58 (m, 2H), 4.30 (m, 1
H), 4.20-3.20 (m, 37H), 1.40-0.85 (m, 18H) IR (KBr) cm ^-1 : 2981, 2933, 2837, 1607, 1584, 1509,
1469, 1446, 1393, 1370, 1294, 1279, 1253, 1179, 1
160, 1101, 1034, 980. (1-2)

[0119]

Embedded image 21 mg of the compound (1-1) was dissolved in 1 mL of acetic acid: water (4: 1) and stirred at room temperature. After 1.5 hours, the solvent was distilled off by azeotropic distillation several times with ethanol, and the residue was purified by preparative thin-layer chromatography (methylene chloride: methanol = 12: 1) to obtain 9.6 mg (92%) of the desired compound. Was.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.32 (s, 1H),
7.54 (d, J = 6.6 Hz, 2H), 7.41 (s, 1H), 7.40-7.30
(m, 3H), 6.68 (m, 1H), 5.91 (d, J = 7.8 Hz, 1H),
5.84 (br s, 2H), 5.65 (m, 1H), 5.51 (d, J = 3.7 Hz,
1H), 4.90 (d, J = 12 Hz, 1H), 4.85 (q, J = 9.1 Hz,
1H), 4.68 (d, J = 12 Hz, 1H), 4.63 (d, J = 4.4 H
z, 1H), 4.42 (q, J = 9.5 Hz, 1H), 4.35-3.53 (m, 19
H), 1.43-1.25 (m, 9H), 1.18 (t, J = 7.5 Hz, 3H),
1.12 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 6.5 Hz, 3H) IR (CHCl ₃ ) cm ^-1 : 3333, 3270, 3207, 2986, 2933, 287
2, 1645, 1601, 1580,1479, 1455, 1444, 1428, 1394,
1371, 1336, 1266, 1163, 1105, 1030, 982. (1-3)

[0121]

Embedded image Dissolve 9 mg of the compound of (1-2) in 1 mL of ethanol, and add
g of palladium black (Pd-black) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 17 hours, the mixture was filtered through celite, washed with ethanol, and the filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure to obtain 8.4 mg (97%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.33 (s, 1H),
7.95 (s, 1H), 6.50 (br s, 1H), 6.10 (d, J = 7.2 H
z, 1H), 5.84 (br s, 2H), 5.60 (m, 1H), 5.23 (d, J
= 3.6 Hz, 1H), 4.70 (m, 2H), 4.42 (m, 2H), 4.30-3.
65 (m, 18H), 1.45-0.80 (m, 18H) IR (CHCl ₃ ) cm ^-1 : 3335, 3213, 2985, 2930, 2872, 164
7, 1601, 1578, 1479,1444, 1419, 1395, 1371, 1333,
1261, 1156, 1101, 1031, 974.

[0123]

Example 2 3′-O- [α-D- ｛3,4-bis-O-di (2-acetoxy)
Siethyl) phosphoryl｝ glucosyl] -2'-O- ｛di (2-acet
Toxiethyl) phosphoryl @adenosine (Exemplary Compound No. 21)

[0124]

Embedded image (2-1)

[0125]

Embedded image 375 μL (4 mmol) of 2-acetoxyethanol and 1.04 mL (6 mmol) of diisopropylethylamine in tetrahydrofuran
It was dissolved in 2 mL and stirred at 0 ° C. under a nitrogen stream. Where N,
N-diisopropylaminodichlorophosphine (N, N-Diiso
After adding 404 mg (2 mmol) of propylaminodichlorophosphine), the mixture was stirred and returned to room temperature after 15 minutes. After further 30 minutes, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. Dissolve the residue in 50 mL of ethyl acetate and add 50 mL of 10% aqueous sodium carbonate solution
After drying twice with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 651.6 mg (96%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 4.22 (m, 4H),
3.80 (m, 4H), 3.60 (m, 2H), 2.06 (s, 6H), 1.18
(m, 12H). (2-2)

[0127]

Embedded image Using 30 mg (0.09 mmol) of the compound of (2-1) instead of N, N-diisopropyldiethyl phosphoramidite,
35.3 mg (80%) of the target compound was obtained in the same manner as in 1).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 7.95 (s, 1H),
7.90 (s, 1H), 7.45 (m, 2H), 7.33-6.64 (m, 44H),
6.30 (d, J = 6.7 Hz, 1H), 5.90 (m, 1H), 5.02 (d, J
= 3.3Hz, 1H), 4.82-3.18 (m, 57H), 2.12-1.90 (m, 18
H). (2-3)

[0129]

Embedded image 35m of the compound of (2-2) instead of the compound of (1-1)
Using g, the desired compound 12.5 was obtained in the same manner as in (1-2).
mg (61%) was obtained.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.32 (s, 1H),
7.69 (s, 1H), 7.50 (m, 2H), 7.37 (m, 3H), 6.60
(m, 1H), 6.00 (d, J = 7.6 Hz, 1H), 5.78 (br s, 2
H), 5.72 (m, 1H), 5.45 (d, J = 3.4 Hz, 1H), 4.86
(m, 2H), 4.66 (m, 2H), 4.50-3.52 (m, 32H), 2.11
(s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H),
2.02 (s, 3H), 2.00 (s, 3H) IR (Liquid film) cm ^-1 : 3420, 3338, 3266, 3214, 295
8, 1741, 1644, 1600,1580, 1477, 1455, 1432, 1378,
1336, 1236, 1102, 1074, 1036, 991. (2-4)

[0131]

Embedded image The compound of (2-3) 12m instead of the compound of (1-2)
Using g, in the same manner as in (1-3), 12 mg of the desired compound
(99%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.32 (s, 1H),
8.01 (s, 1H), 6.40 (br s, 1H), 5.75 (br s, 2H), 5.
60 (m, 1H), 5.23 (d, J = 3.7 Hz, 1H), 4.78-3.55
(m, 34H), 2.15-2.00 (m, 18H) IR (Liquid film) cm ^-1 : 3347, 3221, 2959, 2928, 285
6, 1740, 1645, 1600,1580, 1434, 1379, 1335, 1256,
1238, 1125, 1076, 1038.

[0133]

Example 3 5 ', 6 "-bis-O- (n-butyryl) -6-N- (n-butyl
Ryl) -adenophostin A (Exemplary Compound No. 51)

[0134]

Embedded image (3-1)

[0135]

Embedded image 3'-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5
-Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-
Yl) glucosyl｝]-2′-O- (3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) adenosine (Japanese Unexamined Patent Publication No. 8-127590) 911 mg (0.854 mmol) was dissolved in 17 mL of tetrahydrofuran, and 1.38 mL of pyridine (17.1 mmo) was dissolved.
l) and butyric anhydride (n-Butylic anhydride) 2.78 mL (17.1 mmol)
Was added and stirred at 50 ° C. for 29 hours. After the reaction, the solvent was distilled off under reduced pressure.The residue was dissolved in ethyl acetate (100 mL), washed successively with 100 mL portions of 5% aqueous sodium bicarbonate, 0.02 N aqueous hydrochloric acid, and 5% aqueous sodium bicarbonate, and dried over magnesium sulfate. Distilled off under. The residue was applied to a silica gel column (100 g), and eluted with 1-1.5% methanol-methylene chloride to give 807.6 mg of the desired compound (74 g).
%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.58 (s, 1H),
8.53 (s, 1H), 7.95 (s, 1H), 7.50-7.10 (m, 17H),
6.26 (d, J = 5.0 Hz, 1H), 5.82 (dt, J = 5.0 and 7.
5 Hz, 1H), 5.48 (ddd, J = 3.0, 10.2 and 14.2 Hz, 2
H), 5.30-4.65 (m, 17H), 4.45 (m, 3H), 4.27 (q, J =
6.5 Hz, 1H), 4.13 (m, 1H), 3.67 (dd, J = 3.4 and
9.8 Hz, 1H), 2.85 (t, J = 7.4 Hz, 2H), 2.37 (m, 2
H), 2.24 (t, J = 7.4 Hz, 2H), 1.90-1.55 (m, 6H),
1.06 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3
H), 0.91 (t, J = 7.3 Hz, 3H) IR (KBr) cm ^-1 : 3030, 2965, 2936, 2877, 1740, 1609,
1587, 1499, 1456, 1415, 1380, 1355, 1292, 1226, 1
167, 1099, 1053, 1027, 979, 948. (3-2)

[0137]

Embedded image 42 mg of the compound of (3-1) was ethanol-water (4: 1) containing 0.1 M triethylammonium acetate (TEAA) 2.
It was dissolved in 5 mL, 100 mg of palladium black (Pd-black) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 24 hours, the mixture was filtered through celite, washed with diluted ammonia water and ethanol, and the filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure. Residue is H
Purification by PLC (PEGASIL ODS (20 × 250 mm), 25% acetonitrile-0.1 M TEAA (pH 7), 7 mL / min) gave 18.9 mg (49%) of the triethylammonium salt of the target compound.

