JP2586411B2 - Radioactive benzodiazepine derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the general formula:

Embedded image [Wherein, R represents a hydrogen atom or a lower alkyl group,
X ^* represents a radioactive iodine atom or a bromine atom, Y represents a halogen atom, and Z represents a halogen atom or a nitro group. The present invention relates to a novel radioactive benzodiazepine derivative or a salt thereof (hereinafter, referred to as the compound of the present invention) and a method for producing them. The compound of the present invention represented by the general formula 8 is a novel compound which has not been described in the literature, has a very high affinity for the benzodiazepine receptor, and is useful as an in vivo or in vitro nuclear medicine diagnostic agent for the benzodiazepine receptor. And are extremely useful as radiopharmaceuticals. Further, since the compound of the present invention has high affinity for benzodiazepine antibodies, it is extremely useful as a radioligand for radioimmunoassay (radioimmunoassay).

[0002]

2. Description of the Related Art In recent years, it has been found that the amount of benzodiazepine receptor is changed in pathological states of the brain (for example, epilepsy and dementia), and the relationship between the benzodiazepine receptor and various brain diseases has been studied in medicine. , Has been attracting attention in the field of pharmacy. Against this background, the emergence of nuclear medicine diagnostics and radiopharmaceuticals targeting benzodiazepine receptors has been strongly desired. As such diagnostic agents or pharmaceuticals, recently, benzodiazepine receptor-directed compounds labeled with positron nuclide C-11,
[C-11] R ₀ 15-1788 has been developed, and studies on benzodiazepine receptors by the PET method have been attempted. (J.
Psychiatr. Res., 19 , 609 (1985); Radioisotopes,
34 , 302 (1985)].

[0003]

However, the method using [C-11] R ₀ 15-1788 requires a cyclotron facility in a clinical setting because the half-life of C-11 is extremely short. In addition, there are many practical problems, such as the need to synthesize a labeled compound in a short time.

[0004]

Means for Solving the Problems The present inventors have conducted research on benzodiazepine receptor-directed diagnostic agents and radiopharmaceuticals having a radioactive iodine atom or bromine atom in the molecule, and obtained the above-mentioned general formula 8 The indicated compounds of the invention have very high affinity for the benzodiazepine receptor,
It was found to specifically bind to it. Also, radioactive I-123 or Br-77 may be selected from the compounds of the present invention.
If the labeled compound containing is selected and the SPECT method is used, the above-mentioned problem of the PET method according to [C-11] R ₀ 15-1788 can be solved, and the measurement of the benzodiazepine receptor can be easily performed.
Not only can diagnosis be made, but also receptor imaging several hours after administration, which cannot be obtained with [C-11] having a very short half-life, will be possible. That is, they have found that the compound of the present invention represented by the general formula 8 has practically excellent properties as a radiodiagnostic agent and a radiopharmaceutical directed to the benzodiazepine receptor, leading to the present invention. Hereinafter, the method for producing the compound of the present invention will be described. The general formula 8
Can be produced by a general method for synthesizing a radioactive compound, for example, according to the following method A or method B.

[Method A] General formula 9

Embedded image [Wherein, R, Y and Z represent the same meaning as described above, and X represents an iodine atom or a bromine atom. Benzodiazepine derivative represented by, for example, in a solvent such as acetonitrile, dimer sulfoxide, dimethylformamide, ethylene glycol, ether derivative of ethylene glycol, ether derivative of diethylene glycol, hexamethylphosphorous triamide (HMPT) and water, After the exchange reaction with a radioactive metal iodide or a metal bromide at a reaction temperature of usually 50 to 180 ° C, the compound of the present invention represented by the above general formula (I) can be obtained by a conventional method such as solvent extraction.

[Method B] Formula 10

Embedded image [Wherein, R, Y and Z represent the same meaning as described above. Is reacted with an alkali metal nitrite in a solvent such as tetrahydrofuran, dioxane or acetonitrile in the presence of an acid such as dilute sulfuric acid or an organic acid to give a compound of the general formula 11

Embedded image [Wherein, R, Y and Z represent the same meaning as described above,
A ^- is a halogen ion, wherein HSO ₄ ^-, wherein of 12

Embedded image Or the general formula R'B ^- represents an anion represented by. Here, R 'represents an alkyl group, a haloalkyl group or an aryl group which may be substituted, and B represents a substituent represented by the formula SO ₃ or CO ₂ . To form a diazonium salt represented by the formula: Then, the diazonium salt represented by the general formula (11) is mixed with a radioactive hydrogen iodide solution, a hydrogen bromide solution, a metal iodide or a metal bromide, and, if necessary, in the presence of copper powder or a copper salt, usually at -5 to 30 ° C. After the reaction in the above temperature range, the product is isolated by a conventional method such as solvent extraction to obtain the compound of the present invention represented by the above general formula (8). The compound of the present invention obtained by the above method A or method B may be optionally used for thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
And the like. In the present invention, examples of the radioactive iodine atom include I-12
3, I-125, I-131, I-132 and the like, and preferably I-123. Examples of the radioactive bromine atom include Br-75, Br-76, Br-77, and B
r-80, Br-82 and the like. Further, the radioactive metal iodide or metal bromide means a metal salt of iodine or bromine atoms of the radioactive, radioactive I ^-
Any substance that gives an ion or Br ^- ion may be used, and examples thereof include sodium iodide, potassium iodide, lithium iodide, sodium bromide, potassium bromide, and lithium bromide. Examples of the halogen atom include atoms such as fluorine, chlorine, bromine, and iodine.
Further, the salt of the radioactive benzodiazepine derivative of the present invention means a pharmaceutically acceptable salt such as a salt of the radioactive benzodiazepine derivative with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid. After intravenously injecting a radioactive benzodiazepine derivative or a salt thereof obtained by the present invention into a patient, scintigrams are taken with time, or radioactivity is measured by a probe method, or SPECT or PET.
By obtaining a tomographic image using a camera and measuring the incorporation of the compound into specific organs and tissues, it is possible to easily and accurately diagnose the site range of the lesion and the degree of the disease. Also, for example, I-125 or I-131
The compound of the present invention labeled with an atom such as a benzodiazepine derivative is used in a radioimmunoassay using a benzodiazepine antibody, in measuring the amount of a benzodiazepine derivative and its metabolite in a biological sample such as blood or urine, and using a benzodiazepine receptor. In the radioreceptor assay, it is suitably used as a radioligand for measuring the amount and affinity of benzodiazepine derivatives and metabolites thereof.

