JPH01113391A - Mitomycin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R is acyl residue obtained by removing hydroxyl group from carboxyl group of fat-soluble or water-soluble carboxylic acid and the fat-soluble carboxylic acid is 8-20 deg.C aliphatic carboxylic acid, 3-5C alicyclic carboxylic acid, steroids having carboxyl group or aromatic carboxylic acid and the water-soluble carboxylic acid is formula II (R1 and R2 are H or methyl; n is 2-4)]. EXAMPLE:1a-{[[(Benzoyloxy)methyl]oxy]carbonyl}mitomycin C. USE:An antiulcer agent. PREPARATION:1a-(Chloromethyloxycarbonyl)mitomycin C expressed by formula III obtained by reacting mitomycin C with chloromethyl chloroformate in the presence of a base is reacted with the formula ROM (M is a salt of carboxylic acid as ROM) in the presence of an inert solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a mitomycin C1 permeable conductor with improved fat solubility or water solubility that regenerates mitomycin C in vivo.

BACKGROUND OF THE INVENTION Mitomycins are generally known as antibiotics having antibacterial and antitumor activities. Typical mitomycins include mitomycin △, mitomycin B1, mitomycin C, polyphyllomycin (all of which are listed in Merck Index, 1st O edition), mitomycin G, and mitomycin E (all of which are listed in JP-A No. 54-122).
797. ), mitomycin F (described in JP-A No. 55-45322), mitomycin G1 mitomycin H (described in JP-A No. 55-154)
It is described in 08. ) etc. These mitomycins can be obtained by culturing strains of Streptomyces cespitosa. Table 1 shows the structures of the mitomycins obtained from the natural world.

Table 1 Structure of mitomycins obtained from nature Among the mitomycins, mitomycin C has strong antitumor activity and a wide antitumor spectrum, and has been shown to be highly effective against various human organ cancers, sarcomas, leukemias, etc.; It is a drug that is widely used clinically as a chemotherapy agent for cancer. However, drug administration may be limited due to side effects such as bone toxicity, and it is desirable to develop mitomycin C derivatives that can be applied to new administration forms that can improve therapeutic effects by improving drug pharmacokinetics. It is rare.

In the field of biopharmaceuticals, one of the methods for revising the biokinetics of drugs is to regenerate chemically modified compounds into decompounds in vivo through enzymatic or non-enzymatic action. A method of making a so-called prodrug (Pr, odrug) exhibiting activity is known.

For example, JP-A-60-23359 discloses prodrugs in which the amino group of a drug is modified with an (acyloxyalkoxy)carbonyl group. However, this publication does not mention mitomycins as drugs, and no mitomycins having an (acyloxyalkoxy)carbonyl group have been known so far.

In addition, mitomycin C has a urethane bond <)N-co□R) at the aziridine moiety a at position 18 as a derivative with improved lipid solubility, for example,
la-benzyloxycarbonyl mitomycin C, la
-Nonyloxycarponyl mitomycin C (Reference 1 below)
) has an amide a bond (˜N-C0R) at the same <ia position, such as la-ben/zylcarbonyl mitomycin C (Reference 2) and 1a-liluoyl mitomycin C (Reference 3).

Further, for example, /ia-benzoyloxymethylmitomycin C (Reference 2.4) has been disclosed, which has an acyloxymethyl group (CN-CH,0COR) at the 13th position.

Reference 1: Chem, Pharm, [1u11. ,
31. 4083 (1983) Document 2: Int.
J, Pharm,, 15.49 (1983) Document 3: JP-A-50-89398 Document, i: Int, J, Pharm, 15.6
1 (1983) However, among these compounds, no compound has been obtained that is satisfactory in terms of chemical stability as a prodrug, regeneration into mitomycin C in vivo, etc.

In other words, regeneration of mitomycin C is slow in human serum for compounds with urethane bonds (Reference 1 above).
Furthermore, in compounds having an acyloxymethyl group, the bond is unstable, and is rapidly cleaved, for example, even in a pH 7.4 phosphate buffer (Reference 4). On the other hand, no prodrug of mitomycin C is known as a derivative with improved water solubility.

There is a need for mitomycin C derivatives that provide lipophilic or water solubility that can be applied to new dosage forms, are stable in solubilizers, and rapidly regenerate mitomycin C in vivo.

