JP2003104967A - Urokinase production inhibitor, vascularization inhibitor, metastasis controller and antitumor agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound having excellent functions for inhibiting urokinase production and vascularization, and useful for therapy and prophylaxis of a disease accompanying the vascularization, e.g. as a metastasis controller and an antitumor agent. SOLUTION: This urokinase production inhibitor contains a peroxide derivative having a structure of general formula (1) (wherein, R1 is a hydroxy group, a lower alkyl group or a lower alkoxy group; R2 is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group or a saturated heterocyclic group; R1 and R2 may form a ring which may be substituted, by bonding to each other) or a pharmacologically acceptable salt thereof as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention belongs to the technical field relating to urokinase production inhibitors, angiogenesis inhibitors, cancer metastasis inhibitors and antitumor agents containing peroxide derivatives.

[0002]

2. Description of the Related Art Clinically, it has been considered that advanced cancer has already metastasized at a fairly early stage. Many cancer chemotherapeutic agents have been developed so far, but most of them are aimed at killing the cancer cells themselves, and when the metastasized cancer is resistant to the chemotherapeutic agent. However, there are limits to the treatments that can effectively deal with cancer cells scattered throughout the body. Considering that the metastasis of cancer has already started at the time of diagnosis or treatment, it is expected to develop a drug that effectively controls the metastasis itself and the cancer that has metastasized. The elucidation of the mechanism at the level has advanced. Tumor cells secrete various angiogenic factors to induce new blood vessels from existing existing blood vessels in the vicinity, and grow by receiving supply of nutrients and oxygen.
The growth of cancer is accelerated along with angiogenesis, the number of cancer cells flowing into the bloodstream is increased, and as a result, the frequency of metastasis is also increased. In other words, if it is possible to inhibit this angiogenesis, it is considered possible to prevent the growth and metastasis of cancer.

Furthermore, urokinase (urinary plasminogen activator, or u-PA) is a proteolytic enzyme highly specific for a single peptide bond in plasminogen. Urokinase converts plasminogen to the active form of fibrinolytic enzyme plasmin. In addition, activated plasmin is fibrin,
In addition to using fibronectin and laminin as substrates, inactive matrix metalloprotease (hereinafter "MM
(Referred to as “P”) into activated MMPs, and promotes melting of collagen, which is a constituent of basement membrane. In addition to its function as a protease, urokinase has an action of promoting the migration of vascular endothelial cells and a function of promoting lumen formation on Matrigel, and plays an important function in angiogenesis.

[0004] Urokinase-related physiological processes include angiogenesis, bone remodeling, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, wound repair, and tissues during organ differentiation. Reconstruction, fibrosis, local invasion of adjacent areas of the tumor, metastatic spread of tumor cells from primary to secondary sites, and tissue destruction in arthritis are included. Therefore, urokinase inhibitors have anti-angiogenic, anti-arthritic, anti-inflammatory, anti-invasive, anti-metastatic, anti-osteoporosis, anti-retinopathy (angiogenesis dependent retinopathy), contraceptive and tumor growth inhibitory activities. Therefore, development of a drug targeting urokinase as a molecular target is expected, and beneficial effects of anti-urokinase monoclonal antibodies and some urokinase inhibitors have been reported. For example, anti-urokinase monoclonal antibodies have been reported to block tumor cell invasiveness in vitro (Canc
er Res., 51 , 3690-3695 (1991); Exp. Cell Res., 19
2 , 453-459 (1991)). In addition, tumor metastasis and invasion in vivo (J. Cell Biol., 107 , 2437-2445 (198
8); Cancer Res., 51 , 274-8 (1991)) and in vivo.
Angiogenesis (J. Cell Biol., 115 [3 Pt 2]: 402
a (1991)), and amiloride, a known urokinase inhibitor with moderate potency,
Preventing tumor metastasis by vo (Anticancer Res., 8 , 1373-13
76 (1988)) and inhibits angiogenesis / capillary network formation in vitro (J. Cell Biol. 115 [3 Pt2]: 40.
2a (1991)) has been reported. The use of the peroxide derivative contained in the present invention is disclosed as an antimalarial drug in Japanese Patent Application Laid-Open No. 2000-229965, but a urokinase production inhibitor and an angiogenesis inhibitor, a cancer metastasis inhibitor and an antitumor agent are disclosed. It was not known to be useful as an agent.

[0005]

DISCLOSURE OF THE INVENTION The present invention, which meets the above-mentioned needs, is characterized by having a urokinase production inhibitory action and an angiogenesis inhibitory action, and is useful as a cancer metastasis inhibitor and an antitumor agent. Pertains to compounds.

[0006]

As a result of intensive studies for solving the above problems, the present inventors have found that a peroxide derivative having a structure of the general formula (1) or a pharmaceutically acceptable salt thereof is The inventors have found that they have excellent urokinase production inhibition and angiogenesis inhibition effects and are useful as cancer metastasis suppressors and antitumor agents, and have completed the present invention. That is,
The present invention relates to a urokinase production inhibitor containing a peroxide derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical 2] (In the formula, R ₁ is a hydroxyl group, a lower alkyl group or a lower alkoxy group, and R ₂ is a hydrogen atom or an optionally substituted lower alkyl group, a lower alkenyl group or a saturated heterocyclic group. R ₁ and R ₂ may be bonded to each other to form a ring, and the ring may be substituted.) Or a peroxide compound having the structure of the above general formula (1) or a pharmaceutically acceptable compound thereof. The present invention relates to an angiogenesis inhibitor containing a salt as an active ingredient. Alternatively, it relates to a cancer metastasis inhibitor containing, as an active ingredient, a peroxide compound having the structure of the above general formula (1) or a pharmaceutically acceptable salt thereof.
Alternatively, the present invention relates to an antitumor agent containing, as an active ingredient, a peroxide compound having the structure of the above general formula (1) or a pharmaceutically acceptable salt thereof.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, the present invention relates to a urokinase production inhibitor containing a peroxide derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. .

[Chemical 3] In the formula, R ₁ is a hydroxyl group, a lower alkyl group, or a lower alkoxy group, and R ₂ is a hydrogen atom, an optionally substituted lower alkyl group, a lower alkenyl group, or a saturated heterocyclic group. In addition, R ₁ and R ₂ may be bonded to each other to form a ring, and the ring may be substituted.

In this, the lower alkyl group represented by R ₁ means a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, methyl group, ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-
Pentyl group, isopentyl group, neopentyl group, ter
Lower alkyl groups such as t-pentyl group and hexyl group can be mentioned. The lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms. Specifically, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec
Examples include lower alkoxy groups such as -butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group and hexyloxy group.

