JPS63183583A - Dc-52 derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R represents H, 1-8C alkanoyloxy, oleoyloxy, linoloyloxy, mercapto, azide, cyano, halogen atom, etc.; X represents cyano, hydroxy, etc.) and salts thereof. USE:An antitumour agent having superior antitumour activity. PREPARATION:First, DX-52-1 expressed by formula II as a starting raw material is reacted with diphenyldiazomethane in an inert solvent such as THF, etc., normally at room temperature for 1- several hr to form a compound expressed by formula III. Then the compound is reacted with a compound expressed by the formula R1H (R1 represents some of the groups defined for R, such as oleoyloxy, etc.) in an inert solvent in the presence of a base such as pyridine, etc., normally at 0-50 deg.C for 1hr-1 day to form a compound expressed by formula IV. Finally, the compound is hydrolyzed with an acid, preferably by reacting with trifluoroacetic acid in the presence of phenol, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel C-52 derivatives having antitumor activity.

Conventional technology DC-52 is an antibiotic represented by the following formula disclosed in Japanese Patent Application Laid-Open No. 57-17089.

DC-52 is a useful substance that not only has antibacterial activity against various bacteria but also has antitumor activity against Lymphocytic rhinichemia P388 and the like.

On the other hand, DX'-52-1, which has antitumor activity and is represented by the following formula, is known as a derivative of D(,-5,2) (Japanese Patent Laid-Open No. 5.9-.210086).

As with other anti-tumor antibiotics, there is a constant need for DC-52M conductors with even better anti-tumor activity.

Means for Solving the Problems The DC-52 derivative of the present invention having excellent antitumor activity is represented by the following formula (I): (wherein R is hydrogen, an alkanoyl group having 1″ to 18 carbon atoms)・
oleoyloxy, silnoyloxy, silnoyloxy, retinoyloxy, unsubstituted or substituted benzoyloxy (substituent is halogen or lower alkyl,
mercapto, alkanoylthio having 1 to 18 carbon atoms, oleoylthio, linoloylthio, lilnoylthio, retinoylthio, unsubstituted or substituted benzoylthio (substituent is halogen or lower alkoxy), azide, amino 1. In the NHjC formula, Z is a residue other than the OH of the carboxyl of the α-amino acid (the amino and/or carboxyl of the residue, if present, may be protected with those protecting groups commonly used in peptide synthesis chemistry) , pyruvoyl, citroyl or acetyl], cyano or halogen, and X is cyano or hydroxy) [hereinafter referred to as Kayamono (I). The same applies to compounds with other formula numbers].

In the definition of R in formula (I>), the alkanoyl having 1 to 18 carbon atoms referred to in alkanoyloxy having 1 to 18 carbon atoms and alkanoylthio having 1 to 18 carbon atoms may be linear or branched. , such as formyl, acetyl, propioyl, ptylinopeiisobutyryl, valeryl, n-hexanoyl, n-heptanoinopene n-occunoinopene n-nonanoyl, n-decanoyl, ゛n'-undecanoinoverauroyl, myristoyl, balmitoyl, Substituted benzoyloxy and substituted benzoyloxy include chlorine, bromine, and iodine, and lower anotoxy includes straight-chain or branched alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, and the like.

Regarding the definition of R in formula (I), the α-amino acid is 0 even in the L form.
L-alanine, L-glutamine M, L-'J are also common in the body.
-,;n, L-phenylalanine, L-proline, L-
Includes histidine, D-alanine, etc. In addition, when the amino and/or carboxyl of residues other than the OH of the carboxyl of α-amino acids are protected, there are no particular limitations on the protecting groups as long as they are commonly used in peptide synthesis chemistry, but formyl, acetyl, For example, trifluoroacetyl, t-butoxycarboninopebenzyloxycarbonyl, benzyl, etc., and carboxyl include methyl, ethyl, benzinobe, t-butyl, p-nitrobenzyl, etc.

In the definition of R, halogen is fluorine, chlorine, bromine, or iodine.

The pharmacologically acceptable salts of Compound (I) also have excellent antitumor activity like Compound (I). Such salts include pharmacologically acceptable acid addition salts, alkali metal salts, alkaline earth metal salts,
Includes ammonium salts and pharmacologically acceptable organic base addition salts. Pharmaceutically acceptable acid addition salts include pharmacologically acceptable inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc. Organic acid addition salts such as acetates, benzoates, maleates, fumarates, succinates, tartrates, citrates, cininates, glyoxylates, aspartates, methanesulfonates, Tansulfonate 1. Propanesulfonate, methanedi, sulfonate, α, β-
Includes ethanedisulfonate, benzenesulfonate, etc. Alkali metal salts include sodium salt, potassium salt, etc.
Alkaline earth metal salts include calcium salts, magnesium salts, and the like. Pharmaceutically acceptable organic base addition salts include addition salts of ethanolamine, triethylamine, morpholine, piperidine, and the like.

Next, a method for producing compound (I) will be explained.

First, DX-521 and diphenyldiazomethane are reacted in an inert solvent to produce a compound represented by formula (II).As the inert solvent, chloroform, methylene chloride, methanol, ethanonopetetrahydrofuran, etc. may be used alone or Diphenyldiazomethane is usually used in an amount of 1 to 1.5 equivalents based on DX-52-1.

The reaction is usually carried out at room temperature and is completed in one to several hours.

Next, compound (n) and formula (I) R, H (m) [wherein, R1 has the same meaning as some of the groups in the definition of R in formula (I), and alkanoyloxy having 1 to 18 carbon atoms, oleoyloxy, linoloyloxy, lylnoyloxy, retinoyloxy, or unsubstituted or substituted benzoyloxy (where the substituents are halogen or lower alkoxy)] By reacting in the presence of a base in a solvent, the formula (
rV) [wherein R3 has the same meaning as in formula (II)] is produced. Reactive derivatives include acid chlorides, acid anhydrides (acid anhydrides produced by N,N'-dicyclohexylcarbodiimide, commercially available acid anhydrides, etc.), active esters (p-nitrophenyl ester, N-oxysuccinic acid, etc.). imide ester, etc.), mixed acid anhydrides (mixed acid anhydrides with monoethyl ester carbonate, monoisobutyl carbonate, etc.), and the like. The appropriate amount of the reactive derivative to be used is 1 to 2 equivalents of compound (■). The base includes pyridine, triethylamine, dimethylaminopyridine, etc., and is usually used in an amount of 1 to 2 equivalents of the compound (■). Inert solvents include methylene chloride, chloroform,
Toluene, tetrahydrofuran, pyridine, acetonitrile, etc. can be used alone or in combination. The reaction is usually carried out at 0 to 50°C and is completed in 1 hour to 1 day.

Alternatively, a compound represented by formula (V) is produced by reacting the compound (,I[')t'p,-)luenesulfonyl chloride in an inert solvent in the presence of an acid scavenger. As the inert solvent, methylene chloride, acetonitrile, toluene, tetrahydrofuran, pyridine, etc. may be used alone or in combination.

A suitable amount of p-)luenesulfonyl chloride to be used is 1 to 5 equivalents of compound (I[). Acid scavengers include pyridine, triethylamine, dimethylaminopyridine, etc.
Usually 1 to 5 equivalents of compound (II) are used. The reaction is usually carried out at 0°C to room temperature and is completed in 1 hour to 1 day.

Compound (V) is then reacted with an alkali metal halide, an alkaline earth metal halide, or tetrabutylammonium fluoride in an inert solvent to form a compound of formula (VI) (wherein, Hal is a halogen). Manufacture a compound that dies. Alkali metal halides are lithium chloride,
Lithium bromide, lithium iodide, potassium fluoride, cesium fluoride, etc. are included, and alkaline earth metal halides include magnesium bromide, calcium bromide, etc. The appropriate amount of the alkali metal halide, alkaline earth metal halide or tetrabutylammonium fluoride to be used is 1 to 10 equivalents of compound (V). As the inert solvent, dimethyl sulfoxide, N,N-dimethylformamide, diethylene glycol, acetonitrinopetetrahydrofuran, etc. can be used alone or in combination. The reaction is usually carried out at 0 to 100°C and is completed in 1 to 48 hours.

Compound (VT) can also be obtained by reacting compound (Ir) with a halogenating agent commonly used in general synthetic chemistry. In particular, the synthesis of fluorine compounds using diethylaminosulfur trifluoride [Synthesis, 787 (1973), Journal of Organic Chemistry 40.574 (1)
975), Tetrahedron Letters, 573 (
1977)).

Alternatively, a compound represented by formula (■) is produced by reacting compound (V) with twice the mole of sodium borohydride in dimethyl sulfoxide at room temperature for two days.

Moreover, compound (V) and radium hydrosulfide 1 to 2
equivalent amount in dimethyl sulfoxide at room temperature to 80°C.
A compound represented by the formula is produced by reacting for 8 hours.

Next, compound (■) and compound (II[) are added to the compound (■).
II) and compound (I) under the same conditions as in the reaction of compound (I) to form formula (IX) [wherein, R2 has the same meaning as some of the groups in the definition of R in formula (I), and the number of carbon atoms is 1 to 18 alkanoylthio, oleoylthio, linoloylthio, lylnoylthio, retinoylthio, or unsubstituted or substituted benzoylthio (
The substituent is halogen or lower alkoxy)]
A compound represented by is produced.