Problems to be Solved by the Invention An object of the present invention is to provide a mitomycin C derivative that is rendered fat-soluble or water-soluble.

Means for Solving the Problems The present invention is based on the formula N) [wherein R represents an acyl residue that removes the hydroxyl group from the carboxyl group of a fat-soluble or water-soluble carboxylic acid.

Here, fat-soluble carboxylic acids include linear or branched saturated and unsaturated aliphatic carboxylic acids having 8 to 20 carbon atoms, and 3 carbon atoms.
~8 represents an alicyclic carboxylic acid, a steroid having a carboxyl group, or an aromatic carboxylic acid, and the water-soluble carboxylic acid is (wherein R3 and R2 are the same or different and represent a hydrogen atom or a methyl group, (represents an integer from 2 to 4)
It relates to a mitomycin derivative represented by

The compound represented by formula (1) is hereinafter referred to as compound (1).
(compounds with other formula numbers are also expressed in the same way)
.

In the definition of formula (1), linear or branched saturated aliphatic carboxylic acids having 8 to 20 carbon atoms include octanoic acid, decanoic acid, lauric acid, myristic acid, valmitic acid, stearic acid, etc. Saturated aliphatic carboxylic acids include oleic acid, linoleic acid, arachidonic acid, and the like.

Examples of the alicyclic carboxylic acid having 3 to 8 carbon atoms include cyclopropanecarboxylic acid and cyclohexanecarboxylic acid. Examples of steroids having a carboxyl group include cholic acid and deoxycholic acid.

Aromatic in aromatic carboxylic acids means substituted or unsubstituted phenyl, naphthyl groups, etc. Substituents include lower alkyl groups such as methyl and ethyl, alkoxy groups such as methoxy and ethoxy, and fluorine, chlorine, and bromine. , iodine and other halogen atoms. Specific examples of aromatic carboxylic acids include benzoic acid, toluic acid, anisic acid,
Examples include chlorobenzoic acid and naphthoic acid.

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

Compound (1) is the following compound obtained by reacting mitomycin C and chloromethyl chloroformate in the presence of a base.
II) [1a-(chloromethyloxycarbonyl)
mitomycin C] and compound (III) ROM ([) (wherein R has the same meaning as above, and M represents a carboxylic acid salt as ROM) in an inert solvent. .

In the definition of R, in the water-soluble carboxylic acids (wherein R, , R2 and n have the same meanings as above) of the raw material represented by compound (IV), R, , R2 are both hydrogen. The compound is a known compound, Carbohydr, Res, 7
8205 (1980) (when n is 3) and L
iebigs Ann.

Chem, 858 (1980) (for n = 2 and 4). Although other carboxylic acids are new compounds, 5ynthesis, 42 (1981
) and Bu I, Chem.

Soc, Japan, 55. 2181 (1982)
It can be synthesized according to the method described in et al. ROM
Examples of the salts of carboxylic acids defined as 1,8-diazabiditaloC5 include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and metal salts such as silver salts. ，
Organic base salts such as 4,01 undec-7-ene and the like are included.

In the reaction, compound (III) is used in an amount of 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to compound (n).

The carboxylic acid salt may be isolated and used, or it may be prepared from carboxylic acid and a base in a 1":J!1 manner in the reaction system and used without isolation. In this case, a molecular sieve or the like is added to the reaction system. It is preferable to add a dehydrating agent such as ) is also possible.

As the reaction solvent, inert solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, and hexamethylphosphoramide are used alone or in combination.

The reaction temperature can be carried out below the boiling point of the solvent used, but 25°C to 90°C is preferable. The reaction time varies depending on the solvent used, temperature, etc., but is from 1 hour to 7 days.

After the reaction is completed, the target compound (1
) can be obtained.

Function The mitomycin C derivative represented by formula (1) of the present invention is fat-soluble or water-soluble and stable in a dissolving agent, but regenerates mitomycin C in serum. These compounds are useful as prodrugs of mitomycin C.

The excellent properties of some of the compounds included in the present invention will be specifically explained below using experimental examples.

The structures of the compounds used in the experimental examples are shown in Table 8.

Experimental Example 1 314 mg of soluble compound for Lipiodol Ultra Puride (Lipidol former tra Fl former d■)
1ml of Lipiodol (Kodama Co., Ltd., Manufacturer: Laboratories Querbe Frassin)
and shaking vigorously. Since no precipitation of the compound was observed, the amount dissolved was determined to be 14 mg/ml or more.