Examples of the optionally substituted lower alkyl group, lower alkenyl group or lower alkyl group of the saturated heterocyclic group represented by R ₂ include the above-mentioned lower alkyl groups. The lower alkenyl group means a linear or branched alkenyl group having 1 to 6 carbon atoms. Specifically, ethynyl group, n-propenyl group, isopropenyl group, n-butynyl group, isobutynyl group, sec-butynyl group, tert.
-Butynyl group, n-pentynyl group, isopentinyl group,
Examples include lower alkenyl groups such as neopentynyl group, tert-pentynyl group and hexynyl group. Further, examples of the saturated heterocyclic group include a saturated heteromonocyclic group having 1 to 3 oxygen atoms, for example, an oxiranyl group,
Oxetanyl group, oxolanyl group, oxanyl group, oxepanyl group, oxocanyl group, 1,2-dioxetanyl group, 1,2-dioxolanyl group, 1,3-dioxolanyl group, 1,2-dioxanyl group, 1,3-dioxanyl group , 1,4-dioxanyl group, 1,2-dioxepanyl group, 1,3-dioxocanyl group, 1,3,5-trioxanyl group, 1,3,5-trioxepanyl group, 1,3,3
Having 1 to 3 oxygen atoms such as a 6-trioxocanyl group,
A saturated heterocyclic group forming a 3- to 8-membered ring can be mentioned. Further, these may optionally have one or more substituents, and examples of the substituent which may be substituted include a hydroxyl group, a carboxyl group which may substitute a lower alkyl group, a halogen atom and an amino group. , A phenyl group, or -O-
R ₃ (R ₃ represents a lower alkyl group, an aryl group or a saturated heterocyclic group) and the like can be mentioned. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the lower alkyl group include those mentioned above. Examples of the aryl group include a phenyl group,
Examples thereof include naphthyl group. As the saturated heterocyclic group,
The saturated heteromonocyclic group having 1 to 3 oxygen atoms mentioned above can be mentioned. Furthermore, the ring formed by combining R ₁ and R ₂ means a saturated heteromonocycle containing 3 to 4 oxygen atoms and forming a 5 to 12-membered ring, for example 1,2,4-
Trioxolane, 1,2,4-trioxane, 1,2,
4-trioxepane, 1,2,4-trioxocane,
1,2,4-trioxonan, 1,2,4-trioxecan, 1,2,4,5-tetraoxane, 1,2,4
5-tetraoxepane, 1,2,4,5-tetraoxocane, 1,2,4,5-tetraoxonan, 1,2,
Examples include 4,5-tetraoxecan and the like. In addition, examples of the substituent that may be substituted on the heterocycle include an oxo group and a hydroperoxide group.

The compound of the present invention is disclosed, for example, in JP-A 2000-2.
29965, Tetrahedron Lett. (2000), 41 (23),
4681-4684, Synth. Commun. (1990), 20 (17), 2589-259.
6, manufactured according to the manufacturing method described in Japanese Patent Publication No. 51-29146. Further, the peroxide derivative represented by the general formula (1) in the present invention may be used as a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is not particularly limited as long as it forms a pharmaceutically acceptable salt with either an acid or a base, but a salt with an acid (inorganic salt or organic salt) is usually used. Specific examples include inorganic salts such as hydrochlorides, sulfates and phosphates, and examples of organic salts include acetates and oxalates.

The active ingredient of the present invention is usually used in the form of a general pharmaceutical preparation. Formulations are commonly used fillers,
It is prepared using a diluent or excipient such as a bulking agent, a binder, a non-humidifying agent, a disintegrating agent, a surface active agent and a lubricant. Various forms of such a pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections. Examples include agents (solutions, suspensions, etc.), ointments and the like.

In the case of molding into tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc., excipients, water, ethanol, propanol, Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, poly Oxyethylenesorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, sucrose, stearin,
Decay inhibitor for cocoa butter, hydrogenated oil, quaternary ammonium base, absorption promoter for sodium lauryl sulfate, humectant for glycerin, starch, adsorption of starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Agents, purified talc, stearates, boric acid powder, lubricants such as polyethylene glycol, and the like can be used. Further, the tablet is a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet,
It may be a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet.

In the case of molding in the form of pills, as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol and the like are bound. Agent,
A disintegrating agent such as laminaran or agar can be used. In the case of molding into a suppository, a carrier such as polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semisynthetic glyceride or the like can be used. Capsules are usually prepared by mixing the compound of the present invention with the various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like according to a conventional method.

When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood. When molding into these forms, a diluent such as water or an aqueous lactic acid solution is used. , Ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol,
Polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.
In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. You may add. If necessary, coloring agents, preservatives,
Flavors, flavors, sweeteners and other pharmaceuticals may be included in the pharmaceutical preparation. When formulating into a paste, cream or gel, white petrolatum, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicone, bentonite, etc. can be used as a diluent. The amount of the compound represented by the general formula (1) of the present invention or a salt thereof (active ingredient compound) to be contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected within a wide range. 1 to 70% by weight is preferable.

The administration method of the above pharmaceutical preparation is not particularly limited,
It is determined according to various formulation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, liquids,
Suspensions, emulsions, granules and capsules are administered orally. The injections are administered intravenously alone or in admixture with a normal replacement fluid of glucose or amino acid sugar, and if necessary, they are administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. Suppositories are administered rectally. The dosage of the above-mentioned pharmaceutical preparation is appropriately selected according to the usage, the age of the patient, the sex and other conditions, the degree of disease, etc., but the amount of the compound of the present invention as an active ingredient is usually about 1 kg (kg) of body weight per day. 1-1000
About mg (milligram), preferably 10 to 100 mg
The dosage is preferably about 1 to 4, and the preparation can be administered in 1 to 4 divided doses per day.

The drug of the present invention has an excellent urokinase production inhibitory action and is useful as a urokinase production inhibitor. Also, by having an excellent angiogenesis inhibitory activity,
It is useful as a therapeutic and preventive agent for diseases associated with angiogenesis. Diseases associated with angiogenesis include malignant tumors, tumor metastases, benign tumors (eg hemangiomas, acoustic neuromas, neurofibromas, trachoma and purulent granuloma), vascular dysfunction, inflammation and immune disorders, Behcet's disease, gout. , Arthritis, rheumatoid arthritis, psoriasis, diabetic retinopathy and other ocular blood vessel-derived diseases (for example, posterior lens fibroplasia, macular degeneration, corneal transplant rejection, neovascular glaucoma), osteoporosis and the like, in particular, the present invention The drug has an excellent tumor growth inhibitory action and tumor metastasis inhibitory action based on the action,
It is useful as a preventive or therapeutic agent for malignant tumors and a preventive or therapeutic agent for tumor metastasis. The malignant tumor is not particularly limited, but includes, for example, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, and Examples include solid malignant tumors such as vertical line cancer, testicular tumor, bone / soft tissue sarcoma, cervical cancer, skin cancer, and brain tumor. The tumor metastasis is not particularly limited, but may be any tumor metastasis that is susceptible to the treatment according to the present invention, for example, multi-organ metastasis such as liver metastasis, lung metastasis, lymph node metastasis, bone metastasis, brain metastasis, etc. Other tissue metastases are mentioned.

[0017]

EXAMPLES Next, the present invention will be specifically described with reference to production examples, examples and test examples, but the present invention is not limited to these examples.

[Production Example 1] Cyclododecane-1,1-
Synthesis of diyl bishydroperoxide (Compound 1)

[Chemical 4] 25 mL (milliliter) of a 2.5 mol (mol) diethyl ether solution of hydrogen peroxide prepared by the method of Saito et al. (Tetrahedron Lett. 1983, 24, 1737), and 630 mg (3.0 mg) of a known compound, methoxymethylenecyclododecane.
0 mmol) was dissolved and ozonization was performed at -70 ° C.
Ordinary ozonizer (Nippon Oz one model ON-1-2
50 L / hr for 15 minutes using Nippon Ozone Co., Ltd.)
By blowing oxygen at a flow rate of (liter / hour), the same amount of ozone as the used methoxymethylenecyclododecane was generated. After completion of the reaction, 70 mL of diethyl ether was added, the organic layer was washed with aqueous sodium hydrogen carbonate and then with saturated saline, and then dried over anhydrous magnesium sulfate. Then, by silica gel column chromatography, diethyl ether / n-hexane (volume ratio: 20/80)
As a fraction developed by the title compound 1 (232 m
g, yield 33%) was obtained. The melting point and analytical values were as follows. Melting point: 140-141 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22 H), 8.13 (br
s, 2H). ¹³ C NMR (CDCl ₃ ) δ: 19.28, 21.86, 22.15, 6.02, 26.
19, 26.29, 112.64.

