JPH07103027B2 - Radiosensitizer - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a radiosensitizer, and more particularly, to a radiosensitizer which contains a specific nitrotriazole compound as an active ingredient and which is present in a malignant tumor and is difficult to cure. It relates to a radiosensitizer that promotes activation.

Conventionally, radiation therapy, surgery, chemotherapy, immunotherapy, etc. have been used as treatments for malignant tumors. Among them, radiation therapy is an effective treatment that has been used for many years. is there.

However, there is a problem that the radiation treatment may not cure the tumor and that the tumor may recur even if it is once cured.

This may be due to the presence of radioresistant cells of the tumor tissue itself and oxygen-deficient radioresistant cells in the tumor. In fact, in the irradiation experiment,
It is known that cells in an atmosphere in which oxygen is excluded are 2-3 times more resistant to radiation than cells in the presence of oxygen.

Under such circumstances, there has been a strong demand for the development of a hypoxic cell sensitizer as a drug for enhancing the sensitivity of hypoxic cells to radiation as an extremely effective means for improving the radiotherapy effect.

From such a viewpoint, some hypoxic cell sensitizers have been conventionally developed, and, for example, nitroimidazole derivatives are known as typical ones.

However, misonidazole, which is one of the typical compounds of nitroimidazole derivative, shows a sensitizing effect about twice as much as that in the case of no addition in animal transplant tumor experiments, but it is difficult to administer in large amounts because of its neurotoxicity. No sensitizing effect was observed from the results of application to the human body at applicable doses.

The inventors of the present invention have conducted extensive studies in order to find a compound having a low toxicity and a higher sensitizing effect. As a result, a nitrotriazole compound having a specific substituent represented by the following general formula (I) has a low oxygen content. It has been found that the sensitivity of cells to radiation can be significantly increased and the effectiveness of radiotherapy can be increased.

(In the formula, R is —R ₁ —O—X ₁ , —R ₂ —CO—X ₂ , From _{-CH 2 -CH (OH) -CH 2} -X 3 or glucose a residue formed by removing one hydroxyl group.

R ₁ represents ethylene and X ₁ represents a hydrogen atom or an acetyl group.

R ₂ represents methylene or ethylene, X ₂ is —O—R ₃ or —
N (R ₄ ) R ₅ is shown.

X ₃ is a halogen atom, acetoxy group, —O—R ₃ or —N
(R ₄ ) indicates R ₅ .

R ₃ represents an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group.

R ₄ is a hydrogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group, R ₅ represents a group or _{-R 6 -N (R 7) R} 8 represented by R _4, R ₆ is ethylene or propylene are shown, R ₇ and R ₈ represents a group represented by R _4, R ₄ and R _5, taken together ethylene may indicate pentamethylene or oxa diethylene, R ₇ and R ₈ are bonded to each other And may represent pentamethylene, or R ₄ and R ₇ may combine with each other to represent ethylene. ) Hereinafter, the nitrotriazole compound having a specific substituent of the present invention will be described in detail.

In the above compound, as the alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Secondary butyl, amyl, hexyl, heptyl, octyl,
Examples thereof include isooctyl and 2-ethylhexyl, and the hydroxyalkyl group includes 2-hydroxyethyl and 2
-Hydroxypropyl and the like, and examples of the alkoxyalkyl group include methoxyethyl, ethoxyethyl, butoxyethyl and the like. Examples of the alkyl group having a hydroxyl and ether bond include 2- (2'-hydroxyethoxy) ethyl and the like.