¹ H-NMR (D ₂ O, external TMS) δ ppm: 8.54
(s, 1H), 8.38 (s, 1H), 6.24 (d, J = 3.9 Hz, 1H), 4.
67 (t, J = 5.0 Hz, 1H), 4.50 (m, 1H), 4.30 (m, 3
H), 4.09 (dd, J = 6.5 and 11.8 Hz, 1H), 3.90 (m, 2
H), 3.62 (dd, J = 4.2 and 9.6 Hz, 1H), 3.02 (q, J
= 7.3 Hz, 18H), 2.41 (t, J = 7.3 Hz, 2H), 2.17 (t,
J = 7.5 Hz, 2H), 2.03 (m, 1H), 1.93 (m, J = 1H),
1.59 (m, 2H), 1.41 (m, 2H), 1.22 (m, 2H), 1.10 (t,
J = 7.3 Hz, 27H), 0.83 (t, J = 7.3 Hz, 3H), 0.72
(t, J = 7.3 Hz, 3H), 0.57 (t, J = 7.3 Hz, 3H) IR (KBr) cm ^-1 : 2970, 2939, 2878, 2803, 2757, 2739,
2678, 2601, 2492, 1737, 1611, 1587, 1514, 1469, 1
434, 1399, 1384, 1365, 1314, 1189, 1171, 1091, 103
7, 993, 931.

[0139]

Example 4 5 ', 6 "-bis-O- (n-octanoyl) -6-N- (n-
Octanoyl) -adenophosphin A (Exemplary Compound No. 5
6)

[0140]

Embedded image (4-1)

[0141]

Embedded image 3'-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5
-Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-
Yl) glucosyl｝]-2′-O- (3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) adenosine (Japanese Unexamined Patent Publication No. 8-127590) 116.5 mg (0.1 mmol), 2 mL of tetrahydrofuran, 162 μL (2 mmol) of pyridine and 594 μL (2 mmol) of octanoic anhydride (n-Octanoic anhydride) in the same manner as in (3-1) using 118.6 mg of the target compound. mg (8
2%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 9.12 (s, 1H),
8.60 (s, 1H), 7.97 (s, 1H), 7.48-7.10 (m, 17H),
6.27 (d, J = 5.0 Hz, 1H), 5.81 (dt, J = 5.0 and 7.
4 Hz, 1H), 5.48 (m, 2H), 5.27-4.65 (m, 17H), 4.43
(m, 3H), 4.27 (m, 1H), 4.13 (m, 1H), 3.67 (dd, J =
3.4 and 9.8 Hz, 1H), 2.82 (t, J = 7.5 Hz, 2H), 2.3
7 (m, 2H), 2.24 (t, J = 7.4 Hz, 2H), 1.86-1.18 (m,
30H), 0.86 (m, 9H) IR (KBr) cm ^-1 : 3065, 3031, 2955, 2928, 2857, 1740,
1610, 1587, 1499, 1457, 1417, 1378, 1354, 1292, 1
226, 1208, 1195, 1164, 1102, 1053, 1028, 979, 947. (4-2)

[0143]

Embedded image Using 118 mg (0.0817 mmol) of the compound of (4-1), (3)
Synthesized in the same manner as in -2) to obtain 80.1 mg (73%) of the target compound triethylammonium salt.

¹ H-NMR (D ₂ O, external TMS) δppm: 8.52
(br s, 1H), 8.40 (br s, 1H), 6.22 (br s, 1H), 5.57
(m, 1H), 5.11 (br s, 1H), 4.70 (m, 1H), 4.55 (m, 1
H), 4.30 (m, 4H), 4.02 (m, 1H), 3.90 (m, 2H), 3.65
(m, 1H), 3.00 (m, 18H), 2.45 (m, 2H), 2.18 (m, 2
H), 2.00 (m, 2H), 1.62-0.50 (m, 66H) IR (KBr) cm ^-1 : 2956, 2930, 2857, 2804, 2739, 1678,
1492, 1739, 1612, 1588, 1515, 1467, 1435, 1399, 1
383, 1357, 1326, 1227, 1167, 1094, 1038, 944.

[0145]

Example 5 5 ', 6 "-bis-O- (n-dodecanoyl) -6-N- (n-
Dodecanoyl) -adenophosphin A (Exemplary Compound No. 5
8)

[0146]

Embedded image (5-1)

[0147]

Embedded image 3'-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5
-Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-
Yl) glucosyl｝]-2′-O- (3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) adenosine (Japanese Unexamined Patent Publication No. 8-127590) Described in 106.5 mg (0.1 mmol), tetrahydrofuran 2 mL, pyridine 162 μL (2 mmol) and lauric anhydride (Lauric anhydride) 765 mg (2 mmol),
63 mg (42%) of the target compound was obtained in the same manner as in (3-1).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.65 (brs, 1
H), 8.58 (s, 1H), 7.94 (s, 1H), 7.48-7.08 (m, 17H),
6.27 (d, J = 5.0 Hz, 1H), 5.81 (dt, J = 5.0 and
7.4Hz, 1H), 5.48 (m, 2H), 5.27-4.65 (m, 17H), 4.43
(m, 3H), 4.27 (m, 1H), 4.13 (m, 1H), 3.67 (dd, J
= 3.5 and 9.9 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H),
2.37 (m, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.85-1.18
(m, 54H), 0.86 (m, 9H) IR (KBr) cm ^-1 : 3031, 2955, 2925, 2854, 1741, 1611,
1587, 1498, 1459, 1416, 1378, 1354, 1292, 1226, 1
208, 1164, 1101, 1053, 1029, 979, 947. (5-2)

[0149]

Embedded image Using 63 mg (0.039 mmol) of the compound of (5-1), (3-
Synthesized in the same manner as in 2) to obtain 52.1 mg (88%) of the target compound triethylammonium salt.

IR (KBr) cm ^-1 : 3428, 2956, 2924, 2854,
2679, 1738, 1613, 1589, 1467, 1399, 1384, 1323, 1
216, 1163, 1094, 1038.

[0151]

Example 6 5 ', 6 "-bis-O- (n-hexanoyl) -6-N- (n-
Hexanoyl) -adenophosphin A (Exemplary Compound No. 5
5)

[0152]

Embedded image (6-1)

[0153]

Embedded image 3'-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5
-Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-
Yl) glucosyl｝]-2′-O- (3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) adenosine (Japanese Unexamined Patent Publication No. 8-127590) Described in (3-1), using 106.5 mg (0.1 mmol), 2 mL of tetrahydrofuran, 162 μL (2 mmol) of pyridine, and 765 mg (2 mmol) of hexane anhydride (n-Hexanoic anhydride) in the same manner as in (3-1). 64mg (69%)
I got

¹ H-NMR (CDCl ₃ + D ₂ O, TMS) δ ppm: 8.65 (br
s, 1H), 8.59 (s, 1H), 7.96 (s, 1H), 7.48-7.08 (m,
17H), 6.29 (d, J = 5.1 Hz, 1H), 5.81 (m, 1H), 5.45
(m, 2H), 5.28-4.68 (m, 17H), 4.45 (m, 1H), 4.40 (m,
1H), 4.30 (m, 1H), 4.13 (m, 1H), 3.67 (dd, J = 3.5
and 9.9 Hz, 1H), 2.82 (t, J = 7.5 Hz, 2H), 2.38
(m, 2H), 2.26 (t, J = 7.4 Hz, 2H), 1.82-1.20 (m, 1
8H), 0.88 (m, 9H). (6-2)

[0155]

Embedded image Using 90 mg (0.066 mmol) of the compound of (6-1),
Synthesized in the same manner as in 2) to obtain 57 mg (68%) of the triethylammonium salt of the target compound.