The amount of mitomycin C dissolved in 1ipiodol was determined as follows. 1 well ground in an agate mortar
0 mg mitomycin C and 1 piodol 8 m
1 and shaken vigorously for 20 minutes. The undissolved mitomycin C was treated with Ekikrodisk (BKICROD).
ISC) (sold by Gelman Science Japan Co., Ltd., manufactured by Kurabo Industries). The lip solution prepared in this way (Lip in which mitomycin C was dissolved)
Add chloroform to 2505 mg of iodol solution) and add 2
It was made into 5m1. On the other hand, chloroform was added to the same weight of flea piodol to make 25 ml, and this was used as a control.

The amount dissolved in piodol was determined by spectrophotometry using the molar extinction coefficient (ε-54,100) of mitomycin C at a wavelength of 355 nm in chloroform. The results are shown in Table 2.

As is clear from Table 2, compound 3 is mitomycin C
It shows more than 1,900 times higher fat solubility than .

Table 2 a) Value when mitomycin C is taken as 1 Experimental example 2 Solubility in water 5 mg of test compound was added to distilled water of 100 animals, stirred for 15 minutes at 22°C, and the entire amount was mixed with BKICRODIS C (
The mixture was filtered using a water-based 0.45 μm (manufactured by Kerman Science Japan Co., Ltd.) to remove insoluble matter. This p-liquid is a saturated solution of the test compound. This saturated solution was subjected to constant ffi high performance liquid chromatography [Column: YMC-A312
(C,,)φ6mm, 150mm5 Elution solvent: 0
．． OIM - ammonium acetate/methanol system, detection wavelength: 254 nm] and the peak area was determined. On the other hand, a calibration curve was prepared using a methanol solution of a test compound with a known concentration, and the solubility of the test compound was calculated using the calibration curve. The results are shown in Table 3.

Table 3 a) Values when mitomycin C is set to 1 As is clear from Table 3, the water solubility of each test compound increases.

Experimental Example 3 Stability in aqueous solution Phosphate buffer (0.03M, pH 7.0>1.[
After dissolving the acclimatized compound, it was left at 21±1°C and sampled over time. Using a high-performance liquid chromatograph, the half-life of each test compound was determined from the decrease in the integrated area in the same manner as in Experimental Example 2. The results are shown in Table 4.

Table 4 As is clear from Table 4, these compounds are sufficiently stable in aqueous solution.

Experimental Example 4 Stability in human serum: 1.65 g of common salt, 1 portion of sodium phosphate decahydrate
．． Each test compound was dissolved in a solution (+)H7,2) of 83 g and 0.21 g of potassium dihydrogen phosphate in distilled water to prepare a 2 mmol/β) sample solution. Add 200 g of each sample solution to 200 serum samples collected from healthy individuals,
Samples were taken over time while shaking at 37°C, and the half-life of each test compound was determined in the same manner as in Experimental Example 3. As a control experiment, the above medium was used instead of serum to determine the half-life of each test compound.

The results are shown in Table 5.

Table 5 In each test, regeneration of mitomycin C corresponding to the amount of decrease in each test compound was observed, and as is clear from Table 5, mitomycin C was rapidly regenerated by the action of human serum. Furthermore, the playback speed can be changed by converting R, , R2 in equation (1).

Experimental Example 5 Antitumor activity and toxicity experiments against Sarcoma 180 solid tumor were conducted by the following method.

(1) Effect on Sarcoma 180 solid tumor 5, X1
06 Sarco-71a os+uawoa ay mice were transplanted intraperitoneally, and cells were collected from ascites on the 7th day.
After washing once with sterile physiological saline, a cell suspension of 5×10' cells/ml was prepared with sterile raw physiological saline. This 0.1 +++ l was subcutaneously transplanted into the right axillary region of a ddy male mouse weighing 20±2 g. The test compound was administered in saline;
Alternatively, Tween 80 was dissolved in physiological saline and administered intraperitoneally to 5 mice per group 24 hours after tumor implantation at 0.1-0.
2 ml was administered. To measure the antitumor activity of the drug, the diameter (a) and short axis of the tumor were measured 7 days after transplantation, and the value of a x b ''/2, which corresponds to the tumor volume, was determined. Control group ( The antitumor effect was determined by the volume ratio (T/C) of drug administration group (T) to C).

