JPS63253077A - Nitrotriazole derivative and production thereof - Google Patents
Nitrotriazole derivative and production thereofInfo
- Publication number
- JPS63253077A JPS63253077A JP8763487A JP8763487A JPS63253077A JP S63253077 A JPS63253077 A JP S63253077A JP 8763487 A JP8763487 A JP 8763487A JP 8763487 A JP8763487 A JP 8763487A JP S63253077 A JPS63253077 A JP S63253077A
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- JP
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- Prior art keywords
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- formulas
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- Prior art date
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Links
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- YXFWFUSVDJIVIV-UHFFFAOYSA-N 4-nitro-2h-triazole Chemical class [O-][N+](=O)C=1C=NNN=1 YXFWFUSVDJIVIV-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 150000003852 triazoles Chemical group 0.000 claims abstract description 9
- CJNRGSHEMCMUOE-UHFFFAOYSA-N 2-piperidin-1-ylethanamine Chemical compound NCCN1CCCCC1 CJNRGSHEMCMUOE-UHFFFAOYSA-N 0.000 claims abstract description 5
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 claims abstract description 5
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- KUEFXPHXHHANKS-UHFFFAOYSA-N 5-nitro-1h-1,2,4-triazole Chemical class [O-][N+](=O)C1=NC=NN1 KUEFXPHXHHANKS-UHFFFAOYSA-N 0.000 claims abstract 5
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 claims abstract 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 21
- 206010021143 Hypoxia Diseases 0.000 abstract description 11
- 230000001146 hypoxic effect Effects 0.000 abstract description 11
- 239000002904 solvent Substances 0.000 abstract description 7
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 239000002534 radiation-sensitizing agent Substances 0.000 abstract description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 description 28
- 238000000034 method Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000000637 radiosensitizating effect Effects 0.000 description 7
- 238000002329 infrared spectrum Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000001235 sensitizing effect Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- -1 1-(2-hydroxypropyl)-3-nitro-1,2,4-triazole Chemical compound 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229940058965 antiprotozoal agent against amoebiasis and other protozoal diseases nitroimidazole derivative Drugs 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 1
- 229950010514 misonidazole Drugs 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 150000004957 nitroimidazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 102220133487 rs149819112 Human genes 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は低酸素性細胞に対して放射線増感作用を有する
ニトロトリアゾール誘導体およびその製法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a nitrotriazole derivative having a radiosensitizing effect on hypoxic cells and a method for producing the same.
［従来の技術および問題点］
癌治療における放射線療法は外科療法や化学療法ととも
に重要な位置をしめている。しかし、固形癌中に存在す
る低酸素性細胞は放射線に対して強く抵抗するため、放
射線照射だけで癌組織を完全に破壊することは困難であ
る。そこで、この低酸素性細胞の放射線感受性を高める
薬物（放射線増感剤）を開発するための努力が行なわれ
ている。[Prior Art and Problems] Radiotherapy plays an important role in cancer treatment, along with surgical therapy and chemotherapy. However, since the hypoxic cells present in solid cancers strongly resist radiation, it is difficult to completely destroy cancer tissue by radiation irradiation alone. Therefore, efforts are being made to develop drugs (radiosensitizers) that increase the radiosensitivity of these hypoxic cells.
たとえばミソニダゾールやメトロニダゾールのようなニ
トロイミダゾール誘導体が放射線増感作用を有するもの
として知られている。しかし、これまでに知られている
放射線増感剤の多くは充分な増感効果を発揮することが
できず、また神経毒性を有するという種々の問題点があ
る。そこで低毒性でより高い放射線増感効果を存する化
合物をうるため、各種化合物を合成し、増感効果を検討
した結果、新規なニトロトリアゾール誘導体が低酸素性
細胞の放射線感受性を著しく増大させ、放射線治療効果
を増大させうることを見出し、本発明を完成するに至っ
た。For example, nitroimidazole derivatives such as misonidazole and metronidazole are known to have radiosensitizing effects. However, many of the radiosensitizers known so far have various problems such as not being able to exhibit sufficient sensitizing effects and having neurotoxicity. Therefore, in order to obtain a compound with low toxicity and higher radiosensitizing effect, we synthesized various compounds and examined their sensitizing effect. As a result, we found that a new nitrotriazole derivative significantly increased the radiosensitivity of hypoxic cells. The present inventors have discovered that the therapeutic effect can be increased, and have completed the present invention.
［問題点を解決するための手段］
本発明の新規なニトロトリアゾール誘導体は、一般式（
Ｉ）：
の１位または２位のチッ素原子に結合している）で示さ
れる３−ニトロ−１，２，４−）リアゾール誘導体であ
り、低酸素性細胞に対して大きな放射線増感作用を有し
ている。[Means for solving the problems] The novel nitrotriazole derivative of the present invention has the general formula (
I): is a 3-nitro-1,2,4-) lyazole derivative shown by (bonded to the nitrogen atom at the 1st or 2nd position of have.