[0007]

The present invention will be described more specifically with reference to the following examples and reference examples. First, a production example of a compound used as a raw material of the compound of the present invention will be described. Reference Example 1 7-chloro-1-methyl-5- (2-fluoro-4-iodophenyl) -3H-1,4-benzodiazepine-2
Preparation of 1-one (4'-iodofludiazepam) 4'-aminofludiazepam (165 mg), acetonitrile (0.
Trifluoroacetic acid (130 μl) was added to a mixture of 8 ml) and an aqueous solution of sodium nitrite while cooling with ice-water, followed by stirring at the same temperature for 20 minutes. An aqueous solution of potassium iodide was added to the obtained diazonium salt solution, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with chloroform, and the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography to obtain 4'-iodofludiazepam (160 mg). Mass spectrum (70 eV) m / e: 428 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.4 (3H, s, CH ₃ ), 3.8 (1
H, d, CH), 4.8 (1H, d, CH), 7.0-7.7 (6H, m, benzene ring H) Next, production examples of the compound of the present invention will be shown.

Example 7-Chloro-1-methyl-5- (2-fluoro- [ ¹²⁵
Production of I] -4-iodophenyl) -3H-1,4-benzodiazepin-2-one ([ ¹²⁵ I] 4′-iodofludiazepam) 4′-iodofludiazepam (6 μm) obtained in Reference Example 1
1) -Naphthalenesulfonic acid, copper sulfate and Na ¹²⁵ I (1 mCi) were added to a DMF solution (20 μl) of
After heating at 0 ° C. for 2 hours, it was allowed to cool. The obtained crude product was purified by TLC (chloroform / acetone = 9/1), and [ ¹²⁵ I] 4′-iodofludiazepam (0.3 m
ci) was obtained. This product was found by TLC to have an Rf value that was identical to that of the standard obtained in Reference Example 1.

[0009]

EFFECT OF THE INVENTION By using the compound of the present invention, not only can the presence of benzodiazepine receptors in the brain and other organs and tissues of humans or animals be detected noninvasively,
Changes in the amount of receptor can also be measured dynamically.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location G01N 33/534 A61K 49/02 A C07M 5:00 43/00 (72) Inventor Akira Yoshitake Hyogo 4-2-1 Takashi, Takarazuka-shi Sumitomo Chemical Co., Ltd. (56) References JP-A-1-106875 (JP, A) JP-A-61-24 (JP, A) JP-A-54-157585 (JP) , A)

Claims (4)

(57) [Claims] 1. A compound represented by the general formula: [Wherein, R represents a hydrogen atom or a lower alkyl group,
X ^* represents a radioactive iodine atom or a bromine atom;
Represents a C androgenic atom, Z is Wath table a halogen atom or a nitro group. And a salt thereof. 2. In the above general formula 1, the substituent X ^* is selected from the group ^consisting of I-123, I-125, I-131, I-132, B
The benzodiazepine derivative or the benzodiazepine derivative according to claim 1, which is an atom selected from the group of radioactive iodine atoms and bromine atom isotopes consisting of r-75, Br-76, Br-77, Br-80, and Br-82. salt. 3. A compound of the general formula [Wherein, R represents a hydrogen atom or a lower alkyl group,
X represents an iodine atom or a bromine atom, Y represents a C androgenic atom, Z is table a halogen atom or a nitro group
You . Wherein the benzodiazepine derivative represented by the general formula (1) is reacted with a radioactive metal iodide or metal bromide. [Wherein, R, Y and Z represent the same meaning as described above,
X ^* represents a radioactive iodine atom or a bromine atom, and is located at the 6, 8 or 9 position. ] The method for producing a radioactive benzodiazepine derivative or a salt thereof represented by the formula: 4. A compound represented by the general formula: [Wherein, R represents a hydrogen atom or a lower alkyl group,
Y represents a halogen atom, and Z represents a halogen atom or a nitro group. A diazotization of an aminobenzodiazepine derivative represented by the following general formula: [Wherein, R, Y and Z represent the same meaning as described above,
A ^- is a halogen ion, wherein HSO ₄ ^-, wherein Formula 6 embedded image Or the general formula R'B ^- represents an anion represented by. Here, R 'represents an alkyl group, a haloalkyl group or an aryl group which may be substituted, and B represents SO ₃ or a substituent represented by the formula CO ₂ . A radioactive aqueous solution of hydrogen iodide, an aqueous solution of hydrogen bromide, a metal iodide or a metal bromide is reacted with the diazonium salt represented by the formula: [Wherein, R, Y and Z represent the same meaning as described above, and X ^* represents a radioactive iodine atom or a bromine atom. ] The method for producing a radioactive benzodiazepine derivative or a salt thereof represented by the formula: