KR900007399B1 - Process for the preparation of 2-radioactive iodo spiroperidol - Google Patents
Process for the preparation of 2-radioactive iodo spiroperidolInfo
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- KR900007399B1 KR900007399B1 KR1019840002810A KR840002810A KR900007399B1 KR 900007399 B1 KR900007399 B1 KR 900007399B1 KR 1019840002810 A KR1019840002810 A KR 1019840002810A KR 840002810 A KR840002810 A KR 840002810A KR 900007399 B1 KR900007399 B1 KR 900007399B1
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- iodine
- spiroperidol
- metal salt
- radioactive iodine
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- 0 Cc1ccc(C)c(*)c1 Chemical compound Cc1ccc(C)c(*)c1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 신규의 방사성 2-요오도 스피로페리돌 및 그의 제조방법에 관한 것이다.The present invention relates to a novel radioactive 2-iodo spiroperidol and a process for preparing the same.
본 발명의 화합물은 문헌에 기재되어 있지 않은 신규 화합물로서, 도퍼민, 수용체에 대하여 높은 친화성을 갖고 있으며, 도퍼민 수용체의 핵의학 진단약으로서, 또한 방사성 의약품으로서 극히 유용한 것이다.The compound of the present invention is a novel compound which is not described in the literature, has a high affinity for dofferin and a receptor, and is extremely useful as a nuclear medicine diagnostic agent for a doffermin receptor and as a radiopharmaceutical.
최근에, 뇌의 병적상태(예를 들면, 파킨슨씨병 또는 정신 분열병 등)에 있어, 도퍼민 수용체의 양이 정상인에 비하여 변화함을 발견하였다. 도퍼민 수용체와 여러가지의 뇌의 질환과의 관계가 의학 및 약학 분야에 있어 주목되고 있다. 이와 같은 상황을 배경으로 하여 도퍼민 수용체를 목적으로 하는 핵의학 진단약과 방사성 의약품의 출현이 강력이 요망되고 있다.Recently, it has been discovered that the amount of dopamine receptor changes in the pathological state of the brain (for example, Parkinson's disease or schizophrenia) compared to normal people. The relationship between dopamine receptors and various brain diseases is drawing attention in the medical and pharmaceutical fields. Against this backdrop, the emergence of nuclear medicine diagnostic drugs and radiopharmaceuticals aimed at doffermin receptors is strongly desired.
본 발명자들은 방사성의 요오드를 분자내에 갖는 도퍼민 수용체 지향성 진단약과 방사성 의약품을 목표로 연구를 행하여 다음 일반식( I )의 신규 요오드 화합물이 도퍼민 수용체에 대하여 높은 친화성을 가지며, 또한 특이적으로 이와 결합함을 발견하였다.The present inventors conducted research aiming at dopamine receptor-directed diagnostic drugs and radiopharmaceuticals having radioactive iodine in a molecule, and the novel iodine compounds of the following general formula (I) have a high affinity for dopamine receptors, and specifically Found binding to this.
본 발명에 의하여 다음 일반식( I )의 신규 방사성 2-요오드 스피로페리돌 및 이의 제조방법이 제공된다.The present invention provides a novel radioactive 2-iodine spiroperidol of the general formula (I) and a method for preparing the same.
[상기식에서 X는 방사성 요오드원자를 나타낸다 ][Wherein X represents a radioactive iodine atom]
본 발명의 화합물( I )은 문헌 기재의 요오드 화합물인 p-요오드 스피로페리돌[J.Nuclear Medicine,23(5),100(1982)]에 비하여 도퍼민 수용체에 대해 횔씬 높은 친화성을 갖고 있으며, 도퍼민 수용체 지향성의 방사성 진단약과 방사성 의약품으로서 대단히 뛰어난 성질을 갖고 있다.Compound (I) of the present invention has a much higher affinity for dopamine receptors than p-iodine spiroperidol (J. Nuclear Medicine, 23 (5), 100 (1982)), an iodine compound described in the literature. In addition, it has excellent properties as a radiopharmaceutical and radiopharmaceutical of dopamine receptor-oriented.