¹ H-NMR (D ₂ O, external TMS) δppm: 8.53
(s, 1H), 8.38 (s, 1H), 6.24 (d, J = 3.7 Hz, 1H), 5.
56 (m, 1H), 5.15 (d, J = 3.7Hz, 1H), 4.67 (t, J =
5.0Hz, 1H), 4.50 (m, 1H), 4.30 (m, 3H), 4.07 (dd,
J = 6.5 and 11.8 Hz, 1H), 3.90 (m, 2H), 3.64 (dd, J
= 3.7 and 9.5 Hz, 1H), 3.02 (q, J = 7.3 Hz, 18H),
2.43 (t, J = 7.3 Hz, 2H), 2.17 (t, J = 7.3 Hz, 2
H), 2.03 (m, 1H), 1.93 (m, 1H), 1.59 (m, 2H), 1.38
(m, 2H), 1.3-0.5 (m, 54H) IR (KBr) cm ^-1 : 2957, 2935, 2874, 2679, 1739, 1612,
1588, 1468, 1213, 1171, 1095, 1038, 929.

[0157]

Example 7 5 ', 6 "-bis-O- (n-decanoyl) -6-N- (n-de
( Canoyl) -adenophosphin A (Exemplary Compound No. 57)

[0158]

Embedded image (7-1)

[0159]

Embedded image 3'-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5
-Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-
Yl) glucosyl｝]-2′-O- (3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) adenosine (Japanese Unexamined Patent Publication No. 8-127590) Described in 106.5 mg (0.1 mmol), tetrahydrofuran 2 mL, pyridine 162 μL (2 mmol) and decanoic anhydride (n-Decanoic anhydride) 737 μL (2 mmol),
In a similar manner to (3-1), 110 mg (72%) of the target compound was obtained.

¹ H-NMR (CDCl ₃ + D ₂ O, TMS) δ ppm: 8.52 (s,
1H), 7.89 (s, 1H), 7.88-7.00 (m, 17H), 6.22 (d, J =
5.1 Hz, 1H), 5.75 (m, 1H), 5.40 (m, 2H), 5.20-4.62
(m, 17H), 4.40 (m, 1H), 4.32 (m, 1H), 4.20 (m, 1
H), 4.05 (m, 1H), 3.60 (m, 1H), 2.74 (t, J = 7.5 H
z, 2H), 2.30 (m, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.7
5-1.15 (m, 42H), 0.80 (m, 9H) IR (KBr) cm ^-1 : 3030, 2955, 2926, 2855, 1741, 1610,
1587, 1498, 1458, 1378, 1353, 1292, 1226, 1208, 1
163, 1102, 1053, 1029, 979, 947. (7-2)

[0161]

Embedded image Using 105 mg (0.068 mmol) of the compound of (7-1), (3)
Synthesized in the same manner as in -2) to obtain 60 mg (61%) of the target compound triethylammonium salt.

IR (KBr) cm ^-1 : 2956, 2925, 2872, 2855,
2757, 2739, 2678, 2492, 1740, 1614, 1589, 1467, 1
399, 1379, 1327, 1221, 1165, 1094, 1058, 1038, 94
3.

[0163]

Example 8 5 ', 6 "-bis-O- ｛6- (t-butyloxycarbo
Nylamino) -n-hexanoyl｝ -adenophosphin A (Exemplary Compound No. 64)

[0164]

Embedded image (8-1)

[0165]

Embedded image 3'-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5
-Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-
Yl) glucosyl｝]-2′-O- (3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) adenosine (Japanese Unexamined Patent Publication No. 8-127590) 106.5 mg (0.1 mmol) was dissolved in methylene chloride 2 mL, N- (t-butoxycarbonyl) -6-aminohexanoic acid 139 mg (0.6 mmol) and dicyclohexylcarbodiimide 124 mg (0.6 mmol) and 4-dimethylaminopyridine 12 mg (0.1 mmol) and stirred at room temperature. After 4.5 hours, the mixture was diluted with 50 mL of methylene chloride, washed successively with 0.1 N aqueous hydrochloric acid and saturated brine in 50 mL portions, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified in the same manner as in (3-1) to obtain 76 mg (51%) of the desired compound.

IR (KBr) cm ^-1 : 3338, 3215, 2974, 2935,
2867, 1739, 1705, 1638, 1596, 1511, 1456, 1419, 1
392, 1367, 1331, 1291, 1226, 1167, 1101, 1053, 102
6, 980, 948. (8-2)

[0167]

Embedded image Using 73 mg (0.049 mmol) of the compound of (8-1), (3-
Synthesized in the same manner as in 2) to obtain 40.8 mg (60%) of the triethylammonium salt of the target compound.

¹ H-NMR (D ₂ O, external TMS) δppm: 8.16
(s, 1H), 8.09 (s, 1H), 6.15 (d, J = 3.0 Hz, 1H), 5.
38 (m, 1H), 5.12 (d, J = 3.7Hz, 1H), 4.52 (m, 2H),
4.35 (m, 2H), 4.21 (dd, J = 4.0 and 12.5 Hz, 1H),
4.05 (dd, J = 6.0 and 11.0 Hz, 1H), 3.84 (m, 2H),
3.63 (dd, J = 4.0 and 9.5 Hz, 1H), 3.02 (q, J = 7.
3 Hz, 18H), 2.87 (m, 1H), 2.80 (m, 4H), 2.19 (t, J
= 7.3 Hz, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.45-
0.90 (m, 45H) IR (KBr) cm ^-1 : 3367, 2977, 2936, 2868, 2757, 2739,
2678, 2492, 1733, 1698, 1643, 1601, 1515, 1477, 1
455, 1393, 1367, 1332, 1250, 1170, 1093, 1039, 93
6.

[0169]

Example 9 3′-O- ｛α-D- (3,4-bis-O-di-n-butylphosphine
Suphoryl) glucosyl｝ -2'-O- (di-n-butylphosphoryl)
Adenosine (Exemplary Compound No. 41)

[0170]

Embedded image (9-1)

[0171]

Embedded image 3'-O- {α-D- (2-O-benzyl-3,4,6-tri-O-acetyl-glucosyl)}-2'-Ot-butyldimethylsilyl-5'-O- (4- Methoxytrityl) -N, N-dibenzoyladenosine
9.5 g (7.65 mmol) was dissolved in 11 mL of tetrahydrofuran, and 1M tetrabutylammonium fluoride-
11 mL of a tetrahydrofuran solution was added, and the mixture was stirred at room temperature. After 1 hour, the solvent was distilled off under reduced pressure, the residue was dissolved in 150 mL of ethyl acetate, and washed with 150 mL of saturated saline. After evaporating the solvent under reduced pressure, the residue was dissolved in 100 mL of pyridine,
300 mL of 28% aqueous ammonia was added thereto, and the mixture was sealed and stirred at room temperature. After 19 hours, the solvent was distilled off under reduced pressure, the residue was azeotropically dried with pyridine, 80 mL of pyridine and 5.18 g (15.3 mmol) of 4,4′-dimethoxytrityl chloride were added, and the mixture was stirred at room temperature.
After 27 hours, the solvent was distilled off under reduced pressure.
The solution was dissolved in mL, washed with 200 mL of 5% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was applied to a silica gel column (300 g) and eluted with ethyl acetate-hexane (1: 2) to obtain 6.66 g (62%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.06 (s, 1H),
7.87 (s, 1H), 7.37-7.10 (m, 41H), 6.80 (m, 4H),
6.70 (m, 4H), 6.03 (d, J = 6.9 Hz, 1H), 4.83 (d, J
= 3.7 Hz, 1H), 4.80 (m, 1H), 4.72 (d, J = 11.7 H
z, 1H), 4.61 (d, J = 11.7 Hz, 1H), 4.39 (br s, 1
H), 4.18 (m, 1H), 4.00 (t, J = 9.0 Hz, 1H), 3.80-
3.10 (m, 22H). (9-2)

[0173]

Embedded image N, N-diisopropylaminodichlorophosphine 4.04 g (2
0 mmol), n-butanol 3.66 mL (40 mmol), diisopropylethylamine 10.45 mL (60 mmol) and tetrahydrofuran 1
Synthesized in the same manner as in Example (2-1) using 6 mL,
5.274 g (95%) of the desired compound were obtained.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 3.60 (m, 4H),
1.59 (m, 4H), 1.39 (m, 4H), 1.17 (d, J = 6.8 Hz,
12H), 0.92 (t, J = 7.3 Hz, 6H) IR (Liquid film) cm ^-1 : 2964, 2934, 2871, 2732, 146
4, 1433, 1396, 1380,1363, 1312, 1299, 1251, 1233,
1200, 1187, 1157, 1128, 1071, 1047, 1027,998, 968. (9-3)

[0175]

Embedded image 2.793 g (2 mmol) of the compound of (9-1), 3.32 g (12 mmol) of the compound of (9-2), and 1.68 g (24 mmol) of 1H-tetrazole
And acetonitrile 40 mL and metachloroperbenzoic acid (> 70%)
Using 4.5 g (24 mmol), synthesis was performed in the same manner as in Example (1-1) to obtain a crude product of the target compound. This compound was used for the reaction of (9-4) without purification. (9-4)