Compound (IX) also has compound (V) and formula (X) R2H (
X) It can also be obtained by reacting an alkali salt of a thiocarboxylic acid represented by the formula (wherein R2 has the same meaning as in formula (IX)), such as a sodium salt, in an inert solvent. Dimethyl sulfoxide as an inert solvent,
N,N-dimethylformamide, tetrahydrofuran,
Acetonitrile and the like can be used alone or in combination.

The reaction is usually carried out between room temperature and 100°C for 1 to 2 hours.
Ends in days.

Compound (IX) furthermore has compound (II) and compound (
It can also be obtained by reacting X) with azodicarboxylate and triphenylphosphine. This reaction can be carried out according to Synthesis, 1 (1981).

Alternatively, by reacting compound (V) with sodium azide, lithium azide, or sodium cyanide in an inert solvent, formula (XI) [wherein R3 is R of formula (1)]
is synonymous with some of the groups in the definition, and is azide or cyano]. As the inert solvent, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, etc. may be used alone or in combination. The usage amounts of sodium azide, lithium azide, and sodium cyanide are as follows:
) is suitable. The reaction usually takes place at room temperature.
It is carried out at 0°C and can be completed in 2 hours to 1 day.

Compound (IV), (Vl), (■), (■),
By subjecting (IX) or (XI) to a normal acid hydrolysis reaction, it is expressed by the formula (I-1> [wherein, R4 is the same as R in formula (I) excluding amino and -NH2]. Such methods are described, for example, by Green, Protective Groups in Organic Synthesis, 174.
(1981), (John Willey and Thump
Incoholaterad). Preferably the compound (■).

Compound (I-1) is obtained by reacting (VI), (■), (■), (IX) or (XI) with trifluoroacetic acid without a solvent or in an inert solvent.

Inert solvents include methylene chloride, toluene, and the like. It is appropriate to use trifluoroacetic acid in an amount of 5 to 100 equivalents of the starting compound. When this reaction is carried out in the presence of 1 to 50 equivalents of anisole, phenol, hydroquinone, ethanethiol, etc. of the starting compound, the production of undesirable by-products can be suppressed. The reaction is usually carried out at 0°C to room temperature and is completed in 30 minutes to 8 hours.

Compound (1-1) where R4 is azide in an inert solvent 5
A compound represented by formula (I-2) is produced by hydrogenation in the presence of a catalyst such as ~10% (W/W) palladium-carbon. Inert solvents include aqueous methanol, aqueous ethanol, and the like. The appropriate amount of the catalyst to be used is 10 to 100% (W/W) based on compound (I-1). When this reaction is carried out under hydrochloric acid acidity (pH 1 to 3), the reaction rate can generally be increased and the production of by-products can be suppressed. The reaction is usually carried out at room temperature and pressure and is completed in 1 to 10 hours.

Next, compound (I-2) and formula (XI) ZI OH (XII) [wherein, Zl has the same meaning as a part of the definition of Z with respect to formula (I), excluding the OH of the carboxyl of the α-amino acid Reactive derivatives of compounds whose amino and, if present, carboxyls are protected with those protecting groups commonly used in peptide synthetic chemistry, pyruvoyl, citroyl or acetyl. The formula (
I- [wherein, 2. is the same as in formula (X■)]
A compound represented by is produced. The reactive derivative includes acid chloride, active ester, acid anhydride, mixed acid anhydride, etc., and is usually used in an amount of 1 to 3 equivalents of compound (I'-2). Inert solvents include tetrahydrofuran, methylene chloride, chloroform, toluene, acetonitrile, pyridine, and the like. Bases include pyridine, triethylamine, dimethylaminopyridine, etc., and are usually used for compound (I-2)
Use 1 to 3 equivalents of The reaction is usually carried out at 0 to 50°C.
Finishes in ~24 hours.

Compounds in which Z is a residue other than OH of the carboxyl of an α-amino acid, and the amino and/or carboxyl, if present, are protected with those protecting groups commonly used in peptide synthesis chemistry ( I-3) is, if necessary, subjected to a deprotection reaction commonly used in peptide synthetic chemistry to give the compound represented by the formula (■ (wherein, Z2 is a residue excluding DH of the carboxyl of the α-amino acid) Convert to compound.

The synthesis of the compound (I-3) and the deprotection reaction are described, for example, in Izumiya et al., Peptide Synthesis, 23-249 (Maruzen, 19
It can be carried out according to the method described in 1975).

Compound (■) where X is hydroxy [hereinafter referred to as compound ()
-5')] can be obtained by maintaining the compound (I) in which X is cyano in the presence of a silver salt in water or an organic solvent, and then treating the reaction solution with water or hydrochloric acid as necessary.

Organic solvents include acetonitrile, methanol, ethanol,
These include tetrahydrofuran, dioxane, etc., and these may be used alone or in combination.

Silver salts include silver nitrate, silver chlorate, silver perchlorate, silver fluoride, and the like. The amount of silver salt used is usually determined for compounds where X is cyano (
Although 1 equivalent of compound (I
In order to improve the yield of -5), an excess of up to about 3 equivalents may be used. The reaction is usually carried out at 0 to 50°C and is completed in 30 minutes to several hours.

Compound (I-5) is also a compound (,1
) in the presence of hydrogen chloride in water or a hydrophilic solvent containing water.

Hydrochloric acid is usually used at 0.1 to 12N. Hydrophilic solvents include methanol, ethanol, tetrahydrofuran, and the like. The reaction is usually carried out at room temperature to 100°C and is completed in 1 hour to 1 day.

In each of the above reactions, the desired product can be obtained by directly concentrating the reaction solution under reduced pressure, or by extracting with an organic solvent such as ethyl acetate, methylene chloride, chloroform, or toluene, and then concentrating the extract under reduced pressure.
The residue can be purified by column chromatography using silica gel, HPl, 0 resin, and HP20 resin (Mitsubishi Kasei).

Compound (I) and its pharmacologically acceptable salts have strong antitumor activity against Lymphocytic rhinichemia P-388 and the like, and are considered to be useful as antitumor agents for mammals including humans. Compounds (I) in which R in formula (I) is alkanoylthio having 1 to 18 carbon atoms, especially 1 to 6 carbon atoms, and X is cyano or hydroxy, especially hydroxy; and compounds (I) in which R is azide and X is hydroxy; ) and their pharmacologically acceptable salts have particularly excellent antitumor activity.

Next, the pharmacological activity of compound (■) will be explained using experimental examples.

Experimental Example 1 Antitumor Activity The antitumor activity of representative compound (I) against Lymphocytic leukemia P'-388 is shown in Table 1.
, Table 1 The experimental method is as follows.

Groups of 5 CDF1 male mice weighing 22 g were inoculated with 1×10 lymphocytic rhinichemia P-388 tumor cells.
Six were implanted intraperitoneally. Twenty-four hours after transplantation, 0.2 ml of a phosphate-buffered saline solution of the drug was intraperitoneally administered once. The life-prolonging effect of the drug was shown by T/C.

Experimental Example 2 Acutely toxic LDso was treated by intraperitoneally administering the drug once to ddy mice.
The survival and death of 5 mice per group were observed for 14 days after administration, and the mortality rate of each administration group was determined according to the Behrens-Kerber method.
D. was calculated.

The results are shown in the table below.　　　　　　.

Compound (I) or a pharmacologically acceptable salt thereof can be used alone or usually together with at least one pharmaceutically acceptable adjuvant as an antitumor composition. For example, the compound (
I) or a salt thereof is dissolved in physiological saline or an aqueous solution of glucose, lactose, mannitol, etc. to prepare a pharmaceutical composition suitable for injection. Alternatively, compound (I) or a salt thereof is freeze-dried according to a conventional method, and sodium chloride is added thereto to prepare a powder injection. The present pharmaceutical composition may contain additives well known in the pharmaceutical field, such as pharmaceutically acceptable salts, as necessary. The dosage of this composition varies depending on the patient's age, symptoms, etc., but it is 0.00:3 to 1 m as Compound (I) to mammals including humans.
Administer g/kg/day.

Administration is carried out, for example, once a day (single administration or daily administration) or intermittently by intravenous injection 1 to 3 times a week, once every 2 or 3 weeks. If desired, oral administration is also possible using the same dosage and administration method. Oral dosage forms include tablets, capsules, powders, granules, ampoules, etc., which contain pharmaceutical adjuvants well known in the pharmaceutical art. In addition, if desired, intraarterial administration, intraperitoneal administration, intrathoracic administration, etc. can also be carried out using the same dosage and administration form.

This antitumor composition is expected to be effective against leukemia, gastric cancer, colon cancer, lung cancer, breast cancer, uterine cancer, etc. in mammals including humans.

The structures and compound numbers of representative compounds (I) of Examples are shown in Table 2.

The physicochemical data shown in the Examples and Reference Examples below in Table 2 were measured using the following instruments.

