JPS63170394A - 3-nitro-1,2,4-triazole derivative, preparation thereof and radiation sensitizer containing said derivative as active component - Google Patents
3-nitro-1,2,4-triazole derivative, preparation thereof and radiation sensitizer containing said derivative as active componentInfo
- Publication number
- JPS63170394A JPS63170394A JP151487A JP151487A JPS63170394A JP S63170394 A JPS63170394 A JP S63170394A JP 151487 A JP151487 A JP 151487A JP 151487 A JP151487 A JP 151487A JP S63170394 A JPS63170394 A JP S63170394A
- Authority
- JP
- Japan
- Prior art keywords
- nitro
- formula
- triazole
- derivative
- acetyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KUEFXPHXHHANKS-UHFFFAOYSA-N 5-nitro-1h-1,2,4-triazole Chemical class [O-][N+](=O)C1=NC=NN1 KUEFXPHXHHANKS-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 239000002534 radiation-sensitizing agent Substances 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 20
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical class N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 230000000850 deacetylating effect Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 4
- -1 tri-O Chemical class 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001235 sensitizing effect Effects 0.000 abstract description 2
- LLPWGHLVUPBSLP-UTUOFQBUSA-N [(2r,3s,4r)-3,4-diacetyloxy-3,4-dihydro-2h-pyran-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O LLPWGHLVUPBSLP-UTUOFQBUSA-N 0.000 abstract 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 230000007096 poisonous effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 11
- 230000000637 radiosensitizating effect Effects 0.000 description 8
- 206010021143 Hypoxia Diseases 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000001146 hypoxic effect Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000005855 radiation Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OPHAQGBSVLXVOL-GGZOMVNGSA-N 1-[(2r,3r,4r)-4,6-diacetyl-3,4-dihydroxy-2-(hydroxymethyl)-2,3-dihydropyran-5-yl]ethanone Chemical compound CC(=O)C1=C(C(C)=O)[C@](O)(C(C)=O)[C@H](O)[C@@H](CO)O1 OPHAQGBSVLXVOL-GGZOMVNGSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000007980 azole derivatives Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001553014 Myrsine salicina Species 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は次の一般式（１）、
（式中、Ｒは水素原子又はアセチル基を示す）で表わさ
れる３−ニトロ−１，２，４−）リアゾール誘導体、そ
の製造法および該誘導体を有効成分とする放射線増感剤
に関する。Detailed Description of the Invention [Industrial Application Field] The present invention relates to a 3-nitro-1,2, 4-) It relates to a lyazole derivative, a method for producing the same, and a radiosensitizer containing the derivative as an active ingredient.
腫瘍内にある低酸素性細胞は放射線抵抗性が強く、放射
線治療の際の難治や再発の重要な原因と考えられている
。一方、正常組織内には低酸素性細胞が存在しないため
、腫瘍内の低酸素性細胞の放射線感受性を高めることは
、腫瘍の放射線による治療効果を向上させるのに重要で
ある。Hypoxic cells within tumors are highly radioresistant and are considered to be an important cause of refractory treatment and recurrence during radiotherapy. On the other hand, since there are no hypoxic cells in normal tissues, increasing the radiosensitivity of hypoxic cells in tumors is important for improving the effectiveness of radiation therapy for tumors.
斯かる実状において、本発明者らは、放射線治療の際、
正常細胞の感受性に変化をおこさず、低酸素性細胞のみ
を増感させる薬剤、つまり低酸素性細胞放射線増感剤（
以下、放射線増感剤と言う）の開発に鋭意とり組んだ結
果、前記（Ｉ）式で表わされる３−ニトロ−１゜２ 、
４− ） ＩＪアゾール誘導体が、従来から最大の問題
となっていた毒性も低く、シかも低濃度においても高い
増感効果を有することを見出し、本発明を完成した。In such a situation, the present inventors, during radiation therapy,
Hypoxic cell radiosensitizers (hypoxic cell radiosensitizers) are drugs that sensitize only hypoxic cells without changing the sensitivity of normal cells.
