CN102276498B - Contrast medium for triiodobenzene compound - Google Patents

Abstract

The invention relates to a novel contrast medium for a triiodobenzene compound and also provides a preparation method of the compound. The triiodobenzene compound is 5-(N-methylacetamide)-N,N'-di(2.3-dyhydroxy n-propyl)-2,4,6-triiodo isophthalamide (I) and has a structural formula shown as the specification.

Description

A kind of new Triiodobenzene compound contrast agent

Technical field:

The invention belongs to the non-ionic x-ray contrast agent field, relate to a kind of contrast medium that has the phenyl triiodide compound of good physico-chemical property and contain this compound.More particularly, compound of the present invention is 5-(N-methyl kharophen)-N, N '-two (2,3-dihydroxyl n-propyl)-2,4,6-triiodoisophthal amide.

Background technology:

Since the Urogranoic acid fifties in last century (first iodine contrast agent) came out, existing more than ten kind of iodine contrast agent was widely used in clinical as diagnostic reagent at present.It is reported annual about 50,000,000 examples of patient [Curr.Opin.Allergy Clin Immunol, 2002 (2): 333-339] of using contrast medium in the whole world.This class contrast medium can be divided into following three classes by perviousness: the first kind is that height oozes iodine contrast agent, and such as Urogranoic acid, urografic acid methylglucamine salt etc., its osmotic pressure is 5-8 times of blood of human body; Equations of The Second Kind is hypotonic iodine contrast agent, comprise ionic dimer (such as Hexabrix) and nonionic monomers (such as metrizamide, iobitridol, Schering AG), Iomeprol, iopamidol, iopentol, Iopromide, ioversol and ioxitol), its osmotic pressure is about 2 times of blood of human body; The 3rd class is oozed iodine contrast agent (being the non-ionic type dimer) for waiting, and mainly comprises Visipaque 320 and iotrolan, and itself and human body basic etc. ooze.

Clinical study finds that all there is such or such shortcoming in above-mentioned three class iodine contrast agents, or toxicity or height oozes or viscosity large [West China pharmaceutical journal, 2000,15 (1): 53-54].Ooze iodine contrast agent because its renal toxicity of hypertonicity is larger such as height, in recent years be eliminated gradually; Non-ionic type dimer contrast medium viscosity is larger, expensive; The perviousness of nonionic monomers contrast medium and viscosity are then oozed between iodine contrast agent and the non-ionic type dimer contrast medium between height, also are present the most widely used class iodine contrast agents clinically.

US Patent No. 4396598 discloses 1-, and a series of phenyl triiodide compounds that 3-position side-chain structure is identical and contain the contrast medium of these compounds, outstanding representative wherein are the ioversols of having succeeded in developing and having been gone on the market by drugs approved by FDA.US Patent No. 4250113 also discloses 1-, a series of phenyl triiodide compounds that 3-position side-chain structure is identical and contain the contrast medium of these compounds, and outstanding representative wherein is the Schering AG) of having succeeded in developing and having gone on the market.The chemical structural formula of ioversol and Schering AG) is respectively:

For the nonionic monomers contrast medium, keeping on the water miscible basis, reducing osmotic pressure and viscosity is the ultimate challenge that this field scientist faces.

The purpose of this invention is to provide a kind of new triiodo benzene ring type compounds contrast medium, this contrast medium has the characteristic that is better than prior art keeping on the water miscible basis suitable osmotic pressure and viscosity being arranged.

Summary of the invention:

The inventor conducts extensive research, and finally finds, suitably reduces the length of hydroxyl value, shortening side chain, is conducive to reduce the viscosity of homogeneous structure iodine contrast agent, improves the iodine content of unit molecule compound, reduces osmotic pressure.For example, compare with iopamidol (containing 6 hydroxyls), hydroxyl value still less its viscosity of Iopromide and the osmotic pressure of (4) is lower.

The inventor conducts extensive research, the final discovery, the compounds of this invention 5-of bibliographical information compound different from the past (N-methyl kharophen)-N, N '-two (2,3-dihydroxyl n-propyl)-2,4, the 6-triiodoisophthal amide, its structure 1-, 3-position side-chain structure all is 2,3-dihydroxyl n-propyl and ioversol and Schering AG) are suitable, but its 5-bit substituent is N-methyl kharophen.On structure, compound provided by the invention is compared with Schering AG) with ioversol, it is the difference of 5-bit substituent, but it has beyond thought more suitable osmotic pressure and viscosity, compare with the nonionic monomers contrast medium (such as Schering AG)) of at present clinically widespread use, osmotic pressure has reduced by 32%, reduced viscosity 23%.

The purpose of this invention is to provide the compound shown in the formula (I).