IR Japan Spectroscopy IR-810 and Hitachi Infrared Spectrophotometer 2
15 type NMR Parian EM-390 (90M) +2) JEOL FX-100 (100MH2) Blue Car AM
40L (400MHz)MS Hitachi B-80
and JEOL JMSOIS GII type Example 1 Synthesis of Compound 1 772 mg of compound b (Reference example 2) was mixed with 15 m of methylene chloride.
Dissolve in A, add 0.75 ml of anisole and 3 mA of trifluoroacetic acid, and stir at room temperature for 1 hour and 30 minutes. After concentrating the reaction mixture under reduced pressure and azeotroping with toluene, the residue was dissolved in acetone and adjusted to pH 7 by adding an aqueous solution of sodium hydrogen carbonate.
Adjust to. This mixture was concentrated under reduced pressure, dried, and chromatographically purified (Wakogel C-200 Looml, chloroform:methanol-1:0-10:1) to obtain compound 1452.
mg (75%).

'H-NMR (CDCj!s; ppm) 9.0
0 (L H.

br, s), 7.17 (IH, t), 6.71
(2H.

m), 4.37 (2H, m), 3.99 (2H, m
).

3.81 (3H,s), 3. '49 (2H,
'm), 3.3-2.9 (2H, m), 2.
4-2.7 (3H, m).

2,35 (3H,s), 2.25 (2H,t)
, 1.95 (IH, dd), 1.53 (2H, m),
1.25 (24H, m), 0.87 (3H, t)
.

IR (KBr; Cm') 3700-2400°29
28.2856.1?32,1705°1594.14
75,1264.1174°109'9.1076;
787゜Mass (Me ester, E I ;m
/Z) 609 (M""), 578 (-0CH3).

Example 2 Synthesis of Compound 2 1509 mg of compound was added to 8 ml of acetonitrile and 2 m of water.
522 mg of silver nitrate was added thereto, and the mixture was stirred at room temperature for 3 hours. Add 3.5 mβ of 1N hydrochloric acid to the reaction mixture, filter the precipitate, and concentrate the filtrate under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with acetonate. After drying the organic layer, it was concentrated under reduced pressure and purified by chromatography (Fuco-gel C
-C-2004Q? , chloroform:methanol-5:
1-4:1) L Compound 2 as sodium salt 203m
g (39%) obtained.

'H-NMR (Na salt, CD30D; l111m
>7,08 (LH,t), 6.67 (IH,d
).

6, 65 (IH, d), 4.76 (IH, m)
, 4.67 (LH, m), 3.74 (38, s)
, 3.51 (IH, m) , 3.11 (1'
H, m), 2.63 (3H.

s), 2.3-2.0 (3H, m), 1.48 (2
H.

m), 1.4-1,1 (24H, m), 0
．． 88 (3H.

t) IR (Na salt, KBr; cm') 3600-240
0, 3370. 2930. 2860°1725,
1594. 1477, 1268°1060° SIMS (m/z), 569 (-0H)
, 524°497, 2.99. 255. 22
7 Example 3 Synthesis of Compound 3 524 mg of Compound a (Reference Example 1) was added to methylene chloride 10
mJ2, triethylamine 0.17 ml l!
, and heptanoyl chloride 0.19 mj! and stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform, washed with saturated brine, dried, and concentrated under reduced pressure.

Chromatographic purification of the residue (Wakogel C-20050mj2
．． ) toluene:ethyl acetate-15:1) L, crude product 60
Get 2 mg. Dissolve this in 12 ml of methylene chloride and 0.5 mJ of anisole! and trifluoroacetic acid2.
4rr+j! and stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in acetone, and the pH is adjusted to 8 by adding an aqueous sodium bicarbonate solution. After concentrating this mixture under reduced pressure, chromatography purification (Wakogel C-2
0080m1. Chloroform:methanol-100:1
) to obtain 270 mg (58%) of the target product.

'H-NMR (CDCI13; ppm) 7. 1
7 (LH, t), 6.72 (2H, m), 4.3
7 (2H.

m), 3.99 (2H,rn>, 3.80
(3H,s).

3.50 (2H,,m), 2.8-3.3 (
2H, m).

2.40-2.77 (3H, m), 2.33
(3H.

s), 2.23 (2H,t), 1.93 (
IH, dd).

1, 07-1.73 (8H, m), 0.83
(3H, t).

IR (KBr; cm-') 2942. 2862°1730.1700, 1594.1460-1480.
1386,1098.788゜Example 4 Synthesis of Compound 4 1,400 mg of X-52 was added to 15Tnjl of pyridine! 1
．． :: Dissolve 1.5 mj of acetic anhydride in this! and stirred at room temperature for 6 hours. While cooling with water, add 3 mβ of water and continue stirring for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in water, the pH was set to 7 with sodium hydrogen carbonate, and this was subjected to column chromatography (
HP-2050m, f! , water-niacetone-8:2) to obtain 57 mg (35%) of the desired product 1'.

'H-NMR (D20-DCI, pDl, 7:
ppm) 7.4-7.2 (IH, m), 7.
0-6.8 (2H, m).

4.73 (LH, d), 4.6-4.0 (5H, m
).

3,82 (3H,s),”3.55 (IH,
dd).

3.4-3.2 (IH, m), 2.92 (3H
,s).

2, 9-2.7 (3H, m), 2.45 (
IH, dd).

2.0 (3H, s).

IR (KBr; Cm-') 2960, 1740°1'
f+80.1598,1483,1398°1273.
1102° Example 5 Synthesis of Compound 5 590 μl of linoleic acid was dissolved in 10 mA of toluene, 116 μl of phosphorus trichloride was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved again in 3 ml of toluene. This solution was added dropwise to 7 ml of a pyridine solution containing 500 mg of compound a, and the mixture was stirred at room temperature for 1 hour. Approximately 1 g of ice was added to the reaction mixture, stirred for 30 minutes, and then extracted with ethyl acetate.

The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and concentrated under reduced pressure.

Dissolve this residue in 10 ml of methylene chloride and add 1 ml of anisole.
ml and 1 ml of trifluoroacetic acid, and stirred at room temperature for 2 hours.
Stir for an hour. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and the residue was purified by chromatography (Wakogel C-20040ml.
Hexane:ethyl acetate=2-1 to O:1) to obtain 5390 mg (66%) of the compound.

'HNMR (CDCj!3:ppm) 10.43
(IH, br, s), 7.20 (IH, t)', 6
．． 75 (2H, d), 5.37 (4H, m), 4.4
5 (LH, m), 4.4-3.9 (4H; m
), 3.86. (3H', s), 3.24 (2
H, m), 2.79 (3H.

s), 2.67 (2H, m), 2.4-1.8
(6H.

m), 1.7-1.0 (16H, m), Q, 89
(3H.

t).

IR(CHCls;c++r') 3500 25
'003360.3015,2940.2868. .

1730.1598, 1479.14651383,
1270. 1060° SIMS (m/z), 593 (-OH)
, 548°521, 299. 255. 227゜Example 6 Synthesis of Compound 6 370 mg of Compound 5 was added to 5 mjl of acetonitrile! The mixture was dissolved in 1 mA' of water, and 464 mg of silver nitrate was added thereto, followed by stirring at room temperature for 5 hours. Add 3 ml of 1N hydrochloric acid to the reaction mixture and filter off the precipitate. The filtrate was concentrated under reduced pressure, and the residue was adjusted to pH 8 by adding an aqueous sodium bicarbonate solution, followed by chromatographic purification (
Diamond Aeon HP-20TOmj! , water: acetone = 1
:0 to 1:1) 150 as sodium salt of L compound 6
mg' (40%).

'H-NMR (Na salt, CDC15:I'pm) 7
．． 10' (II, t), 6.70 (IH, d).

6.64'(LH, d), 5. '35 (4H, m)
.

4.81 (IH, m), 4.65 (IH, s)
.

4.21 (IH, d), 3.98 (2H,?
71).

3.77 (3H1s), 3.68 (IH, m)
.

3.49 (IH, d), 3.17 (LH, m)
.

2.77 (2H, t), 2.20 (2H, m)
.

2.04 (4H, m), 1.50 (2H,
t), 1.4-1.2 (14H, m), 0.
89 (3H, t).

IR (Na salt, CHCj!3; am-') 350
0-2500, 3360. 3015. 2940°2868, 1730. 1598. 1479°14
65, 1383. 1270. 1060° SIMS
(m/z), 593 (=OH), 548°52
1, 299° Example 7 Synthesis of Compound 7 313 mg of compound a was dissolved in 6 ml of methylene chloride.
Add 0.37 ml of triethylamine and 0.32 ml of parafluorobenzoyl chloride, and stir at room temperature for 4 hours. The reaction mixture was diluted with chloroform, washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by chromatography (Wako Gel C-20075mj!, toluene:ethyl acetate-15:1) to obtain 377m of the ester form of the target product.
get g.

Next, this product is dissolved in 3.5 ml of methylene chloride, 70 μl of anisole and 0.7 rrl of trifluoroacetic acid are added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, adjusted to pH 7 with aqueous sodium bicarbonate, and purified by chromatography (HP 20.50 mA!, methanol) to obtain a crude product. This product was dissolved in chloroform and further chromatographically purified (Wakogel C-20040rrl, chloroform:methanol=100:1-10:1) to obtain 274 mg (95%) of the desired product.