[0176]

Embedded image 200 mL of acetic acid-water (4: 1) was added to the total amount of the compound of (9-3).
And left at room temperature. After 3 days, the solvent was distilled off under reduced pressure, azeotroped with ethanol several times to remove acetic acid, the residue was applied to a silica gel column (200 g), and eluted with 3% methanol-methylene chloride to give 1.75 g of the desired compound. (80%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.30 (s, 1H),
7.55 (m, 2H), 7.36 (m, 4H), 6.63 (br s, 1H), 5.95
(br s, 2H), 5.88 (d, J = 7.9 Hz, 1H), 5.63 (m, 1
H), 5,57 (d, J = 3.7 Hz, 1H), 4.93 (s, J = 11.7 H
z, 1H), 4.85 (t, J = 9.0 Hz, 1H), 4.68 (d, J = 11.7
Hz, 1H), 4.63 (d, J = 4.3 Hz, 1H), 4.40 (q, J = 9.
5 Hz, 1H), 4.30 (s, 1H), 4.25-3.60 (m, 18H), 3.42
(m, 1H), 1.75-0.75 (m, 42H) IR (KBr) cm ^-1 : 3334, 3205, 2961, 2935, 2875, 1645,
1600, 1578, 1467, 1429, 1381, 1336, 1264, 1150, 1
108, 1028, 959. (9-5)

[0178]

Embedded image 1.74 g (1.59 mmol) of the compound of (9-4) and ethanol 20 m
It was synthesized in the same manner as in Example (1-3) using L and 200 mg of palladium black. The crude product is passed through a silica gel column (10
0g) and eluted with 3-5% methanol-methylene chloride to give 226.4 mg (14%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.32 (s, 1H),
7.93 (s, 1H), 6.52 (m, 1H), 6.10 (d, J = 7.2 Hz,
1H), 5.79 (br s, 2H), 5.58 (m, 1H), 5.25 (d, J =
3.8 Hz, 1H), 4.69 (m, 2H), 4.40 (m, 2H), 4.22-3.65
(m, 20H), 1.80-0.80 (m, 42H) IR (Liquid film) cm ^-1 : 3334, 3210, 2961, 2935, 287
5, 1646, 1600, 1579,1467, 1430, 1381, 1333, 1261,
1151, 1122, 1100, 1028, 961, 910, 867.

[0180]

Example 10 3′-O- ｛α-D- (3,4-bis-O-di-n-butyl
Phosphoryl) -2-deoxyglucosyl｝ -2'-O- (di-n-butyl
Ruphosphoryl) adenosine (Exemplary Compound No. 43)

[0181]

Embedded image (10-1)

[0182]

Embedded image 193.6 mg (0.192 mmol) of the compound of (9-5) was treated with pyridine 4m
Dissolve in L, 4,4'-dimethoxytrityl chloride 400mg
(1.15 mmol) was added and the mixture was stirred at room temperature. After 2 days, the reaction was quenched with 0.1 mL of water, and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed successively with 50 mL of 5% aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was applied to a silica gel column (50 g),
Elution with hexane-ethyl acetate (1: 1) gave 329.9 mg (90%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 7.99 (d, J =
3.5 Hz, 2H), 7.40-6.64 (m, 39H), 6.34 (d, J = 6.7 H
z, 1H), 5.77 (m, 1H), 5.06 (d, J = 3.8 Hz, 1H), 4.
77 (m, 1H), 4.63 (m, 1H), 4.53 (m, 1H), 4.20-3.40
(m, 35H), 3.25 (m, 2H), 1.72-0.75 (m, 42H) IR (KBr) cm ^-1 : 3415, 3058, 3035, 2960, 2934, 2874,
2837, 1607, 1584, 1509, 1466, 1447, 1415, 1371, 1
328, 1281, 1252, 1178, 1153, 1119, 1032, 956. (1
0-2)

[0184]

Embedded image 327 mg (0.171 mmol) of the compound of (10-1) was treated with pyridine (2 m).
Dissolve in L and add phenylchlorothionoformate (Phenyl c
hlorothionoformate) 141μL (1.026mmol), 50 ℃
And stirred. After 2 days, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed successively with 50 mL of 5% aqueous sodium bicarbonate and saturated saline, and dried over anhydrous sodium sulfate.
The solvent was distilled off. The residue was applied to a silica gel column (25 g) and eluted with hexane-ethyl acetate (1: 1) to obtain 263.8 mg (75%) of the desired compound.

IR (KBr) cm ^-1 : 2960, 2934, 2910, 2874,
2838, 1770, 1607, 1585, 1509, 1491, 1466, 1447, 1
379, 1371, 1329, 1282, 1253, 1179, 1155, 1118, 103
2. (10-3)

[0186]

Embedded image 262 mg (0.128 mmol) of the compound of (10-2)
Dissolve in mL and add 138 μL of tributyltin hydride (0.512 mmo
l) and α, α'-azobisisobutyronitrile 10 mg (64.8 mmo
l) was added and heated to reflux. After 26 hours, the solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column (30 g).
Elution with ethyl acetate (1: 1) gave 89.7m of the desired compound.
g (37%) was obtained.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 7.97 (m, 2H),
7.40-6.60 (m, 39H), 6.30 (d, J = 5.9 Hz, 1H), 5.68
(m, 1H), 5.18 (m, 1H), 4.63 (m, 2H), 4.50 (m, 1
H), 4.25 (q, J = 9.4 Hz, 1H), 4.15-3.40 (m, 22H),
3.20 (m, 1H), 2.60 (m, 1H), 1.90 (m, 1H), 1.70-0.70
(m, 42H) IR (KBr) cm ^-1 : 3415, 3059, 3034, 2960, 2934, 2874,
2838, 1768, 1607, 1585, 1509, 1466, 1447, 1415, 1
379, 1372, 1329, 1281, 1253, 1179, 1153, 1116, 103
4. (10-4)

[0188]

Embedded image 89 mg (0.0469 mmol) of the compound of (10-3) was dissolved in 10 mL of acetic acid-water (4: 1) and stirred at room temperature. After 2 hours, the solvent was distilled off under reduced pressure, azeotroped with ethanol several times to remove acetic acid, and the residue was purified by preparative thin-layer chromatography (methylene chloride: methanol = 92: 8) to give the desired compound 3
3.2 mg (72%) was obtained.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.33 (s, 1H),
7.91 (s, 1H), 6.55 (m, 1H), 6.03 (d, J = 7.3 Hz,
1H), 5.85 (br s, 2H), 5.57 (m, 1H), 5.29 (d, J =
3.2 Hz, 1H), 4.77 (m, 1H), 4.63 (d, J = 5.0 Hz, 1
H), 4.41 (q, J = 9.4 Hz, 1H), 4.26 (s, 1H), 4.20-
3.60 (m, 15H), 2.68 (dd, J = 5.4 and 12.8 Hz, 1H),
2.00-0.80 (m, 43H) IR (Liquid film) cm ^-1 : 3429, 3350, 3230, 3114, 296
1, 2935, 2875, 1648,1604, 1467, 1417, 1381, 1330,
1264, 1196, 1136, 1118, 1057, 1031, 963,916.

