WO2001028982A1

WO2001028982A1 - Diethylenetriaminepenta acetic acid derivatives

Info

Publication number: WO2001028982A1
Application number: PCT/JP1999/005860
Authority: WO
Inventors: Hisao Takayanagi
Original assignee: Mitsubishi Pharma Corporation
Priority date: 1999-10-22
Filing date: 1999-10-22
Publication date: 2001-04-26
Also published as: AU6229399A

Abstract

Compounds represented by general formula (1), and contrast media containing the same as essential component. These contrast media are utilizable as novel ones exhibiting selectivity among organs and tissues and blood pooling property.

Description

Specification

Diethylenetriamine 5-acetic acid derivative

Technical field

The present invention relates to a novel diethylenetriaminepentaacetic acid (hereinafter abbreviated as DTPA) derivative containing four or more sugar chains as a sugar acid amide, and a derivative complexed with a metal ion. An intermediate, a contrast agent containing the derivative as an essential component, and a pharmaceutical composition for in vivo diagnosis. The present invention particularly relates to the use of a metal chelate as a contrast agent in X-ray imaging and magnetic resonance imaging (hereinafter abbreviated as MRI).

Background

Chelating agents are used as metal carriers in X-ray and nuclear magnetic resonance scintigraphy diagnostics. In particular, gadolinium (Gd) complexes of polyaminopolycarboxylic acids, including DTPA, have already been used in clinical practice as MRI diagnostics as contrast agents. However, although the usefulness of these clinically applied Gd complexes is widely recognized, their extracellular fluidity, i.e., the cells rapidly leak from blood vessels after intravenous administration and are not taken up by cells There was a limit due to the property of diffusion distribution in the interstitium. Breaking this down and increasing the MRI contrast or organ relaxation specific to organs and tissues could not only reduce the dose but also provide information that would be difficult to obtain with conventional diagnostic methods. It is expected. For example, by adding blood pooling properties to contrast agents, extracellular fluid properties, MR angiography that was impossible or limited with contrast agents, evaluation of capillary permeability (information on tumor malignancy, etc. Can be obtained), and myocardial ischemia can be evaluated. In addition, taking contrast agents that are selectively taken into hepatocytes as an example, it will be possible to more easily detect liver tumors and differentiate the degree of differentiation of liver cancer, and MRI will be able to use dynamic CT and CTAP. It is expected to be a test that can be omitted (see Inner Vision, 12, 62 (19997)).

Many attempts have been made to make organs and tissues specific to contrast agents. In particular, blood pooling, liver-selective contrast agent research is active. However, conventional blood boo Most of the contrast agents are biomolecules, such as proteins and polysaccharides, coupled with a chelator moiety, and are not a single compound for manufacturing, handling, or a single compound (a certain distribution where the binding position of the chelator moiety is uncertain) An aggregate of compounds having different molecular weights having different molecular weights) caused metabolic and toxicity problems. Regarding organ selectivity, those targeting organs are best studied, but the mechanism of uptake into the liver is to add lipophilic groups to the structural formula to increase lipophilicity and increase transmembrane permeability. There are many paramagnetic contrast agents designed to enhance the activity, and some of them have undergone clinical trials, but their efficiency in taking up into the liver and excreting bile is not so high. On the other hand, as a mechanism of incorporation into hepatocytes, studies of contrast agents targeting asia oral glycoprotein receptor (hereinafter abbreviated as GSGP-R) present in hepatocytes have been conducted. Tc-chelate albumin, an iron oxide colloid that resembles the ashia glycoprotein (hereinafter abbreviated as GSGP), which is the natural ligand of GSGP-R, and has a number of terminal galactose residues bonded to it, has been developed. (See, for example, AJR, 1550, 1161 (1990); Radiology, 178, 769 (1991)). Recently, a DTPA derivative with two galactose ends was reported (see Chemical 1 Journalof C ninese Universities, 18, 1072 (19997)). In order to further increase the efficiency, it is required that the molecule has many terminal galactose residues. Incidentally, it is known that a typical glycoprotein derived from human glycoprotein in human serum having a high affinity for lectin has 14 terminal galactose residues. This suggests that the DTPA derivative having two galactose terminals of the above lacks the efficiency of discrimination and uptake by the receptor. Therefore, a new DTPA derivative with improved receptor identification and uptake efficiency has been desired.

Disclosure of the invention

The present inventors have conducted intensive studies to achieve the above-mentioned object, and as a result, have found that in a molecule, four or more sugar chains that are recognized or bound to or not bound by a receptor existing in a living body are converted to sugar acid amides. For the first time found that the above problems can be achieved with the DT PA derivative contained as The present invention has been completed. Examples of sugar chains that can be recognized as receptors in the body include, for example, the aforementioned galactose residues for hepatocytes, mannose residues for liver Kupffer cells and fibroblasts, and α-Darcose residues for Lewis lung cancer cells. The compound of the present invention to which these groups are attached at the end makes it possible to selectively image a target organ or (lesion) tissue by the compound of the present invention, thereby diagnosing the presence of a lesion site. In addition to differential diagnosis of malignancy, etc., function diagnosis of organs can be performed in some cases. On the other hand, by selecting an arbitrary sugar chain that is not taken up by the receptor and binding it to a number having a high molecular weight sufficient to exhibit blood pooling properties, it is possible to produce a contrast agent having blood bleeding properties. Of course, the sugar chain identified as a receptor may be bound to the extent that blood pool properties appear, or rather, diffusion outside the target organ may be suppressed, and favorable effects such as a reduced dose may be obtained in some cases. In any case, the sugar chain compound of the present invention is greatly characterized in that it is a single compound, unlike a conventional contrast agent bound with polysaccharide.