'HNMR (CDCA3: ppm), 9.95
(IH, br, s), 7.92 (2H, dd
), 6.67-7.33 (5H, m), 4.75
(IH, dd).

4.50 (LH, t), 4.30 (IH, dd).

4.0 (LH, d), 3:83 (3H, s>
, 3.37-3.60 (2H, m), 2.3-
3.2 (5H, m).

2, 3 (3H, s), 1.93 (LH, dd)
.

IR (KBr; c++r') 2950, 2844°1
69o-i'zo, 1595,1509°1476.1
260.1153.1095° 855.766° Example 8 Synthesis of Compound 8 Compound a, 2.03. g in 40 ml of pyridine and cooled with water to form p-toluenesulfonylchloride)'2.
Add 96 g and react overnight at 0-5η. After concentrating the reaction solution under reduced pressure to about 10 ml, dimethyl sulfoxide 4
Add 0ml, add 1.65g of lithium chloride,
React at 0°C for 5 hours. After diluting with toluene, IN-
After washing with hydrochloric acid and brine, dry and concentrate under reduced pressure. 12mj of methylene chloride for the residue! Dissolved in anisole 0.2m
1 and 2 mb of trifluoroacetic acid and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in acetone, and an aqueous sodium bicarbonate solution was added to adjust to pi (8).

This mixture is concentrated under reduced pressure, and the residue is purified by chromatography (Wakogel C-200, 100 ml, ooform:methanol-150,:1) to obtain 928 mg of the desired product.

'H-NMR (CDCI13: pp, m) 10.
4 (IH.

b r, s), 7.377, 05 (IH, m,
), 6. ．． 72 (2H, d) , 4.46 (
IH,t), 4.08 (1H,d), 3.81
(3H,s), 3.8-3.6 (2H,m
), 3.6f-2,85 (4H, m), 2.8=2.4
(3H, m), 2.36 (3H,, +q), 2
．． 15 (iH, dd). , I R (KBr ; cm"-') 295.2.1
712°1573.1474', -1441,1386
゜1265.1222.10'97.1075゜Example 9 Synthesis of Compound 9 Dissolve 120 mg of Compound 8 in 1.2 ml of concentrated hydrochloric acid,
Heat and stir at ℃ for 1 hour. After cooling, the reaction mixture was purified by chromatography (Diaion HP-20, 2QmA).
, water:acetone-1:0-7:3) and compound 9'1
8.4 mg (16%) is obtained.

'H-NMR (CD30D; ppm) 7.23
(IH.

t), 6.8. ! ] (IH, d), 6.7.9
(LH,,d).

4.76 (IH, dd), 4.62 (IH, d).

4.27 (IH, dd), 4.25 (LH, s).

3.85 (3H1,s), 3.82 (LH,dd)
.

3.74 (11-!, dd,), 3.73 (IH, m
).

3, 52 (IH,, dd), 2.9-2.6 (3
H, m).

2.66 (3H, s), 2.53 (LH, dd
).

IR (KBr; c++r') 3600-240
0°3375, 2970. 2940. 2850°1727, 1598. 1478. 12-67゜1
190, 1026° SIMS (m/z), 367 (MH+),
349 (-○H).

Example 10 Synthesis of Compound 10 15.1 mg of bromine compound d was dissolved in 3 ml of methylene chloride, and 0.3 rrl of anisole was added! J Fluoroacetic acid 0.
Add 3 ml and stir at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, the residue was dissolved in acetone, and dehydrated water was added.
Let's call it H8. After concentration under reduced pressure, chromatographic purification (Wako gel c
-200,15mj? , Rio.

Form: Acetone = 10: 1), target 22m
g (20%).

'H' NMR (CDC, A3: ppm) 7
．． 4 7.2(IJ(, m>, 6.72 (2H, d)
, 6.5-5.8 (LH, br, s), 4.4
5 (1)! ,,m) ,4.0.5(IH,br
o,s), 3.83 (3'H,s).

2.38 (3H, s), 2.2 (LH, dd)
.

IR (KBr; cm') 2948. 1?15°159
3, 1474. 1385. 1298°1264,
1097. 1074. 787゜Example 11 Synthesis of Compound 11 204 mg of compound c was dissolved in 4 ml of dimethyl sulfoxide, 201 mg of lithium iodide was added, and the mixture was heated at 50°C.
Stir for an hour. The reaction solution was diluted with ethyl acetate, washed with brine, dried, and concentrated under reduced pressure. The residue is purified by chromatography (Fuco-gel C-C-2O010, toluene:ethyl acetate-20:1) to obtain a crude product. This product was dissolved in 3rrl of methylene chloride, 0.3ml of anisole and 0.3ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 1.5 hours.

After concentrating the reaction solution under reduced pressure, chromatography purification (Wakogel C72
,00,,1,0ml,chloroform:acetone=,2
0:1) to obtain 47 mg (33%) of the desired product.

'H-NMR (CDC13:ppm) 8.6 7.
8 (LH, b r, s)', 7.4-7.1 (IH
, m).

6.72 (2H, d), 4. ．． 11. (LH, m>
, 3. ．． 99(,L H,d)'+3. ．． 8
．． 6. (3H,,s),, 3.77 =2,50
(9H,m),,2.39 (3H,S).

2.18 (LH, dd).

IR (KBr; cm') 2948. 1?20°15L
:3. ．． 147.4. 138. ．． 3. 12.62°1219, 128.5. 1097. 1,073° Example 12 Synthesis of Compound 12 Compound e, 2. Dissolve jllllg in 4 ml of methylene chloride, add anisole 0.2 mβ, trifluoroacetic acid Q,
Add 4rrl and stir at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, dissolve the residue in acetone and add deuterated water to make pt (8). After concentrating under reduced pressure, chromatography purification (Wakogel C7200. 20mji!, Rioloform:methanol = 20.:1) Target 104mg (7.3%)
get.

'H-NMR (CDCj!3-CD, OD: ppm
) 7, 3-7.0 (jH, m), 6.976, .
6 (,2H,' m).

4,10 (IH,t),, 3.89 (14(,c
l),.

3,79,(3H,s),,3. ．． 7-3. j
(2)(,m,).

3.3-2.4 (5H, m), 2.40 (3H
,s).

1. 9.5 (IH, dd), 1.2! 11(3
H, d).

IR (KBr ; cm-') 2950.1?20°16
! j? ,,1592,1475.1263°1098,
1074,1058゜Example 13 Synthesis of compound 13 Compound f 2.81 mg, hydroquinone 280mβ
Fuyobi Ethanethiol 0.55. , 5.5 ml of trifluoroacetic acid was added to the mixture of . ml and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene and purified by chromatography ('') = r-gel C-200, j9 ml/hexane:ethyl acetate = 2:1 to 1.:1) to give compound 13.
．． 1'! 9 mg (quantitative) is obtained.

' HN, MR, (, CD3 C"QCD3 ':p
pm)? , ,2 o.

(IH,,,t,) +6.86 (LH,,d),
, 6. ．． 8.0 (IH, d), 5. (18(LH,
br, s), 4.42 (IH, t), 3.87.
(,IH,m),, 3.8. j(3I(,s),,
3.82(jH,,s) , :3.57(,1,H
,.

2, 24 (IH, [d), 1.40 (LH
,t).

IR (KBr ; am-') 3600-2400°3440.2940,2850,2578°1720.
1673, 1594, 1479° 1267.1198,
1140,786,721 SIMS (m/z), 374
(MH”), 347 (-CN), 326, 227
゜Example 14 Synthesis of compound 14 805 mg of compound g was mixed with 8.5 mj of methylene chloride! Dissolved in anisole 0.34mj! , )! J Fluoroacetic acid 1.7 mjl! and stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, it was purified by chromatography (HP-2050
ml, acetone) to obtain 891 mg of crude product.

Further chromatographic purification (Wakogel C-200, 5'Om
Ii, Chloroform:methanol=5:1L to obtain a crude product. Furthermore, it was dissolved in heavy water and subjected to chromatographic purification (
HP-2060ml, water:acetone=1:1) L, 415mg (73%) of the target product was obtained as the sodium salt.

IH-NMR (D20. pD6.7; plum
)7.18-7.13 (IH, m), 6.76-
6.71 (2H, m), 4.38 (IH, s), 4.
20 (LH, s), 3.71 (3H, s), 3
．． 8-3.65 (2H, m), 3.47 (IH, d
), 3.34 (LH, (i), 3.08 (IH
,br,S), 2.95-2.62 (3HSm),
2.53 (IHSm).

2.37 (3H,s), 2.11 (3H,s)
.

1.94 (LH, dd).

IR(KBrScm-')2948.1683°159
3.1474.1'387,1354°1297.12
63,1134.1097゜1074.1038.78
7゜Example 15 Synthesis of Compound 15 1.24 g of the sodium salt of Compound 14 was added to 1 part of methanol.
The mixture was dissolved in 2 ml of acetonitrile and 12 mA of acetonitrile, 823 μm of silver nitrate was added thereto, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure, 10 ml of 1N hydrochloric acid was added to the residue, and the precipitate was filtered off. Chromatographic purification of the filtrate (Diaion HP
-20 water:methanol = 1:1) L compound 15,
Obtain 1.13 g (98%).