[Production Example 2] Synthesis of 1-methoxycyclododecyl hydroperoxide (Compound 2)

[Chemical 5] In a 50 mL two-necked eggplant flask equipped with a gas introduction tube, cyclododecan vinyl methyl ether (570 mg, 3.00 mol), which is a known compound, and 10 m of methanol
L and 20 mL of ethyl acetate were put therein, and 1.2 equivalent of ozone was aerated with respect to cyclododecan vinyl methyl ether at -70 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure at 40 ° C or lower. Then, the residue was recrystallized from n-hexane / diethyl ether to give the title compound 2 (620 m
g, yield 90%) was obtained. The melting points and analytical values were as follows: Melting point: 88-90 ° C (from n-hexane / diethylether). ¹ H NMR (CDCl ₃ ) δ: 1.4-1.8 (m, 22 H), 3.31 (s, 3
H), 7.55 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.61, 22.12, 22.55, 26.33, 2
7.93, 48.90, 110.17. Elemental analysis: Anal. Calcd for C ₁₃ H ₂₆ O ₃ : C, 67.79; H, 1
1.38., Found: C, 67.74; H, 11.34.

[Production Example 3] Synthesis of 1- (methyldioxy) cyclododecyl hydroperoxide (Compound 3)

[Chemical 6] Silver oxide (812 m in an eggplant flask under argon atmosphere)
g, 3.50 mmol) in ethyl acetate suspension (20 m
L) with stirring at room temperature while stirring the compound 1 (1160
mg, 5.00 mmol) in ethyl acetate (20 m
L) was added dropwise. Then, an ethyl acetate solution (20 mL) of iodomethane (710 mg, 5.00 mmol) was added dropwise to this mixture, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, silver iodide produced as a by-product was removed by suction filtration using Celite, poured into an aqueous solution of sodium thiosulfate, and extracted with diethyl ether. After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. Then, the residue was subjected to silica gel column chromatography to obtain 1-bis (methyldioxy) cyclododecane (149 mg, yield 12%) as a fraction developed with n-hexane / diethyl ether (volume ratio 98/2). The cyclododecanone (104 mg, yield 11%) was obtained as a fraction developed with n-hexane / diethyl ether (volume ratio 95/5). Then, the title compound 3 (757 mg, yield 62%) was obtained as a fraction developed with n-hexane / diethyl ether (volume ratio 90/10). The melting points and analytical values are shown below. Melting point: 37-39 ° C (from n-hexane / diethylether). ¹ H NMR (CDCl ₃ ) δ: 1.3-1.8 (m, 22 H), 3.93 (s, 3
H), 7.94 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.23, 21.80, 22.16, 25.91, 2
6.35, 63.33, 114.16. Elemental analysis: Anal. Calcd for C ₁₃ H ₂₆ O ₄ : C, 63.38; H, 1
0.64., Found: C, 63.38; H, 10.48.

Production Example 4 Synthesis of 1- (2-propenyldioxy) cyclododecyl hydroperoxide (Compound 4)

[Chemical 7] The same reaction as in Production Example 3 was performed using bromopropylene instead of iodomethane to give the title compound 4 (yield 34
%)was gotten. The melting points and analytical values are shown below. Melting point: 40-42 ° C (from n-hexane / ethyl acetate). ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22 H), 4.55 (d, J
= 6.3 Hz, 2 H), 5.34 (d, J = 10.3 Hz, 1 H), 5.41
(D, J = 17.2 Hz, 1 H), 6.08 (ddt, J = 17.2, 10.3,
6.3 Hz, 2 H), 8.18 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.23, 21.76, 22.10, 25.90, 2
6.04, 26.35, 76.16, 114.20, 119.89, 133.80. Elemental analysis: Anal. Calcd for C ₁₅ H ₂₈ O ₄ : C, 66.14; H, 1
0.11., Found: C, 66.23; H, 10.36.

[Production Example 5] 1- (1-methoxy-1-)
Synthesis of methylethyldioxy) cyclododecyl hydroperoxide (Compound 5)

[Chemical 8] The compound 1 (696 m
g, 3.00 mmol) in methylene chloride (10 m
L) was prepared, 2-methoxypropene (216 mg, 3.00 mmol) was added dropwise with stirring at 0 ° C., and a catalytic amount of pyridinium-p-toluenesulfonate (PPTS; 38 mg, 0.15 mmol) was further added. Plus 3
Stir for 0 minutes at room temperature. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate, extracted twice with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure at 40 ° C or lower. The product was then isolated by silica gel column chromatography of the residue. As a fraction developed with n-hexane / diethyl ether (volume ratio 95/5), the title compound 5 (719 mg, yield 7) was obtained.
9%) was obtained. The melting points and analytical values are shown below. Melting point: 75-76 ° C (from n-hexane / diethylether). ¹ H NMR (CDCl ₃ ) δ: 1.3-1.8 (m, 28 H), 3.41 (s, 3
H), 10.18 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.32, 21.82, 22.09, 22.93, 2
5.90, 26.11, 26.24, 50.51, 105.93, 113.80. Elemental analysis: Anal. Calcd for C ₁₆ H ₃₂ O ₅ : C, 63.13; H, 1
0.60., Found: C, 63.24; H, 10.58.

Production Example 6 Synthesis of 1- (tetrahydropyran-2-yldioxy) cyclododecyl hydroperoxide (Compound 6)

[Chemical 9] The reaction similar to that in Production Example 5 was performed using 3,4-dihydro-2H-pyran in place of 2-methoxypropene to obtain the title compound 6 (yield 93%). The melting points and analytical values are shown below. Melting point: 123-125 ° C (from diethylether). ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 28 H), 3.7-3.8
(M, 1 H), 4.20 (dt, J = 11.2, 5.6 Hz, 1 H), 5.20
(M, 1 H), 10.39 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.30, 19.34, 19.84, 21.85, 2
2.12, 22.18, 24.80, 25.88, 25.93, 26.11, 26.51, 2
7.6, 63.95, 101.40, 114.03. Elemental analysis: Anal. Calcd for C ₁₇ H ₃₂ O ₅ : C, 64.53; H, 1
0.19., Found: C, 64.45, H, 10.35.

[Production Example 7] Synthesis of 1- (3-phenylpropyldioxy) cyclododecyl hydroperoxide (Compound 7)

[Chemical 10] In a 50 mL eggplant flask under a nitrogen atmosphere, 0.7 equivalent of silver oxide (487 mg, 2.1 mmo relative to Compound 1) was used.
1) An ethyl acetate solution (5 mL) of compound 1 (696 mg, 3.0 mmol) was added dropwise to an ethyl acetate suspension solution (5 mL) at room temperature with stirring, and then 1.0 equivalent of (3-iodo) was added. Propyl) benzene (738 mg, 3.
(0 mmol) in ethyl acetate (5 mL) was added dropwise and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the silver iodide by-product is removed by suction filtration using Celite, and the temperature is 40 ° C.
The solvent was distilled off under reduced pressure. The product was then isolated by residual silica gel column chromatography.
As a fraction developed with n-hexane / diethyl ether (volume ratio 98/2), 1,1-bis (3-phenylpropyldioxy) cyclododecane (127 mg,
Yield 9%) (by-product) was obtained, and then cyclododecanone (165 mg, yield 30%) was obtained as a fraction developed with n-hexane / diethyl ether (volume ratio 98/2). It was Further, by developing with n-hexane / diethyl ether (volume ratio 94/6), the title compound 7 (626 mg, yield 60%) was obtained. The melting points and analytical values are shown below. Melting point: 51-52 ° C (from n-hexane / ethyl acetate). ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22 H), 1.98 (m, 2
H), 2.71 (t, J = 6.6Hz, 2H), 4.09 (t, J = 6.6H
z, 2 H), 7.1-7.3 (m, 5 H), 7.85 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.30, 21.85, 22.21, 25.99, 2
6.06, 26.47, 29.40, 32.19, 74.34, 114.05, 125.93,
128.39, 128.46, 141.42. Elemental analysis: Anal. Calcd for C ₂₁ H ₃₄ O ₄ : C, 71.96; H,
9.78., Found: C, 72.12; H, 10.00.

[Production Example 8] 1- [6- (naphthalene-
2-yloxy) hexyldioxy] cyclododecyl
Synthesis of hydroperoxide (Compound 8)

[Chemical 11] A reaction similar to that in Production Example 7 was performed using 2- (6-iodohexyloxy) naphthalene instead of (3-iodopropyl) benzene to give the title compound 8 (yield 51%).
was gotten. The melting points and analytical values are shown below. Melting point: 67-68 ° C (from n-hexane / ethyl acetate). ¹ H NMR (CDCl ₃ ) δ: 1.3-1.9 (m, 30 H), 4.07 (t, J
= 6.9 Hz, 2 H), 4.10 (t, J = 6.9 Hz, 2 H), 7.1-
7.8 (m, 7 H), 7.91 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.28, 21.82, 22.18, 25.88, 2
5.95, 26.04, 26.45, 27.77, 29.09, 67.75, 75.13, 10
6.45, 114.07, 118.94, 123.45, 126.27, 126.65, 127.
60, 128.84, 129.29, 134.54, 156.96. . Elemental _{analysis: Anal Calcd for C 28 H 42} O 5: C, 73.33; H,
9.23., Found: C, 73.10; H, 9.01.

[Production Example 9] 1- [6- (tetrahydro-2H-pyran-2-yloxy) hexyldioxy]
Synthesis of cyclododecyl hydroperoxide (compound 9)

[Chemical 12] A reaction similar to that in Production Example 7 was performed using 2- (6-iodohexyloxy) tetrahydropyran in place of (3-iodopropyl) benzene to obtain the title compound 9 (yield 47%). Compound 9 is an oily substance, and the analytical values are shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 36 H), 3.3-3.5
(M, 2 H), 3.7−3.9 (m, 2 H), 4.07 (t, J = 6.6 H
z, 2 H), 4.58 (t, J = 3.5 Hz, 1 H), 7.98 (s, 1
H). ¹³ C NMR (CDCl ₃ ) δ: 19.28, 19.64, 21.85, 22.19,
25.43, 25.86, 25.97, 26.06, 26.47, 27.71, 29.54, 3
0.71, 62.36, 67.46, 75.15, 98.85, 113.96. Elemental analysis: Anal. Calcd for C ₂₃ H ₄₄ O ₆ : C, 66.31; H, 1
0.65., Found: C, 66.40; H, 10.67.

Production Example 10 Synthesis of butylperoxycyclododecylhydroperoxide (Compound 10)

[Chemical 13] The same reaction as in Production Example 3 was carried out using iodobutane instead of iodomethane to give the title compound 10 (yield 66%).
was gotten. The melting points and analytical values are shown below. Melting point: 46-47 ° C (from n-hexane) ¹ H NMR (CDCl ₃ ) δ: 0.94 (t, J = 7.3 Hz, 3 H), 1.2-
1.8 (m, 26 H), 4.08 (t, J = 6.6 Hz, 2 H), 7.91
(S, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 13.89, 19.27 (2 C), 21.84 (2
C), 22.19 (2 C), 25.97 (3 C), 26.06, 26.44 (2
C), 29.87, 75.02, 114.03. Elemental analysis: Anal.Calcd for C ₁₆ H ₃₂ O ₄ : C, 66.63; H, 1
1.18. , Found: C, 66.52; H, 11.08.

[Production Example 11] 1- (butyldioxy)
-1- (methyldioxy) cyclododecane (Compound 1
Synthesis of 1)

[Chemical 14] Silver oxide (1160
mg, 5.00 mmol) in ethyl acetate suspension (20
mL) with stirring at room temperature, compound 10 (720 m
g, 2.50 mmol) in ethyl acetate (20 mL)
Was dripped. The mixture was then charged with iodomethane (71
(0 mg, 5.00 mmol) in ethyl acetate was added dropwise, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the silver iodide by-product was removed by suction filtration using Celite, and the mixture was poured into an aqueous sodium thiosulfate solution and extracted with diethyl ether. After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. Then, the residue was subjected to silica gel column chromatography to
-As a fraction developed with hexane / diethyl ether (volume ratio 98/2), the title compound 11 (625 m
g, yield 83%) was obtained. Compound 11 is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 0.93 (t, J = 7.3 Hz, 3 H), 1.2
-1.8 (m, 26 H), 3.91 (s, 3 H), 4.08 (t, J = 6.6
Hz, 2 H). ¹³ C NMR (CDCl ₃ ) δ: 13.91, 19.30, 19.37, 21.87, 2
2.23, 26.04, 26.90, 29.87, 63.15, 74.49, 113.23. Elemental analysis: Anal. Calcd for C ₁₇ H ₃₄ O ₄ : C, 67.51; H, 1
1.33., Found: C, 67.43; H, 11.46.

[Production Example 12] 1- (1-methoxy-1)
-Methylethyldioxy) -1- (methyldioxy) cyclododecane (Compound 12)

[Chemical 15] In a 50 mL eggplant-shaped flask, Compound 3 (492 mg,
A solution of 2.00 mmol) in 10 mL methylene chloride was prepared, and 2-methoxypropene (21
6 mg, 3.00 mmol) was added dropwise, and a catalytic amount (5 mol%) of pyridinium-p-toluenesulfonate (PPTS) (25 mg, 0.10 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate, extracted twice with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure at 40 ° C or lower. The product was then isolated by silica gel column chromatography of the residue. n-
As a fraction developed with hexane / diethyl ether (volume ratio 95/5), the title compound 12 (588 m
g, yield 92%) was obtained. Compound 12 is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.3-1.6 (m, 24 H), 1.69-1.72
(M, 4 H), 3.35 (s, 3 H), 3.89 (s, 3 H). ¹³ C NMR (CDCl ₃ ) δ: 19.39, 21.89, 22.32, 22.93,
26.04, 26.11, 27.14, 49.29, 62.77, 104.19, 112.5
6. Elemental analysis: Anal. Calcd for C ₁₇ H ₃₄ O ₅ : C, 64.12; H, 1
0.76., Found: C, 64.08; H, 10.65.

Production Example 13 Synthesis of 1- (1-ethoxyethyldioxy) -1- (methyldioxy) cyclododecane (Compound 13)

[Chemical 16] The same reaction as in Production Example 12 was performed using ethoxyethylene instead of 2-methoxypropene to obtain the title compound 13 (yield 85%). Compound 13 is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.228 (t, J = 7.0 Hz) +1.231
(T, J = 7.0 Hz) (3 H), 1.3-1.8 (m, 25 H), 3.6
-3.7 (m, 1 H), 3.898 (s) + 3.902 (s) (3 H), 3.
9-4.0 (m, 1 H), 5.23 (q, J = 5.6 Hz, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 15.35, 18.42, 19.21, 21.82, 2
2.18, 25.95, 26.00, 26.83, 62.82, 64.44, 103.67, 1
13.28. Elemental analysis: Anal. Calcd for C ₁₇ H ₃₄ O ₅ : C, 64.12; H, 1
0.76., Found: C, 64.08; H, 10.93.

[Production Example 14] Synthesis of 1-methoxy- (1-methyldioxy) cyclododecane (Compound 14)

[Chemical 17] Under an argon atmosphere, a 10 mL ethyl acetate suspension solution of silver oxide (160 mg, 5.00 mmol) was prepared in a 50 mL eggplant flask, and the compound 2 was stirred at room temperature.
A 10 mL ethyl acetate solution of (575 mg, 2.5 mmol) was added dropwise. Then, iodomethane (710 mg,
10 mL of ethyl acetate solution (5.00 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours while shielded from light. After completion of the reaction, silver iodide produced as a by-product was removed by suction filtration using Celite, poured into an aqueous solution of sodium thiosulfate, and extracted with diethyl ether. After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. The product was then isolated by silica gel column chromatography of the residue. The title compound 14 (430 mg, yield 70%) was obtained as a fraction developed with n-hexane / diethyl ether (volume ratio 98/12). Compound 14 is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22 H), 3.31 (s,
3 H), 3.87 (s, 3 H). ¹³ C NMR (CDCl ₃ ) δ: 13.32, 21.89, 26.02, 26.11, 2
8.11, 48.56, 62.86, 109.11. Elemental analysis: Anal. Calcd for C ₁₄ H ₂₈ O ₃ : C, 68.81; H, 1
1.55., Found: C, 68.72; H, 11.52.

[Production Example 15] 1- (methyldioxy)
Synthesis of -1- [6- (2-tetrahydropyranyloxy) hexyldioxy] cyclododecane (Compound 15)

[Chemical 18] Under a nitrogen atmosphere, the silver oxide (23
2 mg, 1.0 mmol) in a suspension of 5 mL ethyl acetate while stirring at room temperature with compound 9 (416 mg, 10 mmol).
mmol) in 5 mL ethyl acetate, and then
A 5 mL ethyl acetate solution of iodomethane (284 mg, 2 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, silver iodide produced as a by-product was removed by suction filtration using Celite, and the solvent was evaporated under reduced pressure at 40 ° C or lower. The product was then isolated by residual silica gel column chromatography. As a fraction eluted with n-hexane / diethyl ether (volume ratio 96/4), the title compound 15
(337 mg, 78%) was obtained. Compound 15 is an oily substance, and the analytical values thereof are shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 36 H), 3.3-3.5
(M, 2 H), 3.7-3.8 (m, 2 H), 3.90 (s, 3 H), 4.
07 (t, J = 6.6 Hz, 2 H), 4.57 (t, J = 3.5 Hz, 1
H). ¹³ C NMR (CDCl ₃ ) δ: 19.25, 19.59, 21.82, 22.18, 2
5.39, 25.97, 26.83, 27.71, 29.56, 30.68, 62.21, 6
3.04, 67.42, 74.88, 98.73, 113.14. Elemental analysis: Anal. Calcd for C ₂₄ H ₄₆ O ₆ : C, 66.94; H, 1
0.77., Found: C, 66.99; H, 10.97.

[Production Example 16] Synthesis of 1- (6-hydroxyhexyldioxy) -1- (methyldioxy) cyclodotecan (Compound 16)

[Chemical 19] Compound 15 (215 mg, 0.
(5 mmol) was added and the mixture was stirred in 4 mL of acetic acid, 4 mL of THF (tetrahydrofuran) and 1 mL of water for 15 hours. After completion of the reaction, the mixture was poured into an aqueous sodium carbonate solution, extracted twice with diethyl ether, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower.
The product was then isolated by silica gel column chromatography of the residue. As a fraction developed with n-hexane / diethyl ether (volume ratio 90/10), unreacted starting material, compound 15 (77 mg, yield 3
6%) was obtained, and then the title compound 16 (100 mg, yield 58%) was obtained as a fraction developed with n-hexane / diethyl ether (volume ratio 73/27). Compound 16 is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.7 (m, 30 H), 1.95 (br
s, 1 H), 3.63 (t, J = 6.6 Hz, 2 H), 3.90 (s, 3
H), 4.08 (t, J = 6.6 Hz, 2 H). ¹³ C NMR (CDCl ₃ ) δ: 19.21, 21.78, 22.16, 25.45, 2
5.86, 25.95, 26.81, 27.69, 32.49, 62.63, 63.02, 7
4.83, 113.15. Elemental analysis: Anal. Calcd for C ₁₉ H ₃₈ O ₅ : C, 65.86; H, 1
1.05., Found: C, 65.91; H, 11.16.

[Preparation Example 17] 6-[(1-methyldioxy) cyclododecyldioxy] hexanoic acid (Compound 1
Synthesis of 7)

[Chemical 20] First, chromium oxide (VI) (260 mg, 2.6 mm
water) to which 0.4 mL of water was added, and concentrated sulfuric acid of 0.
Add 23 mL, then add 1.0 mL of water
Ones reagent was prepared. Next, Compound 16 (450 mg, 1.30 mmol) was placed in a 50 mL two-necked eggplant flask.
Of 5 mL of acetone solution was prepared and prepared in advance at 0 ° C.
Ones reagent was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was poured into an aqueous sodium carbonate solution, extracted three times with diethyl ether, washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. Then, by a residue silica gel column chromatography, as a fraction developed with n-hexane / ediethyl ether (volume ratio 90/10),
Cyclododecanone (48 mg, yield 20) was obtained, then n-hexane / diethyl ether (volume ratio 75/2
As the fraction developed by 5), the title compound 17
(150 mg, yield 32%) was obtained. The melting point and the analytical value are shown below. Melting point: 37-38 ° C (from n-hexane / diethylether). ¹ H NMR (CDCl ₃ ) δ: 1.3-1.8 (m, 28 H), 2.37 (t, J
= 7.3 Hz, 2 H), 3.90 (s, 3 H), 4.08 (t, J = 6.3 H
z, 2 H), 11.06 (br s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.21, 21.76, 22.14, 24.33, 2
5.55, 25.93, 25.99, 26.78, 27.42, 33.86, 63.00, 7
4.57, 113.15, 180.16. Elemental analysis: Anal. Calcd for C ₁₉ H ₃₆ O ₆ : C, 63.31; H, 1
0.07., Found: C, 63.16; H, 10.00.

Production Example 18 Synthesis of 6- (1-hydroperoxycyclododecylperoxy) hexane) -1-ol (Compound 18)

[Chemical 21] Compound 9 (166 mg, 0.
4 mmol), and acetic acid 4 mL, THF 4 mL, water 1
Stir in mL for 15 hours. After completion of the reaction, the mixture was poured into an aqueous sodium carbonate solution, extracted twice with diethyl ether, washed with saturated saline, and then dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure at 40 ° C or lower. The product was then isolated by silica gel column chromatography of the residue. n-hexane / diethyl ether (volume ratio 97 /
As a fraction developed by 3), cyclododecanone (18 mg, yield 25%) was obtained, and as a fraction developed by n-hexane / diethyl ether (volume ratio 90/10), unreacted raw materials were obtained. Compound 9 (3m
g, yield 2%) was obtained. Then, as a fraction developed with n-hexane / diethyl ether (volume ratio 55/45), the title compound 18 (90 mg, yield 68%) was obtained.
was gotten. Its melting point and analytical value are shown below. Melting point: 81-82 ° C (from n-hexane / diethylether). ¹ H NMR (CDCl ₃ ) δ: 1.2-1.7 (m, 30 H), 2.14 (br
s, 1 H), 3.63 (t, J = 6.6 Hz, 2 H), 4.06 (t, J =
6.6 Hz, 2 H), 8.78 (s, 1 H). ¹³ C NMR (CDCl ₃ ) δ: 19.23, 21.78, 22.16, 25.34, 2
5.72, 25.95, 26.00, 26.45, 27.59, 32.26, 62.64, 7
5.02, 113.89. . Elemental _{analysis: Anal Calcd for C 18 H 36} O 5: C, 65.03; H, 1
0.91., Found: C, 64.54; H, 10.59.

Production Example 19 Synthesis of 1-but-3-enylperoxycyclododecyl hydroperoxide (Compound 19)

[Chemical formula 22] A reaction similar to that in Production Example 3 was carried out using 4-
The reaction was performed using iodobutene to obtain the title compound 19 (yield 54%). Compound 19 is an oily substance, and the analytical values are shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22H), 2.43 (qt, J
= 6.6 and 1.3 Hz, 2 H), 4.12 (t, J = 6.6 Hz, 2
H), 5.0-5.2 (m, 2H), 5.85 (ddt, J = 17.2, 10.2and
6.6Hz, 1H), 7.85 (s, 1H). ¹³ C NMR (CDCl ₃ ) δ: 19.21 (2C), 21.80 (2C), 22.1
4 (2C), 25.91 (2C), 26.02 (2C), 26.38, 32.38, 7
4.09, 113.91, 116.86, 134.61. Elemental analysis: Anal. Calcd for C ₁₆ H ₃₀ O ₄ : C, 67.10; H, 1
0.56., Found: C, 66.97; H, 10.62.

[Production Example 20] Synthesis of 1,2,6,7-tetraoxaspiro [7.11] nonadeca-3-yl-hydroperoxide (Compound 20)

[Chemical formula 23] Compound 19 (373 mg, 1.3 mmol), 5 mL of trifluoroethanol and 25 mL of methylene chloride were prepared in a 50 mL two-necked eggplant flask equipped with a gas introduction tube, and the amount was 1.5 equivalent to compound 19 at -70 ° C. Of ozone (2.0 mmol) was bubbled through. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate and extracted with diethyl ether. After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. The residue was subjected to silica gel column chromatography. Cyclododecanone (15 mg, yield 6%) was obtained from the fraction developed with diethyl ether / n-hexane (volume ratio 5/95) and developed with diethyl ether / n-hexane (volume ratio 15/85). The title compound 20 (266 mg, yield 57%) was obtained from this fraction. The melting points and analytical values are shown below. Melting point: 108-109 ° C (from diethylether / n-hexane). ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22H), 1.97 (dt, J
= 15.8 and 4.6 Hz, 1H), 2.42 (dddd, J = 15.8, 10.
9, 9.6 and 2.2Hz, 1H), 4.13 (ddd, J = 15.4, 4.6 an
d 2.2 Hz, 1H), 4.28 (dd, J = 15.4 and 10.9Hz, 1
H), 5.40 (dd, J = 9.6 and 4.6Hz, 1H), 9.04 (s, 1
H). ¹³ C NMR (CDCl ₃ ) δ: 19.02, 19.44, 21.84 (2C), 22.
21 (2C), 25.78, 25.80, 25.83, 25.99, 26.15, 31.2
0, 71.07, 108.50, 112.20. Elemental analysis: Anal. Calcd for C ₁₅ H ₂₈ O ₆ : C, 59.19; H,
9.27., Found: C, 59.12; H, 9.25.

Production Example 21 Synthesis of 1,2,6,7-tetraoxaspiro [7.11] nonadecan-3-one (Compound 21)

[Chemical formula 24] In a 50 mL eggplant flask, the compound 20 (214 m
g, 0.7 mmol) in 5 mL of methylene chloride was prepared, and acetic anhydride (216 mg, 2.
1 mmol) and triethylamine (107 mg, 1.0
6 mmol) was added dropwise as a 5 mL methylene chloride solution. After confirming that the reaction substrate is exhausted by TLC,
1 mL of methanol was added, and the mixture was further stirred at room temperature for 15 minutes. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate and extracted with diethyl ether. After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. The residue was subjected to silica gel column chromatography. The title compound 21 (162 mg, yield 81%) was obtained from the fraction developed with diethyl ether / n-hexane (volume ratio 5/95). The melting points and analytical values are shown below. Melting point: 126-127 ° C (from diethylether / n-hexane). ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22H), 2.51 (ddd, J
= 12.7, 3.8 and 1.0Hz, 1H), 3.35 (ddd, J = 12.7, 1
1.9 and 3.8Hz, 1H), 4.23 (dt, J = 14.2 and 3.8Hz,
1H), 4.46 (ddd, J = 14.2, 11.9 and 1.0Hz, 1H) ¹³ C NMR (CDCl ₃ ) δ: 18.98, 19.25, 21.20 (2C), 21.
93 (2C), 25.39, 25.54, 25.61, 25.64, 26.04, 35.2
4, 72.26, 117.11, 177.61. Elemental analysis: Anal. Calcd for C ₁₅ H ₂₆ O ₅ : C, 62.91; H,
9.15., Found: C, 62.79; H, 9.26.

Production Example 22 Synthesis of 1- (3-butenylperoxy) -1- (1-methoxy-1-methylethylperoxy) cyclododecane (Compound 22)

[Chemical 25] Compound 19 (320 mL, 1.12 mmol) equivalent to
2-Methoxypropene methylene chloride solution (10 mL)
To this, a catalytic amount of pyridinium-p-toluenesulfonate (PPTS) was added with stirring at 0 ° C., and the mixture was further stirred at room temperature for 15 minutes. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate and extracted with diethyl ether. After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. The residue was subjected to silica gel column chromatography. The title compound 22 (165 mg, yield 74%) was obtained from the fraction developed with diethyl ether / n-hexane (volume ratio 4/96). Compound 22 is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 28H), 2.37 (qt, J
= 6.9 and 1.3Hz, 2H), 3.33 (s, 3H), 4.10 (t, J =
6.9Hz, 2H), 4.9-5.1 (m, 2H), 5.80 (ddt, J = 17.2
10.2 and 6.6 Hz, 1H). ¹³ C NMR (CDCl ₃ ) δ: 19.48 (2C), 21.96 (2C), 22.3
9 (2C), 22.99 (2C), 26.06, 26.18 (2C), 27.28 (2
C), 32.38, 49.33, 73.87, 104.21, 112.65, 116.55,
134.63.