［作用および実施態様］
一般式（１）のニトロトリアゾール誘導体は置換基Ｒを
トリアゾール環の１位に有する一般式（■）：（式中、
Ｘは前記と同じ）で示される化合物と、トリアゾール環
の２位にＲを有する一般式０１０゜（式中、Ｘは前記と
同じ）で示される化合物がある。[Operation and embodiments] The nitrotriazole derivative of general formula (1) has a substituent R at the 1-position of the triazole ring, and has general formula (■): (in the formula,
There are compounds represented by the general formula 010° (wherein X is the same as above) having R at the 2-position of the triazole ring.
本発明のニトロトリアゾール誘導体ＣＩ）は、３−ニト
ロ−１，２，４−）リアゾールとプロピレンオキシドと
を反応させてえられる一般式Ｎ：Ｉ
Ｃ）Ｉｓ
（式中、Ｒ１は−ＣＨ２−ＣＨ−ＯＨであり、トリアゾ
ール環の１位または２位のチッ素原子に結合している）
で示される化合物傳にクロル炭酸フェニルを反応させて
、一般式Ｍ：
υ
トリアゾール環の１位または２位のチッ素原子に結合し
ている）で示される化合物Ｍをえ、これと各種アミンと
を反応させることによってえられる。The nitrotriazole derivative CI) of the present invention has the general formula N:IC)Is (wherein R1 is -CH2-CH -OH and is bonded to the nitrogen atom at the 1st or 2nd position of the triazole ring)
A compound represented by the formula M is reacted with phenyl chlorocarbonate to obtain a compound M represented by the general formula M: It is obtained by reacting.
化合物■に対してクロル炭酸フェニルは２当量程度の過
剰量使用することが好ましい。この反応に使用する溶媒
としては塩化メチレンが適しており、反応においてはク
ロル炭酸フェニルと当量のピリジンを塩基として使用す
る。目的物を収率よくうるため、反応は０℃付近で進行
させることが好ましい。反応後、反応溶液を水で洗浄し
たのち、溶媒を情夫してえられる残渣をカラムクロマト
グラフィーにより分離して目的物をうる。化合物Ｍは再
結晶によって精製することができる。It is preferable to use phenyl chlorocarbonate in an excess amount of about 2 equivalents relative to compound (1). Methylene chloride is suitable as a solvent for this reaction, and pyridine in an amount equivalent to phenyl chlorocarbonate is used as a base in the reaction. In order to obtain the desired product in good yield, the reaction is preferably allowed to proceed at around 0°C. After the reaction, the reaction solution is washed with water, and the residue obtained by removing the solvent is separated by column chromatography to obtain the desired product. Compound M can be purified by recrystallization.
化合物Ｍに反応させるアミンは、ｎ−アミノプロピルモ
ルホリン、Ｎ−アミノエチルピペリジン、■−ビベラジ
ンエタリノールおよび４−ピペリジノビベリジンである
。化合物Ｍに対してアミンは１．２当量程度の過剰１１
２１使用することが好ましい。The amines to be reacted with Compound M are n-aminopropylmorpholine, N-aminoethylpiperidine, ■-biverazine ethalinol and 4-piperidinobiberidine. The amine is in excess of about 1.2 equivalents to compound M11
21 is preferably used.
この反応に使用する溶媒としては塩化メチレンが適して
おり、反応は室温で進行する。反応後、溶媒を留去して
えられる残渣をカラムクロマトグラフィーにより分離し
て目的物をうる。Methylene chloride is suitable as a solvent for this reaction, and the reaction proceeds at room temperature. After the reaction, the solvent is distilled off and the resulting residue is separated by column chromatography to obtain the desired product.
本発明の化合物（Ｉ）は低毒性でかつ低酸素性細胞に対
して優れた放射線増感作用を示しており、放射線増感剤
として有用である。Compound (I) of the present invention has low toxicity and exhibits an excellent radiosensitizing effect on hypoxic cells, and is useful as a radiosensitizer.
つぎに本発明を実施例に基づいて説明する。Next, the present invention will be explained based on examples.
参考例１
［化合物（Ｖａ） （化合物Ｍのうちトリアゾール環の
１位に置換基を有するもの）の合成］１−（２−ヒドロ
キシプロピル）−３−ニトロ−１，２，４−トリアゾー
ル１，５ ｇの塩化メチレン溶液３０ｍ１にクロル炭酸
フェニル２．７ｇとピリジン１．４ｇを加え、窒素雰囲
気下、０℃で４時間撹拌した。Reference Example 1 [Synthesis of compound (Va) (compound M having a substituent at the 1-position of the triazole ring)] 1-(2-hydroxypropyl)-3-nitro-1,2,4-triazole 1, 2.7 g of phenyl chlorocarbonate and 1.4 g of pyridine were added to 30 ml of a 5 g methylene chloride solution, and the mixture was stirred at 0° C. for 4 hours under a nitrogen atmosphere.
