WO2008044443A1

WO2008044443A1 - Gadolinium compound and contrast medium for mri

Info

Publication number: WO2008044443A1
Application number: PCT/JP2007/068298
Authority: WO
Inventors: Norio Miura; Mitsuji Yamashita
Original assignee: National University Corporation Shizuoka University; Konica Minolta Holdings, Inc.
Priority date: 2006-10-06
Filing date: 2007-09-20
Publication date: 2008-04-17
Also published as: JPWO2008044443A1

Abstract

A novel gadolinium compound which (1) has a high T1 relaxation ability and can form an image with high sensitivity even when administered in a small amount, (2) is highly effective in imaging systemic blood vessels and the liver, (3) is highly effective in imaging the pancreas, and (4) has such safety that most of the compound is discharged from the body within 24 hours. Also provided is a contrast medium containing the compound. The gadolinium compound is characterized by being represented by the following general formula (1). (In the formula, G1 represents a residue formed by reacting a sugar lactone with an amino group, the sugar of the sugar lactone representing allose, altrose, mannose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose, lactose, or maltotriose.

Description

Specification

Gadolinium compounds and contrast media for MRI

Technical field

[0001] The present invention relates to a novel gadolinium compound and a contrast agent for MRI containing the same.

Background art

[0002] Gd (III) -DTPA (gadolinium (III) complex of diethylenetriaminepentaacetic acid, hereinafter referred to as Magnevist) was first used as a gadolinium compound and in 1988 as a contrast agent for MRI (nuclear magnetic resonance imaging). It has been used in over 45 million cases worldwide (see, for example, Chem. Rev. 1999, 99, 2293-2352). Since Magnevist is water-soluble and has a low molecular weight, it has been difficult to clearly image blood vessels, especially veins, that quickly migrate from blood vessels to organs and tissues. Therefore, a product in which a substituent which binds to albumin in plasma was introduced into Magnevist was developed (see, for example, Chem. Rev. 1999, 99, 2293-2352 and Tokuhei Hei 10-513445). Its representative ί row power MS-325 is a compound.

[0003] MS-325 has improved blood retention compared to Magnevist, and has greatly improved the contrast effect of systemic blood vessels. However, it was toxic and could not be administered in a sufficient amount, and there was a problem in the imaging of ischemic diseases (myocardial infarction, cirrhosis, etc.). On the other hand, in recent years, there has been a strong demand for imaging of minute diseases of specific organs (for example, metastatic cancers such as liver, spleen and lung). However, since the above-mentioned Magnevist and MS-325 have no organ specificity, it is difficult to satisfy the demand.

[0004] On the other hand, gadolinium complexes whose ends are modified with glucose rataton or galactose lactone (for example, Tetrahedron Lett., 41 (2000) 8485-8488, Chemical Reviews, 1999, Vol. 99, No. 9, 2293-2352, JP 2004-307356 and pamphlet of International Publication No. 06/095745) and gadolinium complexes modified with galactosamine and ratatosamine (for example, Gaodeng Xuexiao Huaxue Xuebao, (1997), 18 (7), 1071-1079)) Power is proposed. These are magnevis Compared to MS-325, it is possible to obtain a sufficient contrast effect with a small dose with a high T1 mitigation ability, so that it is possible to contrast peripheral blood vessels with little blood flow. In addition, since the accumulation effect in the liver is high, it is possible to image liver lesions with high sensitivity and high resolution, which is expected to contribute greatly to the early detection of fine metastatic cancers in the liver. . However, there was a problem that the ability to specifically contrast the lesion, which has low accumulation in the viscera, is low. There was concern about toxicity because it remained in the body for more than 24 hours after imaging.

Disclosure of the invention

Problems to be solved by the invention

[0005] The object of the present invention is to (1) be capable of high-sensitivity imaging even with a small dose with a high T1 alleviation ability, (2) excellent in systemic blood vessel and liver imaging, (3)

In addition, a novel gadolinium compound having the safety of being largely excreted outside the body within 24 hours and a contrast medium containing the same are provided.

Means for solving the problem

[0006] The object of the present invention is achieved by the following constitution.