'H-NMR (CDCj23+CD30D:ppm)
7, 17 (IH, t), 6', 77 (I
H, d), 6.72 (IH, d), 4.77 (I
H, dd), 4.29 (IH, d), 4.03 (
IH,s), 3.93 (IH,d), 3.87
(3H,S), 3.47 (IH.

dd), 3.40 (IH, da>, 3126
(IH.

dd), 2.90 (IH, dd), 2.73 (3
H.

s), 2.6C1 (2H, m), 2.24 (3H
,s).

2, 17 (LH, dd).

rR (KBr ; cm') 3700-2200°34
00.2945,1690,1595°1475.13
78L 1262,1131゜1097.1078,
1055,1033°S I MS (m/z>,
389 (-OH) 347°331.317,3
01゜Example 16 Synthesis of Compound 16 Compound f, 500 mg, was added to 10 m of pyridine! ! 0.5.4 ml of balmitoyl chloride was added to the mixture, and the mixture was stirred at room temperature for 20 hours. Approximately 1 g of ice was added to the reaction mixture, stirred for 3 minutes, and then extracted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried, and concentrated under reduced pressure.

Dissolve the residue in 9 mA of methylene chloride and add 0.9 mA of anisole.
mj! Add 1.8 mJ of trifluoroacetic acid and stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and purified by chromatography (C-200, 40ml.
8xane: ethyl acetate = 1:1) and compound 16 58
Obtain 0 rng (quantitative).

'H-NMR (CDCI3:99m) 9. '27
(IH,br,'s), 7.22 (iH,t)
, 6.75 (IH, d), 6. '73 (IH, d)
, 4.54 (, IH, m), 4.23 (IH,
m), 4.10 (2H.

m), 3.79, (3H, s), 3.5-3.1
(4H.

m), 2.77 (3H, s), 2.44 (2H
,t).

2.22 (IH, m), 1.50 (2H, m)
.

1, '21 ('24H, m), 0.8"6 (3
H,t).

I R (KBr ; cm-') 370 (1-24
00°2928.2860.1706.1690°15
95.1473.1267.1078°784. 73
8゜Example 17 Synthesis of Compound 17 580 mg of Compound 16 was dissolved in 8 ml of acetonitrile and 4 mj2 of water, 1.13 g of silver nitrate was added, and the mixture was stirred at room temperature for 6 hours. 7 mj2 of 1N hydrochloric acid was added to the reaction mixture, and the precipitate was filtered off. After concentrating the filtrate under reduced pressure, chromatography purification (Diaion HP-20° 100 ml. Water: Acetone - 1:0 to 0:1) L Compound 17 224 mg (39%
).

'H-NMR (CDCA3: ppm) 7.32
(IH, br, s), 7.09 (LH, t)
, 6.68 (LH, d), 6.61 (LH, d
), 4.94 (LH, m), 4.58 (lH, m)
, 3.93 (IH.

S), 3.83 (3H, s), 3.69. (IH,
m).

3.56 (IH, d), 3.47 (IH, d).

3.33 (LH, dd,), 3.2E+ (IH,
dd).

2.87 (LH, t), 2.54 (2H, m).

2.49 (3H,, s), 2.35 (2H, m).

2.08 (LH, t), 1.44 (2H, m).

126 (24H, m), 0.88 (3H, t)
.

IR (KBr ; cm-') 3400-2400°3410.2930.2858. 1685°1582
, 147? , 1391.1265°1098,
1029,771,610°S IMS (m/z)
, 585 (-0H) , 3472.55,
227° Example 18 Synthesis of Compound 18 410 mg of the compound was dissolved in 5 ml of methylene chloride, 50 μm of anisole and 0.8 mA of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, the residue was dissolved in dimethyl sulfoxide and deuterated water, and purified by chromatography (HP-2040m!, acetone). The obtained crude product was further purified by chromatography (Wakogel C-2
00,40mj! .

Chloroform:methanol-100:1)L, target product 2
Obtain 78 mg (90%).

'H-NMR (CDCj3; ppm) 9.1 (
LH.

br, s), 7.90 (2H, dd), 6.60-7
．． 30 (5H, m) , 4.57 (LH, t)
, 4.05 (LH, d), 3.87 (3H, s)
, 3.7 (2H.

m), 3.47 (2H, m), 2.3-3.2
(5H.

m), 2.33 (3H, s), 1.95 (IH
, dd).

IR (KBr; cm-') 2946, 2842°170
,L-1735,1657,,1,595°1505
．． 1475.1260.1226°1200.115.
5. 918,844° Example 19 Synthesis of Compound 19 1.21 g of Compound i was dissolved in 25 mA of methylene chloride, 2.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, it was purified by chromatography (Wako Gel C-200, 120 mj!, chloroform:methanol =, 20:1) L, 874 mg (10:1) of the target product.
0%).

'H-NMR<CDC15;ppm) 7.3-7.
1 (IH, m), 6.73 (2H,, d),
4.4-4.2 (IH, m), 4. Ofj('I
H, d), 3. ．． 82 (3H, s), 3.7-2.
45 (9H, m), 2.38 (3H, s), 2
．． 05 (LH, dd).

IR(KBr;car') 2955. 2120
゜1720, 1596. , 1480. 1395°1272, 1100. 1080° Example 20 Synthesis of Compound 20 223 mg of Compound 19 was dissolved in 5 ml of acetonitrile and 1 ml of water, and 476 mg of silver nitrate was added thereto at room temperature.
Stir for an hour. Add 3 ml of 1N hydrochloric acid to the reaction mixture and filter off the precipitate. After concentrating the filtrate under reduced pressure, chromatography purification (Diaion HP-2050ml, water: acetone = 0 to 4
:1) Obtain 118 mg (54%) of L compound 20.

IH-NMR (D20;I)I)m') 7.20
(IH.

t), 6.85 (IH, d), 6.78 (IH, d
)4.61 (LH, dd), 4゜47 (IH
, dd).

4.14 (IH, ad), 4.12 (IH, s).

3.83 (IH, dd), 3.61 (IH, dd)
.

3.42 (IH, m), 3.38 (IH, dd).

3.35 (LH, dd), 2.82 (IH, m).

2.78 (3H,s), 2.7-2.6 (2H
, m).

2.30 (IH, dd).

I R (KBr; cm'-') 3700-2400
゜3400, 2110. 1594. 1479°1
395. 1379. ．． 1267, 109'8°10
58, 1032. 791° SIMS (m/z), 374 <MH=), 35
6(-OH), 300, 255, 227° Example 21
Synthesis of Compound 21 Compound j, 130 mg was dissolved in 2.6 ml of methylene chloride, 0.2 m of anisole C) 0.3 m of refluoroacetic acid
1 and stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, it is dissolved in acetone, added with deuterated water, and stirred for 10 minutes. After concentration under reduced pressure, the residue was purified by chromatography (Wakoge) It
C-20El', 12mj! ; Chloroform:methanol=100:1) L. The obtained target product is further crystallized from chloroform-niteryl n-hexane to obtain 81 mg (89%) of the target product.

'H-NMR<CDCl! 3CD'30D: ppm
) 7, 4-7.1 (LH, m), '6.84
("2H, d').

4.40 (IH, t), 3.99 (LH,
d), 3.89 (3H, s), 3.7-2.5
(9H, rr+), '2.38 (3H, s>, 2.
08 (LH, dd).

IR (KBr; cm') 2954. 1725°159
3, 1474. 13'86. 1298°1266
, 1096. 1073 788゜Example 22 Synthesis of Compound 22 19.1.6 g of water was added to 40 TTI j! -,)
/ Dissolved in 50 ml of IN=hydrochloric acid 10 ml2
Add.

Fliomg of 5% palladium on carbon is added and catalytic reduction is carried out under a hydrogen atmosphere at normal pressure. After removing the catalyst by filtration, the mixture is concentrated under reduced pressure. Chromatographic purification of the residue (HP-20゜1'00m
jl! , methanol:water-1:'9)L, 811 mg (46%) of the target product was obtained as a hydrochloride.

'H-NMR (CD30D; ppm) 7.4-6
．． 7 (3H, m), 4.42 (IH, rri)
, 4.20 (LH, d), 3.83 (3H, s
)', 2.35 (3H.

S).

Example 23 Synthesis of Compound 23 88 mg of pyruvic acid was dissolved in 2 mA of tetrahydrofuran, and 115 mg of N-hydroxysuccinimide 5N, N
206 mg of '-dicyclohexylcarbodiimide CI'l) was added and stirred at room temperature for 20 minutes. This is filtered to obtain an active ester solution. Compound 22.17
Dissolve 2 mg in 3.2 ml of anhydrous tetrahydrofuran,
Add 112 μl of triethylamine. The previously prepared active ester solution is added to this solution, and the mixture is stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by C17 column (H
P'-20',"5-'Om1. Water: Acetone-7:
3 to 1:1) to obtain 114 mg (67%) of the desired product.