[0190]

Example 11 6-N- (n-octanoyl) -adenophostine
A (Exemplary Compound No. 48)

[0191]

Embedded image (11-1)

[0192]

Embedded image 3'-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5
-Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-
Yl) glucosyl｝]-2′-O- (3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) adenosine (Japanese Unexamined Patent Publication No. 8-127590) 213 mg (0.2 mmol) was dissolved in 2 mL of dimethylformamide, and 90.4 mg (0.6 mmol) of t-butyldimethylsilyl chloride and 81.7 mg of imidazole (1.
2 mmol) and stirred at room temperature. After 12 hours, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed twice with 20 mL of saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was applied to a silica gel column (10 g) and eluted with 2.5% methanol-methylene chloride to obtain 164 mg (63%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 9.35 (brs, 1
H), 8.26 (br s, 1H), 8.08 (s, 1H), 7.5-6.8 (m, 16
H), 6.35 (br s, 1H), 5.50-4.80 (m, 17H), 4.70 (m,
2H), 4.45 (m, 2H), 3.90 (m, 4H), 3.65 (m, 1H), 0.93
(s, 9H), 0.92 (s, 9H), 0.11 (s, 6H), 0.10 (s, 3
H), 0.07 (s, 3H) IR (KBr) cm ^-1 : 3323, 3066, 3031, 2954, 2929, 2887,
2857, 1638, 1595, 1499, 1472, 1464, 1419, 1363, 1
329, 1292, 1259, 1225, 1208, 1160, 1054, 1026, 97
9, 946. (11-2)

[0194]

Embedded image 160 mg (0.12 mmol) of the compound of (11-1) was dissolved in 2 mL of tetrahydrofuran, and octanoic anhydride (n-octanoic anhydride) was dissolved.
ydride) 0.71 mL (2.4 mmol) and pyridine 0.19 mL (2.4 mmol)
Was added and stirred at 50 ° C. After 23 hours, the solvent is distilled off under reduced pressure, and the residue is dissolved in 30 mL of ethyl acetate.
After washing sequentially with aqueous hydrochloric acid and 5% aqueous sodium bicarbonate, it was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was applied to a silica gel column (10 g) and eluted with 1% methanol-methylene chloride to obtain 130 mg (76%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 11.12 (brs,
1H), 8.63 (s, 1H), 8.52 (s, 1H), 7.50-7.10 (m, 17
H), 6.44 (d, J = 5.9 Hz, 1H), 5.55-4.65 (m, 19H),
2.30-1.30 (m, 12H), 0.90 (m, 21H), 0.10 (m, 12H) IR (KBr) cm ^-1 : 2955, 2929, 2857, 1703, 1610, 1587,
1463, 1378, 1361, 1292, 1260, 1226, 1162, 1101, 1
054, 1027. (11-3)

[0196]

Embedded image 125 mg (0.088 mmol) of the compound of (11-2) was dissolved in 0.26 mL of tetrahydrofuran, 0.26 mL of a 0.1 M tetrabutylammonium fluoride-tetrahydrofuran solution was added, and the mixture was stirred at room temperature. After 70 minutes, the solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of ethyl acetate, washed twice with 30 mL of saturated saline, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was applied to a silica gel column (10 g) and eluted with 2% methanol-methylene chloride to obtain 53 mg (51%) of the desired compound.

IR (KBr) cm ^-1 : 3376, 2958, 2928, 2857,
1702, 1611, 1588, 1457, 1383, 1355, 1329, 1284, 1
264, 1226, 1098, 1056, 1019, 979. (11-4)

[0198]

Embedded image Using 50 mg (0.041 mmol) of the compound of (11-3), (3-3)
The compound was synthesized in the same manner as in -2) to obtain 8 mg (18%) of the target compound triethylammonium salt.

¹ H-NMR (D ₂ O, external TMS) δppm: 8.53
(s, 1H), 8.42 (s, 1H), 6.22 (d, J = 6.6 Hz, 1H), 5.
18 (m, 2H), 4.33 (s, 1H), 4.17 (m, 1H), 3.98-3.30
(m, 8H), 3.02 (q, J = 7.3 Hz, 18H), 2.44 (t, J = 7.
3 Hz, 2H), 1.58 (m, 2H), 1.30-0.90 (m, 35H), 0.67
(t, J = 7.3 Hz, 3H) IR (KBr) cm ^-1 : 3392, 3267, 2935, 2739, 2678, 2492,
1683, 1615, 1588, 1519, 1468, 1434, 1399, 1384, 1
356, 1331, 1229, 1189, 1152, 1094, 1037, 927.

[0200]

Example 12 2 "-Deoxy-adenophostin A (Exemplary Compound No. 65)

[0201]

Embedded image (12-1)

[0202]

Embedded image 2'-O- (t-butyldimethylsilyl) -5'-O- (4-methoxytrityl) -N, N-dibenzoyladenosine (Chemgenes) 1.38
g (1.6mmol), molecular sieve 4A 6g and γ-collidine
636 μL (4.81 mmol) and 3,4,6-tri-O-acetyl-α-D-2-deoxyglucosyl bromide (J. Thiem et al., Chem. Be
1.7 g (4.81 mmol) of r. 113, 3075-3085 (1980) was dissolved in 16 mL of chloroform, 997 mg of silver perchlorate (4.81 mmol) was added, and the mixture was stirred at room temperature. After 24 hours, filter through Celite, dilute to about 200 mL while washing with chloroform,
After washing with a 0.01N aqueous hydrochloric acid solution, a 5% aqueous sodium bicarbonate solution and a saturated saline solution in that order, the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was applied to a silica gel column (300 g) and eluted with hexane-ethyl acetate (2: 1) to give the desired compound
612.3 mg (34%) were obtained.

IR (KBr) cm ^-1 : 2954, 2933, 2859, 2748,
1709, 1600, 1577, 1510, 1493, 1449, 1414, 1368, 1
340, 1281, 1237, 1179, 1153, 1119, 1085, 1047. (12-2)

[0204]

Embedded image Using 544.9 mg (0.48 mmol) of the compound of (12-1),
Synthesized in the same manner as in (9-1) to obtain the target compound 193.9 mg
(31%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.02 (m, 2H),
7.50-6.65 (m, 40H), 5.92 (d, J = 6.5 Hz, 1H), 5.19
(m, 1H), 4.95-4.75 (m, 2H), 4.33 (m, 1H), 3.95
(m, 1H), 3.85-3.08 (m, 21H), 2.54 (m, 1H), 2.24
(m, 1H) IR (KBr) cm ^-1 : 3412, 3058, 3034, 3000, 2933, 2836,
1735, 1607, 1584, 1509, 1466, 1447, 1414, 1373, 1
330, 1297, 1252, 1180, 1153, 1132, 1118, 1036. (12-3)

[0206]

Embedded image 83.2 mg (0.0645 mmol) of the compound of (12-2) and N, N-diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin
-3-amine 69.4mg (0.29mmol) and 1H-tetrazole 27.1
mg (0.387 mmol), 1 mL of acetonitrile and 100 mg (0.58 mmol) of metachloroperbenzoic acid (> 70%), synthesized in the same manner as (1-1) to obtain 105 mg (89%) of the target compound. It was used for the next (12-4). (12-4)

[0207]

Embedded image 105 mg (0.057 mmol) of the compound of (12-3) was dissolved in 22 mL of chloroform, and 0.44 mL (5.7 mmol) of trifluoroacetic acid was dissolved.
Was added and stirred at 4 ° C. After 50 minutes, the mixture was washed twice with 50 mL of 5% aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was applied to a silica gel column (10 g), and eluted with 5% methanol-methylene chloride to obtain the desired compound 42.
5 mg (78%) were obtained.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.17 (s, 1H),
7.94 (s, 1H), 7.45-7.10 (m, 12H), 6.23 (br s, 1
H), 6.10 (d, J = 6.3 Hz, 1H), 5.89 (br s, 2H), 5.6
0 (m, 1H), 5.48-4.65 (m, 16H), 4.29 (s, 1H), 4.10-
3.62 (m, 6H), 2.83 (dd, J = 5.1 and 12.9 Hz, 1H),
2.06 (m, 1H) IR (KBr) cm ^-1 : 3337, 3213, 2929, 1641, 1597, 1473,
1424, 1373, 1332, 1288, 1226, 1207, 1055, 1028. (12-5)

[0209]

Embedded image 42 mg (0.0437 mmol) of the compound of (12-4) was ethanol
Dissolve in 3 mL and 1 mL of water, add 200 mg of palladium black,
The mixture was stirred at room temperature under a hydrogen atmosphere. After 26 hours, the mixture was filtered through celite, washed with ethanol and dilute aqueous ammonia, and ethanol was distilled off under reduced pressure to obtain an aqueous solution.
After washing twice with 0 mL and freeze-drying, 36.4 mg (91%) of the ammonium salt of the target compound was obtained.

¹ H-NMR (D ₂ O, external TMS) δppm: 8.17
(s, 1H), 8.07 (s, 1H), 6.04 (d, J = 5.9 Hz, 1H), 5.
27 (s, 1H), 5.02 (m, 1H), 4.46 (t, J = 4.4 Hz, 1
H), 4.37 (m, 1H), 4.24 (d, J = 2.9 Hz, 1H), 3.85-
3.50 (m, 8H), 3.35 (m, 1H), 2.30 (m, 1H) IR (KBr) cm ^-1 : 3158, 1660, 1608, 1576, 1402, 1339,
1303, 1080, 977, 939.

[0211]

Example 13 3′-O- [α-D- ｛3,4-bis-O- (thiophospho
Ryl) -2-deoxy-glucosyl {] -2'-O- (thiophosphoryl
A) Adenosine (Exemplary Compound No. 47)

[0212]

Embedded image (13-1)

[0213]

Embedded image 104.6 mg (0.081 mmol) of the compound of (12-2) and 102 mg (1.46 mmol) of 1H-tetrazole were dissolved in 4 mL of methylene chloride, and bis (2-cyanoethyl) -N, N-diisopropylphosphoramidite (C. Sund et al.) ., Tetrahedron 48, 695-718
(1992).) 315 mg (1.21 mmol) was added, and the mixture was stirred at room temperature. 1
After an hour, a solution of 128 mg of sulfur dissolved in 1.3 mL of pyridine was added, and the mixture was stirred at room temperature. After 22 hours, the solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column (30 g).
Elution with ethyl acetate (1: 2) gave 123.1 of the desired compound.
mg (80%) was obtained.

IR (KBr) cm ^-1 : 3414, 3159, 3059, 2839,
2713, 2575, 2256, 1816, 1607, 1510, 1468, 1446, 1
414, 1385, 1331, 1299, 1247, 1180, 1146, 1085, 103
5, 1016. (13-2)

[0215]

Embedded image Using the compound (13-1) (123 mg, 0.0648 mmol),
24.3 mg (37%) of the target compound
%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.33 (s, 1H),
7.98 (s, 1H), 6.19 (d, J = 7.5Hz, 1H), 5.75 (m, 3
H), 5.32 (m, 1H), 5.00 (m, 1H), 4.69 (d, J = 4.2 H
z, 1H), 4.59 (m, 1H), 4.50-3.65 (m, 20H), 2.90-2.60
(m, 13H), 2.04 (m, 1H). (13-3)

[0219]

Embedded image To 24 mg (0.0235 mmol) of the compound of (13-2), 0.349 mL (1.41 mmol) of N, O-bis (trimethylsilyl) acetamide, 2.1 mL of pyridine and 32 μL of diazabicycloundecene (0.2 μL)
12 mmol) and stirred at room temperature. Ten minutes later, 1 mL of water was added, the solvent was distilled off under reduced pressure, the residue was dissolved in 20 mL of water, washed with 20 mL of ether, and the solvent was distilled off under reduced pressure. Residue H
PLC (PEGASIL-B ODS, 20x250mm, 9% acetonitrile-0.
1M triethylammonium acetate (pH7), 7mL / min)
Purification by triethylammonium salt of the target compound 1
5.8 mg (67%) were obtained.

¹ H-NMR (D ₂ O, external TMS) δ ppm: 8.18
(s, 1H), 8.08 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 5.
35 (d, J = 2.9 Hz, 1H), 5.20 (m, 1H), 4.49 (dd, J
= 2.8 and 5.2 Hz, 1H), 4.28 (m, 1H), 4.18 (q, J =
10.0 Hz, 1H), 3.82-3.58 (m, 5H), 3.01 (q, J = 7.3
Hz, 18H), 2.33 (dd, J = 5.3 and 13.3 Hz, 1H), 1.72
(m, 1H), 1.09 (t, J = 7.3 Hz, 27H) IR (KBr) cm ^-1 : 3309, 3236, 3106, 3033, 2935, 2879,
2811, 1647, 1599, 1474, 1448, 1385, 1362, 1324, 1
298, 1269, 1244, 1207, 1107, 1089, 1064, 983.

[0219]

Example 14 3-O- [α-D- ｛3,4-O-bisphosphoryl-6-O
-(n-Butyryl) -glucosyl｝]-2-O-phosphoryl-5-O- (n-
( Butyryl) -1-deoxyribose (Exemplary Compound No. 12)

[0220]

Embedded image (14-1)

[0221]

Embedded image 3-O- [α-D- ｛2-O-benzyl-3,4-bis-O- (3-oxo-1,5-
Dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) -6-O- (4,4'-dimethoxytrityl) glucosyl｝]-2-O
-(3-oxo-1,5-dihydro-benzo [e] [1,3,2] dioxaphosphepin-3-yl) -5-O- (4-methoxytrityl) -1-deoxyribose ( Described in JP-A-9-316093) 4.11 g (2.72 mmo
The compound was synthesized in the same manner as (12-4) using l) to obtain 1.923 g (76%) of the desired compound.

¹ H-NMR (CDCl ₃ + D ₂ O, TMS) δ ppm: 7.45-7.17
(m, 15H), 7.12 (m, 1H), 7.07 (m, 1H), 5.57 (dd, J
= 11.0 and 14.2 Hz, 1H), 5.37 (t, J = 3.3 Hz, 1
H), 5.30-4.68 (m, 17H), 4.60 (d, J = 11.7 Hz, 1H),
4.30 (m, 1H), 4.15 (m, 2H), 4.02 (dd, J = 3.0 and
13.4 Hz, 1H), 3.85 (m, 2H), 3.69 (m, 2H). (14-2)

[0223]

Embedded image Using 400 mg (0.428 mmol) of the compound of (14-1),
Synthesized in the same manner as in (3-1), 422 mg of the desired compound (9
2%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 7.45 (m, 2H),
7.38-7.22 (m, 13H), 7.13 (m, 2H), 5.47 (t, J = 1
0.2Hz, 1H), 5.43 (t, J = 10.2 Hz, 1H), 5.30-4.77
(m, 15H), 4.68 (d, J = 12.1 Hz, 1H), 4.35 (m, 3H),
4.25 (m, 1H), 4.18-4.00 (m, 5H), 3.66 (dd, J = 3.
4 and 9.8 Hz, 1H), 2.44-2.30 (m, 4H), 1.73-1.55
(m, 4H), 1.00-0.90 (m, 6H) IR (KBr) cm ^-1 : 3434, 3065, 3030, 2965, 2937, 2878,
1738, 1499, 1458, 1417, 1378, 1292, 1225, 1167, 1
100, 1053, 1029, 949. (14-3)

[0225]

Embedded image Using 422 mg (0.939 mmol) of the compound of (14-2), (3
It was synthesized in the same manner as in -2). The crude product was subjected to Sephadex G-15 (30 g) and purified by elution with water to obtain 297 mg (77%) of the target compound triethylammonium salt.

¹ H-NMR (D ₂ O, external TMS) δppm: 5.04
(d, J = 3.6 Hz, 1H), 4.65 (m, 1H), 4.30 (m, 3H),
4.10 (m, 4H), 3.90 (m, 4H), 3.60 (m, 1H), 3.02 (q,
J = 7.3 Hz, 18H), 2.24 (m, 4H), 1.45 (m, 4H), 1.1
0 (t, J = 7.3 Hz, 27H), 0.74 (t, J = 7.3 Hz, 6H) IR (KBr) cm ^-1 : 3197, 2970, 2938, 2878, 2803, 2756,
2739, 2677, 2602, 2492, 2354, 1736, 1469, 1434, 1
398, 1384, 1365, 1306, 1187, 1169, 1088, 1036, 99
6, 939.

[0227]

Example 15 3-O- [α-D- ｛3,4-O-bis (ethylphospho
Ryl) -glucosyl {]-2-O-ethylphosphoryl-1-deoxy
Ciribose (Exemplary Compound No. 11)

[0228]

Embedded image (15-1)

[0229]

Embedded image 3-O- [α-D- {2-O-benzyl-6-O- (4,4'-dimethoxytrityl) glucosyl}]-5-O- (4-methoxytrityl) -1-deoxyribose 400mg (0.416mmo described in Kaihei 9-316093)
l) and 349 mg (4.99 mmol) of 1H-tetrazole and O- (2-cyanoethyl) -N, N-diisopropyl-O'-ethyl phosphoramidite (C. Sund et al., Tetrahedron 48, 695-718 (199
2).) Using 1.22 g (4.99 mmol), 10 mL of acetonitrile and 1.07 g (6.24 mmol) of metachloroperbenzoic acid (> 70%),
Synthesized in the same manner as in -1) to obtain the desired compound (600 mg, 100%)
Was used for the following (15-2). (15-2)

[0230]

Embedded image Using 600 mg (0.416 mmol) of the compound of (15-1),
Synthesized in the same manner as in (1-2), 298 mg of the desired compound (8
2%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 7.35 (m, 5H),
5.30-3.55 (m, 24H), 2.85-1.25 (m, 15H) IR (Liquid film) cm ^-1 : 3421, 2970, 2936, 2918, 225
5, 1475, 1455, 1414,1395, 1372, 1338, 1265, 1163,
1098, 1035. (15-3)

[0232]

Embedded image 298 mg (0.342 mmol) of the compound of (15-2) was added to 4 m of pyridine.
L and 4 mL of 28% aqueous ammonia were dissolved and stirred at room temperature. 1
After a period of time, the solvent is distilled off under reduced pressure, the residue is hydrogenolyzed and decomposed in the same manner as in (3-2), and the obtained crude product is subjected to Sephadex G-15 (30 g). And eluted with
172 mg (55%) of the triethylammonium salt of the target compound was obtained.

