JPS61263996A - Novel nucleotide derivative and its production - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel nucleoside 9 derivatives and formulas (wherein B
is adenine, cytosine, 5-fluorouracil, 5-azacytosine, 6-mercazotoprine or 7-zoazaadeni/, A and C are each hydrogen or a human 90x group, W has 8-20 carbon atoms a saturated or unsaturated alkyl group or a 2- or 3-alkoxyalkyl group having 7 to 19 carbon atoms), which is useful as an anticancer agent and an antiviral agent. This invention relates to novel nucleosibial derivatives and methods for producing their salts.

In 2m, phospholipids include optical isomers L=D and DL forms, and representative nucleoside 9 includes 9-β-D-arabinofuranosyl atenine (hereinafter referred to as al'a
-A), 1-β-D-arabinofuranosylcytosine (hereinafter referred to as ara-C), 5-fluoro-2'-deoxyuridine or other anticancer and antiviral agents. There is a nucleoside 9 that can

The present invention relates to a novel method for producing a conjugate of 1-0-alkyl phospholipid and nucleoside 9.

A new compound with formula (11) was first synthesized by the inventor.

The inventors [Journal of Medical Chemistry]
25.1322 (1982), Biochemical and Biophyei.
calResearch Communication
) 85, 715 (1978)] and other researchers [Biohimicae Biophysica Acta (B.
iochimica at BiophysicaAc
ta) 69,604 (1980) is one of the similar compounds.
．． 2-:) Acylglyceronucleoside 9 conjugates are disclosed. In this prior art, this analogous compound was obtained by reaction with nucleonobi-5'-monophosphoglycero-3-phosphate. However, the phospholipid moiety of the present invention
The novel conjugate with nucleosides, consisting of alkyl-2-0-7 frucrycerose 3-phosphate, has not been reported in the prior art and was prepared for the first time by the present inventors.

The present invention will be explained in detail below.

The aim of the present invention is to provide novel anticancer and antiviral agents with unique molecular structure and physicochemical properties.

Another object of the present invention is to provide a new and high-yield method for producing the above-mentioned novel anticancer and antiviral agents with unique molecular structure and physicochemical properties.

Yet another object of the present invention is to provide a method for producing a new class of phospholipid conjugates as anticancer and antiviral agents.

Another object of the present invention is that lipids that act as a novel delivery system for tumor cells of anticancer and antiviral agents and that penetrate into cancer cells by the process of sosomotropism or related membrane phenomena. An object of the present invention is to provide a new class of polymeric nucleotide compounds that form vesicles (lysosomes).

After the anticancer agent of the present invention penetrates into tumor cells, it is separated into anticancer and antiviral nucleosides or nucleotides by a phospholipid-enzyme specific reaction or a non-specific mechanism, and the cells are treated with phospholipid-specific nucleosides or nucleotides. If it has a binding site, it becomes a specific target compound.Furthermore, nucleoside 9 requires phosphorylation for effective activity.
For nucleoside 9, the conjugate serves such a function.
Resisting cells lacking kinase (resi tin
gc011 day) produces an excellent therapeutic effect. Furthermore, this 1-0-alkylphospholipid 9 itself has pharmaceutical effects,
Especially anti-cancer and immunomodulative effects.
ating aati-vity), and the combination of a nucleoside and a 1-0-alkylphospholipid produces advantageous additive or synergistic effects. In other words, 1-0
-alkylphospholipyl-', 1-0-alkyl-2-
Among lysophospholipid 9 and its derivatives, 1-0-
It is disclosed that alkyl-2-0-methylphosphatidyl-choline or monoethanolamine has suppressive and preventive effects and immune-expanding effects on cancer in various animals [Antican Research
cer Research) 1, 135 and 3
45 (1981); Seminar in Immunopathol
ogy) Vol. 3, 187-203 (1979) 1° As long as the conjugate remains, the amino group of ara-C or ara-A is prevented from being deamined by cytidine deaminase or adenosine deaminase. Since the conjugate itself is lipophilic, it is a kind of sustained release protein.
odruq) and reaches the target cell where it hydrolyzes the conjugate to phospholipid and nucleoside 9. Since this is the same result as administering two types of pharmaceuticals, it is possible to expect the pharmaceutical effects of both to increase the therapeutic index of anticancer drugs.