As a result of our intensive efforts to develop 3-nitro-1゜2 expressed by the above formula (I),
4-) We have completed the present invention by discovering that IJ azole derivatives have low toxicity, which has traditionally been the biggest problem, and have a high sensitizing effect even at low concentrations.
従って、本発明は、新規な３−ニトロ−１゜２ 、４−
ト！Ｊアゾール誘導体（Ｉ）及びその製造法を提供す
るものである。更にまた、本発明はこれを有効成分とし
て含有する放射線増感剤を提供するものである。Therefore, the present invention provides novel 3-nitro-1゜2,4-
to! The present invention provides a J azole derivative (I) and a method for producing the same. Furthermore, the present invention provides a radiosensitizer containing this as an active ingredient.
本発明化合物（Ｉ）のうち、Ｒがアセチル基で表わされ
る化合物（Ｉａ）は、例えば３−ニトロ−１，２，４−
トリアゾールとトリー〇−アセチルーＤ−グルカールを
直接又は有機溶媒の存在下に反応させることにより製造
される。Among the compounds (I) of the present invention, the compound (Ia) in which R is an acetyl group is, for example, 3-nitro-1,2,4-
It is produced by reacting triazole and tri-0-acetyl-D-glucal directly or in the presence of an organic solvent.
有機溶媒としては種々のものを使用出来るが、例えば酢
酸エチル、アセトニトリル、ベンゼン、トルエン、キシ
レン、上リンク、トリエチルアミン等が好ましい。また
反応促進物質としてｐ−）ルエンスルホン酸、無水塩化
アルミニウム、塩化亜鉛、無水塩化第二すず、塩駿、硫
酸等を触媒量乃至等モル添加することも出来る。反応に
用いられる３−ニトロ−１，２，４−）リアゾールおよ
びトリー〇−アセチルーＤ−グルカールの使用割合は任
意に定めることも出来るが、通常は前者に対して後者を
等モル乃至少過剰用いるのが良い。反応温度は特に限定
されないが、通常、直接反応させる場合は１００〜１３
０℃、有機溶媒中で反応させる場合は使用する溶媒の沸
点で行なわれる。反応時間は反応試薬、溶媒、温度、反
応促進物質等によって異なるが、通常は５分乃至６時間
である。Various organic solvents can be used, but preferred examples include ethyl acetate, acetonitrile, benzene, toluene, xylene, OEM, and triethylamine. Further, p-)luenesulfonic acid, anhydrous aluminum chloride, zinc chloride, anhydrous stannic chloride, sulfuric acid, sulfuric acid, etc. can be added in catalytic amounts or equimolar amounts as reaction accelerators. The ratio of 3-nitro-1,2,4-) lyazole and tri-acetyl-D-glucal used in the reaction can be determined arbitrarily, but usually the latter is used in equimolar or slightly excess proportion to the former. It's good. The reaction temperature is not particularly limited, but usually 100-13 in the case of direct reaction.
When the reaction is carried out at 0°C in an organic solvent, it is carried out at the boiling point of the solvent used. The reaction time varies depending on the reaction reagent, solvent, temperature, reaction promoter, etc., but is usually 5 minutes to 6 hours.
反応終了後、目的物は常法によって反応液から分離精製
される。例えば反応液を抽出し、洗浄後濃縮し、残留物
をクロマトグラフィー等によって分離精製すれば高収率
で化合物（Ｉａ）が得られる。After the reaction is completed, the target product is separated and purified from the reaction solution by a conventional method. For example, if the reaction solution is extracted, washed and concentrated, and the residue is separated and purified by chromatography or the like, compound (Ia) can be obtained in high yield.
このようにするとき、化合物（Ｉａ）はα体とβ体の混
合物として得られるが、これらは分離することができ、
それぞれの立体構造は毘スペクトルによって確認された
。When doing so, compound (Ia) is obtained as a mixture of α-form and β-form, but these can be separated,
The three-dimensional structures of each were confirmed by bispectral spectra.