Therefore, as the compound represented by the above general formula of the present invention, methyl 2- (3′-nitro-1′-triazolyl) acetate, ethyl 2- (3′-nitro-1′-triazol) acetate, 2- Hydroxyethyl (3'-nitro-1'-triazolyl) acetate, ethoxyethyl 2- (3'-nitro-1'-triazolyl) acetate, 2- (3'-nitro-
1'-triazolyl) acetic acid morpholide, 2- (3'-nitro-1'-triazolyl) acetic acid morpholide, 2-
(3'-nitro-1'-triazolyl) acetic acid diethylamide, 2- (3'-nitro-1'-triazolyl) acetic acid butylamide, 2- (3'-nitro-1'-triazolyl) acetic acid amide, 2- (3 ′ -Nitro-1′-triazolyl) acetic acid-3 ″ -dimethylaminopropylamide, 2
-(3'-Nitro-1'-triazolyl) acetic acid diethanolamide, 2- (3'-nitro-1'-triazolyl) acetic acid ethanolamide, 2- (3'-nitro-1 '
-Triazolyl) acetic acid isopropanolamide, 2-
(3'-Nitro-1'-triazolyl) acetic acid propanolamide, 2- (3'-nitro-1'-triazolyl)
Acetic acid-2 "-methoxyethylamide, 2- (3'-nitro-1'-triazolyl) acetic acid piperidide, 2- (3 '
-Nitro-1'-triazolyl) acetic acid-4 "-methylpiperazide, 3- (3'-nitro-1'-triazolyl)
Methyl propionate, 3- (3'-nitro-1'-triazolyl) propionic acid ethanolamide, 3- (3 '
-Nitro-1'-triazolyl) propionic acid dimethylamide, 3- (3'-nitro-1'-triazolyl) propionic acid ethylamide, 3- (3'-nitro-1'-
Triazolyl) propionic acid morpholide, 3- (3'-
Nitro-1'-triazolyl) propionic acid-2 "-piperidinoethylamide, 1- (2 ', 3'-epoxypropyl) -3-nitrotriazole, 1- (2'-hydroxy-3'-methoxypropyl) ) -3-Nitrotriazole, 1- (2'-hydroxy-3'-ethoxypropyl) -3-nitrotriazole, 1- (2'-hydroxy-3'-chloropropyl) -3-nitrotriazole, 1- ( 2'-hydroxy-3'-dimethylaminopropyl) -3-nitrotriazole, 1- (2'-hydroxy-3'-piperidinopropyl) -3-nitrotriazole, 1- (2'-hydroxy-3 ' -Morpholinopropyl) -3-nitrotriazole, 1- [2'-hydroxy-3 '-(3 "-dimethylaminopropylaminopropyl)]-3 Nitrotriazole, 1- (2 '
-Hydroxy-3'-acetyloxypropyl) -3-nitrotriazole, 1- (2'-hydroxyethyl)-
3-nitrotriazole, 1- (2'-acetyloxyethyl) -3-nitrotriazole, 1- (2'-hydroxy-3'-N-aziridinopropyl) -3-nitrotriazole, 1- (3'- And nitro-1'-triazolyl) glucose, and the like.

When these compounds have an amino group, of course, they may be acid addition salts, and examples of the acid forming the acid addition salt include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. And inorganic acids such as acetic acid, propionic acid, oxalic acid, citric acid, tartaric acid, adipic acid, lactic acid and p-toluenesulfonic acid.

Some of these compounds are known, and some are new compounds.
A method in which 3-nitro-1,2,4-triazole is reacted with a halocarboxylic acid ester or an unsaturated carboxylic acid ester, and then, if necessary, the desired product is obtained by operations such as hydrolysis, transesterification, and amide formation; epihalohydrin A method of obtaining a desired product by reacting and then adding carboxylic acid, amines or alcohols as needed; a method of adding alkylene oxide and then acylating as necessary; a method of reacting a saccharide, etc. It can be manufactured.

Next, specific production examples of the compound of the present invention will be described, but the present invention is not limited to these production examples.

Production Example 1 Production of 2- (3'-nitro-1'-triazolyl) acetic acid morpholide Methyl 2- (3'-nitro-1'-triazolyl) acetate
1 g was added to 2 ml of morpholine, and the mixture was stirred at 80 to 90 ° C for 5 hours. Excess morpholine was distilled off under reduced pressure to obtain a pale yellow solid product.

Recrystallization from chloroform gave 800 mg of colorless crystals with a melting point of 157.5-159 ° C.

The results of infrared spectroscopic analysis and elemental analysis are as follows:
It was confirmed that it was the target product.

IR (KBr method): 3170, 1670, 1550, 1510, 1320 and 1120 cm
^-1 elemental analysis _{(C 8 H 11 O 4 N} 5) Production Example 2 Production of 2- (3'-nitro-1'-triazolyl) acetic acid piperidide Methyl 2- (3'-nitro-1'-triazolyl) acetate
1 g was added to 2 ml piperidine, and the mixture was stirred at 80 to 90 ° C for 5 hours. Excess piperidine was distilled off under reduced pressure to obtain a pale yellow solid product.