The method for producing the compound of formula (Il) is schematically shown in the reaction process diagram below.
Morphoresort (■) or P-nucleoside 9-5'
-P2-) Phenylpyrophosphate (■) After treatment,
(T(1) is obtained from the conjugate (Ta) by reaction with 1-0-alkyl-2-0-acylglycero-phosphate (■) (reaction scheme, method A or method B)
. Another route is to convert the phospholipid (■) to its morphorezoate (■) or pi-taliceroFi'-P2--J
After forming phenylpyrophosphate (X), it was reacted with nucleotide)'' (III) to form the conjugate (1(+
) to obtain (Id) (reaction scheme, method C and method D).

The compounds of the invention and their salts can be used in admixture with conventional pharmaceutically acceptable organic and inorganic carrier materials. The compounds of the invention may be in one of the usual acceptable forms such as emulsions, suspensions, ampoules, powders, granules, capsules, tablets, and the like. It may also contain the usual fillers, preservatives, stabilizers, dispersants, fumigants, buffers and colorants.

The following implementation series are merely illustrative and are not intended to limit the invention.

Example 1 1-β-D-arabinofuranosylcytosine-57-diphosphate-1-〇-octadecyl-2-0-valmitoyl-5n-glycerol or 1-β-D-arabinofuranosylcytosine-5' -diphosphate-β-
Valmitoyl-L-batyl alcohol (I a, a
ra-CDP-L-PBA) 1.7 g (2.6 mmol) of 1-〇-octadecyl-2-〇-valmitoyl-θn-glycero~3-phosphate (■,' n=17.m=14.L- isomer) with pyridine without evaporation to dryness, 1.8S+(2
, 6 mmol) of ara-CMP morpholitate 4-
Morpholine-N', N'-dicyclohexylcarboxamidinium salt (Vl, B-cytosine) was mixed. The mixture was dissolved in 150-degree dry pyridine and stirred at room temperature under anhydrous conditions for 5 days.

Pyridine was then removed under reduced pressure and traces of pyridine were removed by co-evaporation of toluene. The residue was mixed with 15-ml dry acetic acid and 150 txl chloroform-CH30H-water (
2:3:1) and stirred at room temperature for 1 hour, and 250 ml of chloroform was added to this solution. The organic solvent layer was separated and concentrated under reduced pressure, and traces of acetic acid present were removed by coevaporation with 10 ml of toluene in three steps. The residue was dissolved in 100 mJ of CMW solvent and applied to I) E-52 (acetate) cellulose column (2,
5X 50cm.

After adsorption at 5°C (jacketed), the column was
o, 15 M NH40Ac linear gradient solvent CMW (
1500 ml each). 900-1500 ml of eluate was collected and evaporated at a temperature below 30° C. under reduced yield to produce white crystals. After washing this white crystalline powder with water and filtering it, it was washed with C to convert it into IJium salt.
Dissolved in MW and then added to Am'be
rlite) CG-5,0, (N'a+) column (2
, 5 x 15 cfn) and the eluate was collected and evaporated under reduced pressure. The residue was crystallized from chloroform and acetone to yield 820 ml (31.2%) of the white desired compound.

1) Melting point: 199-202°C 2) [α]D −+33.5° cc=0.23. Chloroform-methanol-water 2:3:1) 3) NMR (90M'H2): Solvent (CDC13-CD
30D-D20°2:3:1): δppm0.95 (6
,t.

2CH'a), 1,14 1.87 (58, m.

29CH2), 2.29(2,t, CH2-C-0),
3.27-4.42 (11, m, H2'.

H3', H4/, H5', CH2-0-CH2 and CH2-0), 515 (1, m-Z recerol C)
1), 5.94 (1, d, Jri 7Hz, cytosine H
5), 6.18 (1°a*J-5Hz, Hl)
, 7.80 (, 1st chapter.

Jm 7 Hz, cytosine H6) 4) Elemental analysis: C46H87N3014P2°1.5
(CH3)2(X), H20CH, -N P Calculated value 56,51 9,20 3,92 5.77 Actual value 56,81 9.27 3.69 5.87 Example 2 1-β-D- arabinofuranosylcytosine-5'-diphosphate)-rac-1-0-octadecyl-2-〇-
Valmitoylglycerol (Tb, ara-CDP-D
L-PBA) (1) Method A (reaction process diagram, method A) The described compound is rac-1-0-octadecyl-2-o
- Nozolmitoylglycerol 3-phosphate (■, n
=17. m-=14. DL-mixture) a r a-C
MP --E: le holiday) (Vl, B = cytosine)
and then separation as described above to give the desired compound in 35% yield.

Chromatographic mobility and NMR data were in agreement with theoretical values.

(2) Method B (reaction process diagram, method B) The title compound was prepared by Shimohi's method.

ara-CMP (■, B = cytosine) of 3219 (1 mmol) and trine of 37111Ig (1 mmol)
The octylamine was dissolved in 7 ml of hot methanol, then the solvent was evaporated under reduced pressure and the residue was purified again with N.

Dissolved in ``N'-dimethylformamide)''(DMF'),
Evaporation under reduced pressure removed traces of water remaining in the residue. The dry ar,a-CMP-tri0-octylammonium salt thus obtained was dissolved in 10 Wt/dioxane and 5 m/DMF', and 0,3 m
l of diphenylphosphochloridate and 0.45 m/
) 1-n-Butylamine was added and the mixture was allowed to react under anhydrous conditions at room temperature for 2 to 3 hours. After distilling off the solvent under reduced pressure, 5011 Ll of ether was added to give P-(1
-β-D-arabinofuranosylcytosine-5'il)-
P2-diphenylpyrophosphate-zv+t,B-cytosine) was precipitated and held at 0°C for 30-60 min to remove the ether. The precipitate was dissolved in 2rnl of dioxane and traces of water in the precipitate were distilled off under reduced pressure. P2O
663779 (1 mmol) of rac-1-0- on 5
Octadecyl-2-0-palmitoglycero-3-phosphx-) (■11', n-17, m=14.DL-
After drying the mixture for one night, it was dissolved in IWLl of anhydrous pyridine, and then the above pyrophosphate (■) was dissolved in 0,5
ml of dioxane under anhydrous conditions at room temperature for one day. After the reaction, the solvent was distilled off under reduced pressure, and 25114' ether was added to the thus obtained residue to precipitate the desired irily product. The precipitate thus obtained was mixed with 100-CM
When dissolved in W and adsorbed on a Dg, -52 (acetate) cellulose column (25 x 50 Cfn1 jacketed, 5°C), eluted and purified as described above, 3
The target compound was obtained with a yield of 0. Chromatographic mobility and NMR data were in agreement with theoretical values.

Example 3 1-β-D-arabinofuranosylcytosine-5'-diphosphate-rac-1-0-hexadecyl-2-0-
Valmitoylglycerol or 1-β-D-arabinofurafusylcytosine-5'-1 phosphate-β-noξlumitoyl-DL-thymyl alcohol (Jc, ara
-CDP-L-PCA) (1) Method A (Reaction Scheme, Method Person) Basically, this compound is prepared in the same manner as described in Example 1. 4,199 coevaporated with pyridine
(6.6 mmol) of rac-1-0-hexadecyl-2-0-normitoylglycerol 3-phosphate (■, n-15.mxl 4°DL-mixture) was added to 30
It was reacted with 3.439 (5 mmol) of ara-CMP mopv holiday) (■, B=cytosine) in 0 m/m anhydrous pyridine for 5 days at room temperature under anhydrous conditions. The pyridine was evaporated under reduced pressure and the residue was treated as described in Example 1 and added to a DE-52 (acetate) cellulose column (2
, 5X50cPn, jacketed, 5 °C), elution with a linear gradient CMW solvent (1500 d each) containing 0 0-15 M NH4AQ, and the fractions containing the target compound were combined at a temperature below 30 °C. Concentrate under reduced pressure,
White crystals were formed. The thus obtained crystals were treated with an Amberlite CG-50 (Na+) column to obtain the target compound with a yield of 30%.

1) Melting point: 202-205°C (decomposition) 2) NMR (90MHz): Solvent (CDC13-
CD3C)D-D2C1,.

2:3:l): δ1111m0.87 (6, t,
2CH3).

1.07-1.78 (54,H,, shi27CH2),
2.35 (2,t.

qH2-C=O), 3.2774.35 (11,, m,
H2', H3'.