また、（Ｉ）式中Ｒが水素原子で表わされる化合物（Ｉ
ｂ）は、化合物（Ｉａ）を自体公知の方法で脱アセチル
化することＫよって得られる。Further, a compound (I) in which R is a hydrogen atom (I)
b) can be obtained by deacetylating compound (Ia) by a method known per se.
脱アセチル化は、例えばナトリウムアルコラードを含む
無水アルコール中、あるいはアンモニアガスを飽和させ
た無水アルコール中で０℃乃至加熱還流下にて数時間乃
至−夜処理する方法によって行なわれる。Deacetylation is carried out, for example, by treatment in absolute alcohol containing sodium alcoholade or absolute alcohol saturated with ammonia gas at 0° C. under heating under reflux for several hours to overnight.
本発明化合物（Ｉ）は、後述の試験例に示すように毒性
が低く、優れた放射線増感作用を有する。本発明化合物
（Ｉ）は、放射線を照射する５分乃至５時間前に投与す
るのが好ましく、投与は経口あるいは非経口等によって
行なわれる。剤型としては賦形剤、安定剤、保存剤、緩
衝剤などの適当な添加剤を加えた形で錠剤、カプセル剤
、顆粒剤、散剤、坐剤または注射剤とする。投与量は、
年令、腫瘍の発生部位、種類、症状等によって異なるが
、通常０．２を乃至５．０ ｔ ／ ｍ”体表が好まし
い。The compound (I) of the present invention has low toxicity and excellent radiosensitizing action, as shown in the test examples below. The compound (I) of the present invention is preferably administered 5 minutes to 5 hours before irradiation with radiation, and administration is carried out orally or parenterally. The dosage form is tablets, capsules, granules, powders, suppositories, or injections with appropriate additives such as excipients, stabilizers, preservatives, and buffers. The dosage is
Although it varies depending on age, site of tumor occurrence, type, symptoms, etc., 0.2 to 5.0 t/m'' body surface is usually preferable.
以下に本発明化合物（Ｉ）の急性毒性試験および放射線
増感効果に関し、試験例を挙げて説明する。The acute toxicity test and radiosensitizing effect of the compound (I) of the present invention will be explained below by giving test examples.
（１）急性毒性試験
生後５週のＩＣＲ系雄性マウスを用い、生理食塩液に溶
解した１−（２’、３’−ゾチオキシーβ−Ｄ−エリス
ローヘキサ−２′−エノピラノシル）−３−二トロー１
．２．４−トリアゾール［（Ｉｂ）のβ体〕を静脈内投
与し、投与後１４日間にわたり観察し、５０％致死率（
ＬＤ５０／１４）を求めた。その結果は第１表のとおり
である。(1) Acute toxicity test Using 5-week old ICR male mice, 1-(2',3'-zothioxy-β-D-erythrohexa-2'-enopyranosyl)-3-2 dissolved in physiological saline was used. Toro 1
．． 2.4-triazole [β form of (Ib)] was administered intravenously and observed for 14 days after administration, with a mortality rate of 50% (
LD50/14) was determined. The results are shown in Table 1.
第１表
（２） 放射線増感効果の試験
■インビトロ試験１
使用細胞：ＥＭＴ−６のａｉｎｇｌｅ ｃｅｌｌ放射線
照射：＠０ＣＯ−γ線
低酸素処理＝９５％窒素＋５％炭酸ガスの混合ガスを細
胞浮遊液に流す。Table 1 (2) Test of radiosensitizing effect ■In vitro test 1 Cells used: EMT-6 aingle cells Radiation irradiation: @0CO-γ-ray hypoxia treatment = 95% nitrogen + 5% carbon dioxide gas mixture suspended in cells Drain into liquid.