Recrystallization from chloroform gave 750 mg of colorless crystals having a melting point of 122.5-123.4 ° C.

IR (KBr method): 3070, 1660, 1560, 1510, 1320 and 1310 cm
^-1 Elemental analysis (C ₉ H ₁₃ O ₃ N ₅ ) Production Example 3 Production of 2- (3'-nitro-1'-triazolyl) acetic acid amide Methyl 2- (3'-nitro-1'-triazolyl) acetic acid
1 g was suspended in 2 ml of methanol, 2 g of 28% aqueous ammonia was added dropwise at 0 to 5 ° C, and then the mixture was stirred at 0 to 10 ° C for 2 hours. After standing overnight, the precipitated solid was filtered off. Recrystallization from methanol / chloroform gave white crystals with a melting point of 191-192 ° C.

IR (KBr method): 3450, 3350, 3150, 1690, 1600, 1550, 15
10, 1320 and 1310 cm ^-1 Elemental analysis (C ₄ H ₅ O ₃ N ₅ ) Production Example 4 Production of 2- (3'-nitro-1'-triazolyl) acetic acid ethanolamide Methyl 2- (3'-nitro-1'-triazolyl) acetate
1 g, dioxane 10 ml and monoethanolamine 1 g were taken and stirred at 80 to 100 ° C. for 1 hour. Dioxane and excess ethanolamine were distilled off under reduced pressure to obtain a pale yellow liquid product. After dissolving in 10 ml of methanol, 3 g of an ion exchange resin (DOWEX 50W manufactured by Dow) was added and stirred for 30 minutes.

After separation by filtration, methanol was distilled off to obtain a colorless liquid purified product.
This product solidified by standing, and was recrystallized from methanol / ethyl acetate to obtain 650 mg of colorless crystals having a melting point of 111.7 to 113 ° C.

IR (KBr method): 3400, 3300, 1665, 1560, 1525, 1315 and
1050cm ^-1 Elemental analysis (C ₆ H ₉ O ₄ N ₅ ) Production Example 5 Production of 2- (3′-nitro-1′-triazolyl) acetic acid butylamide By the same procedure as in Production Example 4 except that 1 g of butylamine was used instead of ethanolamine, a colorless solid product was obtained,
This is recrystallized from chloroform / benzene, melting point 89-
91 ° C. colorless crystals were obtained.

IR (KBr method): 3300, 3150, 1670, 1550, 1510, 1320 and
1310cm ^-1 Elemental analysis (C ₈ H ₁₃ O ₃ N ₅ ) Production Example 6 2- (3′-nitro-1′-triazolyl) acetic acid-2 ″
-Production of methoxyethylamide By following the same procedure as Production Example 5 except that 1 g of 2-methoxyethylamine was used instead of butylamine, a colorless solid purified product was obtained, which was recrystallized from chloroform / benzene.
Colorless crystals having a melting point of 122.9-123.5 ° C were obtained.

IR (KBr method): 3400, 3100, 1670, 1560, 1510 and 1210 cm
^-1 Elemental analysis (C ₇ H ₁₁ O ₄ N ₅ ) Production Example 7 Production of methyl 3- (3'-nitro-1'-triazolyl) propionate 3-nitro-1,2,4-triazole 5 g, methanol 50 m
1, 6 g of methyl acrylate and 5 ml of triethylamine were taken and stirred under reflux for 12 hours.

After distilling off methanol, triethylamine and excess methyl acrylate, the residue was dissolved in chloroform and washed 3 times with a dilute aqueous sodium hydrogen carbonate solution.

After drying over anhydrous magnesium sulfate, the solvent was removed to obtain a pale yellow solid product. Recrystallized from chloroform, melting point 7
6.2 g of colorless crystals at 6.0 to 76.6 ° C. were obtained.