That is, the gist of the present invention is represented by the following general formula (1)

RCO

(Wherein R is a general formula—N ((CH 2) kNHR ¹ ) 2 (where k represents an integer of 2 to 5, and R ^{1 is a} benzyloxycarbonyl group (hereinafter referred to as “Z group” ), A t-butyloxycarbonyl group (hereinafter sometimes also referred to as a “B oc group”), a hydrogen atom, or a glycan residue of a sugar chain), one NH (CH 2) 1 N ( (CH 2) kNHR ¹ ) 2 (wherein, k and R ¹ have the same meanings as above, and 1 has the same meaning as k, which may be the same as or different from k.), -NHCHm (CH 2 AR ² ) 3— m (where m represents 0 or 1, A represents a single bond, one (CH 2) 2, -CH 2 C 0, -O (CH 2) 3, one O (CH 2) 2 CO, or one CO, and R ² is `` NHR ¹ , -NH (CH 2) kNHR ¹ , one N ((CH 2) kNHR ¹ ) 2, or — NH (CH 2) IN ((CH 2) kNHR ¹ ) 2 (where k, 1 and R ¹ have the same meanings as above), provided that when m represents 1, A is _CO only Is expressed.)

A diethylenetriaminepentaacetic acid derivative represented by the formula:

R is -N ((CH2) kNHR ") 2 (where k represents an integer of 2 to 5,

R ¹ represents a sugar chain residue), wherein said diethylenetriamine 5 acetic acid derivative;

The diethylene triamine pentaacid derivative described above, wherein the glycan residue is represented by the following general formula (3);

(In the above formula, p represents an integer of 0 to 10)

The above derivative complexed with a metal ion;

The above derivative, wherein the metal ion is selected from the group consisting of a paramagnetic metal ion and a radioactive metal ion;

A diethylenetriaminepentaacetic acid derivative represented by the following formula (5):

A contrast agent containing the above derivative as an essential component; A pharmaceutical composition for in vivo diagnosis comprising the derivative derivative and a pharmaceutically acceptable carrier;

And the following general formula (2).

R '— R (2)

(In the formula, R has the same meaning as described above. However, R ¹ in R represents a meaning excluding a hydrogen atom, and when R is -N ((CH 2) kNHR ¹ ) 2, R ¹ is a sugar R 'represents a hydrogen atom, a Z group, or a Boc group, but when R has a Z group or a Boc group, each of them does not represent their meaning.) Present in the amino compound represented.

Hereinafter, the present invention will be described in detail.

In the above definition, the “sugar chain residue” defined by R ¹ is not particularly limited as long as it is a single sugar carboxylic acid residue, but from the viewpoint of availability, for example, The following general formula (3)

(Where p represents an integer of 0 to 10)

The monosaccharide oligosaccharide (polysaccharide) represented by In addition, when it is desired to impart organ or tissue selectivity, a saccharide whose terminal is a saccharide unit exhibiting affinity for the receptor (in the case of a monosaccharide itself) is selected. Specific examples include acyl residues of monosaccharide acids such as D-dalconic acid, D-galactonic acid, D-mannonic acid, D-fuconic acid, D-maltobionic acid, and D-lactobionic acid. Malt tris (q = 2), represented by the acyl residue of disaccharide acid, (Glcal → 4) qG1c (G1c: glucose) Manoletote traose (q = 3), manoleto pentaose (q = 4), maltohexaose (q = 5), maltoheptaose (q = 6), etc. Examples include the acyl residue of a sugar acid oxidized to an acid.

Hereinafter, specific examples of the compound represented by the general formula (1) will be shown. However, the sugars constituting the glycan are represented by abbreviations (G1c: glucose, Gal: galactose, Man: mannose), and the reducing terminal sugar is CO and is an acyl residue. Indicates that

(1) R = — N ((CH 2) k NHR ¹ ) 2

R = -N ((CH2) 2NHZ) 2, 1N ((CH2) 2NHBoc) 2, 1N ((CH2) 2NH2) 2, 1N ((CH2) 2 NHG 1 c CO) 2, — N ((CH 2) 2 NHGa 1 CO) 2, 1 N ((CH 2) 2 NH (M an CO)) 2, 1 N ((CH 2) 2 NH ( G a 1 a 1 → 4 G 1 c CO)) 2, 1 N ((CH 2) 2 NH ((G 1 ca 1 → 4) 2 G 1 c CO) 2, 1 N ((CH 2) 2 NH ((G 1 ca 1-→ 4) 3 G 1 c CO)) 2, N ((CH 2) 2 NH ((G 1 ca 1 → 4) 4 G 1 c CO)) 2, — N (( CH 2) 2 NH ((G 1 ca 1 → 4) 5 G lc CO)) 2, 1 N ((CH 2) 2 NH ((G 1 ca 1 → 4) 6 G 1 c CO)) 2 1 N ((CH 2) 3 NH Z) 2, N ((CH 2) 3 NH B oc) 2, N ((CH 2) 3 NH 2) 2, N ((CH 2) 3 NHG a ICO) 2, one N ((CH 2) 3 NH (M an CO)) 2,-N ((CH 2) 3 NH (G a 1 a 1 → 4 G 1 c CO)) 2,

(2) R = — NH (CH 2) 1 N ((CH 2) k NHR ¹ ) 2 One NH (CH 2) 2 N ((CH 2) 2 NH Z) 2 One NH (CH 2) 2N ((CH2) 2NHBoc) 2,1NH (CH2) 2N ((CH2) 2NH2) 2, -NH (CH2) 2N ((CH2) 2NHGa 1 CO) 2, NH (CH 2) 2 N ((CH 2) 2 NHM an CO) 2, -NH (CH 2) 2 N ((CH 2) 2 NHG lc CO) 2, NH (CH 2) 2 N ((CH 2) 2 NH (G a 1 a 1 → 4 G lc CO)) 2, 1 NH (CH 2) 2 N ((CH 2) 2 NH ((G 1 ca 1 → 4) 2 G 1 c CO)) 2,-NH (CH 2) 2 N ((CH 2) 2 NH ((G lc