¹ H-NMR (D ₂ O, external TMS) δppm: 5.21
(d, J = 3.8 Hz, 1H), 4.36 (q, J = 8.5 Hz, 1H), 4.30
(m, 1H), 4.15-3.90 (m, 7H), 3.85 (m, 1H), 3.82
(m, 1H), 3.70 (m, 2H), 3.20 (m, 6H), 1.28 (m, 9H) IR (Liquid film) cm ^-1 : 3406, 2976, 2939, 2879, 280
4, 2756, 2739, 2676,2601, 2571, 2528, 2491, 1650,
1476, 1434, 1398, 1385, 1366, 1222, 1168,1159, 103
7.

[0234]

Example 16 3′-O- [α-D- ｛3,4-O-bis (ethylphospho
Ryl) -glucosyl｝]-2'-O-ethylphosphoryl-adenosine
Down (Compound No. 45)

[0235]

Embedded image (16-1)

[0236]

Embedded image 444.5 mg (0.318 mmol) of the compound of (9-1), 267 mg (3.82 mmol) of 1H-tetrazole and O- (2-cyanoethyl) -N, N-diisopropyl-O'-ethyl phosphoramidite (C. Sund et.
al., Tetrahedron 48, 695-718 (1992).) 941 mg (3.82 mm
ol) and acetonitrile 10 mL and metachloroperbenzoic acid (> 70
%) Using 823 g (4.77 mmol), it was synthesized in the same manner as in (1-1) to obtain 469 mg (79%) of the desired compound.

IR (KBr) cm ^-1 : 3417, 3059, 3033, 2925,
2934, 2911, 2838, 2255, 1719, 1607, 1585, 1509, 1
471, 1447, 1413, 1370, 1329, 1282, 1253, 1180, 115
8, 1035. (16-2)

[0238]

Embedded image Using 469 mg (0.249 mmol) of the compound of (16-1),
Synthesized in the same manner as in (1-2), and the target compound (135 mg, 5 mg
4%).

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.33 (s, 1H),
7.75-7.28 (m, 6H), 6.58 (m, 1H), 6.07 (m, 1H), 5.
73 (m, 1H), 5.67 (br s, 2H), 5.39 (m, 1H), 4.88
(m, 2H), 4.67 (m, 2H), 4.50-3.40 (m, 20H), 2.88-2.
40 (m, 6H), 1.45-0.80 (m, 9H) IR (KBr) cm ^-1 : 3336, 3212, 2965, 2928, 2873, 2255,
1645, 1600, 1477, 1426, 1385, 1372, 1336, 1272, 1
162, 1102, 1034. (16-3)

[0240]

Embedded image Using 135 mg (0.134 mmol) of the compound of (16-2),
It was synthesized in the same manner as in (15-3) to obtain 66 mg (47%) of the target compound triethylammonium salt.

¹ H-NMR (D ₂ O, external TMS) δ ppm: 8.18
(s, 1H), 8.10 (s, 1H), 6.15 (d, J = 7.7Hz, 1H), 5.2
0 (d, J = 4.0 Hz, 1H), 5.15 (m, 1H), 4.47 (d, J =
4.2Hz, 1H), 4.33 (s, 1H), 4.25 (q, J = 8.5 Hz, 1
H), 3.93-3.58 (m, 12H), 3.34 (m, 1H), 3.02 (q, J =
7.3 Hz, 18H), 1.10 (m, 33H), 0.57 (t, J = 7.1 Hz,
3H).

[0242]

Example 17 5 ', 6 "-bis-O-acetyl-6-N-acetyl-
Adenophosphin A (Exemplary Compound No. 49)

[0243]

Embedded image (17-1)

[0244]

Embedded image Synthesis was carried out in the same manner as in (3-1) using acetic anhydride instead of butyric anhydride to obtain 201 mg (70%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.57 (s, 1H),
8.47 (s, 1H), 7.93 (s, 1H), 7.45-7.10 (m, 17H),
6.25 (d, J = 5.0 Hz, 1H), 5.82 (m, 1H), 5.48 (m, 2
H), 5.30-4.68 (m, 16H), 4.47 (m, 2H), 4.41 (m, 2
H), 4.28 (m, 1H), 4.12 (m, 1H), 3.68 (dd, J = 3.6
and 9.8 Hz, 1H), 2.63 (s, 3H), 2.14 (s, 3H), 2.02
(s, 3H). (17-2)

[0246]

Embedded image The compound (17-1) was synthesized in the same manner as in (3-2) using 200 mg of the compound to obtain 175.8 mg (96%) of the triethylammonium salt of the target compound.

¹ H-NMR (D ₂ O, external TMS) δppm: 8.54
(s, 1H), 8.39 (s, 1H), 6.25 (d, J = 5.0 Hz, 1H), 5.
35 (m, 1H), 5.18 (d, J = 3.7 Hz, 1H), 4.51 (m, 1
H), 4.37-4.25 (m, 4H), 4.12 (dd, J = 6.3 and 12.1
Hz, 1H), 3.02 (q, J = 7.3 Hz, 18H), 2.17 (s, 3H),
1.93 (s, 3H), 1.85 (s, 3H), 1.10 (t, J = 7.3 Hz, 2
7H).

[0248]

Example 18 5 ', 6 "-bis-O-propionyl-6-N-propion
Onyl-adenophostin A (Exemplary Compound No. 50)

[0249]

Embedded image (18-1)

[0250]

Embedded image Using propionic anhydride instead of butyric anhydride, (3-
Synthesized in the same manner as in 1) to obtain 255 mg (75%) of the desired compound.

¹ H-NMR (CDCl ₃ , TMS) δ ppm: 8.56 (s, 1H),
8.43 (s, 1H), 7.92 (s, 1H), 7.45-7.10 (m, 17H),
6.25 (d, J = 5.1 Hz, 1H), 5.82 (m, 1H), 5.48 (m, 2
H), 5.30-4.68 (m, 16H), 4.47 (m, 2H), 4.41 (m, 2
H), 4.28 (m, 1H), 4.12 (m, 1H), 3.68 (dd, J = 3.6
and 9.9 Hz, 1H), 2.93 (q, J = 7.4 Hz, 2H), 2.43
(m, 2H), 2.29 (t, J = 7.4 Hz, 2H), 1.30 (t, J = 7.4
Hz, 3H), 1.16 (t, J = 7.4 Hz, 3H), 1.10 (t, J =
7.4 Hz, 3H). (18-2)

[0252]

Embedded image The compound (18-1) was synthesized in the same manner as in (3-2) using 200 mg of the compound to obtain 178.5 mg (97%) of the triethylammonium salt of the target compound.

¹ H-NMR (D ₂ O, external TMS) δ ppm: 8.53
(s, 1H), 8.39 (s, 1H), 6.25 (d, J = 4.6 Hz, 1H), 5.
38 (m, 1H), 5.18 (d, J = 3.7 Hz, 1H), 4.51 (m, 1
H), 4.37-4.25 (m, 4H), 4.10 (dd, J = 6.5 and 12.1
Hz, 1H), 3.90 (m, 2H), 3.62 (dd, J = 3.6 and 9.6 H
z, 1H), 3.02 (q, J = 7.4 Hz, 18H), 2.47 (q, J = 7.
6 Hz, 2H), 2.22 (q, J = 7.6 Hz, 2H), 2.10 (m, 2H),
1.10 (m, 30H), 0.90 (t, J = 7.6 Hz, 3H), 0.78 (t,
J = 7.6 Hz, 3H).

[0254]

[Formulation Example 1] Powder A powder is obtained by mixing 5 g of the compound of Example 2, 895 g of lactose and 100 g of corn starch with a blender. The powder was 5 mg / g of Example 2.
Of the compound.

[0255]

Formulation Example 2 Granules 5 g of the compound of Example 2, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose were mixed, and then mixed with 10% aqueous solution of hydroxypropylcellulose 300
Add g and knead. This is granulated using an extrusion granulator and dried to obtain a granule. The granules contain 5 mg of the compound of Example 2 per gram.

[0256]

Formulation Example 3 Capsule 5 g of the compound of Example 2, lactose 115 g, corn starch 58 g and magnesium stearate 2
g using a V-type mixer and then 1
A capsule is obtained by filling 80 mg each. The capsule contains 5 mg of the compound of Example 2 per capsule.