[Production Example 23] 1-methoxy-3- [1
Synthesis of-(1-methoxy-1-methylethylperoxy) cyclododecylperoxy] -1-propylhydroperoxide (Compound 23)

[Chemical formula 26] A compound 22 (307 mg, 0.85 mmol), 5 mL of methanol and 25 mL of methylene chloride were prepared in a 50 mL two-necked eggplant flask equipped with a gas introduction tube, and -70 was prepared.
1.5 equivalents of ozone to compound 22 (1.3
a) was aerated. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate and extracted with diethyl ether. After washing with saturated saline,
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. The residue was subjected to silica gel column chromatography. From the fraction developed with diethyl ether / n-hexane (volume ratio 20/80), the title compound 2 was obtained.
3 (287 mg, 80% yield) was obtained. Compound 23
Is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-2.2 (m, 30H), 3.28 (s, 3
H), 3.46 (s, 3H), 4.0-4.2 (m, 2H), 4.84 (t, J =
5.9Hz, 1H), 9.28 (s, 1H). ¹³ C NMR (CDCl ₃ ) δ: 19.34 (2C), 21.82 (2C), 22.2
7 (2C), 22.73, 22.90, 25.91, 26.04 (2C), 27.12
(2C), 30.37, 49.40, 55.99, 70.40, 104.31, 106.1
8, 112.71.

[Production Example 24] Synthesis of 3- [1- (1-methoxy-1-methylethylperoxy) cyclododecyl] propionic acid methyl ester (Compound 24)

[Chemical 27] A methylene chloride solution (5 mL) of acetic anhydride (130 mg, 1.26 mmol) and triethylamine (64 mg, 0.63 mmol) in a methylene chloride solution (5 mL) of compound 23 (172 mg, 0.42 mmol) was stirred at 0 ° C. Was dripped. After confirming that the reaction substrate was consumed by TLC, 1 mL of methanol was added, and the mixture was further stirred at room temperature for 15 minutes. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate and extracted with diethyl ether. After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 40 ° C or lower. The residue was subjected to silica gel column chromatography. The title compound 24 (126 mg, yield 77%) was obtained from the fraction developed with diethyl ether / n-hexane (volume ratio 9/91). The analysis value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 28H), 2.67 (t, J =
6.3Hz, 2H), 3.30 (s, 3H), 3.66 (s, 3H), 4.30
(T, J = 6.3Hz, 2H). ¹³ C NMR (CDCl ₃ ) δ: 19.36 (2C), 21.87 (2C), 22.3
2 (2C), 22.88 (2C), 26.00, 26.09 (2C), 27.14 (2
C), 33.26, 49.26, 51.61, 69.67, 104.19, 112.63, 1
71.59. Elemental analysis: Anal. Calcd for C ₂₀ H ₃₈ O ₇ : C, 61.51; H,
9.81., Found: C, 61.40; H, 9.40.

Production Example 25 Synthesis of 3- (1-hydroperoxycyclododecylperoxy) propionic acid methyl ester (Compound 25)

[Chemical 28] Compound 24 (95 mg, 0.25 mmol) in THF
(2 mL) -Dissolved in water (1 mL), 4 mL of acetic acid was added with stirring at room temperature, and the mixture was reacted for 15 hours. After completion of the reaction, the mixture was poured into aqueous sodium hydrogen carbonate and extracted with diethyl ether. After washing with saturated saline, drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure at 40 ° C or lower. The residue was subjected to silica gel column chromatography. Diethyl ether /
The title compound 25 (70 mg, yield 88%) was obtained from the fraction developed with n-hexane (volume ratio 15/85). Compound 25 is an oily substance, and its analytical value is shown below. ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22H), 2.74 (t, J =
5.6Hz, 2H), 3.74 (s, 3H), 4.33 (t, J = 5.6Hz, 2
H), 9.40 (s, 1H). ¹³ C NMR (CDCl ₃ ) δ: 19.18 (2C), 21.81 (2C), 22.1
4 (2C), 25.91 (2C), 26.08, 26.45 (2C), 34.13, 5
2.29, 70.37, 114.11, 173.53 Elemental analysis: Anal. Calcd for C ₁₆ H ₃₀ O ₆ : C, 60.35; H,
9.05., Found: C, 60.50; H, 9.26.

Next, preparation of tablets, ointments and suppositories was tried using some of the compounds of the present invention described above. [Example 1] Preparation of tablets 100 g of the compound 1 described above, 40 g of Avicel (trade name, manufactured by Asahi Kasei Corporation), 30 g of corn starch and 2 g of magnesium stearate were weighed and mixed and polished, and then coated with sugar coated R10 mm kine. Tablet. About the obtained tablets, TC-5 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose) 10 g, polyethylene glycol-6000 3 g, castor oil 40 g
By coating a film coating agent comprising 40 g of ethanol and 40 g of ethanol, a film coated tablet having the above composition could be produced.

Example 2 Preparation of Ointment 5 g of beeswax was heated to form a liquid, and then 2 g of compound 3, 5 g of purified lanolin and 8 of white petrolatum.
After adding 8 g and heating until it became liquid, it was stirred until it began to solidify to obtain an ointment of the above composition (total amount 100 g).

Example 3 Preparation of Suppository 50 mg of Compound 4, Witepsol W-35 (trade name, manufactured by Dynamite Nobel, mono-, di- and tri-glyceride mixture of saturated fatty acids from lauric acid to stearic acid) A suppository was prepared according to a conventional method at a compounding ratio of 1400 mg).

Next, the test of the efficacy of the compound of the present invention was specifically tried. [Test Example 1] Confirmation of u-PA production inhibitory activity As for the u-PA production inhibitory activity, human fibrosarcoma cells HT-1080 cells (purchased from American type culture collection) that constantly produce u-PA at a high level. It was examined by an in vitro test method using. 1.0 x 1
0 ⁵ / mL HT-1080 cells prepared in suspension 96-well flat-bottom culture plates (Nunc, Roskilde, Denmark)
Dispense 200 μL (microliter) into the tube and store at 37 ° C for 4
After culturing for a period of time, the medium was replaced with the same amount of serum-free medium and culturing was continued for 20 hours. Next, replace with 199 μL of serum-containing medium and add 1 μL of a sample dimethyl sulfoxide (DMSO) solution,
The cells were cultured at 37 ° C for 24 hours. Then remove the supernatant by suction,
200 μL of serum-free medium was dispensed, and 24 hours later, the supernatant was collected. The u-PA activity in the culture supernatant was measured by isovaleryl-Phe-Lys-pNA which is a specific synthetic substrate of plasmin.
(BACHEM AG, Hauptstrase, Switzerland). 15 μL synthetic substrate reaction solution [427 mmol / L tris-H
Cl (pH 8.0), 27 mmol / L EDTA (pH 8.0), 1.5 mmol / L
isovaleryl-Phe-Lys-pNA, 125 μg / mL plasminogen (CHROMOGENIX, Moln del, Sweden)] and 85 μL
The culture supernatants of the
After reacting at 30 ° C. for 30 minutes, the absorbance at a wavelength of 405 nm (nanometer) was measured using an immuno reader (Japan Intermed Co., Ltd., Tokyo) (Biochem. Biophy.
S. Res. Commun., 142: 147-54, (1987)). In this test, at least 3 holes were used for one specimen. u
The calculation rate of the PA production inhibition rate is shown in the following formula. u-PA production inhibition rate (%) = (1−T / C) × 100 where T is the average absorbance of the sample-treated group and C is the average absorbance of the control group. And, in Table 1, u-of the HT-1080 cells of the peroxide compounds 1 to 9, 11 to 21, and 25.
The PA production inhibition rate is shown.