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CO

(〇 ϋ CHs Ηυ No H◦ ◦NN-Sus (HN 〇〇 No SH υ 〇 Kus u 983dso / 66df / OAV one

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Re

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1 → 4 G 1 c CO) 2) 3,-NH C (CH 20 (CH 2) 2 CO N ((CH 2) 2 NH (G 1 ca 1 → 4) 2 G 1 c CO) 2) 3, -NH C (CH 20 (CH 2) 2 CO N ((CH 2) .2 NH (G 1 ca 1 → 4) 3 G lc CO) 2) 3,-NH C (CH 20 (CH 2) 2 CO N ((CH 2) 2NH (G 1 ca 1 → 4) 4 G lc CO) 2) 3,-NH C (CH 2 O (CH 2) 2 CO N ((CH 2) 3 NHZ) 2) 3, -NH C (CH 20 (CH 2) 2 CO N ((CH 2) 3 NH 2) 2) 3,-NH C (CH 20 (CH 2) 2 CO N ((CH 2) 3 NH B oc) 2 ) 3,-NH C (CH 2 O (CH 2) 2 CO N ((CH 2) 4 NH Z) 2) 3,-NH C (CH 20 (CH 2) 2 CO N ((CH 2) 4 NH 2) 2) 3

2) When m = 1

-NH CH (CH 2 CO N ((CH 2) 2 NH Z) 2) 2, 1 NH CH (CH 2 CO N ((CH 2) 2 NH 2) 2) 2, 1 NH CH (CH 2 CO N ((CH 2) 2 NHG a 1 CO) 2) 2,-NH CH (CH 2 CO N ((CH 2) 2 NHM an CO) 2) 2,-NHCH (CH 2 CO N ((CH 2) 2 NH (G a 1 a 1 → 4 G 1 c CO) 2) 2) 2, 1 NH CH (CH 2 CO N ((CH 2) 2 NH (G lcal → 4 G lc CO) 2) 2) 2 ,-NH CH (CH 2 CO N (CH 2) 2 NH (G 1 ca 1 → 4) 2 G 1 c CO) 2) 2, 1 NH CH (CH 2 CO N ((CH 2) 2 N (( G 1 ca 1 → 4) 4 G 1 c CO) 2) 2,-NH CH (CH 2 CO NH (CH 2) 2 NH Z) 2, — NH CH (CH 2 CO NH (CH 2) 2 NH 2 ) 2,-NH CH (CH 2 CONH (CH 2) 2 NHG alal → 4 G lc CO) 2,-NH CH (CH 2 CO NH (CH 2) 2 NH (G a 1 a 1 → 4) 4 G lc CO) 2,-NH CH (CH 2 CO NH (CH 2) 2 N ((CH 2) 2 NH Z) 2) 2,-NH CH (CH 2 CO NH (CH 2) 2 N ((CH 2 ) 2 NH 2) 2) 2,-NH CH (CH 2 CO NH (CH 2) 2 N ((CH 2) 2 NH G a 1 a 1 → 4 G 1 c C〇) 2) 2,-NH CH (CH 2 CO N H (C H 2) 2 N ((C H 2) 2 NH (G 1 c a 1 → 4) 4 G l c C O) 2) 2

Next, the production method of the compound of the present invention will be described. The compound represented by the general formula (1) (hereinafter abbreviated as compound (1)) is, for example, a compound represented by the general formula (2) Compound (hereinafter abbreviated as compound (2)), R '= hydrogen atom, DTPA dianhydride and water, i-propyl alcohol, dimethylformamide (DMF), dimethylsulfoxide. (DMS O) in a suitable solvent such as 150 ° C to 200 ° C. C, preferably from 30 ° C to 50 ° C, for 30 minutes to 5 days, preferably from 1 hour to 24 hours, and R ′ is a Z or Boc group. The compound (2) in which R 'is a hydrogen atom can be produced via (2). First, a method for producing the compound (2) in which R' is a hydrogen atom will be described. Among the amino compounds represented by the general formula HN ((CH 2) k NHR ”, compounds in which R ¹ is G lc CO and k is 3 are known in the literature (Analytical Biochemistry, 130, 4 85 (see 1983)), and other sugar chain compounds that do not appear in the literature can be produced by the same method.

(1) R = — N ((CH 2) kNHR ¹ ) 2

For example, it can be manufactured by the method of Scheme 1.

Scheme 1

R ¹ HN (CH 2) k NH 2 + X (CH 2) kNHR ¹

(A) (B)

→ HN ((CH 2) kNHR ¹ ) 2

(2 a)

(Wherein, R ¹ represents Z or B oc, and X represents C 1 or B r)

That is, it can be prepared from a compound represented by the general formula (A) (hereinafter abbreviated as compound (A)) which can be easily produced from diamine H 2N (CH 2) k NH 2 and a hydrohalide of an alkylamine halide. Compounds represented by the general formula (B) (hereinafter abbreviated as compound (B)) are combined with tetrahydrofuran in the presence of an organic base such as triethylamine and diisopropylethylamine and an inorganic base such as sodium hydrogencarbonate. The compound (2a) can be produced by reacting in a suitable solvent such as drofuran and ethanol. In order to suppress the tertiary amine by-product, it is preferable to use the compound (A) in excess. In this case, since the excess compound (A) plays the role of a base, it is not necessary to use a base. (2) In the case of R = -NH (CH 2) 1 N ((CH 2) kNHR ¹ ) 2 For example, it can be produced by the route of Scheme 2.