[0007] 1. A gadolinium compound represented by the following general formula (1):

[0008] [Chemical 1]

One

(In the formula, G represents a residue obtained by reacting a sugar rataton and an amino group, and the sugar of the sugar rataton is arose, ananolose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, (Treose, cellobiose, manoleose, ratatoose or maltriolose)

2. A gadolinium compound represented by the following general formula (2). [0010] [Chemical 2]

— 2)

[In the formula, G represents a residue obtained by reacting a sugar rataton with an amino group, and the sugar of the sugar rataton is

2

, Anoletrose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, manoleose, latatoose or maltriose. ) [0012] [Chemical 3]

(3)

(In the formula, G represents a residue obtained by reacting a sugar rataton with a hydroxyl group, and the sugar of the sugar rataton is

Three

Represents loin, anoletros, gnolecose, mannose, gurose, idose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose, ratatoose or maltriose. )

4. A gadolinium compound represented by the following general formula (4):

[0014] [Chemical 4]

(In the formula, G represents a residue obtained by reacting a sugar rataton with an amino group, and the sugar of the sugar rataton is a sugar.

Four

, Anoroleose, gnolecose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose or maltriose. )

5. A gadolinium compound represented by the following general formula (5).

[0016] [Chemical 5]

Five

, Anoretose, gnolecose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, manoletose, ratatoose or maltriose. )

6. A gadolinium compound represented by the following general formula (6):

[0018] [Chemical 6] one

6

7. A contrast agent for MRI, comprising at least one of the gadolinium compounds according to any one of 1 to 6 above.

The invention's effect

[0020] According to the present invention, (1) high-sensitivity imaging can be performed even with a small dose with a high T1 alleviation ability, (2) excellent in systemic blood vessel and liver imaging, (3) (4) Furthermore, it is possible to provide a novel gadolinium compound and a contrast medium containing the same that have the safety of being largely excreted outside the body within 24 hours.

BEST MODE FOR CARRYING OUT THE INVENTION

As a result of intensive studies, the present inventor has found that the gadolinium compounds having the specific structures represented by the general formulas (1) to (6) are (1) highly sensitive even at a small dose with a high 1 relieving ability. Contrastable, (2) Excellent for imaging of whole body blood vessels and liver, (3) Also excellent for visceral imaging, (4) In addition, it is safe to be excreted mostly outside the body within 24 hours It was found that a novel gadolinium compound and a contrast medium containing the compound is an excellent contrast medium.

[0022] Hereinafter, the present invention will be described in detail.

<< Gadolinium compounds represented by general formulas (1) to (6) >>

First, the gadolinium compound represented by the general formula (1) of the present invention will be described in detail.

[0024] In the general formula (1), G represents a residue obtained by reacting a sugar rataton with an amino group, The sugars of allose, alanose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose, ratatoose or maltriose , Mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose or threose, more preferably, ararose, ananolose, mannose, gurose, idose, galactose, talose, ribose, arabinose, It represents xylose or lyxose, particularly preferably mannose or galactose.

[0025] In the general formula (2), G represents a residue obtained by reacting a sugar rataton with an amino group, and the sugar rataton

2

The sugars of allose, alanose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose, ratatoose or maltriose , Mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose or threose, more preferably, ararose, ananolose, mannose, gurose, idose, galactose, talose, ribose, arabinose, It represents xylose or lyxose, particularly preferably mannose or galactose.

[0026] In the general formula (3), G represents a residue obtained by reacting a sugar rataton with a hydroxyl group, and the sugar

Three

Rataton's sugar represents allose, ananolose, gnoleose, mannose, gurose, idose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose, ratatoose or maltriolose. Represents gnolesole, mannose, gurose, idose, talose, ribose, arabinose, xylose, lyxose, erythrose or threose, more preferably araose, anoretrose, gnolecose, mannose, gurose, idose, talose, ribose, arabinose, xylose or lyxose And particularly preferably glucose or mannose.

[0027] In the general formula (4)! /, G represents a residue obtained by reacting a sugar rataton with an amino group, and the sugar rataton

Four

The sugars are allose. Anoleoptose, gnolecose, mannose, gurose, idose, galacto Represents sesame, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose or maltriolose, preferably galose, ananolose, gnolecose, mannose, gurose, idose, galactose, talose, ribose , Arabinose, xylose, lyxose, erythrose or threose, more preferably galose, altrose, glucose, mannose, gurose, idose, galatose, talose, ribose, arabinose, xylose or lyxose, particularly preferably glucose, Represents mannose or galactose.

[0028] In the general formula (5), G represents a residue obtained by reacting a sugar rataton with an amino group, and the sugar rataton

Five

The sugar of galose, anoreose, gnoleose, mannose, gurose, idose, galatatose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, maltose, ratatoose or maltriolose. , Anoretolose, gnolecose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose or throse, more preferably, allose, altrose, glucose, mannose, gurose, idose, galactose, Represents talose, ribose, arabinose, xylose or lyxose, particularly preferably glucose, mannose or galactose It is.