H4/ , H5/ , 0H2-0-CH2, CH2-0
).

5.15 ('1.m, glycerol OH'), 5.92
(1, d.

J-7Hz, cytosine H5), 6.14 (1, d, J
=51'lz.

Hl"), 7.88 (1, d, J = 7Hzs cytosine H6) 3) Elemental analysis:' C44H8□N30□4P
2Na2 ” 0.5020CHNP Calculated value 53,21 8,43 4,23 6.24 Actual value 53,69 9,27 3,92 5,723.
179 (5 mmol) of rac-1-0-hexadecyl-2-balmitoylglycero-3-phosphate (■,
m=15. n-14. DL-mixture) and 1.7 m/(
4.12 g (20 mmol) of morpholine and 50 M/t-butyl alcohol were added to a refluxing mixture of morpholine (20 mmol)
mmol) of N,N/-dicyclohexylcarbodiimide! A solution of (DCC) and 751 Ll of t-butyl alcohol was added dropwise, and the mixture was reacted under reflux conditions for 2 hours. After stirring the reaction mixture overnight at room temperature, 20 d of water was added and
The remaining DCC was decomposed by stirring at room temperature for 2 hours. The white crystals thus formed were filtered off and the filtrate was concentrated by evaporation under reduced pressure and extracted with ether. The extract was evaporated under reduced pressure and the product residue (■, n-15, m-14,
After co-evaporating the DLC-mixture), 2
．． 139 (6.6 mmol) of ara-CMP (11,
200 mA! The mixture was dissolved in pyridine and reacted under anhydrous conditions with stirring at room temperature for 7 days. The pyridine was distilled off under reduced pressure, and the remaining traces of pyridine were co-evaporated with a small amount of toluene to be completely removed. The residue was mixed with 30w1l of acetic acid and 300trtl.
After stirring for 1 hour at room temperature, 5
00WLl of chloroform was added. The organic layer was separated and concentrated under reduced pressure, and the remaining traces of acetic acid were completely removed by coevaporation with 10 ml of toluene in three steps. The residue was dissolved in 100-CMW solvent and DI-
52 (acetate) cellulose column (2,5X50c
tn, jacketed at 5° C.) and then 0-015 M NH4 as in the method described in Example 1.
Elution with a linear gradient CMW solvent containing 0AC afforded the desired product in 30% yield. Chromatographic mobility and NMR data were in agreement with theoretical values.

Example 4 9-β-D-arabinofuranosyladenine-57-diphosphate) -rac-1-0-hexadecyl-2-0
- balmitoylglycerol or 9-β-D-arabinofuranosyladenine-5'-diphosphate-β-balmitoyl-DL-thymyl alcohol () d, ara
-ADP-DL-PCA) (reaction process diagram, method A) 1
．． 909 (3 mmol) of raclo-hexadecyl-
2-〇-balmitoylclycero-3-phosphate (■
+n=15. m=14. DL-mixture) was dried by co-evaporation with pyridine in three steps and 2
．． 13 g (3 mmol) of ara-AMP morphores-4-morpholine-N, N/-dicyclohexyl-carboxamidinium salt (■, B-adenine) t-2
00- in pyridine and the solution was heated under anhydrous conditions at room temperature.
The mixture was stirred for several days.

1 lysine was distilled off under reduced pressure and the residue was treated in a manner similar to that described in Example 1 and added to a DE-52 (acetate) cellulose column (2,5X50, jacketed, 5°C).
After adsorption with a linear gradient CMW solvent containing 0-0.15MNI (40A c), Amberlite CG
−50 (Na+) column, s5t+v (21%
) was obtained.

1) NMR (90MHz): Solvent (CD(J3-CD3
0D-D20.

2:3:1'):δppm0.92(6,t,2cH3
).

1.07-1.78 (54H, m, 27CH2'
) −2,35(2,t.

0H-C=O), 3.27-4.35 (11, m, H
2'+H3ZH4',H5', CH2-0-CH
2; CHz-0), 5.07(], ]m, glycerol CH, 6,33(1+deJ-4,5H2,l(
□'), 8.17(], s, adenine H2).