[Table 1] From these results, it was confirmed that the compounds 1 to 9, 11 to 21 and 25 have an action of inhibiting urokinase production which is deeply involved in angiogenesis.

Test Example 2 CAM (Chorio-allantoi)
Angiogenesis Inhibition Test by C Membrance Method The in vivo angiogenesis inhibition test used a method in which the CAM method which has been conventionally used is slightly modified (Adv.
Cancer Res., 175-203, (1985)). Illuminate the eggs on the 3rd day of incubation, with the start date of inoculation as 0 days for fertilized eggs.
The position of the air chamber was determined, and a rotary file was used to scratch the upper part of the air chamber and the side of the egg of the egg shell. About 3 mL of egg white was sucked and removed from the side hole with a syringe, and air was evacuated from the upper part of the temperament using a dropper. Open the side holes to Opsite (Sm
ith and Nephew, Welwyn Garden City, England), a 1 cm square wound was made on the upper part of the air chamber with a rotating file, the eggshell and eggshell membranes were removed, and sealing was performed with Opsite. On the 5th day of incubation, opsites were removed to make a window, and the window was sealed with Tegaderm (3mol / L Health Care, St Paul, MN). 20 μL of 1% methylcellulose containing the sample was overlaid on a disk prepared by drying 20 μL of 1% gelatin, and then dried again. The Tegaderm was peeled off, the disc was allowed to stand on the allantoic membrane, and it was sealed again using the Tegaderm.
On the 7th day of incubation, the upper part of the eggshell is removed, and 20% intralipos (Welfide Co., Ltd., Osaka) is placed under the allantoic membrane for about 1 m.
L was injected. Under a surgical microscope (Olympus, Tokyo)
Then, the allantoic membrane was observed and photographs were taken at a magnification of 4 to 8 times. The effect is determined by Oikawa et al. (Cancer Lett., 48: 157).
-62, (1989), J. Antibiot., (Tokyo), 42: 1202-
4 (1989)), an angiogenesis-inhibiting activity is positive (+) when an avascular region is observed at 2 mm or more outside the disc, and is negative (-) when an avascular region is not observed at 2 mm or more. At least 5 or more fertilized chicken eggs were used for the test, and the angiogenesis inhibition rate was determined by the ratio of the number of points to the total number of fertilized chicken eggs, with (+) as 1 point and (-) as 0 point. The results are shown in Table 2.

[Table 2] As a result, the compounds 1, 2, 3, 4, 7, 18, 19,
20 had an angiogenesis-inhibiting effect even at a low concentration of 10 μg / egg to 16.6 μg / egg.

Test Example 3 Mouse Lewis lung cancer (L
Suppression test for lung metastasis and primary tumor using LC) cells Solid tumors of LLC that had been passaged subcutaneously in C57BL / 6 mice were aseptically collected. It is known that LLC grows as a solid tumor and frequently metastasizes to the lung. The necrotic portion was removed and the tumor finely chopped was passed through a stainless mesh (150 μm) and washed with serum (−).
Serum (-) to 1.0 × 10 ⁶ / mL,
100 μL of the cell suspension was subcutaneously transplanted into the groin of C57BL / 6 mice. From the day after transplantation, the sample was suspended in a 10% ethanol-5% Tween80 solution and intraperitoneal administration was started, and 10% ethanol-5% Tween80 was used as a control group.
The solution was administered. The body weight of the mouse and the major axis and minor axis of the primary tumor were measured every other day. TNP-470 was similarly tested as a comparative control in evaluation. TNP-4
70 specifically inhibits methionine aminopeptidase 2 which is one of the processing proteases, and is known as a typical angiogenesis inhibitor. 18 days after tumor transplantation, the mice were sacrificed under ether anesthesia to remove the lung tissue and the primary tumor, and the lung tissue was fixed with Bouin's solution (saturated picric acid: formalin: acetic acid = 15: 5: 1). Was measured. The lung metastasis inhibition rate was calculated using the following formula. Lung metastasis inhibition rate (%) = (1−T / C) × 100 where T is the median number of lung metastatic nodules in the sample administration group and C is the median number of lung metastatic nodules in the control group. In addition, the volume of the primary tumor was roughly estimated according to the following calculation method, the daily change of the tumor volume was plotted, and the inhibitory effect on the primary tumor was calculated by the following method. Primary tumor volume ^(mm 3) = major axis (mm) × minor axis (mm)
² × 0.5 Primary tumor growth inhibitory rate (%) = (1−T / C) × 100 where T is the average weight of primary tumor 18 days after tumor implantation in the sample administration group, and C is 18 days after tumor implantation in the control group. The average primary tumor weight in The results are shown in Table 3.

[Table 3] As a result of this test, the compounds 3 and 4 showed a higher effect in suppressing the primary tumor than the representative angiogenesis inhibitor TNP-470, and in the effect of suppressing lung metastasis, TN.
It showed an effect comparable to P-470.

[0049]

INDUSTRIAL APPLICABILITY As described above, in the present invention, the peroxide derivative or a pharmaceutically acceptable salt thereof has an excellent urokinase production inhibitor and angiogenesis inhibitor, and the treatment and prevention of diseases associated with angiogenesis. , For example solid tumors,
Tumor metastases, benign tumors (eg hemangiomas, acoustic neuromas, neurofibromas, trachoma and pyogenic granulomas), vascular dysfunction, inflammation and immune disorders, Behcet's disease, gout, arthritis, rheumatoid arthritis, psoriasis, diabetic It has been found to be useful for the treatment or prevention of retinopathy and other ocular blood vessel-derived diseases (for example, posterior lens fibroplasia, macular degeneration, corneal transplant rejection, neovascular glaucoma), osteoporosis, etc., and has excellent effects. Can be confirmed.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07C 409/18 C07C 409/18 409/20 409/20 409/22 409/22 C07D 309/12 C07D 309/12 323 / 00 323/00 (72) Takuma Sasaki 4-12-5-40, Izumino-cho, Kanazawa-shi, Ishikawa Prefecture (72) Masatomo Nojima 3-7 Shinsenri-higashi-cho, Toshima-shi, Osaka Prefecture A37-105 F-term (reference) 4C022 NA06 NA08 4C062 AA17 4C206 AA02 AA03 CA40 DA11 DB11 DB43 KA01 MA01 MA04 NA14 ZA36 ZB26 4H006 AA01 AA03 AB20 AB28

Claims (4)

[Claims] 1. A urokinase production inhibitor containing, as an active ingredient, a peroxide derivative having the structure of the general formula (1) or a pharmaceutically acceptable salt thereof. [Chemical 1] (In the formula, R ₁ is a hydroxyl group, a lower alkyl group or a lower alkoxy group, and R ₂ is a hydrogen atom or an optionally substituted lower alkyl group, a lower alkenyl group or a saturated heterocyclic group. R ₁ and R ₂ may be bonded to each other to form a ring, and the ring may be substituted.) 2. An angiogenesis inhibitor containing the peroxide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A cancer metastasis inhibitor containing the peroxide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. An antitumor agent containing the peroxide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.