[0029] In the general formula (6), G represents a residue obtained by reacting a sugar rataton with an amino group, and the sugar rataton

6

Next, specific examples of the compounds represented by the general formulas (1) to (6) of the present invention are shown. However, the present invention is not limited to these.

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[0085] The synthesis methods of these exemplary compounds are shown in the Examples.

[0086] <Contrast agent>

Next, the contrast agent for MRI containing the gadolinium compound of the present invention will be described in detail.

[0087] The contrast agent of the present invention contains at least one of the gadolinium compounds represented by the above general formulas (1) to (6). Preferably, the general formula (1), the general formula (2), It contains at least one gadolinium compound represented by general formula (5) or general formula (6), more preferably It contains at least one gadolinium compound represented by general formula (1), general formula (5) or general formula (6), and particularly preferably at least one gadolinium compound represented by general formula (1). It contains 1 type. A gadolinium compound may be used in combination of two or more. Preferably, it contains only one compound.

[0088] The gadolinium compound of the present invention has good water solubility. Preferably, it is soluble in water to a concentration of at least 1. OmM, preferably 10 mM, and more preferably lOOmM at room temperature. A contrast agent of the invention formulated for injection should have only a moderate viscosity to allow for quick and convenient injection. ^{Viscosity, 10. 20 X 10- 4 kgf '} s / m 2 (10mPa' s, 10cP) less than, or preferably 5 · 10 X 1 O ^ kgf - less than - (s, 5 cP 5mPa) s / m 2 , or more preferably ^{2 · 04 X 10- 4 kgf '} s / m 2 (2mPa' s, 2cP) is less than. Also, the contrast agent of the present invention formulated for injection should not have excessive osmotic pressure. This is because it can increase toxicity. The osmotic pressure is less than 3000 milliosmol / kg, or preferably less than 2500 milliosmol / kg, or most preferably less than 900 milliosmol / kg.

[0089] The contrast agent of the present invention can contain a salt derived from an inorganic or organic acid and base. Specific examples of the salt include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, kenate, camphorate, camphorsulfonate Salt, cyclopentanepropionate, didarconate, dodecyl sulfate, ethane sulfonate, fumarate, darcoheptanoate, glycephosphate, hemisulfate, heptanoate, hexanoate, Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate , Pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, Silates, undecanoates, ammonium salts, alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts (eg, calcium, magnesium and zinc salts), salts with organic bases (eg, dicyclo Hexylamine salts, N-methyl-D-dalkamine), and salts with amino acids (eg, arginine, lysine). The basic nitrogen-containing group is a lower alkyl halo group. Id (eg, methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfate (eg, dimethyl, jetyl, dibutyl and diamyl sulfate), long chain halides (eg, decyl, lauryl, myristyl and stearyl chloride, bromide and Benzoyl), aralkyl halides (eg, benzyl and phenethyl bromide) and others. Thereby, a water-soluble or oil-soluble or water-dispersible or oil-dispersible product is obtained. Preferred salts of the present invention are N-methylol D-dalkamine, calcium and sodium salts.

[0090] The contrast agent of the present invention may contain any carrier, adjuvant or vehicle. Carriers, adjuvants and vehicles that can be used in the contrast agents of the present invention include ion exchange materials, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffering materials (eg, phosphate), glycine, Sorbic acid, potassium sorbate, TRIS (tris (hydroxymethyl) aminomethane), a partial glyceride mixture of vegetable saturated fatty acids, water, salt or electrolyte (eg protamine sulfate, ninatrium hydrogen phosphate, potassium hydrogen phosphate, chloride) Sodium, zinc salts), colloidal silica, magnesium trisilicate, polyvinylenopyrrolidone, cenorelose-based material, polyethylene glycolenole, canolepoximethinoresenorelose sodium, polyacrylate, wax, polyethylene polyoxy Propylene block polymers, but are not limited to polyethylene glycol and lanolin encompasses force S, to these.

[0091] The contrast agents of the present invention may be in the form of sterile injectable pharmaceutical preparations (eg, sterile injectable aqueous or oily suspensions). This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Injectable, sterile preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents (eg, as a solution in 1,3-butanediol). May be). Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, conventionally, sterile, fixed oils are used as solvents or suspending media. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids (eg, oleic acid and its glyceride derivatives) are naturally occurring pharmaceutically acceptable oils (eg, olive oil or It is useful in the preparation of injectables, in particular in these polyoxyethylated variants as well as (masi oil). These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant (eg, Ph. Helv or similar alcohol).