[0257]

Formulation Example 4 Tablets After mixing 5 g of the compound of Example 2, lactose 90 g, corn starch 34 g, microcrystalline cellulose 20 g and magnesium stearate 1 g with a blender,
Tableting with a tablet machine gives tablets weighing 150 mg.
The tablets contain 5 mg of compound per tablet.

[0258]

Industrial Applicability The novel phosphate derivative of the present invention has an excellent activity of increasing intracellular calcium ion concentration,
Moreover, since it has low toxicity, it is useful for treating brain diseases such as senile dementia, Alzheimer's disease, and Huntington's disease. It is also useful as a vasopressor, an immunopotentiator that activates immunocompetent cells, a pressure sore, a therapeutic agent for upper skin ulcer, or a therapeutic agent for type I diabetes by promoting insulin secretion.

Further, since the novel phosphate derivative of the present invention has excellent cell membrane permeability, it can increase the intracellular calcium ion concentration when added to an extracellular solution. Therefore, the efficiency of artificial fertilization can be improved, and for example, it can be used for animal cloning technology.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/7076 A61K 31/70 620 (72) Inventor Masaaki Takahashi 1-258 Hiromachi, Shinagawa-ku, Tokyo No. Sankyo Co., Ltd. (72) Inventor Kazuko Tanzawa 1-258 Hiromachi, Shinagawa-ku, Tokyo F-term (reference) 4C086 AA03 EA07 EA18 NA11 NA14 ZC01 ZC41 4H050 AA01 AB20

Claims (18)

[Claims] 1. A compound of the general formula (I) [Wherein R ¹ is a hydrogen atom or a formula (II)] (Wherein, R ⁸ represents a hydrogen atom or a group forming an amide.) R ² and R ³ are the same or different and represent a hydrogen atom or a group forming an ester, R ⁴ , R ⁵ and R ⁶ may be the same or different and have the formula (III): (Wherein R ⁹ and R ¹⁰ are the same or different and each is a hydroxyl group, a mercapto group, a C ₁ -C ₄ alkoxy group, a (C ₁ -C ₅ aliphatic acyl) oxy- (C ₁ -C ₃ alkyl) oxy Group or (C ₁ -C ₅
X represents an aliphatic acyl) thio- (C ₁ -C ₃ alkyl) oxy group, and X represents an oxygen atom or a sulfur atom. ), And R ⁷ represents a hydrogen atom or a hydroxyl group which may form an ester. However, R ¹ is not a hydrogen atom, and R ² , R ³ and R ⁸
Are all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues (P (= O) (OH) ₂ ), and R ⁷ is a hydroxyl group;
And R ¹ is not a hydrogen atom, R ² and R ⁸ are hydrogen atoms, R ³ is an acetyl group, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues, and R ⁷ is a hydroxyl group And R ¹ ,
Except for compounds in which R ² and R ³ are all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues, and R ⁷ is a hydroxyl group. Or a pharmacologically acceptable salt thereof. 2. A compound of the general formula (IV) [Wherein R ¹ is a hydrogen atom or a formula (II)] (Wherein, R ⁸ represents a hydrogen atom or a group forming an amide.) R ² and R ³ are the same or different and represent a hydrogen atom or a group forming an ester, R ⁴ , R ⁵ and R ⁶ may be the same or different and have the formula (III): (Wherein R ⁹ and R ¹⁰ are the same or different and each is a hydroxyl group, a mercapto group, a C ₁ -C ₄ alkoxy group, a (C ₁ -C ₅ aliphatic acyl) oxy- (C ₁ -C ₃ alkyl) oxy Group or (C ₁ -C ₅
X represents an aliphatic acyl) thio- (C ₁ -C ₃ alkyl) oxy group, and X represents an oxygen atom or a sulfur atom. ), And R ⁷ represents a hydrogen atom or a hydroxyl group which may form an ester. However, R ¹ is not a hydrogen atom, and R ² , R ³ and R ⁸
Are all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues (P (= O) (OH) ₂ ), and R ⁷ is a hydroxyl group;
And R ¹ is not a hydrogen atom, R ² and R ⁸ are hydrogen atoms, R ³ is an acetyl group, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues, and R ⁷ is a hydroxyl group And R ¹ ,
Except for compounds in which R ² and R ³ are all hydrogen atoms, R ⁴ , R ⁵ and R ⁶ are all phosphoric acid residues, and R ⁷ is a hydroxyl group. Or a pharmacologically acceptable salt thereof. 3. Any one selected from claim 1 or 2
Wherein R ¹ is of the formula (II) (Wherein R ⁸ represents a hydrogen atom or a group forming an amide) or a pharmacologically acceptable salt thereof. 4. One of the first to third aspects
In the section, R^TwoAnd R^ThreeAre the same or different and have a hydrogen atom or a substituent.
May be C₁−C_{1 Two}Has an aliphatic acyl group or a substituent
May be C₆−C₁₄Compounds that are aromatic acyl groups or
Is a pharmacologically acceptable salt. 5. One of the first to third aspects
In the above item, the compound or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are the same or different and are a hydrogen atom or a C ₁ -C ₁₂ aliphatic acyl group optionally having a substituent. 6. One of the first to third aspects
In the above, R ² and R ³ are the same or different and each represents a hydrogen atom, C ₁ -C ₆ aliphatic acyl or (C ₁ -C ₄ alkyl) oxycarbonylamino- (C ₃ -C ₈ aliphatic acyl) Or a pharmacologically acceptable salt thereof. 7. One of the first to third aspects selected from the above.
In the above item, the compound or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are a hydrogen atom. 8. One of the first to seventh aspects
In the above item, the compound or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a hydrogen atom or a hydroxyl group. 9. One of the first to seventh aspects
In the above item, the compound wherein R ⁷ is a hydroxyl group, or a pharmaceutically acceptable salt thereof. 10. The method according to claim 1, wherein R ⁸ has a hydrogen atom, a C ₁ -C ₁₂ aliphatic acyl group which may have a substituent or a substituent. Or a pharmaceutically acceptable salt thereof, which is an optionally substituted C ₆ -C ₁₄ aromatic acyl group. 11. The method according to claim 1, wherein R ⁸ is a hydrogen atom or a C ₁ -C ₁₂ which may have a substituent.
A compound which is an aliphatic acyl group or a pharmacologically acceptable salt thereof. 12. The compound according to any one of claims 1 to 9, wherein R ⁸ is a hydrogen atom or a C ₁ -C ₆ aliphatic acyl group, or a pharmaceutically acceptable salt thereof. 13. The compound according to any one of claims 1 to 9, wherein R ⁸ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 14. The method according to claim 1, wherein R ⁹ and R ¹⁰ are the same or different and each is a C ₁ -C ₄ alkoxy group, (C ₁ -C ₅ aliphatic acyl) An oxy- (C ₁ -C ₃ alkyl) oxy group or a (C ₁ -C ₅ aliphatic acyl) thio- (C _1-
A compound which is a C ₃ alkyl) oxy group or a pharmacologically acceptable salt thereof. 15. The method according to claim 1, wherein R ⁹ and R ¹⁰ are the same or different and each is a C ₁ -C ₄ alkoxy group, (C ₁ -C ₅ aliphatic acyl) oxy - methyl group or (C ₁ -C ₅ aliphatic acyl) thio - compound or pharmacologically acceptable salt thereof is ethyloxy group. 16. The method according to claim 1, wherein R ⁹ and R ¹⁰ are the same and are ethoxy, acetoxymethyloxy, pivaloyloxy-methyloxy or acetylthio-ethyloxy. A compound or a pharmacologically acceptable salt thereof. 17. The compound according to any one of claims 1 to 16, wherein X is an oxygen atom, or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 2, or a pharmaceutically acceptable salt thereof. 3'-O- ｛α-D- (3,4-
Bis-O-diethylphosphoryl) glucosyl｝ -2′-O- (diethylphosphoryl) adenosine, 3′-O- [α-D- ｛3,4-bis-O
-Di (2-acetoxyethyl) phosphoryl｝ glucosyl] -2'-
O- ｛di (2-acetoxyethyl) phosphoryl｝ adenosine,
3′-O- {α-D- (3,4-bis-O-di-n-butylphosphoryl) glucosyl} -2′-O- (di-n-butylphosphoryl) adenosine,
Or, 3′-O- {α-D- (3,4-bis-O-di-n-butylphosphoryl) -2-deoxyglucosyl} -2′-O- (di-n-butylphosphoryl) adenosine.