Scheme 2

R ³ HN (CH2) 1 NH2 + X (CH2) kNHR ⁴

(C) (D)

→ R ° HN (CH2) 1 N ((CH2) k NHR ⁴ ) 2 → R ³ HN (CH2) 1 ((CH2) kNH2) 2

(E) (F)

1 Ϊ

H2N (CH2) 1N ((CH2) k secret ¹ ) 2 ― R ³ HN (CH2) 1 N ((CH2) kNHR ¹ ) 2

(2 b) (G)

(Wherein, R. and R ⁴ represent Z or B oc and X represents C 1 or Br). That is, they can be prepared by the same reaction as used in the production of compound (A) or (B). Alternatively, the same compound represented by the general formulas (C) and (D) (abbreviated as the compounds (C) and (D), respectively) is subjected to the same reaction as in (1), and the compound represented by the general formula (E ) (Hereinafter abbreviated as compound (E)). At this time, a compound in which the Z group and the Boc group represented by R ³ and R ⁴ in the compounds (C) and (D) are different from each other is used. From compound (E), Shaku ³ was 80. When the group is a group, a method capable of deprotecting the Boc group in the presence of the Z group (Protecctive Grupsin Organic Synthesis, TW Greene, PGM Wuts, John Wiley & Sons, Inc. 19) 91), for example, by reacting trifluoroacetic acid in a suitable solvent such as methylene chloride or without solvent, or by reacting hydrogen chloride or hydrobromic acid in a suitable solvent such as acetic acid or ethyl acetate. ^{When 3} is a Z group, R ³ is removed by a method such as hydrogenolysis in the presence of a Pd catalyst to produce a compound (2b) in which R ¹ is a Z group or a Boc group . Further, from the compound (E), the compound represented by the general formula (F) (hereinafter abbreviated as compound (F)) can be produced by removing R ⁴ using the above-mentioned method. From compound (F), For example, a sugar lactone compound represented by the following general formula (4) (hereinafter abbreviated as “compound (4)”), and p has the same meaning as described above.

A compound represented by the general formula (G) (hereinafter abbreviated as compound (G)) can be produced by a condensation reaction with

Compound (4) can be obtained as a commercial product, but can be produced from the corresponding commercially available saccharide by an ordinary method for dehydrating a sugar acid obtained by oxidation with, for example, bromine or iodine under alkaline conditions. This dehydration reaction can be performed by a simple operation such as adding an alcohol such as methanol or ethanol to a sugar acid, repeating distillation under reduced pressure, and azeotropically dehydrating with toluene. In the condensation reaction between compound (4) and compound (F), for example, both are reacted with an alcohol-based solvent such as methanol, ethanol, and ethylene glycol, and a non-protonic polar solvent such as dimethylformamide and dimethylsulfoxide. In a suitable solvent, for example, at 150 ° C. to 200 ° C., preferably at room temperature to 150 ° C., and in some cases, in the presence of a suitable catalyst such as NaCN, for 10 minutes to 120 hours. The reaction can be carried out preferably for 1 hour to 10 hours. In addition, in the case of an amine having low reactivity, a reaction under high pressure (see Bui 1. Soc. Chem. J pn., 62, 31 38 (19989)) is also used. it can. In addition, instead of compound (4), it is also possible to use sugar acid ratatones such as sugar acid γ-lactone and glucuronic acid lactone.

From the compound (G), the Ζ group or the Boc group is removed by the method described above to produce a compound (2b) in which R ¹ is a glycan residue.

Two

(3) R = -NHCHm (C H 2 A R 3— m

1) When m = 0

(a) A = single bond For example, it can be manufactured by the route of Scheme 3,

Scheme 3

H ₂ NC (CH ₂ OH) 3 R ³ HNC (CH ₂ OH) 3

(H) (I)

HN ((CH ₂ ) _k NHR ¹ ) ₂

(2 a)

R ³ HNC (CH ₂ OMs) ₃

(J)

R ³ HNC (CH ₂ N ((CH ₂ ) k NHR ¹ ) ₂ ) ₃

(K)

H ₂ NC (CH ₂ N ((CH ₂ ) _k NHR ¹ ) ₂ ) ₃

(2 c)

(Wherein, R ^ iZ, represent B oc or carbohydrate Ashiru residues. Although R ³ represents Z or B oc, R ¹ and R ⁰ is represent different meanings from each other. K is the same meaning, M s represents a methanesulfonyl group)

That is, it can be easily prepared from a commercially available tris (hydroxymethyl) aminoamino compound (H), or can be prepared by a method known in the literature (see Chem. Eur. J., 2, 1116 (1996)). The compound of the formula (I) is reacted with methanesulfonyl chloride in pyridine or in a suitable solvent such as methylene chloride or tetrahydrofuran to give the compound of the formula (J). (Hereinafter abbreviated as compound (J)) can be produced. The compound (J) is reacted with the compound (2a) produced in the above scheme 1 in the same manner as in the production of the compound (E) shown in the scheme 2 to give a compound represented by the general formula (K) (Hereinafter abbreviated as compound (K)). At this time, R ¹ in the compound (2a) to be reacted is Use a compound different from R ³ in compound (J). From compound (K), R ³ can be removed in the same manner as above to produce compound (2c) in which R is Z or Boc. In addition, 1) removal of R ¹ from compound (K), 2) sugar, from compound (E) in Scheme 2 via compound (F) (G) and compound (2b). the reaction of acid lactone, 3) can be prepared a compound wherein R ¹ is a sugar acid Ashiru residue (2) by removal of R.

Furthermore, R ¹ using literature known tristriethylene scan methane Sno Reho inert (non Dorokishimechiru) nitromethane (see S ynthesis, 7 4 2 (1 9 8 7)) instead of Ihigo product (J) is B By reacting the compound (2a) which is oc, a nitro compound corresponding to the compound (K) can be produced. The compound (2c) (R ¹ = Boc group) or Boc is removed from this compound by reduction of the nitro group to an amino group, and after reacting the lactone sugar acid, the amino group of the nitro group is removed. in conversion to, compounds wherein R ¹ is a sugar acid Ashiru residues (2 c) can be produced.

(b) A = — (CH 2) 2

For example, it can be produced by using a commercially available bishomotris in place of the compound (H) in the aforementioned scheme 3. In addition, instead of tris (hydroxymethyl) nitromethane, the carboxyl group can be reduced from commercially available dinitromethane tris-pionate (for example, sodium borohydride acts in the presence of methanol in tetrahydrofuran). Using the obtained tris (3-hydroxypropyl) nitromethane, compound (2) can be produced by a similar reaction.