(2) How to determine ED. ED is the dose that reduces the Sarcoma 180 solid tumor volume to 50% of the tumor volume of the non-administered control group.

And so. Plot the T/C at each dose on a graph with T/'CS on the normal scale on the vertical axis and the dose on the logarithmic scale on the horizontal axis, and plot the relationship between the dose and T/C as a straight line using the least squares method. I asked for it. From the linear regression equation obtained, T/C
The dose at which 0.5 was calculated.

(3) Acute toxicity LD. administered the drug once intraperitoneally 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. produced.

Tables 6 and 7 show the antitumor activity and toxicity of some compounds from Compound (I) against Sarcoma 180 solid tumor.

Table 6 Molecular weight of the test compound Molecular weight of the test compound Table 7 Molecular weight of the test compound As is clear from Table 6, the acute toxicity (LDso”) of each test compound converted to the dose of mitomycin C.
The antitumor activity (E[]SG”) showed good agreement with that of mitomycin C within the experimental error.
It is also suggested that mitomycin C is regenerated from the viewpoint of toxicity and antitumor activity. Also, from Table 7, the dose of the test compound in terms of mitomycin C weight ([D“
]) and T/C showed a good correlation, suggesting that each test compound regenerated mitomycin C in the mouse body.

As shown in the above experimental examples, the compound (1) of the present invention was shown to be a prodrug of mitomycin C that is more lipophilic or water soluble than mitomycin C, which is widely used clinically. Application to new dosage forms is expected. For example, water-soluble derivatives have advantageous properties when used for intravenous injection, while fat-soluble derivatives increase intestinal absorption rate and can be applied to new dosage forms such as emulsions and liposomes.

Compound (1) is useful as an antitumor agent, and can be used together with at least one pharmaceutical diluent, adjuvant, or carrier, if necessary. For example, administering each compound to mammals, particularly humans, at a dose of 0.06 to 5 mg/kg;
It is usually administered intravenously as an injection by dissolving it in physiological saline, glucose injection, lactose injection, or mannitol injection. Furthermore, intraarterial administration, intraperitoneal administration, and intrathoracic administration are also possible at similar doses. It may also be freeze-dried according to the Japanese Pharmacopoeia, or it may be made into a powder injection containing IJum chloride. In addition, well-known pharmaceutically acceptable diluents (Ringer's solution), adjuvants [polyethylene glycol, HCO-60 (surfactant, manufactured by Nikko Chemical Co., Ltd.)], such as salts that meet pharmaceutical uses;
It may also contain ethanol and/or a carrier (emulsion, liposome, cyclodextrin). The dosage can be increased or decreased as appropriate depending on age and symptoms. The administration schedule can also be changed depending on the symptoms and dosage; for example, intermittent administration may be used, such as once a week or once every three weeks. Oral administration and rectal administration are also possible using the same dosage and administration method. For oral administration, it can be administered in the form of tablets, powders, granules, syrups, skewers, etc. with appropriate adjuvants.

The present invention will be specifically explained below with reference to Examples, Reference Examples, and Formulation Examples.

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

IR: Shimadzu IR-27GNMR Nijan BM 390. JBOL FX-100
MS: 1Iitach+ M-80B, the structure of a representative example of compound (1) obtained in the Examples is as shown in Table 8.

Table 8 Example 1 1a-([[(benzoyloxy)methyl]oxy-1carbonyl)mitomycin C (Compound I) 1a-(chloromethyloxycarbonyl)mitomycin C (compound a) obtained in Reference Example 1 200mg to 12ml 92 mg of sodium iodide and 200 mg of benzoic acid were added to the mixture, and the mixture was stirred at room temperature for 3.5 days.

Water was added to the reaction solution and extracted with chloroform, and the chloroform layer was dried with sulfuric acid (IJ) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform acetone (6:4, v/v).
The blue-purple components were collected, and the solvent was distilled off under reduced pressure to obtain 1152 mg of a black-purple paste compound (yield 59%).
%) was obtained. The physicochemical properties of Compound 1 are shown in Table 9 and Table 1O.

Examples 2 to 4 Fat-soluble compounds 2 to 4 were synthesized by operations similar to those described above.