IR (KBr method): 3100, 1730, 1560, 1555, 1500, 1315 and
1220cm ^-1 Elemental analysis (C ₆ H ₈ O ₄ N ₄ ) Production Example 8 Production of 3- (3'-nitro-1'-triazolyl) propionic acid ethanolamide Methyl 3- (3'-nitro-1'-triazolyl) propionate 1 g, dioxane 10 ml and monoethanolamine
1 g was taken and stirred at 90 to 100 ° C for 1 hour. Dioxane and excess ethanolamine were distilled off under reduced pressure to obtain a pale yellow liquid product. After dissolving in 10 ml of methanol, 3 g of an ion exchange resin (DOWEX 50W manufactured by Dow) was added and stirred for 30 minutes.

After separation by filtration, the solvent was distilled off to obtain a light yellow solid purified product. This was recrystallized from methanol / ethyl acetate and had a melting point of 111-112.
600 mg of colorless crystals at ℃ were obtained.

IR (KBr method): 3450, 3350, 1660, 1570, 1510, 1320 and
1060cm ^-1 Elemental analysis (C ₇ H ₁₁ O ₄ N ₅ ) Production Example 9 Production of 3- (3′-nitro-1′-triazolyl) propionic acid morpholide 3-nitro-1,2,4-triazole 1 g, methanol 20 m
1, 1.41 g of acrylic acid morpholide and 0.55 ml of 28% sodium methoxide methanol solution were taken and stirred for 12 hours under reflux.

After distilling off methanol, the residue was dissolved in water and extracted with toluene. After desolvation, recrystallized from xylene, melting point 115-116
A colorless crystalline product at ℃ was obtained.

IR (KBr method): 3100, 1650, 1550, 1505, 1310 and 1120 cm
^-1 Elemental analysis (C ₉ H ₁₃ O ₄ N ₅ ) Production Example 10 1- (2'-hydroxy-3'-chloropropyl) -3
-Production of nitrotriazole 3-Nitro-1,2,4-triazole (3.4 g), epichlorohydrin (15 g) and anhydrous potassium carbonate (0.6 g) were taken at 20 ° C at 100 ° C.
Stir for minutes. The insoluble material was filtered off and washed with ethanol. The filtrates were combined and ethanol and unreacted epichlorohydrin were distilled off under reduced pressure to obtain a yellow oily product.

Purification by silica gel column chromatography using chloroform / ethanol as a developing solvent gave 5.8 g of the desired product as a pale yellow liquid.

IR: 3350, 3100, 1560, 1510, 1310 and 1040 cm ^-1 Elemental analysis (C ₅ H ₇ O ₃ N ₄ Cl) Production Example 11 Production of 1- (2 ', 3'-epoxypropyl) -3-nitrotriazole 1- (2'-hydroxy-3'-chloropropyl) -3
-Nitrotriazole (5.8 g) and 10% aqueous sodium hydroxide solution (50 ml) were taken and stirred at room temperature for 15 minutes. Chloroform was extracted three times with 50 ml each, activated carbon was added, and the mixture was stirred at 60 ° C. for 30 minutes, then the activated carbon was filtered off and chloroform was distilled off to obtain 4.3 g of a colorless oily product.

IR: 3100, 1560, 1510, 1310, 1260 and 1130 cm ^-1 Elemental analysis (C ₅ H ₆ O ₃ N ₄ ). Production Example 12 1- (2'-hydroxy-3'-methoxypropyl)-
Production of 3-nitrotriazole Boron trifluoride etherate was added to a mixture of 1 g of 1- (2 ', 3'-epoxypropyl) -3-nitrotriazole and 20 ml of methanol, and the mixture was stirred under reflux for 2 hours. After removing the solvent under reduced pressure, the product was purified by silica gel column chromatography using chloroform / ethanol as a developing solvent to obtain a colorless solid product. Recrystallization from chloroform / hexane gave 0.8 g of colorless crystals having a melting point of 67-69.5 ° C.

IR (KBr method): 3300, 3100, 1560, 1510, 1310 and 1110 ~
1080cm ^-1 Elemental analysis (C ₆ H ₁₀ O ₄ N ₄ ) Production Example 13 1- (2'-hydroxy-3'-ethoxypropyl)-
Production of 3-nitrotriazole 0.8 g of a colorless oily product was obtained in the same manner as in Production Example 12 except that ethanol was used instead of methanol.