8.40 (1, s, adenine H8) Experiment I Antitumor activity against phosphorylated leukemia mice by intraperitoneal administration of I L 1210: Ix10 or 1x10 L in DBA/2J mice
1210 1J, 6 leukemia cells were administered intraperitoneally,
After 24 hours, the drug was dissolved in O, 1% Na (J) and injected into mice, and the survival rate was measured for 45 days.The test was conducted according to the National Cancer Institute protocol (Cancer Chemotherapy Reports 3 .1-103'.

1972). Processing plan is %qdll
qdl, 5, 9 and q(11-5. This was determined by comparing the average lifespan of test and control mice.

Table 1 shows ara-C and its conjugate ara-DCP.
-DL-PBA (Tb) and ara-CDP-
The treatment results of DL-PCk (■c) are shown. The first part shows the results of ara-C susceptible L1210 rhinopathies mice. Untreated control mice died 7 or 8 days after inoculation with tumor cells. ara-C to 40 (
When injected at the optimal single dose of ly (1644 μmol)/U, the increase in lifespan (%ILS) was 14 μL;
Intermittent injection resulted in 129% ILS.

However, the conjugate ara-CDP-DL-PBA (Ib'
) and ara-CD P-DL-PCA (I c
) of 4001 ng (395 and 407 mic or-
The optimal single administration of 9 and 9 showed excellent ILS of 257 and 293, respectively. Five injections at the optimal dose also produced excellent LLS of 229 and 264, respectively. A single dose comparison of ara-C and its conjugates is out of scope. In a 5-dose regimen, the conjugate is administered at 1/8 or 1/1 of the ara-C molar dose.
It was twice as effective at a dose of 0 and had much less toxicity. Second, therapeutic treatment of ara-C-resistant L12]01J lymphocytic leukemia mice with low amounts of deoxycytidine kinase resulted in untreated control mice dying 8 to 11 days after inoculation with tumor cells. Treatment with a single dose of ara-C showed almost no effect (ILSG), and 5-day treatment resulted in 65 IL8.

These results indicate that ara-C contains only a minimal amount of deoxycytidine kinase. However, a
Conjugate of ra-c, i.e. ara-CDP-DL-P
BA (Ib) and ara-CDP-DL-P
CA (I c ) has produced significant therapeutic outcomes and holds great promise for fighting cancer. Optimal dose 4 (l n mli/kL; for l, IL S is 259 ~) used for 5 days with a single □ administration or 80 mli/kl per day was 356%, and among 6 mice. One to three mice survived for more than 45 days and were completely cured. Historically, the ara-CDP-PBA-
(Ib) indicates ILS of 290 cm or more, ara-CD
P-PGA-(IC) indicates an ILS of 374 chi or more;
3 or more mice, especially ara-CDP-DL-PCA
In this case, 6 out of 6 mice survived for more than 45 days and were cured.

For example, a 173 mole dose of ara-C produced a 5-fold effect. The fact that the conjugate is effective in deoxykinase-deficient ara-C resistant L1210 lymphocytic white disease mice indicates that the conjugate is introduced into the cell by endocytosis or other mechanisms and is enzymatically linked to phospholipids and ar.
is hydrolyzed into a-CMP, thereby liberating a
ra-CMP continuously phosphorylates ara-C'['PK. Therefore, the deoxycytidine kinase required for phosphorylation of ara-C is not required since a,ra-CMP is released from the conjugate.

Advantages As shown in the above trials, these conjugates exhibit greater activity than the parent drug ara-C even at lower doses, which in turn has implications for the improved therapeutic index of the parent drug. I will do it. Additionally, ara-C had a short half-life and required sequential administration to be effective, whereas the conjugate has greater and greater activity in a single dose. Therefore, the conjugate can be used as a sustained release pharmaceutical. In particular, the fact that the conjugate is effective in ara-C resistant L12101J non-ξ leukemia mice suggests that it hydrolyzes in cancer cells to release ara-C and phospholipids, and is highly effective in deoxycytidine kinase-deficient resistant cells. means that it is valid. Phospholipids are 1-0-alkyl-2-0-
Acylglycero-3-phosphate, which after biochemical reactions is converted into 1-0-alkyl-2-lysophosphatidyl-choline or monoethanolamine, and these compounds themselves.

Since they have growth and transformation-inhibiting effects and immune-expanding effects on cancer cells, they are expected to exhibit additive and synergistic effects. The conjugate is considered a novel drug rather than a single cara-C prodrug.