1H-NMR (CDC13; ppm > 7.3-7.
1(IH,' m), 7.05'-6,83'(1
B, m).

6.82-6', 60' (2H, m), 4.34
(LH, m).

3.93 ('IH, d), 3', 85 (3H,
s), 3.7-3.4 (4H, m), '3.2-
2. '8 (2H, 'm).

2, 41' (3H, s), 2", 3'7' (
3H,s).

2, 07 (IH, dcl).

IR(KB?;cm')2946. '1'722
．． '1683.1'592,1525,1474゜13
58, 1265゜Example 24 Synthesis of compound 24
g was dissolved in anhydrous tetrahydrofuran, 69 mg of N-hydroxysuccinimide was added, and further N, N'
-Add 124 mg of dicyclohexylcarbodiimide and stir at room temperature for 30 minutes. Filter to obtain an active ester solution. 22.171 mg of the compound is dissolved in 5 ml of anhydrous tetrahydrofuran, and 112 μβ of triethylamine is added. Add the previously prepared active ester to this solution,
React for 2 hours at room temperature. Dilute the reaction solution with ethyl acetate,
After washing with brine, dry and concentrate under reduced pressure. The residue was purified by chromatography (Wako gel c-200', '1' Om
1. Chloroform:methanol-25:1) L, 179 mg (80%) of the desired product was obtained.

' HN M R (CD 30D; ppm) 7',
32 (5H, S), 7.3-6.5-'(3'H, m)
', 5. '09 (2H, s), 4.4-3.
9'(3H,'m), 3.85'(3H,s),
, 2.3'5 (3H,s) , 1.20 (3H
.

d).

IR"(KBr;cm') 3350, 2960°1
725, 1670. 1600. 1485°127
3. 1.0.79° Example 25 Synthesis of Compound 25 177 mg of Compound 24 was dissolved in 48% hydrogen bromide-acetic acid solution 3
．． Dissolve in 5 mA and stir at room temperature for 4 hours.

The reaction solution was adjusted to pH 5 by adding soybean water, and then concentrated under reduced pressure. The residue was purified by chromatography (HP-20, 30mJ2, water:acetone-9:1), L, target product 3L+++g (28
%).

IH-NMR (D20; ppm) 7.4-7.1
(LH, m), 7.05-6.8 (2H, m),
3.83 (3H, s), 2.22 (3H, b
r,,s).

1.35 (3H, br, s).

IR (KBr ; cm-') 3400, 2946°16
77.1591, 1560, 1474°1389.12
62.1098,1075゜Example 26 Synthesis of Compound 26 39Qmg of compound k was dissolved in 3ml of methylene chloride, 3ml of anisole Q and 0.8ml of fluoroacetic acid were added.
1 and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure at 55°C, azeotroped with toluene, and the residue was purified by chromatography (Wakogel C-20020ml, hexane:ethyl acetate-1:
1 to O:1) to obtain 26280 mg (84%) of the compound.

'H-NMR (CDCC: ppm) 7.3-5.6 (
9H,m), 4.6-4.3 (2H,rn),
4.1-3.7 (2H, m), 3.80 (,
3H,s), 3.45(2H,nn), 3.3
-2.8 (2H, m), 2.7-2.2 (3H
, m), 2.31 (6H,s), 2.2-
1.3 (7H, m), 1.98 (3H, s), 1.
69 (3H, s), 1.00 (6, H, s).

Example 27 Synthesis of Compound 27 170 mg of Compound 26 was dissolved in 7 ml of acetonitrile and 1.5 ml of water, 226 mg of silver nitrate was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to about 1 ml and hydrogen carbonate was added. After adjusting the pH to 8 by adding an aqueous IJum solution, chromatography purification (Diaion HP-205Qml,
acetone:water=1:0~0:1) and compound 27 29
．． 8 mg (17%) is obtained.

'H-NMR (CDC13:ppm) 7.2-5.
5 (9H, m), 4.82 (IH, m), 4.64 (I
H, m), 4.0-3.7 (3H, m), 3.76
'(3H,s), 3.61 (LH,,rn), 3:
43 (IH.

m), 3.16 (IH, m), 2-. 48 (3
H,'s).

2.28 (3H,s), 1.98 (3H,s
), 1.9-1.2 (6H, m), 1.71 (
3H,s), 1.01 (6H,s).

I R<CHC, 1s ; cm-') 360'
0 3200°2970.2940. ．． 1705,45
96°1477.1268,1152°S IMS (m/z) 62・9 (-Na
)', 613° Example 28 Synthesis of Compound 28 500 mg of Compound A was dissolved in 10 ml of methylene chloride, 5 mi of thioanisole Q and 1 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and purified by chromatography (Wakogel C-2'0'0 40ml, hexane:ethyl acetate = 1
:'2) to obtain 28353 mg (94%) of the compound.

IH-NMR (CDCC; ppm') 7.14'
(1H, t), 6.69 (IH, d), 6.66
(IH.

d), 4y52, (IH, m), 4.33 (IH
,rn).

4.2-4.0 (2H, m), 3.83 (3H
,s).

3, 5-3.2 <4H, m), 2.9-1.9
(6H, m).

2.74 (3H,s>, 1.7-1.0 (IO
H, m).

0,82 (3H, m).

IR (KBr; cm') 3700-2200゜2
924.2858. 1?18. 1699. 166
9°1593, 1266, 11? , 3. 1124
, 720° Example 29 Synthesis of Compound 29 353 mg of Compound 28 was dissolved in 7 ml of acetonitrile and 2 ml of water, and 782 mg of silver nitrate was added thereto at room temperature.
Stir for an hour. The reaction mixture was filtered, the r liquid was concentrated under reduced pressure to about 2 ml, and then purified by chromatography (Diaion HP-201
00ml, water:acetone-1:1) to prepare compound 2.
Obtain 9.216 mg (59%).

'H-NMR (CDCIts; ppm) 7.9
5 (IH,br,'s),' 7.09 (I
H,t'),'6. fl+8(IH,dy, 6
．． 60 (LH, a), 4.94 (1H, m),
4.5t (IH, m), 3.90 (LH.

s), 3.82 (3H, s), 3.66 (IH
, m).

3.56 (IH, dd), 3.45 (IH, d
).

3.34 (IH, dd), 3.25 (IH, d
d).

2.87 (IH,t), 2.51 (2H
, m).

2.47 (3H,s), 2.35 (2H
, m).

2.06 (IH, dd), 145 (2H, m)
.

1, 3-1.1 (6H, m), 0.84 (3H
,t).

IR (KBr ; cm') 3700-220
03420, 2940. 2860. 1690°1
594, 1476, 1264. 1078°SIM
S (m/z) 459(-OH), 387°347
, 313゜Example 30 Synthesis of Compound 30 Compound ml, 1g is dissolved in 20ml of methylene chloride, 1ml of anisole and 2ml of trifluoroacetic acid are added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and purified by chromatography (Diaion HP-2
020Qml and water:acetone=0 to 0:1) to obtain 604 mg (79%) of Compound 30.

'H-NMR (CDCj!3-CD30D: ppm
)7.20 (LH,t), 6.80 (IH,d
).

6.76 (LH, d), 4.59 (IH, dd
d).

4.45 (IH, ddd), 4.17 (LH,
ddd).

4.09 (IH, d), 3.85 (3H, s)
, 3.52 (1'H,s) , 3.49 (IH
, dd), 3.2'2 (IH, dd), 3.
00 (LH, dd), 2.8-2.6 (3H, m)
, 2.35 (3H,s), 2.08 (IH.

dd).

IR (KBr; am') 3700-3200゜2
960.2700-2200.1706,1594゜1
477, 1266.978,739゜S IMS
(m/z) 360 (MH+).

333 (-CN), 286.261° Example 31
Synthesis of Compound 31 331 mg of Compound 30 was added to 3 ml of dimethyl sulfoxide.
! and 3 ml of water, 234 mg of silver fluoride was added thereto, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered and the reactor liquid was directly purified by chromatography (Diaion HP-20 100
m1, water: acetone = 1:0 to 1:1) Compound 31
Obtain 261 mg (80%).

'H-NMR (CD30D; 119m) 7.22
(LH, dd), 6.86 (IH, d), 6.7
8 (IH.

d), 4.9-3.8 (4H, m), 4.
44 (IH.

m), 4.11 (LH,s), 3.84
(3H,s)'.

3.6-3.2 (2H, m), 2.78 (3
H,s).

2.9-2.5 (3H, m), 2.32 (I
H, dd).

IR (KBr ; cm-') 3700-2400
3380.3130,15.92.157'4°147
6.1401,1390,1265°1037.999
゜SIMS (m/z) 425 (-OH, + glycerol), 351 (MH+), 334.3.33
(-DH>, 288.261゜Example 32 Synthesis of Compound 32 580 mg of linoleic acid is dissolved in 10 ml of toluene, 155.d of phosphorus trichloride is added, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure to form a residue. was dissolved again in 5 ml of toluene. This solution was added dropwise to a solution of 539 mg of compound f in 5 ml of methylene chloride, and 0.70 ml of triethylamine was added.
Add Hi and 65 mg of dimethylaminopyridine, and stir at room temperature for 3 hours. Water is added to the reaction mixture and extracted with methylene chloride. The organic layer is washed with saturated brine, dried, and concentrated under reduced pressure to obtain a crude product.