反応液を水で洗浄し、芒硝にて乾燥してから溶媒を減圧
留去してえられた残渣をシリカゲルカラムクロマトグラ
フィー（溶出溶媒として塩化メチレン：メタノール−９
：１を使用した）により分離精製し、無色油状の目的化
合物（Ｖａ）（収率９９％）をえた。The reaction solution was washed with water, dried over Glauber's salt, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (methylene chloride:methanol-9 as eluent)
:1) to obtain the target compound (Va) as a colorless oil (yield 99%).
ＭＳスペクトルのピークＨＭ” （ＩＩ／＋３） ２９
２Ｍ５ （高分解能）スペクトルのビーク：Ｍ” （
ａｌｅ）２９２．０８２４
ＣＩ２１’ｃ Ｎ４０５としての計算値 ２９２．０８
０８ＮＭＲスペクトル：δｐｐａ＋ （ＣＤＣｆ３）
１．４９ （３Ｈ，ｄ）、４．３〜４．７ （２１１
、ｍ）５．０〜５．４ （ＩＩＩ、 ｍ）、７．０
〜７．５ （５Ｈ，ｉ）８．２５ （ＩＨ，５）
ＩＲスペクトルニジｍａＸ（溶液法、ＣＨ（Ｊｓ）１７
８０、１５６０、１５００、１３１０、１２５０、８４
０ ｃｍ−”参考例２
［化合物（Ｖｂ） （化合物Ｍのうちトリアゾール環の
２位に置換基を有するもの）の合成コ参考例１の方法に
従い２−（２−ヒドロキシプロピル）−３−ニトロ−１
，２，４−トリアゾール２．Ｏｇとクロル炭酸フェニル
３８７ｇを反応させ、無色針状晶の目的化合物（Ｗｂ）
３．１ ｇ （収率９２％）をえた。MS spectrum peak HM” (II/+3) 29
2M5 (high resolution) peak of spectrum: M” (
ale) 292.0824 CI21'c Calculated value as N405 292.08
08NMR spectrum: δppa+ (CDCf3)
1.49 (3H, d), 4.3-4.7 (211
, m) 5.0-5.4 (III, m), 7.0
~7.5 (5H,i)8.25 (IH,5) IR spectrum Niji maX (solution method, CH(Js)17
80, 1560, 1500, 1310, 1250, 84
0 cm-” Reference Example 2 Synthesis of Compound (Vb) (Compound M having a substituent at the 2-position of the triazole ring) 2-(2-hydroxypropyl)-3-nitro -1
,2,4-triazole2. By reacting Og with 387 g of phenyl chlorocarbonate, the desired compound (Wb) was obtained as colorless needle-like crystals.
3.1 g (yield 92%) was obtained.
ＭＳスペクトルのビーク： Ｍ” （ａｌｅ） ２！
１１２Ｍ５ （高分解能）スペクトルのビーク：Ｍ”
（ｉｌｏ） ２９２．０８２８
ＣＩ２ ’ｒＪｕ Ｎ４０Ｓとしての計算値 ２９２．
０８０８ＮＭＲスペクトル：δｐｐｍ （ＣＤＣｆ３
）１．４８ （３ＨＳ ｄ）、４．６〜５．１ （２
Ｌ ｍ）５．２ 〜５．４ （１Ｂ、ｍ）、７．０
〜７．５ （５Ｂ％ ｍ）７．９９ （ＩＨ，ｓ）
実施例１
化合物（Ｖａ）１．８ Ｈの塩化メチレン溶液２０ｍ１
にＮ−アミノプロピルモルホリン１．Ｊ、ｇを加え、チ
ッ素雰囲気下室温で２８時間撹拌した。反応液から溶媒
を減圧留去してえられた残渣をシリカゲルカラムクロマ
トグラフィー（溶出溶媒として塩化メチレン：メタノー
ル−９＝１を使用した）より分離精製して黄色油状の目
的化合物１．８ｇ（収率８８％）をえた。MS spectrum peak: M” (ale) 2!
112M5 (high resolution) spectrum peak: M”
(ilo) 292.0828 CI2 'rJu Calculated value as N40S 292.
0808NMR spectrum: δppm (CDCf3
) 1.48 (3HS d), 4.6-5.1 (2
L m) 5.2 ~ 5.4 (1B, m), 7.0
~7.5 (5B% m) 7.99 (IH, s) Example 1 Compound (Va) 1.8 H methylene chloride solution 20 ml
and N-aminopropylmorpholine 1. J and g were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 28 hours. The residue obtained by evaporating the solvent from the reaction solution under reduced pressure was separated and purified by silica gel column chromatography (methylene chloride:methanol-9=1 was used as the eluent) to obtain 1.8 g of the target compound as a yellow oil (yield). rate of 88%).