IR: 3400, 3100, 1560, 1510, 1310 and 1140-1060 cm ^-1 Elemental analysis (C ₇ H ₁₂ O ₄ N ₄ ). Production Example 14 1- (2'-hydroxy-3'-piperidinopropyl)
Preparation of 3-nitrotriazole hydrochloride 1- (2 ', 3'-epoxypropyl) -3-nitrotriazole 1g, piperidine 4g and tetrahydrofuran 10ml
And was stirred at 60 ° C. for 30 minutes. After removing the solvent under reduced pressure, 10 ml of an aqueous solution of sodium carbonate was added, and each of chloroform was added.
Extract 3 times with 30 ml.

The chloroform solution was extracted three times with 20 ml each of 1N hydrochloric acid, and then the aqueous hydrochloric acid layer was adjusted to pH 10 with an aqueous sodium carbonate solution, and then extracted three times with 30 ml each of chloroform. Chloroform was distilled off under reduced pressure to obtain 1.1 g of a pale yellow oily product.

Add 10 ml of water to this and adjust the pH to 5 with 1N hydrochloric acid, then add 3 at room temperature.
Stir for 0 minutes.

Water was distilled off under reduced pressure, and the residue was recrystallized from methanol / ether to give a white crystalline product having a melting point of 189.5 to 191.5 ° C (1.0 g).
Got

IR (KBr method): 3200, 3100, 2700 to 2500, 1560, 1510, 13
10 and 1050 cm ^-1 Elemental analysis (C ₁₀ H ₁₈ O ₃ N ₅ Cl) Production Example 15 Production of 1- (2'-hydroxy-3'-diethylaminopropyl) -3-nitrotriazole hydrochloride Production Example except that diethylamine is used instead of piperidine
Similarly to 14, a white solid product was obtained. Recrystallization from methanol gave white crystals with a melting point of 131-132 ° C.

IR (KBr method): 3200, 3100, 2700 to 2500, 1560, 1510, 13
10 and 1050 cm ^-1 Elemental analysis (C ₉ H ₁₈ O ₃ N ₅ Cl) Production Example 16 Production of 1- (2′-hydroxy-3′-N-aziridinopropyl) -3-nitrotriazole 1- (2 ′, 3′-epoxypropyl) -3-nitrotriazole 1 g, ethyleneimine 0.5 g And 10 ml of methanol were taken and stirred under reflux for 2 hours.

Methanol and excess ethyleneimine were distilled off under reduced pressure, and the obtained solid was recrystallized from ethanol / isopropyl alcohol to give a white crystalline product having a melting point of 118 to 119.5 ° C.
Obtained 0.72 g.

IR (KBr method) 3400, 3150, 1550, 1360, 1310, 1270, 112
0 and 1040 cm ^-1 Elemental analysis (C ₇ H ₁₁ O ₃ N ₅ ) The above-mentioned compound of the present invention is useful as a sensitizer in radiotherapy, and its dose varies depending on the type of tumor and compound, but in general, it is 20 to 10000 mg for oral preparations, 0.5 to 10000 mg for injection preparations, and suppositories. Is 20 to 10,000 mg,
The optimal dose is determined according to the type of radiation, irradiation dose, irradiation division degree, etc., based on the judgment of the doctor according to the symptoms.

In addition, there is no particular limitation on the administration form of the compound of the present invention,
As the carrier, those usually used in the pharmaceutical field can be used,
It is prepared according to the means commonly used in this field.

The radiation sensitizing effect of the compound of the present invention will be shown below by specific examples.

Example-1 In order to examine the radiation sensitizing effect on V-79 Chinese hamster cells, 100,000 V-79 cells were cultured in a monolayer on a glass dish to prepare logarithmic phase V-79 cells.

A medium solution of the test compound having a predetermined concentration was added to the petri dish, allowed to stand at 37 ° C for 60 minutes, and then placed in a closed container at room temperature,
Oxygen was eliminated by flowing nitrogen gas for 10 minutes, and X-ray irradiation was performed at a dose rate of 1.6 Gy / min.

After irradiation, the cells were washed with a phosphate buffer solution and made into single cells with trypsin. Then, a predetermined amount was put in a culture dish, 5 ml of medium was added, the mixture was cultured at 37 ° C for 7 days, washed with water after staining, and the number of generated colonies was measured.