The present invention also comprises with compound of the present invention and prepares contrast medium.

The present invention also comprises the pharmaceutical composition that contains the compounds of this invention, and said composition is contrast medium, wherein can contain the medicine acceptable carrier that is fit to be prepared into contrast medium.

Compound shown in the formula (I) can prepare by following reaction scheme.

(1) preparation: 5-(N-methyl kharophen)-N, N '-two (2,3-dihydroxyl n-propyl)-2,4,6-triiodoisophthal amide (I)

Method shown in the following specific explanations reaction scheme.

5-acetylaminohydroxyphenylarsonic acid N, N '-two (2,3-dihydroxyl n-propyl)-2,4,6-triiodoisophthal amide (I ') under acid binding agent (such as sodium hydroxide and potassium hydroxide etc.) and iodomethane reaction, reacts the afterwards salt of elimination generation in suitable solvent (such as ethylene glycol monomethyl ether), concentrating under reduced pressure, obtaining white solid through plastic resin treatment is compound (I).

Resin can adopt macroporous adsorbent resin, and described plastic resin treatment specifically can be to carry out resin regeneration with methyl alcohol, get the resin absorption feed liquid more than 20 times, and gradient elution obtains product.

As previously mentioned, the compounds of this invention I compares with the non-ionic contrast agent monomer and has more suitable osmotic pressure and viscosity.For example, compare with non-ionic contrast agent monomer Schering AG) (at present clinically use the most extensive), the compounds of this invention molecular weight is less, hydroxyl value still less, and iodine content is higher.Under the typical concentrations (300mgI/ml) of commercially available contrast medium medium, compare osmotic pressure with Schering AG) and reduced by 32%, reduced viscosity 23%, concrete data are as shown in table 1.

The physico-chemical property of table 1 Compound I and Schering AG) is * relatively

* the concentration of Compound I and Schering AG) is 300mgI/ml

Embodiment

In following examples, will more specifically explain the present invention.But should be understood that the following example to be intended to the present invention is described and scope of the present invention is not consisted of any restriction.

Embodiment 15-(N-methyl kharophen)-N, N '-two (2,3-dihydroxyl n-propyl)-2,4,6-triiodoisophthal amide (I)

Under ice-water bath cooling and the mechanical stirring, 5-(kharophen)-N, N '-two (2,3-dihydroxyl n-propyl)-2,4,6-triiodoisophthal amide (I) (2000g, 2.677mol) (production of Zhejiang Si Taili Pharmacy stock Co., Ltd), sodium hydroxide (139.2g, 3.480mol) is dissolved in 50% the ethylene glycol monomethyl ether aqueous solution, stirring at room, add methyl iodide (380.1g, 2.677mol), TLC follows the tracks of reaction process, and the 6h reaction is complete.Concentrating under reduced pressure, separate with resin purification, concrete grammar is: 5 liters the macroporous adsorbent resin that pre-for subsequent use 40% Mathanol regenerating is crossed, and the dress post is in the glass column of 100mm, product water solution to be poured into wherein to diameter, static absorption is more than two hours, with the methanol aqueous solution gradient elution of different concns, liquid phase is followed the tracks of the content of product, Fractional Collections, collect content greater than 98% wash-out composition, underpressure distillation.Getting white solid is product (I) (1933.4g, 94.9%). ¹HNMR(DMSO-d6，400MHz)：δ2.14(brs，3H)，3.45(s，3H)，3.21-3.39(m，2H)，3.56-3.61(m，4H)，3.67-3.71(brs，4H)，3.83(m，2H)，3.95(m，2H)，8.50-8.66(m，2H)；LC-MS(ESI，m/z)：761.8(M+H) ⁺。

Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.

Claims (8)

1. the compound shown in the formula (I)

2. the pharmaceutical composition that contains compound claimed in claim 1.

3. pharmaceutical composition as claimed in claim 2 is contrast agent composition.

4. pharmaceutical composition as claimed in claim 3 contains the needed medicine acceptable carrier of preparation contrast medium.

5. the application of the compound of claim 1 in the preparation contrast medium.

6. the preparation method of compound as claimed in claim 1 is characterized in that, may further comprise the steps:

With 5-acetamido-N, N '-two (2,3-dihydroxyl n-propyl)-2,4, the 6-triiodoisophthal amide with iodomethane reaction, reacts the salt that rear elimination generates in the presence of acid binding agent in organic solvent, concentrating under reduced pressure obtains white solid through plastic resin treatment, i.e. compound (I).

7. preparation method as claimed in claim 6, wherein organic solvent is ethylene glycol monomethyl ether.

8. preparation method as claimed in claim 6, wherein acid binding agent is sodium hydroxide or potassium hydroxide.