ＭＳスペクトルのビーク： Ｍ” （ａｌｅ） ３４
２Ｍ５ （高分解能）スペクトルのビーク：Ｍ” （ａ
ｌｅ） ８４２．１ＢＥ１８ＣＩ３ Ｈ２２Ｎ５０Ｓ
としての計算値 ３４２．１８５２Ｎ月Ｒスペクトル：
δｐｐｍ （ＣＤ（Ｊ３ ）１．３３ （３Ｈ，ｄ）
、１．５〜１．８ （２Ｈ，ｍ）２．３〜２．５
（６Ｂ％ｍ）、３．１〜３．３ （２Ｈ，ａ＋）３．
６〜３．８ （４Ｈ，■）、４．２〜４．８ （２
Ｂ１ｍ）５．０〜５Ｊ （ＩＨｌｌ）、８．２４ （
ＩＨ，Ｓ）５．９ 〜ｅ、ｌ （ＬＨ−′；ＮＨ）Ｉ
Ｒスペクトルニジｍａｘ（溶液法、ＣＨＣｌ３）１７２
０．１５６０．１５００．１３００．１１２０．８４０
Ｃｍ−１実施例１の方法に従い化合物（Ｖａ）１．９
１：とＮ−アミノエチルピペリジンｔ、ｏ ｇを反応さ
せ、黄色油状の目的化合物１．７ ｇ （収率７８％）
をえた。MS spectrum peak: M” (ale) 34
2M5 (high resolution) peak of spectrum: M” (a
le) 842.1BE18CI3 H22N50S
Calculated value as 342.1852N Monthly R spectrum:
δppm (CD(J3)1.33 (3H, d)
, 1.5-1.8 (2H, m) 2.3-2.5
(6B%m), 3.1-3.3 (2H, a+)3.
6-3.8 (4H, ■), 4.2-4.8 (2
B1m) 5.0-5J (IHll), 8.24 (
IH,S)5.9 ~e,l (LH-';NH)I
R spectrum rainbow max (solution method, CHCl3) 172
0.1560.1500.1300.1120.840
Compound (Va) 1.9 according to the method of Cm-1 Example 1
1: was reacted with t,o g of N-aminoethylpiperidine to obtain 1.7 g of the target compound as a yellow oil (yield 78%).
I got it.
ＭＳスペクトルのビーク： Ｍ” （ａｌｅ） ３２
８Ｍ５ （高分解能）スペクトルのビーク：Ｍ” （ａ
ｌｅ） ３２６，１６７８
Ｃ１３Ｈ２２Ｎ６０４としての計算値 ３２６．１７０
１ＮＭＲスペクトル：δｐｐｍ （ＣＤＣｆｚ ）１
．３３ （３ＨＳｄ）、１．３〜１．８ （６１１％
ｍ）２．３〜２．６ （ＯＨＳｉ）、３．１〜３．４
（２Ｈ，ｓ＋）４．２〜４．６ （２Ｌ ｍ）、５
．０〜５．３ （Ｌｔ（、＠）８．３０ （１）１．
ｓ）、５．４〜５．６ （ＬＨ，ンＮＨ）ＩＲスペ
クトルニジ１ａＸ（溶液法、ＣＩＣ１３）１７２０．１
５６０．１５００．１３１０．８４０ ａ「’実施例１
の方法に従い化合物（１／ａ）１．４ ｇ−と１−ピペ
ラジンエタノール０．７３ ｇを反応させ、目的化合物
１．４ ｇ （収率８９％）をえた。MS spectrum peak: M” (ale) 32
8M5 (high resolution) peak of spectrum: M” (a
le) 326,1678 Calculated value as C13H22N604 326.170
1NMR spectrum: δppm (CDCfz)1
．． 33 (3HSd), 1.3-1.8 (611%
m) 2.3-2.6 (OHSi), 3.1-3.4
(2H,s+)4.2~4.6 (2L m), 5
．． 0~5.3 (Lt(,@)8.30 (1)1.
s), 5.4-5.6 (LH, NH) IR spectrum 1aX (solution method, CIC13) 1720.1
560.1500.1310.840 a"'Example 1
1.4 g of compound (1/a) and 0.73 g of 1-piperazine ethanol were reacted to obtain 1.4 g (yield: 89%) of the target compound.
ＭＳスペクトルのビーク： Ｍ” （ａｌｅ） ３２
ｇＭ５ （高分解能）スペクトルのビーク：Ｍ” （ａ
ｌｅ） ３２８．１５１０
Ｃ１ｔ ｌｈａ Ｎ＠Ｏｓとしての計算値 ３２８
．１４９５ＮＭＲスペクトル：δｐｐａ＋ （ＣＤＣ
ｆ３ ）ＩＪ６ （３Ｈ，ｄ）、２．４〜２．８ （
７Ｈ，、ｍ）３．３〜８．５ （４Ｈ，、ｍ）、３．
８５ （２Ｈ，ｔ）４．２〜４．７ （２Ｈ，ｍ）、
５．０〜５．３ （１８、ｍ）８．１８ （１８，ｓ
）、
ＴＲスペクトルニジｍａｘ（溶液法、ＣＨＣｌ５）８５
００ （ブロード） 、１７００．１５６０．１３００
ｅ ｔｘ −”実施例４
実施例１の方法に従い化合物（Ｖａ）１．１ ｇと４−
ピペリジノビベリジン０．７８ｇを反応させ、目的化合
物１．３ ｇ （収率９５％）をえた。MS spectrum peak: M” (ale) 32
gM5 (high resolution) peak of spectrum: M” (a
le) 328.1510 C1t lha Calculated value as N@Os 328
．． 1495 NMR spectrum: δppa+ (CDC
f3) IJ6 (3H, d), 2.4-2.8 (
7H,, m) 3.3-8.5 (4H,, m), 3.
85 (2H, t) 4.2 to 4.7 (2H, m),
5.0~5.3 (18, m) 8.18 (18, s
), TR spectrum max (solution method, CHCl5) 85
00 (broad), 1700.1560.1300
e tx -”Example 4 According to the method of Example 1, 1.1 g of compound (Va) and 4-
0.78 g of piperidino biveridine was reacted to obtain 1.3 g (yield 95%) of the target compound.
ＭＳスペクトルのビーク： Ｍ” （＋ｉ／ｅ） ３
ＯａＭＳ （高分解能）スペクトルのビーク：Ｍ” （
ｍ／ｅ） ３６８．２０４２
ＣＩ６ Ｈｉ Ｎ５Ｏａとしての計算値 ３８８．
２０１５ＮＭＲスペクトル＝δｐｐｍ （ＣＤＣＩ！
３）１．３５ （３Ｈ，ｄ）、１．３〜２．１ （Ｉ
ＯＨＳａ＋）２．５〜２．９ Ｃ７Ｈ％耐、３．９〜
４．３（２８Ｓｍ）４．２〜４．７ （２Ｈ，ｍ）
、 ５．０〜５．３ ＜ｉｌｌ、 膳）８．２３
（ＬＨ％Ｓ）、
ＩＲスペクトルニジｍａｘ（溶液法、Ｃ１１（Ｊ３）１
７００．１５６０．１３００．８４０ ａｍ−１実施例
１の方法に従い化合物（Ｖｂ）１．３ ｇとＮ−アミノ
プロピルモルホリン０．７８ｇを反応させ、目的化合物
１．３ ｇ （収率８θ％）をえた。MS spectrum peak: M” (+i/e) 3
Peak of OaMS (high resolution) spectrum: M” (
m/e) 368.2042 CI6 Hi Calculated value as N5Oa 388.
2015 NMR spectrum = δppm (CDCI!
3) 1.35 (3H, d), 1.3-2.1 (I
OHSa+)2.5~2.9 C7H% resistance, 3.9~
4.3 (28Sm) 4.2~4.7 (2H, m)
, 5.0~5.3 <ill, zen) 8.23
(LH%S), IR spectrum max (solution method, C11(J3)1
700.1560.1300.840 am-1 1.3 g of compound (Vb) and 0.78 g of N-aminopropylmorpholine were reacted according to the method of Example 1 to obtain 1.3 g of the target compound (yield 8θ%). I got it.
ＭＳスペクトルのビーク： Ｍ” （ｍ／ｅ） ３４
２Ｍ５ （高分解能）スペクトルのビーク：Ｍ” （＋
ｇ／ｅ） ３４２．ＩＨＩ
Ｃ１３Ｎ２２ Ｎ５０４としての計算値 ３４２．１
ｆ１５１ＮＭＲスペクトル：δｐｐｍ （ＣＤＣｆ３
）ＩＪＯ（３８，、ｄ）、１．５〜１．８ （２Ｈ，
ｍ）２．３〜２．５ （１３Ｈ，ｍ）、３．０〜３．
３（２Ｈ，、ｍ）３、Ｂ 〜３．８ （４１，謙）
、 ４．５〜４．９ （２Ｈ，ｍ）５．１〜５．４
（ＩＨＳｍ）、７．９４ （ＩＨｌＳ）５．７〜５
．９ （ＩＨ，＞Ｎｕ＞
ＪＲスペクトルニジｔａａｘＣ溶液法、ＣＨＣｉ）１７
２０．１５６０．１５２０．１１１０％ ８４０ ｃｍ
−’実施例１の方法に従い化合物（Ｖｂ）１．２ ｇと
Ｎ−アミノエチルピペリジン０．６５ｇを反応させ、目
的化合物１．２ ｇ （収率８６％）をえた。Peak of MS spectrum: M” (m/e) 34
2M5 (high resolution) peak of spectrum: M” (+
g/e) 342. Calculated value as IHI C13N22 N504 342.1
f151NMR spectrum: δppm (CDCf3
) IJO (38,, d), 1.5-1.8 (2H,
m) 2.3-2.5 (13H, m), 3.0-3.
3 (2H,, m) 3, B ~3.8 (41, Ken)
, 4.5-4.9 (2H, m) 5.1-5.4
(IHSm), 7.94 (IHLS) 5.7-5
．． 9 (IH,>Nu> JR Spectral Niji taxC solution method, CHCi) 17
20.1560.1520.1110% 840 cm
-' 1.2 g of compound (Vb) and 0.65 g of N-aminoethylpiperidine were reacted according to the method of Example 1 to obtain 1.2 g (yield: 86%) of the target compound.
ＭＳスペクトルのビーク： Ｍ” （ｔａ／θ）３２
ＢＭＳ （高分解能）スペクトルのビーク：Ｍ” （
ｓ／ｅ） ３２８．１７０１ＣＩ３ Ｎ２２ Ｎ
１１０４としての計算値 ３２８．１７０１ＮＭＲスペ
クトル：δＩ）Ｉ）ｍ （ＣＤＣｆａ ）１．３１
（３１１％ ｄ）、１．４〜１．７ （６Ｈ，、ｍ）
２．３〜２．５ （６Ｈ，ｍ）、３．０〜３．３（２
Ｈ％ ａ＋）４．５〜４．９ （ＺＨ％ ｍ）、
５．１ 〜５．５ （２Ｈ，ｍ 、 ′；Ｎ１１
） ７．９３（ｉＨ、５）ＩＲスペクトルニジｍａｘ
（溶液法、ＣＨ（Ｊ３）１７２０．１５６０．１５１０
．８４０ ａ「１実施例１の方法に従い化合物（Ｖｂ）
１．１ ｇと１−ピペラジンエタノール０．７０ｇ−を
反応させ、目的化合物１．２ ｇ （収率８２％）をえ
た。Peak of MS spectrum: M” (ta/θ)32
Peak of BMS (high resolution) spectrum: M” (
s/e) 328.1701CI3 N22 N
Calculated value as 1104 328.1701 NMR spectrum: δI)I)m (CDCfa) 1.31
(311% d), 1.4-1.7 (6H,, m)
2.3-2.5 (6H, m), 3.0-3.3 (2
H% a+) 4.5 to 4.9 (ZH% m), 5.1 to 5.5 (2H, m, '; N11
) 7.93 (iH, 5) IR spectrum max
(Solution method, CH(J3) 1720.1560.1510
．． 840 a "1 Compound (Vb) according to the method of Example 1
1.1 g and 0.70 g of 1-piperazine ethanol were reacted to obtain 1.2 g (yield: 82%) of the target compound.
Ｍ／Ｓスペクトルのビーク： Ｍ” （＋＋＋／ｅ）
３２８Ｍ５ （高分解能）スペクトルのビーク：Ｍ”
（ｍ／ｅ） ３２８．１４７５
ＣＩ２ １ｂｅ Ｎ６０ｓとしての計算値 ３２８．
１４９４ＮＭＲスペクトル：δｐｐｔｉ （ＣＤＣｆ
ａ ）１．３３ （３８Ｓｄ）、２６３〜２．６ （
７Ｈ，ｍ）３．２〜３．４ （４Ｈ，ａ＋）、３．６
２ ＜２Ｈ，ｔ）４．７〜４．９ （２Ｈ，ｆｆ１）
、５．１〜５．４ （ＩＨＳｉ）７．９１ （ＩＨ，
Ｓ）、
ＩＲスペクトルニジｍａｘＣ溶液法、ＣＨＣｆ３）８５
００ （ブロード） 、１７００．１５８０．１１２０
゜８４０ｃｍ−’
実施例８
実施例１の方法に従い化合物（ｖｂ）ｉ、ｉ ｇと４−
ピペリジノビベリジン０．７７ｇを反応させ、目的化合
物１．１ ｇ （収率７８％）をえた。Peak of M/S spectrum: M” (+++/e)
328M5 (high resolution) spectrum peak: M”
(m/e) 328.1475 Calculated value as CI2 1be N60s 328.
1494NMR spectrum: δppti (CDCf
a) 1.33 (38Sd), 263-2.6 (
7H, m) 3.2-3.4 (4H, a+), 3.6
2 <2H, t) 4.7 to 4.9 (2H, ff1)
, 5.1-5.4 (IHSi) 7.91 (IH,
S), IR spectrum maxC solution method, CHCf3)85
00 (broad), 1700.1580.1120
゜840 cm-' Example 8 According to the method of Example 1, compounds (vb) i, i g and 4-
0.77 g of piperidino biveridine was reacted to obtain 1.1 g (yield 78%) of the target compound.