細胞生存率判定：コロニー計数法
放射線増感比（Ｅｎｈａｎｃｅｍｅｎｔ Ｒａｔ ｉ
ｏ ＝ ＥＲ）上記の条件で得た結果は以下のとおりで
ある。Determination of cell viability: colony counting method, radiosensitization ratio (Enhancement Ratio)
o = ER) The results obtained under the above conditions are as follows.
ｌ ｍＭの濃度における
化合物（Ｉｂ）のβ体のＥＲ：１．４３■インビトロ試
験２
使用細胞：ＥＭＴ−６の５ｐｈｅｒｏｉｄ放射線照射、
６０（’０−γ線
放射線増感効果の判定ニ一定の大きさの５ｐｈｅｒｏｉ
ｄ ６個を採取し、化合物（Ｉｂ）のβ体を含む培養液
中
に入れ、３０〜６０分間３７
℃でインキュベートした後、
放射線を照射する。次いでト
リプシンで５ｐｈｅｒｏｉｄを分解し、コロニー計数法
を用いて放射
線増感比（ＥＲ）を求め効果の
判定を行なう。ER of β-form of compound (Ib) at a concentration of 1 mM: 1.43 In vitro test 2 Cells used: EMT-6 5pheroid irradiation,
60 ('0 - Determination of γ-ray radiosensitization effect: 5 pheroids of a certain size
d 6 pieces are collected, placed in a culture medium containing the β-form of compound (Ib), incubated at 37°C for 30 to 60 minutes, and then irradiated with radiation. Next, the 5pheroid is digested with trypsin, and the radiosensitization ratio (ER) is determined using a colony counting method to determine the effect.
上記の条件で得た結果は以下のとおりである。The results obtained under the above conditions are as follows.
１ｍＭの濃度における
化合物（Ｉｂ）β体のＥＲ：１．４７
■インビボ試験
使用動物： Ｂａ１ｂ／ｃマウス
使用腫瘍： ＥＭＴ −６
化合物（Ｉｂ）のβ体の投与量：２００醇／ＫＮ投与方
法：放射線照射の２０分前に、生理食塩液に溶解した化
合物（Ｉｂ）の
β体を腹腔内投与。ER of compound (Ib) β form at a concentration of 1mM: 1.47 ■ In vivo test animals used: Ba1b/c mice Tumor used: EMT-6 Dosage of compound (Ib) β form: 200/KN Administration method: Twenty minutes before radiation irradiation, the β form of compound (Ib) dissolved in physiological saline was administered intraperitoneally.
放射線照射： ６０ Ｃｏ −ｒ線、全身照射放射線増
感効果の判定：放射線量と腫瘍細胞減少率より放射線増
感比
（ＥＲ）を求め効果の判定を行
なう。Radiation irradiation: 60 Co-r rays, whole body irradiation Judgment of radiosensitization effect: The radiosensitization ratio (ER) is calculated from the radiation dose and tumor cell reduction rate to judge the effect.
上記の条件で得た結果は以下のとおりである。The results obtained under the above conditions are as follows.
２００叩／へにおける 化合物（Ｉｂ）β体ＯＥＲ二１．３０ 〔実施例〕 次に実施例を挙げて説明する。200 hits/to Compound (Ib) β form OER2 1.30 〔Example〕 Next, an example will be given and explained.
実施例１
４−トリアゾールおよび１−（４’、６’−シー（方法
人）：３−二トロー１．２．４−トリアゾール１．１４
Ｆとトリー〇−アセチルーＤ−グルカールＺ７２Ｐの
混合物にｐ−トルエン−スルホン酸０．１ｒを加え、水
流？ンデで減圧しながら、１１０〜１２０℃で２０分間
攪拌する。放冷後、反応液をクロロホルム２００１Ｒｔ
に溶解し、これを水で洗い、無水硫酸ナトリウムで乾燥
した後減圧濃縮する。残留物をシリカゲルを用いた分順
高速液体クロマトグラフィーで、溶離液として酢酸エチ
ル−ベンゼン混液を用いて精製すると、はじめに標記化
合物のα一体０．７８Ｆ（２４ｅｓ）が粘稠な油状物と
して、次いで標記化合物のβ一体１．３０ｆ（４０％）
が無色結晶として得られる。Example 1 4-Triazole and 1-(4',6'-C): 3-nitro 1.2.4-triazole 1.14
Add 0.1r of p-toluene-sulfonic acid to the mixture of F and tri-acetyl-D-glucal Z72P, and wash with water. Stir at 110 to 120° C. for 20 minutes while reducing the pressure using a cold water bottle. After cooling, the reaction solution was dissolved in chloroform 2001Rt.