As a comparison, a test was also conducted on a medium solution containing no compound, which was irradiated under nitrogen and irradiated in the presence of air.

A linear relationship is obtained by calculating the cell survival rate from these values and plotting the logarithm of the survival rate against the irradiation dose.

Find the intersection of this straight line and the horizontal straight line where the survival rate is 1.0, and derive the induction period dose: Dq (Gy)
The irradiation dose required to reduce to 0: D ₁₀ (Gy) was calculated.

Also, the irradiation dose (D _0.1% = Dq + 3D ₁₀ ) required to inactivate cells by 99.9% was obtained, and the value of irradiation in air (▲ D
ratio with ^air _0.1% ▼) (▲ D ^air _0.1% ▼ / D _0.1% ) and ratio with irradiation under nitrogen flow Were determined and defined as air-based sensitization ratio (SARA number) and nitrogen-based sensitization ratio (N ₂ -based SARA number), respectively.

The results obtained are shown in Table 1.

Example-2 10 ⁵ EMT-6 tumor cells were subcutaneously inoculated into male and female Balb / C strain mice (8 weeks old, 4 mice per group) on both legs. After tumor cell inoculation,
A physiological saline solution of the test compound was intraperitoneally administered (200 mg / kg) when the tumor size reached about 1 cm in diameter, and 40 minutes later
X-rays were irradiated at 450 rad / min, and the mice were killed 5 minutes after irradiation.

After systemic sterilization with 70% ethanol, the tumor area is cut off,
The tissue was minced and mixed with 22 ml trypsin and stirred for 50 minutes at 37 ° C. Take the supernatant, count the number of cells,
Spread on a 5 cm plastic plate, add 5 ml of medium and culture in a carbon dioxide incubator. Cells that have not been irradiated with X-rays are taken out after 9 days, cells that have been irradiated with X-rays are taken out from the incubator after 10 days, The cells are fixed with methanol, the cells are stained with Giemsa stain, and the number of generated colonies is counted.

The cells not irradiated with X-ray were used as a control, and the survival rate was measured. The results are shown in Table-2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication C07H 19/056 (72) Inventor Minanobu Minagawa 1-207-3, Koshigaya, Koshigaya, Saitama (72) ) Inventor Yutaka Nakahara 406-71 Minamishitaraii, Iwatsuki-shi, Saitama Prefecture (72) Ryoji Kimura 56 Ryouji Kimura, Sajo-ku, Kyoto City, Kyoto Prefecture 3F-C-8, Haimu Freuden Ichijoji Temple (72) Tsuneo Tsubakimoto Osaka Prefecture Toyonaka 2-10-4, Shinsenrikitamachi, Ichi (72) Inventor Kouichi Kouichi 3-19-7, Shindo, Ibaraki-shi, Osaka (72) Inventor Koichi Sakano 3 Ishigaki, Ishida Sakuragi-cho, Fushimi-ku, Kyoto-shi, Kyoto Field housing complex 13-508 (56) Reference JP-A-61-167616 (JP, A)

Claims (1)

[Claims] 1. A radiation sensitizer comprising a nitrotriazole compound represented by the following general formula (I) as an active ingredient. (In the formula, R is —R ₁ —O—X ₁ , —R ₂ —CO—X ₂ , From _{-CH 2 -CH (OH) -CH 2} -X 3 or glucose a residue formed by removing one hydroxyl group. R ₁ represents ethylene and X ₁ represents a hydrogen atom or an acetyl group. R ₂ represents methylene or ethylene, X ₂ is —O—R ₃ or —
N (R ₄ ) R ₅ is shown. X ₃ is a halogen atom, acetoxy group, —O—R ₃ or —N
(R ₄ ) indicates R ₅ . R ₃ represents an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group. R ₄ is a hydrogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group, R ₅ represents a group or _{-R 6 -N (R 7) R} 8 represented by R _4, R ₆ is ethylene or propylene are shown, R ₇ and R ₈ represents a group represented by R _4, R ₄ and R _5, taken together ethylene may indicate pentamethylene or oxa diethylene, R ₇ and R ₈ are bonded to each other And may represent pentamethylene, or R ₄ and R ₇ may combine with each other to represent ethylene. )