The raw materials and the yield and MS data of the obtained compound (1) are shown in Table 9, and the [R and NMR data are shown in Table 1O.

Example 5 1a-[[[C(2-Methyl-3,6,9,12-tetraoxatridecanoyl)oxy]methyl]oxy)carbonyl] Mitomycin C (Compound 8) 2- obtained in Reference Example 2 93n+g of methyl-3,6;9,12-tetraoxatrite'canoic acid was dissolved in 1 ml of dimethylformamide, 23 mg of silver oxide, 85 mg of compound a and crushed molecular sieves (5 people) were added, and the mixture was dissolved under a nitrogen atmosphere. Stirred at 75°C for 3.5 hours. After the solid matter was separated, saturated brine was added and extracted with chloroform. After drying the chloroform layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate-methanol (95:5, V/
ν) and the same operation as in Example 1 yielded 846 mg of a black-purple paste compound (yield: 37%).
) was obtained. The physicochemical properties of Compound 8 are shown in Tables 11 and 12.

Examples 6 to 9 By performing the same operation as above, water-soluble compound 5
~7 and 9 were synthesized.

The raw materials and the yield and MS data of the obtained compound (r) are shown in Table 11, and the NMR data are shown in Table 12.

Reference example 1 1a-talolomethyloxycarponyl mitomycin C
(Compound a) 5' 01 + ng of mitomycin C was dissolved in 25 ml of tetrahydrofuran, 0.25 ml of triethylamine was added, and 5 ml of a tetrahydrofuran solution of 0.13 ml of chloromethyl chloroformate was added dropwise under water cooling.

After stirring at room temperature for 2 hours, ice water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform-methanol (95:5, v/
v), and both blue parts were collected. Concentrate the solvent under reduced pressure, dissolve in a small amount of acetone, add n-hexane to powder, distill off the solvent under reduced pressure, and thoroughly dry to obtain 8602 mg of a purple powder compound (yield 95%). I got it.

SLMS: m/z 428 (M++2), C-7
111sL07Cjl' =426.5IR(K[lr
) cm-': 3450.3350.1740.172
0.160 (1°1560, 1550.1340.
1250. 1075NMR (11075N, Py
ridine-d,) δ: 2.04 (3H, s),
3.19 (311, sL3.59 (LH, dd),
3.60. , (111,dd), 3.92(LH
.

d), 4.01 (IH, dd), 4.69 (i
ll, dd>, 4.70 (IH, d).

5.49 (III, dd), 5.96 (211, s)
, about 7.6 (4)1. bs) Reference Example 2 20 g of 2-methyl-3,6,9,12-tetraoxatridecanoic acid in triethylene glycol monomethyl ether (
710 mg of gold was added to 3,6,9-trioxadecanol) and dissolved by heating.

2. Add 33 g of 2-bromopropionic acid and add 100 g of 2-bromopropionic acid.
After heating for 5 hours at °C, excess unreacted 3.6.9-) I
J oxadecanol was distilled off under reduced pressure. After adding 6 ml of 3N hydrochloric acid, the chlorine salt was separated into P and the ρ solution was concentrated under reduced pressure to obtain the title crude carboxylic acid. It was converted into a methyl ester to facilitate purification. That is, this crude carboxylic acid was dissolved in 20 ml of methanol, 0.4 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 10 hours. After neutralization with aqueous sodium carbonate, extraction was performed with chloroform, and after drying, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and developed with chloroform acetone (9:Lv/ν),
After distilling off the solvent, a pale yellow oily substance of 2-methyl-3,6,9
, 12-tetraoxatridecanoic acid methyl ester2.
44 g (yield 61%) was obtained.

The ester was then hydrolyzed to regenerate the carboxylic acid. In other words, 2.28 g of methyl ester is converted into 15.3 m
l of water, add 610 mg of caustic potassium, -
The mixture was heated to reflux for an hour. After cooling, DOIIIEX50W x
4 (11"-form), eluted with water, and distilled off the water under reduced pressure to obtain 2.13 g of the title carboxylic acid (yield 98
%) was obtained.