따라서, 본 발명 화합물( I )을 사용하면, 사람 또는 동물의 뇌와 기타의 장기, 조직의 도퍼민 수용체의 존재를 안전하게 검출할 수 있을 뿐 아니라, 수용체의 양의 변화를 동적으로 측정할 수 있으므로 뇌의 질환등의 핵의학 진단과 치료에 대단히 유용하다. 또한 유방암 등의 암과 도퍼민 수용체와의 관련성에 의하여 이 방면에의 응용에 있어서도 유용하다.Therefore, by using the compound (I) of the present invention, it is possible not only to safely detect the presence of dopamine receptors in the brain and other organs and tissues of human or animal, but also to dynamically measure changes in the amount of receptors. It is very useful for the diagnosis and treatment of nuclear medicine such as diseases of the brain. Moreover, it is useful also in the application to this aspect by the relationship between cancer, such as breast cancer, and a doffermin receptor.
다음에 본 발명 화합물의 제조방법에 대하여 설명한다.Next, the manufacturing method of the compound of this invention is demonstrated.
상기 일반식( I )로 나타낸 본 발명 화합물은 방사성 요오드 화합물의 일반적 합성법에 의하여 제조할 수있으나, 예를 들면 다음에 나타낸 방법 A 또는 방법 B에 따라서 제조할 수가 있다.The compound of the present invention represented by the general formula (I) can be produced by a general synthesis method of a radioactive iodine compound, but can be produced according to, for example, Method A or Method B shown below.
방법AMethod A
다음 일반식(II)Next Formula (II)
로 나타낸 아미노 화합물을 적당한 용매, 예를 들면, 테트라 히드로푸란, 디옥산 또는 아세토니트릴 등 중에서 묽은 황산 또는 묽은 염산 등의 산의 존재하에 아질산 알칼리 금속염과 반응시켜서 다음 일반식(III)The amino compound represented by the following reaction is reacted with alkali metal nitrite salt in the presence of an acid such as dilute sulfuric acid or dilute hydrochloric acid in a suitable solvent such as tetrahydrofuran, dioxane or acetonitrile and the following general formula (III)
[상기 식중에서 Z-는 할로겐 이온 또는 식로 나타내는 음이온을 나타낸다]로 나타낸 디아조늄염을 형성 시킨다.[Wherein Z- is a halogen ion or a formula To form a diazonium salt.
이어서 화합물(III)을 방사성 요오드 금속염과 반응시킴으로써 상기 식( I )의 본 발명 화합물을 얻는다. 본 반응은 -5 내지 30℃의 범위에서 실시된다.The compound of the present invention of formula (I) is obtained by reacting compound (III) with a radioactive iodine metal salt. This reaction is performed in the range of -5 to 30 ° C.
얻어진 화합물( I )은 박층 크로마토그래피{TLC) 또는 고속 액체 크로마토그래피(HPLC) 등의 일반적 방법에 의하여 정제할 수가 있다.The obtained compound (I) can be purified by a general method such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
방법BMethod B
일반식 (IV)General formula (IV)
[상기 식중에서, Y는 할로겐원자를 나타낸다]로 나타낸 할로겐 화합물을 적당한 용매, 예를 들면, 아세토니트릴, 디메틸포름아미드, 에틸렌글리콜, 에틸렌글리콜의 에테르유도체, 디에틸렌글리콜의 에테르유도체, 물 등에서 50 내지 180℃의 반응 온도로 방사성 요오드 금속염과 교환 반응시킨다. 얻어진 화합물( I )은 TLC 또는 HPLC 등의 일반적 방법에 의하여 정제할 수가 있다.Wherein the halogen compound represented by [wherein Y represents a halogen atom] is used in a suitable solvent such as acetonitrile, dimethylformamide, ethylene glycol, ether derivative of ethylene glycol, ether derivative of diethylene glycol, water and the like. Exchange reaction with the radioactive iodine metal salt at a reaction temperature of from 180 ° C. The obtained compound (I) can be purified by a general method such as TLC or HPLC.