(c) A = -CH 2CO

For example, it can be manufactured by the route of Scheme 4. H ₂ NC ((CH ₂ ) ₂ C0 ₂ t-Bu) ₃ H ₂ NC ((CH ₂ ) ₂ C0 ₂ H) ₃

(L) (M)

HN ((CH ₂ ) _k NHR ¹ ) ₂

(2 a)

R ³ HNC ((CH ₂ ) 2C0 ₂ H) 3

(N)

R ³ HNC ((CH ₂ ) ₂ CON ((CH ₂ ) _k NHR ¹ ) 2 Compound (2)

(0)

(Wherein, R ¹ R ¹³ and k have the same meanings as R ¹ , R °, and k in Scheme 3.) That is, the compound (L) known in the literature (J. Org. Chem., 56) , 7162 (1991)), hydrolyze t-butyl ester, for example, by allowing trifluoroacetic acid to act at room temperature, or adding p-toluenesulfonic acid in acetic acid and heating. Compound (M) can be produced by such a method. From the compound (M), a compound represented by the general formula (N) (hereinafter abbreviated as compound (N)) can be produced by a method used for Z-formation and Boc-formation of an amino group of an amino acid. A method using a condensing agent such as carbonyldiimidazole or dicyclohexylcarbonyldiimide, or a compound (N) with a corresponding acid chloride, i-butyl carbonate anhydride, methanesulfonyl A compound represented by the general formula (O) (hereinafter, abbreviated as compound (O)) can be produced by a normal amide bond forming reaction such as activation of an anhydride or the like after activation. In this case, instead HN of ^{((CH 2) k NHR 1} ) 2 as § Mi emissions reactant, H 2N (CH 2) kNHR ^ H 2N (CH 2) IN (CH 2) k NHR L) 2 ( any The corresponding amide compound corresponding to compound (O) can be produced by using the above. By removing R ¹ or R ³ from these compound (◦) and the corresponding compound, the desired compound (2) can be produced. (d) A = -0 (CH 2) 3

For example, it can be manufactured by the route of Scheme 5.

Scheme 5

H 2NC (CH 20 (CH 2) 2 CN) 3

(P)

→ Boc HNC (CH 2 O (C H 2) 2 CN) 3

(Q)

→ B o c HNC (CH 20 (C H 2) 3 NH 2) 3

(R)

→ B oc HNC (CH 20 (CH 2) 3 NHR ¹ ) 3

(S)

→ H 2NC (CH 2 O (CH 2) 3 NH R ¹ ) 3

(2 d)

(In the formula, R ¹ represents a Z group or a glycan residue)

That is, the compound (R) can be produced by subjecting the known compound (P) to Boc to give the compound (Q), and then subjecting it to a reduction reaction such as catalytic hydrogenation reaction using a Raney nickel catalyst in the presence of ammonia. From the compound (R), the compound (2) in which R ¹ is Z or a sugar chain residue can be produced by the method described above.

(e) A = — 0 (CH 2) 2CO

For example, it can be produced by repeating the same reaction using a known amine, H 2NC (CH 20 (CH 2) 2 CO 2 Et) 3, instead of the compound (L) in the above-mentioned scheme 4.

The compound (2) of the present invention is a single sugar derivative having an amino group or a compound useful for producing the same, and is given to a compound obtained by containing or using these. Targeting and blood pooling functions can also be exerted when applied to other diagnostic or therapeutic agents as well as chelating agents. For example, if the compound (2) of the present invention is added to a 5-amino-1,2,4,6-tridoisophthalic acid derivative used for X-ray diagnosis, organ selectivity or blood booting can be obtained. It is a new contrast agent for X-ray diagnostics.

In the present invention, a compound in which a metal ion is complexed with the compound represented by the general formula (1) obtained as described above is also included as a gist thereof. Here, the metal ion may be any of a paramagnetic metal ion and a radioactive metal ion. In particular, lanthanide cations such as Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, and Yb have visible to near-infrared regions, long lifetimes, and narrow wavelengths. It is preferable in that it emits fluorescence having characteristics such as width, and when utilizing the paramagnetism of cations such as MRI contrast agents, Pr, Nd, Eu, Gd, Tb, Dy, H Lanthanide cations such as o, Er, Tm, and Yb are preferred. Others, Mg, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Sr, Zr, Tc, Ru, Icons such as In, Hf, W, Re, Os, Pd, La, and Bi can also be mentioned as preferred examples.

The compound obtained by complexing the compound represented by the general formula (1) obtained as described above with a metal ion can be used as a contrast agent. Further, it can also be used as a pharmaceutical composition for in vivo diagnosis comprising a pharmaceutically acceptable carrier.

When the compound of the present invention is used as an MRI contrast medium, a parenteral administration method such as intravenous administration is usually used, but it can also be administered orally. Examples of the preparation for parenteral administration, that is, a solvent or a suspending agent used in the production of an injection or the like include water and water. Examples include propylene glycol cornole, polyethylene glycol cornole, penzinoleanol cornole, ethyl ethyl oleate, and lecithin. Preparation of the preparation may be performed by a conventional method. For oral administration, alone or in combination with a pharmaceutically acceptable carrier, for example, granules, fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, Oral administration in the form of suspensions, ribosomes, solutions, etc. Examples of excipients used in producing a solid preparation include lactose, sucrose, starch, talc, cell mouth, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, ie, emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents such as vegetable oils. The preparation may contain, in addition to the inert diluent, auxiliary substances such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents or preservatives. Can also be. Liquid preparations may be included in capsules of absorbable substances such as gelatin.