Furthermore, compared to other lipophilic proto-9 rugs, the present conjugate has the advantage of being transparently suspended in water by ultrasound. In the treatment of leukemia patients with ara-Cf, it has been reported in the literature that the development of resistance to this drug is related to the relative cellular content of deoxycytidine kinase and cytidine deaminase [Annals Op New York Academy of Sciences]. o
f New York Academy of 5ci
ence) 255.247 (1975)]. On the other hand, ar
The a-C conjugate is resistant to cytidine deaminase and does not hydrolyze amino groups. This conjugate is a
It is considered to have great effects in the treatment of ra-C-resistant Shiromen disease patients.

a: Each group of 6 DB'A/2J mice (average body weight, 2
5 g, male) on day 0 of I XIOL 121010 cells or I X 10 L 1210/ara
-C cells were inoculated intraperitoneally.

b = maximal active half-life dose.

C: Lifespan increase rate, (T/C-1)XI 00° (1:
ara-C sensitive L 12108: ara-C resistant L 1210°f due to deoxycytidine deficiency: 45 days.

g: ara-CMP (■, B-cytosine) and rac-1-0-hexadecytb-2-0-2en
.

Midoylglycerol-3-phosphate (■+”
”15<em>=14 , DL-mixture).

(4 other people) Procedural amendment June 7, 1986

Claims (7)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (where B is adenine, cytosine, 5-fluorouracil, 5-azacytosine, 6-mercaptopurine or 7
-deazaadenine, A and C are each hydrogen or a hydroxy group, W is a saturated or unsaturated alkyl group having 8-20 carbon atoms or a 2- or 3-alkoxyalkyl group, and W' is a 7- a saturated or unsaturated alkyl group having 19 carbon atoms) and pharmaceutically acceptable non-toxic salts. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, B is adenine, cytosine, 5-fluorouracil, 5-azacytosine, 6-mercaptopurine, or 7
- deazaadenine) is condensed with a nucleoside having the formula ▲ mathematical formula, chemical formula, table, etc. There are tables etc.▼(VII) P^1- with (where B is as defined above)
Nucleoside-5'-P^2-diphenylpyrophosphate, followed by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (VIII) (wherein W is a saturated or unsaturated alkyl group having 8 to 20 carbon atoms or 2- or 3-alkoxyalkyl group, W' is saturated or unsaturated alkyl having 7 to 19 carbon atoms). By reacting with the formula ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ ( I
) (wherein A and C are each a hydrogen or hydroxy group) or a salt thereof. A method for producing a nucleoside conjugate having the formula (I). (3) Formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (VIII) (In the formula, W is a saturated or unsaturated alkyl group or a 2- or 3-alkoxyalkyl group having 8 to 20 carbon atoms, W′ is a saturated or unsaturated alkyl group having 7 to 19 carbon atoms) is condensed to form a phospholipid having the formula ▲mathematical formula, chemical formula, table, etc.▼(IX) (wherein W and Phospholipid morpholinate or P^ having the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (X) (where W and W′ are as defined above) (where W and W′ are as defined above) As 1-glycero-5'-P^2-diphenylpyrophosphate, this is then expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, B is adenine, cytosine, 5-fluorouracil, 5-azacytosine , 6-mercaptopurine or 7
-deazaadenine) to produce a nucleoside conjugate or its A process for producing a nucleoside conjugate having the formula (I), characterized in that a salt is obtained. (4) Claim 1, wherein the target compound is 1-β-D-arabinofuranosylcytosine-5'-diphosphate-1-O-octadecyl-2-O-palmitoyl-sn-glycerol. Compound. (5) The compound according to claim 1, wherein the target compound is 1-β-D-arabinofuranosylcytosine-5'-diphosphate-rac-1-O-octadecyl-2-O-palmitoylglycerol. . (6) The compound according to claim 1, wherein the target compound is 1-β-D-arabinofuranosylcytosine-5'-diphosphate-rac-1-O-hexadecyl-2-O-palmitoylglycerol. . (7) The compound according to claim 1, wherein the target compound is 9-β-D-arabinofuranosyladenine-5'-diphosphate-rac-1-O-hexadecyl-2-O-palmitoylglycerol. .