본 발명에 있어 방사성의 요오드 원자로서는 예를 들면, I -123, I -125, I -131, I -132 등이 예시되며, 바람직하기로는 I -123, I -125, I -131이다. 방사성 요오드 금속염이란 상기 방사성 요오드의 금속염을 의미하며, 방사성 I-이온을 제공하는 것이면 관계가 없지만 바람직하기로는 예를 들면, 요오드화나트륨, 요오드화칼륨. 요오드화리튬과 같은 알칼리금속염이다. 일반식(III)에 있어서의 할로겐이온으로서는 예를 들면, 염소, 브롬, 요오드 등의 음이온이 예시되며, 일반식(IV)에 있어서의 할로겐원자로서는 예를 들면, 불소원자, 염소원자, 브롬원자, 요오드원자를 예시할 수가 있다.In the present invention, examples of the radioactive iodine atoms include I-123, I-125, I-131, I-132, and the like, and preferably I-123, I-125, and I-131. The radioactive iodine metal salt refers to the metal salt of the radioactive iodine, irrespective of providing radioactive I - ions, but preferably, for example, sodium iodide, potassium iodide. Alkali metal salts such as lithium iodide. Examples of the halogen ions in the general formula (III) include anions such as chlorine, bromine and iodine. Examples of the halogen atoms in the general formula (IV) include a fluorine atom, a chlorine atom and a bromine atom. For example, the iodine atom can be illustrated.
본 발명에 의하여 얻어지는 방사성 2-요오드 스피로페리돌( I )을 환자에게 정맥주사하여 경시적으로 신티그램을 취하며, 또는 프로프법에 의하여 방사능을 측정하여 해당하는 화합물(I)의 특정기관에의 취입을 측청함으로써 병소부위 범위와 질환의 정도를 간편하게 할 수 있으며, 또한 정확하게 진단할 수가 있다.The radioactive 2-iodine spiroperidol (I) obtained by the present invention is intravenously injected to a patient to take a syntgram over time, or the radioactivity is measured by the Prop method to determine the corresponding compound (I) to a specific organ. By measuring the blowing, the range of the lesion site and the degree of disease can be simplified, and the diagnosis can be made accurately.
또한, 본 발명에 관한 방사성 2-요오드 스피로페리돌은 뇌의 질환과 유방암 등의 진단에 유용한데, 기타 도퍼민 수용체의 변화에 유래하는 각종 질환의 진단과 치료에도 유용하다.In addition, the radioactive 2-iodine spiroperidol according to the present invention is useful for diagnosing diseases of the brain and breast cancer and the like, and is also useful for diagnosing and treating various diseases resulting from changes in other dopamine receptors.
다음에 실시예를 들어서 본 발명을 더욱 구체적으로 설명한다.Next, an Example is given and this invention is demonstrated further more concretely.
참고예Reference Example
8-[4-(4-플루오로-2-요오드페닐)-4-옥소부틸]-1-페닐-1,3,8-트리아자스피로[4,5]데칸-4-온(2-요오드 스피로페리돌)의 제조.8- [4- (4-fluoro-2-iodinephenyl) -4-oxobutyl] -1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one (2-iodine Spiroperidol).
2-아미노 스피로페리돌(410mg)을 2N-염산 및 아세토니트릴에 현탁하고 얻어진 현탁액에 빙냉하에 아질산나트륨(95mg)의 수용액을 한방울씩 가한다. 얻어진 혼합물을 5℃이하에서 30분간 교반하고, 얻어진 디아조늄염에 빙냉하에 요오드화칼륨(166mg)의 수용액을 한방울씩 가한다. 첨가 후, 얻어진 혼합물을 동 온도에서 1.5시간 교반한다. 반응후 반응 혼합물을 알칼리성으로하여 용매 추출하여 용매를 유거하면 조생성 물을 얻는다. 이를 실리카겔 컬럼 크로마토그래피에 의하여 정제하여 2-요오드 스피로페리돌(427mg)을 얻는다.2-amino spiroperidol (410 mg) is suspended in 2N-hydrochloric acid and acetonitrile and an aqueous solution of sodium nitrite (95 mg) is added dropwise to the obtained suspension under ice cooling. The obtained mixture was stirred at 5 ° C. or lower for 30 minutes, and an aqueous solution of potassium iodide (166 mg) was added dropwise to the obtained diazonium salt under ice cooling. After addition, the resulting mixture is stirred at the same temperature for 1.5 hours. After the reaction, the reaction mixture is made alkaline and the solvent is extracted and the solvent is distilled off to obtain crude product. It is purified by silica gel column chromatography to give 2-iodine spiroperidol (427 mg).