The MRI contrast agent according to the present invention is generally administered at a dose that provides the desired contrast effect without side effects. The specific value should be determined at the discretion of the physician, but is generally 0.1 mg to 10 g, preferably 1 mg to 5 g per component per diagnosis. The compound of the present invention may be administered as an active ingredient in an amount of 1 mg to 5 g, more preferably 3 mg to 3 g per adult per one diagnosis. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to the following without departing from the gist thereof.

Example 1

A mixture of 2.25 g of the amine, 1.0 g of the bromo compound, and 8 ml of tetrahydrofuran was heated to reflux while stirring for 2 days and nights. The reaction mixture once becomes a solution, and then crystals precipitate. After cooling to room temperature, the crystals were separated by filtration, washed (cold tetrahydrofuran), and the filtrate was concentrated. The resulting residue was subjected to SiO 2 column chromatography (developing solution C HC 13: MeOH 20: 1 → 5 : 2) to give 1.26 g (87%, based on the bromo compound) of the desired secondary amino compound.

¹ HNR (300 MHz, CDC 13) δ 1.32 (bs, 1 H), 2.69 (bt, J = 5.3 Hz, 4 H), 3.24 (bm , 4H), 5.07 (s, 4H), 5.32 (bt, J = 5.5Hz, 2H), 7, 30 (m, 10H).

Example 2

Amine 1. DTPA dianhydride was added to a solution of 24 g of DMF in 4 ml with stirring. The temperature was raised to about 3 0 ^D C, became a homogeneous solution in about 1 hour. After standing at room temperature overnight, the solvent was distilled off using a vacuum pump. Water and CH 2 C 12 were added to the residue, and the CH 2 C 12 layer was separated, washed with water and concentrated to obtain 1.75 g (95%) of the desired diacid.

¹ H-NMR (300 MHz, DMS O-d 6) δ 2.88 (bm, 4 H), 2.94 (bm, 4 H), 3.15 (bm, 8 H) , 3.29 (bm, 8H), 3.42 (bs, 4H), 3.46 (bs, 2H), 3.60 (bs, 4H), 5.01 and 5.02 (each s, each 2H), 7.33 (m, 2H), 7.50 (bt, J = 5.6Hz, 2H).

Example 3

O '

Lactone lactobionate (72 g) was added to a solution of dimethylene triamine (260 mg) in DMS O (4 ml), and the mixture was stirred at room temperature. After the lactone had dissolved, stirring was continued for another 3 o'clock on a 50 ° C oil bath. Analysis of a very small portion revealed that the sugar amide was almost pure.

¹ ° C-i \ 4 R (125 MHz, DMSO-d 6) δ 3 8. 3 4 8.16 .0.7 6 2.4 6 8.3 7 0.5 .7 .1 7] 4 7 2. 1 7 3 .2, 7 5.7, 8 2.9, 10 4.6, 1 7 2.3

To the reaction mixture, 12 ml of DMI 'was added, and a solution of 450 mg of DT dianhydride in 10 ml of DMS O was added dropwise with stirring on an ice water bath. Remove the bath and use 1 S night power at room temperature I mixed. The residue obtained by distilling off the solvent under reduced pressure (70 ° C) is dissolved in a small amount of water, purified with an ion-exchange resin (Diaion WK-40), and the target lactobionic acid group is removed. 1.55 g (65%) of the DTPA derivative was obtained.

¹³ C-NMR (125 MHz, DMS O-d 6) δ 36.6, 37.0, 45.1, 46.5, 50.2, 51.4, 5 4.9, 56.1, 60.7, 62.4, 68.3, 70.6, 71.2, 71.4, 73.3, 75.7, 8 3.0, 1 0 4.5, 1 69.5, 1 7 0.2, 1 72.7, 1 72.8, 1 73.0

1.4 g of the DTDT derivative obtained above was dissolved in 5 ml of water, and 13 mg of gadolinium oxide was added thereto, followed by stirring for 6 hours in an oil bath at 100 ° C. The reaction mixture was concentrated to obtain an almost pure target Gd complex.

Analysis conditions: L-column (ODS), eluent 20 mM phosphate buffer (pH 7.0) — l% MeOH, 215 nm detection, Rt = 4.5 min

Example 4 Member Z,

B r + HN AZ

B o cHN ^ z

The mixture of 9.66 g of the bromo compound, 3.0 g of amide, 6.5 ml of di-propylethynoleamine and 25 ml of tetrahydrofuran was heated and refluxed for 2 days and night while stirring. After cooling in an ice-water bath, the precipitated crystals were separated by filtration and washed with cold tetrahydrofuran. The residue obtained by concentrating the filtrate was subjected to SiΟ2 column chromatography (developing solution n-hexane: ethyl acetate 2: 1: 3: 2 → 4: 3) to give the desired tertiary amine compound 3.93 g (4 0%).

¹ H-NMR (300 MHz, CDC 13) δ 1.37 (s, 9H), 2.52 (m, 6H), 3.12 (bm, 2H), 3 20 (bm, 4 H), 5.06 (bs, 5 H), 5.51 (bs, 2 H), 7.28 (m, 10 H)

Example 5

B o c HN

NHZ,

To 1.75 g of the Boc form, 6 ml of trifluoroacetic acid was added dropwise while stirring on an ice water bath. The bath was removed, and the mixture was stirred at room temperature, concentrated by an evaporator, and a 1 N aqueous sodium hydroxide solution was added to the residue. Extraction with methylene chloride, washing of the organic layer with water and concentration gave 1.32 g (93%) of the desired primary amine.

¹ ^ C-NMR (75 MHz, CD C 13) δ 39.1, 39.6, 53.9, 56.6, 66.4, 12.77.85, 1 2 7.89, 1 2 8.31, 1 36.7, 15.6.7

Example 6

920 mg of the di-Z form was reacted with 80 mg of Pd / C (10%) in 10 ml of a methanol solution at room temperature for 24 hours to undergo hydrogenolysis. After filtering off and washing the catalyst, the filtrate was concentrated to obtain 446 mg (quantitative) of the desired free amine compound.