ＭＳスペクトルのビーク： Ｍ” （ｍ／ｅ） ａ６
ｅＭＳ （高分解能）スペクトルのビーク：Ｍ” （ｇ
／ｅ） ３８６．１９９９
ＣＩ６ Ｈｉ Ｎ６０ａとしての計算値 ３８６．
２０１４ＮＭＲスペクトル： ６ ｐｐｍ （ＣＤＣ
ｆ ｓ ）１．３３（３Ｈ１ｄ）、１．２〜２．０
（ＩＯＨＳｍ）２．４〜２．９ （７Ｈ，ｉ）、３．
８〜４．２（２Ｈ％ａ＋）４．７〜４．９ （２Ｈ％
謹）、５．１〜５．４ （ＩＨ，ｍ）７．９２（０１
，５）
ＩＲスペクトルニジｔｘａｘＣ溶液法、ＣＨＣｌｇ）１
７００、１５１３０．１５１０．８４０本発明の化合物
は放射線治療における低酸素性細胞の放射線増感剤とし
て有用であり、その投与量は腫瘍の種類および化合物に
よっても異なるが、一般には、経口剤では２０〜ｌＯ口
００ｍｇ ｓ注射剤では０．５〜１００ＯＯＢ 、原剤
では２０〜１００００ Ｂであり、最適投与量は、症状
に応じた医師の判断に基づき、放射線の種類、照射線量
、照射分割度などに応じて決定される。Peak of MS spectrum: M” (m/e) a6
Peak of eMS (high resolution) spectrum: M” (g
/e) 386.1999 CI6 Hi Calculated value as N60a 386.
2014 NMR spectrum: 6 ppm (CDC
f s ) 1.33 (3H1d), 1.2-2.0
(IOHSm)2.4-2.9 (7H,i),3.
8-4.2 (2H% a+) 4.7-4.9 (2H%
5.1-5.4 (IH, m) 7.92 (01
, 5) IR spectrum txaxC solution method, CHClg) 1
700, 15130.1510.840 The compounds of the present invention are useful as radiosensitizers for hypoxic cells in radiotherapy, and the dosage varies depending on the tumor type and the compound, but in general, the oral dosage is 20. ~lO 00mg s 0.5 to 100 OOB for injections and 20 to 10,000 B for bulk drugs.The optimal dose is based on the doctor's judgment according to the symptoms, and depends on the type of radiation, irradiation dose, irradiation fraction, etc. Determined accordingly.
また、本発明の化合物の投与形態には特に制約はなく、
担体として薬学分野で通常使用されるものが使用でき、
この分野で慣用されている手段に従って調整される。Furthermore, there are no particular restrictions on the dosage form of the compound of the present invention,
As carriers, those commonly used in the pharmaceutical field can be used.
Adjustments are made according to means customary in this field.
つぎに本発明の化合物の放射線増感作用の試験例を示す
。Next, a test example of the radiosensitizing effect of the compound of the present invention will be shown.
試験例１
［１ｎ ｖｉｔｒｏでの低酸素性細胞に対する放射線増
感作用］
試験にはつぎの方法を採用した。Test Example 1 [Radiosensitizing effect on hypoxic cells in 1n vitro] The following method was adopted for the test.
すなわち、チャイニーズハムスターＶ７９細胞４〜５
Ｘ １０５１０．５ ｍｌに第１表に示す濃度で同表に
示す試験化合物を加え、混合チッ素ガス（９５％チッ素
、５％二酸化炭素）を通じ低酸素状態としたのちＧｏＣ
ｏのγ線（線量率２．３４Ｇｙ／ｗｉｎ ）を７．ＯＬ
９．３８、Ｊ、１．７０．１４．０７．１８．７２．
２３．４０Ｇｙの線量照射した。細胞をハンクス液で洗
浄し試験化合物を除いたのち、１０％牛血清添加ＨＥＭ
培地にまき、１０〜１２日後に形成されたコロニー数に
より生存率を求めた。試験化合物を含まない低酸素状態
の細胞にγ線を照射した群を対照とした。対照および各
濃度での生存率と線量め関係から、細胞生存率を１％ま
で減少させるのに必要な線量を対照（Ｄｏ）および各濃
度（Ｄｏ’）について求め、式：
％式％
により算出した。結果を第１表に示す。That is, Chinese hamster V79 cells 4-5
The test compounds shown in Table 1 at the concentrations shown in Table 1 were added to 10.5 ml of X 105, and the mixture was brought into a hypoxic state by passing nitrogen gas mixture (95% nitrogen, 5% carbon dioxide), followed by GoC.
7.o gamma rays (dose rate 2.34Gy/win). OL
9.38, J, 1.70.14.07.18.72.
A dose of 23.40 Gy was irradiated. After washing the cells with Hank's solution to remove the test compound, add HEM supplemented with 10% bovine serum.
The survival rate was determined by the number of colonies formed after 10 to 12 days of inoculation on a medium. A group in which cells in hypoxic conditions without the test compound were irradiated with gamma rays served as a control. From the survival rate and dose relationship for the control and each concentration, determine the dose required to reduce the cell survival rate to 1% for the control (Do) and each concentration (Do'), and calculate using the formula: % Formula % did. The results are shown in Table 1.