융점 : l70 내지 175℃Melting Point: l70 ~ 175 ℃
IR(CHC13)cm-1: 1710(C=O)IR (CHC1 3 ) cm -1 : 1710 (C = O)
1H-NMR(CDC13)δ(ppm):1.40~3.18(l4H,m,메틸렌),4.72(2H,s,),6.31∼7.79(8H,m,벤젠환) 1 H-NMR (CDC1 3 ) δ (ppm): 1.40 ~ 3.18 (l4H, m, methylene), 4.72 (2H, s, ), 6.31 to 7.79 (8H, m, benzene ring )
질량 스펙트럼(70ev) m/e : 521[M+],244Mass spectrum (70ev) m / e: 521 [M + ], 244
실시예1Example 1
[125I]-8-[4-(4-플루오로-2-요오드페닐)-4-옥소부틸]-1-페닐-1,3,8-트리아자스피로[4,5]데칸-4-온([125I ]-2-요오드 스피로페리돌)의 제조.[ 125 I] -8- [4- (4-fluoro-2-iodinephenyl) -4-oxobutyl] -1-phenyl-1,3,8-triazaspiro [4,5] decane-4- Preparation of on ([ 125 I] -2-iodine spiroperidol).
2-아미노 스피로페리돌(40μg)과 2N-황산과 아질산 나트륨을 사용하여 조제한 디아조늄염에 빙냉하에 Na125I(2mCi)을 참고예와 같이하여 반응시키고 얻어진 조 생성물을 HPLC(컬럼 : Licrosorb RP-18)에 의하여 정제하고, [125I]-2-요오드 스피로페리돌(1.4mCi)을 얻는다.Na under ice-cooling in a diazonium salt prepared using 2-amino spiroperidol (40 μg), 2N-sulfuric acid, and sodium nitrite.125I (2mCi) was reacted as in the Reference Example, and the obtained crude product was purified by HPLC (column: Licrosorb). By RP-18), [125I] -2-iodine spiroperidol (1.4 mCi) is obtained.
수득된 본 제품은 TLC와 HPLC의 Rf치가 참고예에서 얻은 표제의 제품과 일치하였다.The obtained product had a Rf value of TLC and HPLC consistent with the title product obtained in Reference Example.
실시예2Example 2
Na123I에 의한 [123I ]-2-요오드 스피로페리돌의 제조.Preparation of [ 123 I] -2-iodine spiroperidol by Na 123 I.
Na123I(5mCi)을 사용하여 실시예 l과 같은 방법에 의하여 [123I]-2-요오드 스피로페리돌(1.4mCi)을 얻는다.[ 123 1] -2-iodine spiroperidol (1.4 mCi) was obtained by the same method as Example 1 using Na 123 I (5 mCi).
본 제품은 TLC와 HPLC의 Rf치가 참고예에서 얻은 표제의 제품과 일치하였다.The product had an Rf value of TLC and HPLC consistent with the title product obtained in the reference example.
실시예 3Example 3
교환법에 의한 [125I]-2-요오드 스피로페리돌의 제조.Preparation of [ 125 I] -2-iodine Spiroperidol by Exchange Method.
참고예의 방법에서 합성한 2-요오드 스피로페리돌(3μg)에 디메틸포름아미드(10μl )와 Na125I(2.2mCi)을 가하고, 또한 미량의 0.lN 황산을 가하여 얻어진 혼합물을 가열한다. 반응 후, 조생성물을 HPLC에 의하여 정제하여 [125I]-2-요오드 스피로페리돌(0.9mCi)을 얻는다.Dimethylformamide (10 μl) and Na 125 I (2.2 mCi) are added to 2-iodine spiroperidol (3 μg) synthesized in the method of Reference Example, and a mixture obtained by adding a trace amount of 0.01 mL sulfuric acid is heated. After reaction, the crude product is purified by HPLC to give [ 125 I] -2-iodine spiroperidol (0.9 mCi).
본 제품은 TLC와 HPLC의 Rf치가 참고예에서 얻어진 표제의 제품과 일치하였다.The product had an Rf value of TLC and HPLC consistent with the title product obtained in Reference Example.
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