H—NMR (300 MHz, DMS O-d 6) δ 1.35 (s, 9H), 2.40 (t, J = 6.0Hz, 6H), 2.60 ( bm, 4H), 2.94 (bm, 2H), 3.63 (bm, 4H), 6.80 (bs, 1H).

206 mg of the crude freeamine obtained above was dissolved in 10 ml of DMS O, and 30 mg of D-dalconolactone was added thereto, followed by stirring at room temperature for 24 hours. After concentration, the residue is stored in an ion-exchange resin (Diaion WK-40), washed with water, developed with 0.5 N aqueous ammonia, and the desired sugar fraction 247 mg ( 4 9%).

¹ ° C-NMR (125 MHz, DMSO-d6) δ28.3, 36.6, 38.3, 53.1, 53.4, 63.4, 70. 1, 71.5, 72.4, 73.7, 77.6, 155.7, 172.5

Example Ί

B oc HNC (CH 20 (CH 2) 2 CN) 3 → B oc HNC (CH 20 (CH 2) 3 NH Z) 3

Trisnitrile 8.15 g, Raney Ni (50% water slurry, Aldrich) 12 ml washed and decanted with water and methanol, 7 N ammonia / methanol 150 The ml was stirred vigorously in an autoclave under a hydrogen atmosphere (7 atm). After completion of the reaction, the catalyst was filtered and washed, and the residue obtained by concentrating the filtrate was dissolved in 20 ml of water. On an ice water bath, ZC10.1 m1 and INNaOH 70 m1 were added alternately while stirring vigorously. After stirring for another 5 hours in an ice water bath, a methylene chloride layer was added, and the mixture was filtered through celite. The methylene chloride layer was separated from the filtrate, dried (MgSO 4), and the residue obtained by concentration was purified by SiO 2 column chromatography (n-hexane: ethyl acetate = 5: 1 → 1: 1). Then, 9.1 g (53%) of the desired Tris Z form was obtained.

¹ H-NMR (300 MHz, CDC 13) δ 1.40 (s, 9 9), 1.68 (bm, 6Η), 3.23 (bm, 6Η), 3 . 4 2 (bs, 6H), 3.59 (s, 6H), 4.90 (s, 1H), 5.07 (s, 6H), 5.25 (bs, 3 H), 7.32 (m, 15 H).

Example 8

B o c HN C (C H 2 O (C H 2) 3 NH Z) 3

→ B o c H N C (C H 20 (C H 2) 3 NH 2) 3

To a solution of 1.94 g (2.44 mmol) of the Z form in methanol (15 ml) was added 180 mg of 10% Pd, and the mixture was vigorously stirred at room temperature for 24 hours in a hydrogen atmosphere. The catalyst was filtered, washed with methanol, and the filtrate was concentrated. 1.0 g (quantitative) of the target triamine was obtained.

¹ H-NMR (500 MHz, DMS O-d 6, 70 ° C) δ 1.37 (s, 9 H), 1.58 (m, 6 H), 2.68 ( bs, 6H), 2.94 (bm, 6H), 3.42 (t, J = 6.OHz, 6H), 3.50 (s, 6H), 6.01 (bs, 1 H).

Example 9 _{B o cHNC (CH 2 0 (} CH 2) 3 NH 2) 3 + <OH

HO

OH

Triamine compound (420 mg) and D-gnorenolactone (572 mg) were dissolved in dimethyl sulfoxide (8 ml) and stirred at room temperature for 24 hours. The residue obtained by concentration was retained on an ion exchange resin (Diaion WK-40), washed with water, developed with 0.5 N aqueous ammonia, and the desired fraction was collected and concentrated. Yield 446 mg (45%).

¹ ° C-NMR (125 Hz, DMSO-d6) δ28.2, 29.2, 35.8, 58.5, 63.3, 68, 5, 6 8.8, 70 · 0, 71.5, 72.4, 73.6, 154.3, 172.3

Example 10

B o c HNC (C Η 2 Ο (CH 2) 3 ΝΗ Ζ) 3

→ Η 2 NC (C Η 2 Ο (C Η 2) 3 ΝΗ Ζ) 3

To a solution of 57 Omg of the methylene chloride in 0.7 ml of methylene chloride, 0.6 ml of trifluoroacetic acid was added dropwise with stirring under ice-cooling. After removing the bath and stirring, the mixture was concentrated with an evaporator, and a 1 N aqueous sodium hydroxide solution was added to the residue, followed by extraction with methylene chloride. The methylene chloride layer was washed with water, dried and concentrated to obtain the desired amine compound (480 mg, quantitative). In the next step, it was used without purification.

H— NMR (300 MHz, CDC 13) δ 1.69 (bt, J = 5.2 Hz, 6 H), 3.25 (t, J = 6.3 Hz, 6 H), 3.27 (s, 6 H) , 3.41 (bm, 6H), 5.06 (s, 6H), 5.36 (bs, 3H) 7.31 (m, 15H)

Example 1 1

+ H ₂ NC (CH ₂₀ (CH ₂ ) ₃ NHZ) ₃

C0 ₂ H

CO ゥ H

o

Two

(ZHN (CH ₂ ) ₃ 0 (CH ₂ ) ₃ CHNC0v

_{_{C0NHC (CH 2 0 (CH 2}} ) 3NHZ) 3

To a 1.5 ml solution of 438 mg of the amine compound synthesized in Example 10 in dimethylformamide (DMF), 113 mg of DTPA dianhydride was added little by little while stirring under ice-cooling. Two hours later, I removed the bath and continued stirring. DMF was distilled off to obtain 5.56 mg (quantitative) of the almost pure target product.