The solution is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by fractional high-performance liquid chromatography using silica gel using a mixture of ethyl acetate and benzene as the eluent, and the α-unit 0.78F (24es) of the title compound was first obtained as a viscous oil, and then Beta of the title compound 1.30f (40%)
is obtained as colorless crystals.
（方法Ｂ）＝３−二トロー１．２．４−）リアゾール１
．１４９とトリー〇−アセチルーＤ−グルカール２７２
ｆをキシレン６０−に溶解し、加熱還流しながらｐ−）
ルエンスルホン酸０．１１を加え１時間反応させる。今
後、キシレン６０ｔ１１ｔを加えた後、水で洗い、無水
硫酸す） ＩＪウムで乾燥した後減圧濃縮する。(Method B) = 3-nitro 1.2.4-) lyazole 1
．． 149 and tri-acetyl-D-glucal 272
f was dissolved in xylene 60-, and p-) was heated under reflux.
Add 0.11 l of luenesulfonic acid and allow to react for 1 hour. After adding 60 tons and 11 tons of xylene, wash with water, dry with anhydrous sulfuric acid, and concentrate under reduced pressure.
残留物をシリカゲルカラムを用いた分取高速液体クロマ
トグラフィーで、溶離液として酢酸エチル−ベンゼン混
液を用いて精製すると、はじめに標記化合物のα一体０
．４２Ｆ（１３％）が粘ｙｉな油状物として、次いで標
記化合物のβ一体！１２２（６５％）が無色結晶として
得られる。The residue was purified by preparative high-performance liquid chromatography using a silica gel column using an ethyl acetate-benzene mixture as the eluent.
．． 42F (13%) as a viscous oil, then β of the title compound! 122 (65%) is obtained as colorless crystals.
α一体のＭ−８−（ｍ／ｅ ） ： ａ ２６ （Ｍ＋
）ＩＲ（ｃｆＩ＠” ） ＝ １７４０ （ＣＯＣ
Ｈ３） 、 １５１０（ＮＯ２） 、ｌ ４３０ （Ｎ
Ｏ２）β一体の融点：１４５℃
Ｍ−８−（ｍ／ｅ ） ： ３２６ （Ｍｉ）ＩＲ（Ｋ
Ｂｒ） （ｃ！１１−”） ：１７４０ （ＣＯＣＨ３
）、１５１０ （ＮＯ２）、１４３０ （ＮＯ２）実施
例２
ｌ−（４’、６’−シー０−アセチル−２’、３’−ジ
デオキシ−α−り一エリスローヘキサー２′−エノぎラ
ノシル）−３−ニトロ−１，２，４−）リアゾール３．
２６ｔを３００−の無水メタノールに溶解させ、室温で
攪拌しながら、ナトリウムエトキシドの２％無水エタノ
ール溶液を反応液のｐＨが９．０になるまで滴下する。α integrated M-8-(m/e): a 26 (M+
)IR(cfI@”) = 1740 (COC
H3), 1510 (NO2), l 430 (N
O2) β melting point: 145°C M-8-(m/e): 326 (Mi)IR(K
Br) (c!11-”) :1740 (COCH3
), 1510 (NO2), 1430 (NO2) Example 2 l-(4',6'-cy0-acetyl-2',3'-dideoxy-α-ri-erythrohexer2'-enogylanosyl) -3-nitro-1,2,4-)lyazole3.