［以下余白］
第１表
試験例２
［１ｎ ｖｉｖｏでの低酸素性細胞に対する放射線増感
作用］
試験にはつぎの方法を採用した。[Margin below] Table 1 Test Example 2 [1n Vivo Radiosensitizing Effect on Hypoxic Cells] The following method was adopted for the test.
すなわち、大腿部皮下にＳＣＣ■癌腫を移植したＣ３１
１ ／ ｌｉｅマウスに、生理食塩水に溶解した試験化
合物を腹腔内投与し、４０分後湾線（線量率５．８Ｇｙ
／ ｍ１ｎ ） をＩＢ、８．１９，８．２２ｏ４．
２５．２Ｇｙの線量を全身照射した。照射後ただちに癌
腫を取り出しｉｎ ｖｌｔｒｏのばあいと同様にコロニ
ー形成法によって細胞生存率を求めた。生理食塩水だけ
を投与して放射線照射した群を対照として１ｎｖ１ｔｒ
ｏのばあいと同様に増感率を算出した。結果を第２表に
示す。That is, C31 with SCC carcinoma implanted subcutaneously in the thigh.
The test compound dissolved in physiological saline was administered intraperitoneally to 1/lie mice, and 40 minutes later the test compound was administered intraperitoneally (dose rate: 5.8 Gy).
/ m1n) to IB, 8.19, 8.22o4.
The whole body was irradiated with a dose of 25.2 Gy. Immediately after irradiation, the carcinoma was removed and the cell survival rate was determined by the colony formation method as in the in vitro case. 1nv1tr with the group receiving only physiological saline and irradiated as a control.
The sensitization rate was calculated in the same manner as in case o. The results are shown in Table 2.
［以下余白］[Margin below]
Claims (1)
、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼ または▲数式、化学式、表等があります▼）であり、ト
リアゾー ル環の１位または２位のチッ素原子に結合している）で
示される３−ニトロ−１，２，４−トリアゾール誘導体
。 ２ 一般式（II）： ▲数式、化学式、表等があります▼（II） （式中、Ｘは前記と同じ）で示される特許請求の範囲第
１項記載の３−ニトロ−１，２，４−トリアゾール誘導
体。 ３ 一般式（III）： ▲数式、化学式、表等があります▼（III） （式中、Ｘは前記と同じ）で示される３−ニトロ−１，
２，４−トリアゾール誘導体。 ４ 一般式（Ｖ） ▲数式、化学式、表等があります▼（Ｖ） （式中、Ｒ＾２は▲数式、化学式、表等があります▼で
あり、 トリアゾール環の１位または２位のチッ素原子に結合し
ている）で示される化合物にＮ−アミノプロピルモルホ
リン、Ｎ−アミノエチルピペリジン、１−ピペラジンエ
タノールおよび４−ピペリジノピペリジンよりなる群か
ら選ばれたアミンを反応させることを特徴とする一般式
（ I ）： ▲数式、化学式、表等があります▼（ I ） （式中、Ｒは▲数式、化学式、表等があります▼（Ｘは
、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼ または▲数式、化学式、表等があります▼）であり、ト
リアゾー ル環の１位または２位のチッ素原子に結合している）で
示される３−ニトロ−１，２，４−トリアゾール誘導体
の製法。[Claims] 1 General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (X is ▲Mathematical formulas, chemical formulas, etc.) , tables, etc. ▼, ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. The 3-nitro-1,2,4-triazole derivatives shown. 2 General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, X is the same as above) 3-nitro-1,2, as described in claim 1, 4-triazole derivative. 3 General formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, X is the same as above) 3-nitro-1,
2,4-triazole derivative. 4 General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R^2 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and it is the tip at the 1st or 2nd position of the triazole ring. A compound represented by (bonded to an elementary atom) is reacted with an amine selected from the group consisting of N-aminopropylmorpholine, N-aminoethylpiperidine, 1-piperazineethanol, and 4-piperidinopiperidine. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is ▲There are mathematical formulas, chemical formulas, tables, etc.) ▼、▲Mathematical formula, chemical formula,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. A method for producing the 3-nitro-1,2,4-triazole derivative shown.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8763487A JPS63253077A (en) | 1987-04-09 | 1987-04-09 | Nitrotriazole derivative and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8763487A JPS63253077A (en) | 1987-04-09 | 1987-04-09 | Nitrotriazole derivative and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63253077A true JPS63253077A (en) | 1988-10-20 |
Family
ID=13920408
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8763487A Pending JPS63253077A (en) | 1987-04-09 | 1987-04-09 | Nitrotriazole derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63253077A (en) |
-
1987
- 1987-04-09 JP JP8763487A patent/JPS63253077A/en active Pending
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