¹ ^ C-NMR (125 MHz, DMSO d 6) δ 29.1, 37.5, 52.1, 52.2, 54.8, 55.2, 58.4, 59.0, 64.7, 68.3, 68.9, 12.6.78, 12.6.68, 12.7.5, 13.6.8, 15.5. 4, 1 69.4, 17.1.1, 171.3

Example 1 2

Lactone maltose is reacted with diethylene triamine and then with di-t-butyl dicarbonate, and the acetylated paracetyl Boc is treated with trifluoroacetic acid and then treated in a conventional manner to give a nearly quantitative yield of the free amine. I got it.

¹³ C-NMR (300Mz, CDC13, part) 5 20.5, 20.7, 20.9, 39.1, 47, 9, 61.5, 62.4, 68.1, 68.2, 69.7, 70.2, 71.1, 71.2, 71.6, 97.3, 166.6, 169.4, 169.7, 16 9.8, 169.9, 170.4, 170.5, 171.0. In dimethylformamide, the free amine was reacted with 1/2 equivalent of DTPA anhydride. After distilling off the solvent, the residue was crystallized from 2-propanol to obtain a peracetyl derivative of the target sugar-added DTPA compound.

¹ C-NMR (300Mz, DMSO-d6, part) δ 20.26, 20.34, 20.5, 20.6, 36.5, 37.3, 45.2, 46.2, 50.6, 51.4, 54.9.55.7, 61.5, 67.7, 67.9, 69.0, 69.5, 70.0, 70.6, 71.4, 75.4, 96.1, 166.0, 166.3, 169.2, 169.5, 169.7, 169.8, 170.0, 1 70.2, 170.3, 172.4.

To a solution of 2.0 _g of the percetyl compound in 8 mL of methanol was added 10 mL of concentrated ammonia water while stirring under ice-cooling. After standing overnight at room temperature, 5 mL of acetic acid was added and concentrated. The white solid was filtered with ethanol, washed, and dried to obtain the target DTPA derivative having maltose in almost quantitative yield.

¹³ C - Luo (300Mz, DMS0-d6) δ 36.8, 44.3, 46.4, 50.1, 51.6, 55.2, 57.2, 60.8, 62.7, 70.0, 71.7, 72.1, 72.2, 72.4, 72.3, 73.3, 73.4, 83.2, 100.9, 169.6, 170.6, 172.8, 173.0, 174.5.

It reacted with gadolinium oxide in the same manner as in Example 3 to obtain a Gd complex.

HPLC analysis conditions: TSKgel Amide-80, eluent: 55% acetonitrile, 1.0 mL / min, detection: 210 nm,

Rt: 34 min.

Example 13

Using the Gd complex of Example 3 and a tumor-bearing rat, an MR imaging test was performed on an animal machine (magnetic field strength: 2T). The measurement conditions were SE 500/18, multi-slice, dose, and drug concentration were 0.01 mmol / Kg and 0.05M. As a result, it was found that the Gd complex of Example 3 had a high signal in the solid part and a low signal in the cyst part. In the upper part of the liver (corresponding to the latter half slice of the multi-slice), the contrast effect was not so high as in the lower part. From this, the BP property of the Gd complex of Example 3 was estimated.

Example 14

The renal imaging effect of the Gd complex of Example 3 was compared with DTPA (Aldrich) using healthy rats. The measurement conditions were the same as in Example 13. The Gd complex of Example 3 was clearer than DTPA. In addition to showing a clear contrast effect, the contrast of the nipple was delayed, and the renal contrast behavior was slightly different from that of DTPA.

ADVANTAGE OF THE INVENTION According to this invention, the compound which has an organ and tissue selectivity and can be used as a novel contrast agent which has a blood pool property is obtained.

Claims

The scope of the claims

1. The following general formula (1)

(Wherein, R represents 1 N ((CH 2) k NHR ¹ ) 2 (where k represents an integer of 2 to 5, R ¹ represents a benzyloxycarbonyl group, and a t-butyloxycarbonyl group. represents water atom or a sugar chain Ashiru residues); over NH (CH 2) 1 N ( (CH 2) k HR 1) 2 ( wherein, k R ¹ represents the same meaning as defined above, 1 k Yo be the same or different from the force k representing the same meaning as Rere);. over ^{NH CHm (CH 2AR 2) 3-} m ( wherein, m represents 0 or 1, a represents a single bond, one (CH 2 ) 2-CH 2 CO O (CH 2) 3 -O (CH 2) 2 C〇 or one CO, R ² is one NHR ¹ , one NH (CH 2) kNHR ¹ , one N ((CH 2 ) kNHR ¹ ) 2 or —NH (CH 2) IN ((CH 2) kNHR ¹ ) 2 (where k 1 and R ¹ have the same meanings as above), provided that when m represents 1, , A represents only one CO.)

A diethylenetriamine pentaacetic acid derivative represented by

2. The method according to claim ^1, wherein R is -N ((CH 2) k NHR ¹ ) 2, wherein k represents an integer of 2 to 5, and R ¹ represents a glycan residue. 2. The ethylenetriamine pentaacetic acid derivative according to item 1.

3. The diethylenetriamine pentaacetic acid derivative according to claim 1 or 2, wherein the glycan residue is represented by the following general formula (3).

(In the above formula, p represents an integer of 0 to 10)

4. The derivative according to any one of claims 1 to 3, which is complexed with a metal ion.

5. The derivative according to claim 4, wherein the metal ion is selected from the group consisting of a paramagnetic metal ion and a radioactive metal ion. ·

6. A diethylenetriaminepentaacetic acid derivative represented by the following formula (5).

7. A contrast agent comprising the derivative according to any one of claims 1 to 5 as an essential component.

8. A pharmaceutical composition for in-vivo diagnosis comprising the derivative according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

9. The following general formula (2)

R '— R (2)

(Wherein, R has the same meaning as above. However, R ¹ in R represents a meaning excluding a hydrogen atom, and when R is —N ((CH 2) k NHR ¹ ) 2, R ¹ is R ′ represents a hydrogen atom, a Z group, or a Boc group, but when R has a Z group or a Boc group, it does not mean any of them.) An amino compound represented by