26t was dissolved in 300 methanol of anhydrous methanol, and while stirring at room temperature, a 2% solution of sodium ethoxide in absolute ethanol was added dropwise until the pH of the reaction solution reached 9.0.
３時間室温で攪拌後、Ｄｏｗｅｘ ５０ Ｗ （Ｈ”）
を反応液のｐＨが７．０になるまでゆっくり加える。次
イテＤｏｖｔｅｘ ５０ Ｗ （Ｈ”）を吸引濾過で除
去後、溶媒を減圧留去し、残留物をＯＤＳカラムを用い
た分取高速液体クロマトグラフィーで溶離液として３５
％アセトニトリル水溶液を用いて精製すると標記の化合
物２−２０ ｆ （９１％）が粘稠な油状物として得ら
れる。After stirring at room temperature for 3 hours, Dowex 50 W (H”)
Slowly add until the pH of the reaction solution becomes 7.0. Next, after removing Dovtex 50 W (H") by suction filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography using an ODS column as an eluent.
Purification using % acetonitrile aqueous solution gives the title compound 2-20 f (91%) as a viscous oil.
Ｍ、Ｓ、 （ｍ／ｅ ） ： ２４２ （Ｍ”）ＩＲ（
α′″’）： ３４３０ （ＯＨ）、１５６０ （Ｎｏ
２）、１５１０ （ＮＯ２）、１４２ Ｑ （ＮＯ２）
ＮＭＲ（ＤＭＳＯ−ｄ、、δ）： ａ７０−＆３０（ｍ
、３Ｈ。M, S, (m/e): 242 (M”)IR(
α′″'): 3430 (OH), 1560 (No
2), 1510 (NO2), 142 Q (NO2)
NMR (DMSO-d,, δ): a70-&30(m
, 3H.
ｓ’−Ｈ，ｓ’−Ｈ，６”−Ｈ）、４．００ （ｍ、
ＩＨ，４’−Ｉ（）、４．６５ （ｔ 、 ＩＨ，６’
−０Ｈ）、５．３０ （ｄ、ＩＨ，４’−０Ｈ）、６．
００ （ｍ、 ＩＨ，３’−Ｈ）、６．２０ （ｍ、
ＩＨ，２’−Ｈ）、６．４５ （ｍ、 ＩＨ，１’−Ｈ
）、９．００ （ｓ 、 ＩＩ（、５−Ｈ）。s'-H, s'-H, 6''-H), 4.00 (m,
IH,4'-I(), 4.65 (t, IH,6'
-0H), 5.30 (d, IH, 4'-0H), 6.
00 (m, IH, 3'-H), 6.20 (m,
IH, 2'-H), 6.45 (m, IH, 1'-H
), 9.00 (s, II (, 5-H).
実施例３
実施例２に準じた方法により、標記化合物が収率９３％
で無色結晶として得られる。Example 3 The title compound was obtained in a yield of 93% by a method similar to Example 2.
Obtained as colorless crystals.
融点：１３５℃
Ｍ、Ｓ、 （ｍ／ｅ ） ： ２４２ （Ｍ”）ＩＲ（
ＫＢｒ） （ａ−’ ） ： ３４１０ （ＯＨ） 、
１５６５ （ＮＯｘ）、１５１５ （Ｎｏｗ ）、１４
３０ （Ｎｏｗ ）ＮＭＲ（ＤＭＳＯ−ｄ、、δ） ：
ａ８０− ＆５０ （ｍ、３Ｈ。Melting point: 135℃ M, S, (m/e): 242 (M'') IR (
KBr) (a-'): 3410 (OH),
1565 (NOx), 1515 (Now), 14
30 (Now) NMR (DMSO-d,,δ):
a80- &50 (m, 3H.
５’−Ｈ，６’−Ｈ，６”−Ｈ）、４．１５ （ｍ、Ｉ
Ｈ，４’−Ｈ）、４．９０ （ｔ 、 ＩＨ，６’−０
Ｈ）、５．２０ （ｄ 、 ＩＨ，４’−０Ｈ）、５．
９６ （ｍ 、 ＩＨ，３’−Ｈ）、６．２２ （ｒｎ
、 ＩＨ，２’−Ｈ）、６．５０ （ｄ、ＩＨ，１’
−Ｈ）、９．０５ （ｓ、ＩＨ，５−Ｈ）。5'-H, 6'-H, 6"-H), 4.15 (m, I
H, 4'-H), 4.90 (t, IH, 6'-0
H), 5.20 (d, IH, 4'-0H), 5.
96 (m, IH, 3'-H), 6.22 (rn
, IH,2'-H), 6.50 (d, IH,1'
-H), 9.05 (s, IH, 5-H).
以上 出願人 ？−ラ化成工業株式会社 １ソ〕 ・ ′＋、、−一 ＋ム」that's all applicant ? −La Kasei Kogyo Co., Ltd. 1 so ・ '+,,-1 +mu'
Claims (1)
る３−ニトロ−１，２，４−トリアゾール誘導体。 ２、３−ニトロ−１，２，４−トリアゾールにトリ−Ｏ
−アセチル−Ｄ−グルカールを反応せしめることを特徴
とする式（ I ａ）、 ▲数式、化学式、表等があります▼（ I ａ） で表わされる３−ニトロ−１，２，４−トリアゾール誘
導体の製造法。 ３、式（ I ａ）で表わされる化合物を脱アセチル化す
ることを特徴とする式（ I ｂ）、 ▲数式、化学式、表等があります▼（ I ｂ） で表わされる３−ニトロ−１，２，４−トリアゾール誘
導体の製造法。 ４、一般式（ I ）、 ▲数式、化学式、表等があります▼（ I ） （式中、Ｒは水素原子又はアセチル基を示す）で表わさ
れる３−ニトロ−１，２，４−トリアゾール誘導体を有
効成分として含有することを特徴とする放射線増感剤。[Claims] 1. 3-nitro-1 represented by the following general formula (I), ▲numerical formula, chemical formula, table, etc.▼(I) (wherein R represents a hydrogen atom or an acetyl group) ,2,4-triazole derivative. 2,3-nitro-1,2,4-triazole with tri-O
3-nitro-1,2,4-triazole derivatives represented by formula (Ia), ▲mathematical formulas, chemical formulas, tables, etc.▼(Ia), which are characterized by reacting -acetyl-D-glucar. Manufacturing method. 3. Formula (Ib), which is characterized by deacetylating the compound represented by Formula (Ia), ▲There are mathematical formulas, chemical formulas, tables, etc.▼3-nitro-1, represented by (Ib) A method for producing a 2,4-triazole derivative. 4. 3-nitro-1,2,4-triazole derivative represented by the general formula (I), ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R represents a hydrogen atom or an acetyl group) A radiosensitizer characterized by containing as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP151487A JPS63170394A (en) | 1987-01-07 | 1987-01-07 | 3-nitro-1,2,4-triazole derivative, preparation thereof and radiation sensitizer containing said derivative as active component |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP151487A JPS63170394A (en) | 1987-01-07 | 1987-01-07 | 3-nitro-1,2,4-triazole derivative, preparation thereof and radiation sensitizer containing said derivative as active component |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63170394A true JPS63170394A (en) | 1988-07-14 |
Family
ID=11503592
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP151487A Pending JPS63170394A (en) | 1987-01-07 | 1987-01-07 | 3-nitro-1,2,4-triazole derivative, preparation thereof and radiation sensitizer containing said derivative as active component |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63170394A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102397270A (en) * | 2010-09-17 | 2012-04-04 | 苏州天人合生物技术有限公司 | Application of glucal and glucal derivative in preparation of drugs |
-
1987
- 1987-01-07 JP JP151487A patent/JPS63170394A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102397270A (en) * | 2010-09-17 | 2012-04-04 | 苏州天人合生物技术有限公司 | Application of glucal and glucal derivative in preparation of drugs |
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