Old-MS: m/z 237 (iJ”+l)
, C,,lI□,06=236IR(neat)c
m″': 3460.2890.1730.14
55.1345°1240, 1195.1110.94
0.845NHR (90Mllz, CDCj! 3)
δ: 1.44 (3+1.d), 3.39 (3) 1°s), 3.6 (]-3,70 (1211, bs),
4.05 (IH, q>, l0J (III, s) Reference Example 3 2.2-di/thyl-3,6,9,12-tetra-thyl-xatrizocanic acid 2-bromoisoacetic acid was substituted for 2-bromopropionic acid. The title carboxylic acid methyl ester was obtained in a yield of 35% in the same manner as in Reference Example 2. By hydrolyzing the ester in the same manner as in Reference Example 2, the title carboxylic acid was obtained in a yield of 98%.

El-! JS: m/z 251 (M”+1), C
++Hz20e=250IR(neat)cm-1:
3450,2930.1?25.1465.1360°1240,1090.1090.980.84ONII
R(90!JHz, CDCjl!3)δ: 1.4
6 (611, s>, 3J9 (3N.

s), 3.60-3.70 (12H, bs), 10
．． 3 (IH, s) Formulation Example 1 After dissolving 5 g of Injectable Compound 8 in 10,100 O of distilled water, it is sterilized by pressure filtration with a Millipore filter (pore size: 0.22 μm). Dispense 1°Oml of the resulting sterile P solution into brown vials (5'mg of active ingredient/vial), freeze at -50°C for 2 hours, and then freeze at -rO°C, vacuum level 0, lmmHg for 24 hours.
Time - Next dry smoke. After confirming that the shelf temperature and product temperature match, secondary drying is performed for 4 hours at a shelf temperature of 30° C., vacuum degree of 0, and lmmHg to remove moisture. Seal with a rubber stopper. Before use, add 5 ml of sterile physiological saline and stir thoroughly to dissolve and prepare an injection solution.

Formulation Example 2 Emulsion Formulation Sterile sesame oil 20ml. Sterile HCO-60 (surfactant,
(manufactured by Nikko Chemical Co., Ltd.), in a solvent consisting of 78 ml of sterile water,
Add 400 mg of sterile powder of Compound 1 and sonicate. Aseptically dispense 2.5 ml of the obtained emulsion into vials and seal with rubber stoppers.

Effects of the Invention - The present invention provides a mitomycin C derivative imparted with fat solubility or water solubility, and is useful as a prodrug of mitomycin C.

Patent applicant (102) Kyowa Hakko Kogyo Co., Ltd. Procedural amendment (voluntary) ■, Indication of the case Patent Application No. 268754 of 1988 2, Name of the invention Mitomycin derivative 3, Person making the amendment Relationship to the case Patent applicant Postal code 100 Address Otemachi-6-1, Chiyoda-ku, Tokyo Name (1
02) Kyowa Hakko Kogyo Co., Ltd. (Tel: 0 3-
2 8 2-0 0 3 6> Column 5 of the detailed description of the invention in the specification, the content of the amendment is corrected to "(The above is Document 1)".

(2) "Deoxycholic acid" in the second line of page 1 of the same book is corrected to "deoxycholic acid."

(3) On page 16, line 13 of the same book, “Be Frasun” is replaced with “
(Baie-France)”.

(4) The solubility of mitomycin C in Table 2, page 13 of the same book, r4.6 J, is corrected to rO,0046.

(5) In the 5th line from the bottom of page 16 of the same book, "addition of head" is corrected to "addition of scraps."

(6) In the second line of page 13 of the same book, "solvent under reduced pressure" is corrected to "solvent under reduced pressure."

(7) Correct r N HRJ to rNMRJ on page 34, line 5 from the bottom and page 35, line 10 of the same book.

(8) r1240.1090 on page 34, line 9 of the same book.
r 1090.980J 1240.1090.980
Correct to J.

(9) In the same book, page 16, line 6, "Sterilized water manufactured by the company" is corrected to "2mL sterile water manufactured by the company".

Claims (1)

[Claims] Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R represents an acyl residue from which the hydroxyl group is removed from the carboxyl group of a fat-soluble or water-soluble carboxylic acid. Here, fat-soluble carboxylic acids include linear or branched saturated and unsaturated aliphatic carboxylic acids having 8 to 20 carbon atoms, and 3 carbon atoms.
It represents an alicyclic carboxylic acid, a steroid having a carboxyl group, or an aromatic carboxylic acid, and water-soluble carboxylic acids have ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are the same or different) a hydrogen atom or a methyl group, and n represents an integer of 2 to 4].