This product was dissolved in 3 Qml of methylene chloride, 1.5ml of anisole and 3ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, azeotropically purified with toluene, and purified by chromatography (Wakogel C-2006Qml).
, hexane:ethyl acetate=2=1 to 1:1) to obtain 534 mg (71%) of Compound 32.

'H-NMR (CDCL; ppm) 10.0
2 (IH, br, s), 7.19 (IH, t)
.

6.74 (IH, d), 6.72 (LH, d
), 5.6-5.1 (4H, m), 4.5
7 (IH, m).

4.25 (IH, m), 4.11 (2H, m
).

3.87 (3H,s), 3.6-3.2 (4
, H, m).

2.9-1.9 (12H, m), 2.78 (3
H,s).

1.8-1.1 (16H, m), 0.89
(3H, m).

IR(KBr;cnr'>3700-22003
450, 2930. 2855. 1?23°168
3, 1594. 1475. 1266°1196,
1140. 720° Example 33 Synthesis of Compound 33 534 mg of Compound 32 was dissolved in 3 ml of dimethyl sulfoxide.
The mixture was dissolved in 2 ml of water, 1.21 g of silver nitrate was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the reaction mixture was directly purified by chromatography (Diaion) IP-2010 [1 ml
, water:acetone=1:0 to 0:1) and composition 256m
get g. This product was further purified by chromatography (Wakogel C-20020ml, Rio.

form:methanol (5:1 to 3:1), then dissolved in methanol, added an equimolar amount of aqueous sodium bicarbonate solution, and concentrated under reduced pressure to convert compound 33 into sodium salt 18.
Obtain 0 mg (38%).

'H-NMR (free carboxylic acid, CDCl3-CD3
0D; ppm) 7.14 (IH, t).

6.73 (IH, 4), 6.69 (IH, d).

5.5-5.2 (4H, m), 4.78 (
LH9dd).

4, 21 (LH, d), 3.97 (LH
,s).

3.86 (3H, s), 3.52 (LH, dd
).

3.42 (IH, d), 3゜33 (LH
, dd).

3.25 (IH, dd), 2.89 (IH, d
d).

2.77 (2H,t), 2.72 (3'
H,s＞.

2.7-2.5 (2H, m), 2.41
(2H, m).

2.1-2.0 (4H, m), 1.6-1.
4 (2H, m).

1.4-. 1.1 (148, m), 0.89
(3H, t).

IR (free carboxylic acid, CHCls; cm-')
3600-2400.2940, 2860°1680.
1596.147? , 1268° SIMS (7-carboxylic acid, m/z) 609 (-OH).

Table 3 shows the structures and compound numbers of the compounds obtained in the reference examples shown below.

Table 3 Reference Example 1 Dissolve 1.15.5 g of acid-containing compound
Add 3.9 g and stir overnight at room temperature. After filtering the reaction solution, the filtrate is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. After adding acetic acid to decompose excess reagent, dehydrated water,
After washing with saturated saline, dry and concentrate under reduced pressure. The obtained residue was purified by chromatography (Wakogel C-200, 600
ryl.

Toluene:ethyl acetate (15:1 to 10:1) to obtain 12.45 g (55%) of the desired product.

'H-NMR (CDCl3; ppm) 7.33
(10H, s), 7.3-7.0 (IH, m)
, 6.89 (IH,s> , 6.8-6.6 (2
H, m), 4.27 (LH, t, J=4.2H
z), 4.01 (IH,' d.

J=3Hz), 3.77 (3H,s), 3.
8-3.55 (2H, m), 3.5-2.8 (4H,
m), 2.78-2.5 (3H, m), 2.15 (
3H,s), 2.0(IH,dd, J=9H2,13,
5H2).

IR (KBr ; cm-') 345 (L 2950° 1730.1594, 1480, 1273° 1170
.

Reference Example 2 Synthesis of Compound A' 785 mg of compound a' was dissolved in 15 ml of methylene chloride, and 0.25 mA of triethylamine, balmitoyl chloride Q, and 5. Add mj2 and stir at room temperature for 2 hours. The reaction mixture was diluted with chloroform, washed with saturated brine, dried, and concentrated under reduced pressure. The residue was filtered and purified (Wakogel C-200, 60ml 1° Toluene: Ethyl acetate = 20
:1) Obtain 1.13 g (98%) of L compound b.

'H-NMR (CDCll5; ppm) 7.4
7.2 (IOH, m), 7.17 (LH, t),
, 6.90 (IH, s), 6.71 (2H, m
), 4.43 (LH, m), 4.34 (LH,
m), 3.99 (2H.

m), 3.79 (3H, s), 3.41 (2H,
m).

3, 3-2.0 (8H, m), 2.0=1.0
(26H.

m>, 0.87 (3H, t).

Reference example 3 Synthesis of compound C Dissolve 1.24 g of compound a in 20 ml of pyridine L, p
-) Add 1.4 g of luenesulfonyl chloride and react overnight at room temperature. Dilute with ethyl acetate, wash with IN hydrochloric acid and brine, dry, and concentrate under reduced pressure. Chromatographic purification of the residue (Wakogel C-200゜100ml 1.n-hexane:
Ethyl acetate (2=1) and then crystallized from ethyl acetate-ethyl ether to obtain 1.09 g (67%) of the desired product.

'HNMR (CDCl2:ppm) 7.60
(2H, d), 7.31 (IOH, s), 7.4
5-6.95 (3H, m), 6.87 (LH, s)
, 6.8y-6,5 (2H, m), 4.40 ('I
H, dd), 4.25-3.6 (3H, m), 3.
63 (3H, s), 3.5-2, 75 (4H, m
), 2.7-2.45 (3H, m).

2.32 (3H, s), 2.06 (3H, s)
, 2.45 (IH, m).

IR (KBr; cm-') 2942.1732; 159
5.1496,1476,. 1456°1367.12
66.1170,742° Reference Example 4 Synthesis of Compound d Compound c, 1.36. g to dimethyl sulfoxide 20
mA, add 869 mg of lithium bromide,
Stir at ℃ for 2.5 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried, and concentrated under reduced pressure. The residue was purified by chromatography (Wako Gel C-20080mj?, n-hexane:ethyl acetate = 5:1) to obtain the desired product 958.
mg (82%).

'H-NMR<CDCll5:ppm) 7.4
7.0 (IIH, m), 6.90 (!H, s),
6.72 (2H, a), 4.42 (IH, t)
,,,4.02 (IH,d),3.80 (3H
, s), 3.7973.58 (2H, m), 3.56-
3.30 (3H, m), 3゜20-2.40 (4
H,TTI), 2.12 (3H,s).

2, 35-1.95 (IH, m).

IR (KBr; cm-') 2950. 1729
゜1592.1495, 147.4, 1457゜138
3.1297,1263,1166°1075.999
, 784, 756, 700° Reference Example 5 Synthesis of Compound e 400 mg of Compound C was dissolved in 8 ml of dimethyl sulfoxide, 45 mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature. 45 mg each after 4 hours and overnight
Add the above reducing agent and stir further overnight. The reaction solution was diluted with ethyl acetate, washed with brine, dried, and concentrated under reduced pressure. Chromatographic purification of the residue (Wakogel C20050mj!
, n-hexane:ethyl acetate-5:1)L, target product 2
Obtain 11 mg (71%).

'H-NMR (CDCj'+': ppm), 7
．． 5-7.0 (11H, m), 6.92 (IH
,s), 6.72(2H,d), 4.1'l
(IH, q), 3.79. (4H,s), 3
．． 6-2.4' (7H, m), 2.15' (3H
,s), 1.9'2 ('IH,dd), 1.
28 (3'H.

d).

IR(KBr;c++r') 2950. 1
? 28°1591,. 1496.14'74.145
8°1262,'1166.1098,1076°10
58.741,700゜Reference Example 6 Synthesis of compound f Compound c, 5.00 g was dimethyl sulfoxide 1
00ml, add 667mg of sodium hydrogen sulfide, and heat and stir at 50°C for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried and concentrated. The residue was purified by chromatography (Wako-gel C-200, 200
mA, hexane: methylene chloride: acetone-21 = 14
:1) Obtain 1.01 g (88%) of L compound f.

'H-NMR (CDCjl!3:ppm) 7.5-
7.1 (IIH, m), 6.92 (LH, s), 6.
75 (LH, d), 6.74 (IH, d), 4.39
(LH, t), 3.94 (IH, d), 3.81
(3H.

s), 3.6-3.3 (3H, m), 3.1
-2.5 (4H, m), 2.15 (3H, s), 2
．． 06 (LH,.

m).

IR (KBr ; cm') 3450, 2950°28
40.1727. ．． 1593.1478°1268,.
1168,1076.700゜Reference Example 7 Synthesis of compound g 950 mg of compound c was mixed with 14 ml of dimethyl sulfoxide.
Add 700 mg of potassium thioacetate and heat at 50°C.
Stir for 2 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried, and concentrated under reduced pressure. The residue was purified by chromatography (100 ml of Wako Gel C-200, toluene:ethyl acetate-20:1) to obtain 805 mg (99%) of the desired product.

'H-NMR (CDCjL; pl)m) 7.
36 (10H, s), 7.3-7.0 (IH, m
), 6.90 (IH, s), 6.69 (2H, d
), 4.48 (LH,t), 3.93 (IH,d
), 3.81 (3H.

s), 3. t3-2.3 (9H, m), 2.18 (
3H.

s), 2.12 (3H, s), 1.95 (
IH, dd).

1, R (KBr; cm') 2946.1730°1
686.15.91, 1495, 14.73°145.
5.1384, 13.54. ．． 1262°1166,.
1074. ．． 698° Reference Example 8 Synthesis of Compound 177 μl of diisopropyl azodicarboxylate was dissolved in 1.5 ml of tetrahydrofuran.

While cooling with water and stirring, 236 mg of triphenylphosphine was added, and the mixture was stirred at the same temperature for 10 minutes. Next, compound a, 306
mg and p-fluorothiobenzoic acid 141 mg
was dissolved in 3 mj2 of tetrahydrofuran, this solution was added to the above reaction solution, and the mixture was stirred at room temperature for 3.5 hours. After distilling off the solvent, the residue was purified by chromatography (Wakogel C-20,050mA, toluene:ethyl acetate-10).
:1) to obtain 312 mg (79%) of the desired product.

'HNMRCCDCl5:ppm) 7.88
(2H, dl, 6.63-7.37 (15H, m).

7.2 (LH, s), 4.58 (LH, t)
, 4.05 (IH, d) , 3.83 (3H, s)
, 3.7 (2H.

m), 3.42 (2H, m),, 2.37-3
．． 23 (5H, m), 2.13 (3H, s)
,4. ．． 95 (IH.

dd).

IR (KBr; cm-') 2946.1?29°165
7.1595,1505. ,,,． 1474°1457
．． 1262, 1227. ．． 12.03°1.075.
917. ．． 8.44. , 69'l.

Reference Example 9 Synthesis of Compound 1 1.5 g of compound c was dissolved in N, N-dimethylformamide)
1.44 g of sodium azide was added, and the mixture was stirred at 50° C. for 6 hours. After dilution with ethyl acetate,
IN-Hydrochloric acid, saline solution! After washing and drying, the mixture was concentrated under reduced pressure to obtain 1.21 g (100%) of the desired product.

'H-NMR (CDCj!a: ppm) 7.5
7.0 (11H, m), 6.90 (LH, s),
6.73 (2H, d), 4.33 (1, H, da)
, 3.99 (IH, d) , 3.81 ('3H,
s),,3.7-2.4(9H,,m),2.1
5. (3H,s), 2.1-1゜95 (I
H, m).

IR (KBr; cm') 2105. 173.0°15
93,... 1479. 1265゜Reference Example 10 Synthesis of Compound J Compound c, , 170 mg was mixed with 3 m of dimethyl sulfoxide.
7511 Ig of sodium cyanide is added thereto, and the mixture is stirred at room temperature overnight. After diluting with ethyl acetate, washing with brine, drying, and concentrating under reduced pressure. The residue was purified by chromatography (Wako gel c72:00..15m 4° toluene:ethyl acetate=15+1) to obtain 132 mg (99%) of the desired product.

'H-NMR (CD (US: ppm) 7.3
4 (10H, s), 7.25-7.05' (IH
,,m).

6.139 (LH,s), 6.85-6. ．． 60
(2H, m).

4, 34 (LH, t), 3.88 (IH, d)
, 3.79 (3H,s), 3.6-3.3 (4
H, m), 3.25-2.4 (5H, m), 2
．． 10 (3H,s), 2.25-1.85
(I H, m).

rR (KBr ; cm') 294B, 1729°15
94, 1496. 1474,1386°1264,
1168.1075,698° Reference Example 11 Synthesis of Compound 654 mg of retinolic acid was dissolved in 10 ml of toluene, 133 ρ of phosphorus trichloride was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved again in 3 ml of toluene. This solution was added dropwise to 7 ml of a pyridine solution of compound a, and the mixture was stirred at room temperature for 1 hour. Add 2 g to the reaction mixture
After stirring for 30 minutes, extract with methylene chloride. The organic layer is washed with an aqueous sodium hydrogen carbonate solution, dried and concentrated under reduced pressure to obtain a crude product. This crude product was purified by chromatography (
Wakogel c-2006Qml, hexane:ethyl acetate-9:1~4:1) to give 390mg (51%) of the compound.
get.

'H-NMR (CDCj!3; ppm) 7.4-
5.5 (20H, m), 4.7-4.3
(2H, m).

4.1-3.9 (2H, m), 3.80
(3H,s).

3.39 (2H, m), 3.3-2.9
(2H, m).

2.8-2.4 (3H, m), 2.23
(3H,s).

2.2-1.4 (6H, m), 2.12
(3H,s).

1.96 (3H,s), 1.71 (3H
,s).

1.04 (6H, s).

Reference Example 12 Synthesis of Compound I 500 mg of compound f is dissolved in 10 ml of methylene chloride, 385 ml of triethylamine and 287 ρ of heptanoyl chloride are added, and the mixture is stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried, concentrated under reduced pressure, and purified by chromatography (Wako Gel C-20030ml. Hexane:ethyl acetate = 4:1) to give 538 mg (89%) of Compound 1.
get.

'H-NMR (CDCj!3:ppm) 7.4-
7.2 (IOH, m), 7.13 (LH,
t), 6.87(IH,s), 6.67
(2H, d), 4.45 (LH, m),
3.92 (IH, d), 3.82 (3H.

s>, 3.5-2.2 (9H, m),
2.10 (3H.

s), 1.92 (IH, dd), 1.
6-1.0 (10H, m”), 0.81 (3H
,t).

IR (KBr; cm-') 2950. 2930°1
733, 1682. 1540. 1263°116
0, 1074. 699° Reference Example 13 Synthesis of compound m Compound b2. oOg was dissolved in 4 Qml of acetonitrile, 4.48 g of cesium fluoride and 61.56 g of 18-crown were added, and the mixture was heated and stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure, an aqueous solution of hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, concentrated under reduced pressure, and purified by chromatography (Wakogel C-200100ml hexane: ethyl acetate: chloroform = 7:2:1) to obtain 1.11 g of compound m (71%).
).

'H-NMR (CDC13; 911m) 7.5
−7.2 (IOH, m), 7.17 (LH, t
), 6.90(LH,s), 6. L2 (2H,
d), 4.9-4.2 (3H, m), 3.9
9 (18, mn, 3.8 1 (3H, S
), 3.5-2.4 (7H, m),
2.13 (3H, m), 2.07 (IH, dd
).

IR (CHCj'+ ; cm') 2960. 17
30°1597, 1480. 1464. 1269
゜1170, 1102. 1000°S IMS (m/z) 526 (MH+)
, 499 (-CN) , 360, 330° Reference Example 1
4 Add distilled water to 15.0.1 g of injection compound and 50 g of glucose to prepare solution 11. This solution was filtered through a membrane filter (Millibore, FGLD) with a pore size of 0.22μ.
14200) and pressurized using N2 gas (0.5k
g/ctj). Dispense 10 ml of the filtrate into a 20 ml white ampoule and seal in the usual manner.

This gives an injection.

Effects of the Invention Compound (I) and its pharmacologically acceptable salts have excellent antitumor activity.

Procedural amendment (voluntary) October 2, 1985 1, Indication of the case 1988 Patent Application No. 207179 2, Name of the invention DC-52 derivative 3, Person making the amendment Relationship to the case Patent applicant postal code 100 Address: 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name
(102) Kyowa Hakko Kogyo Co., Ltd. (TBL: 03-
282-0036) Column 5 of detailed description of the invention in the specification, contents of amendment Structural formula -5CO(CH2) 7CH=CflCH2CH
= (C112), CH3J is “5CO(CH2)t
cH=c)ICH2CH=CH(Correct to CLLCL J.

(2) "rKBr" on page 58, line 7 and page 60, line 11 of the specification is corrected to "rKBr".

(3) “One hour” on page 62, line 9 of the specification is “1 hour”
Correct.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ {In the formula, R is hydrogen, alkanoyloxy having 1 to 18 carbon atoms, oleoyloxy, linoloyloxy, linolenoyloxy, retinoyloxy, Substituted or substituted benzoyloxy (the substituent is halogen or lower alkoxy), mercapto, alkanoylthio having 1 to 18 carbon atoms, oleoylthio, linoloylthio, linolenoylthio, retinoylthio, unsubstituted or substituted benzoylthio (the substituent is halogen or lower alkoxy)
, azide, amino, -NHZ [wherein Z is a residue other than OH of the carboxyl of the α-amino acid (the amino and/or carboxyl of the residue is a protecting group thereof commonly used in peptide synthesis chemistry) may be protected),
pyruvoyl, citroyl or acetyl], cyano or halogen, and X is cyano or hydroxy}, and pharmacologically acceptable salts thereof.