[0092] The contrast agent of the present invention is an oral administration, parenteral administration, administration by inhalation spray, topical administration, rectal administration, nasal administration, vaginal administration, vaginal administration or a conventional non-toxic pharmaceutically acceptable carrier, Administration may be via a reservoir embedded in a dosage formulation containing an adjuvant and vehicle. As used herein, the term `` parenteral '' refers to subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or Includes infusion technology.

[0093] When administered orally, the pharmaceutical compositions of the invention may be in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Can be administered. When tablets are used orally, commonly used carriers include lactose and corn starch. Typically, a lubricant such as magnesium stearate is also added. For oral administration in a capsule form, useful diluents include latatoose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added. Alternatively, when administered in suppository form for rectal administration, the contrast agents of the present invention are mixed with a suitable nonirritating excipient that is solid at room temperature but liquid at rectal temperature. So that it dissolves in the rectum and releases the drug. Such materials include cocoa butter, beeswax and polyethylene renders.

[0094] Also, as described above, this is particularly true when the treatment target includes an area or organ that is easily accessible by topical application (including the eye, skin, or lower intestinal tract). The inventive contrast agents can be administered locally. Appropriate topical formulations are readily prepared for each of these areas or organs.

[0095] Topical application for the lower intestinal tract can be made with a rectal suppository formulation or a suitable enema formulation. Topically-transdermal patches may also be used. For topical application, the contrast agents of the invention are suitable ointments containing the active ingredients suspended or dissolved in one or more carriers. Can be formulated. Carriers for topical administration of the contrast agents of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the contrast agent of the present invention may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0096] For ophthalmic use, the contrast agent of the present invention may or may not contain a preservative (eg, benzylalkonium chloride). It can be formulated as a micronized suspension in pH adjusted isotonic sterile saline, or preferably as a solution in pH adjusted isotonic sterile saline. Alternatively, for ophthalmic use, the contrast agents of the invention can be formulated in an ointment such as petrolatum.

[0097] For administration by nasal aerosol or inhalation, the contrast agents of the present invention are prepared according to techniques well known in the pharmaceutical formulation arts and have benzyl alcohol or other suitable preservatives, bioavailability. It can be prepared as a solution in saline using increasing absorption enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0098] Dosing depends on the sensitivity of the diagnostic imaging device as well as the composition of the contrast agent. For example, for MRI imaging, contrast agents containing the gadolinium compounds of the present invention are generally more effective than contrast agents containing a paramagnetic material having a lower magnetic moment, such as iron (III). Requires low dosing. Preferably, the dosage ranges from about 0.001 per day; active metal ligand complex of Immol / kg body weight. More preferably, the dosage is in the range of about 0.005 to 0.05 mmol / kg body weight per day.

[0099] However, the specific dosage regimen for any particular patient may also vary according to various factors (age, weight, health status, sex, diet, time of administration, excretion rate, combination of drugs and treating physicians). It should be understood that it depends on

[0100] In the present invention, MRI imaging is performed following administration of an appropriate dose of contrast agent. Pal Series (reverse recovery (IR); spin echo (SE); echo tomography (EPI); time of flight (TOF); turboflash; gradient echo (GE)) and imaging parameter values (echo time (TE); The choice of inversion time (TI); repeat time (TR); flip angle, etc.) is governed by the diagnostic information required. In general, if it is desired to obtain a T1-weighted image, TE should be less than 30 milliseconds or the smallest value to maximize T1-weighting. Conversely, if T2 measurement is desired, TE should be greater than 30 milliseconds to minimize competing T1 effects. TI and TR are kept approximately the same for both T1— and T2—weighted images; in general, TI and TR are about 5 to 1000 milliseconds and 2 to respectively; It is on the order of 1000 milliseconds.

Example

[0101] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto. Unless otherwise specified, “%” in the examples represents “mass%”.

[Synthesis Example 1]

Exemplified compound Allo-4-Gd-DTPA was synthesized according to the following scheme (Scheme 1).

[0103] [Chemical 61]

[0104] The sixth step was performed according to the method described in Tetrahedron Lett. 41 (2000) 8486, using galonolactone (1) 17.8g (0. Imol) and diethylenetriamine (2) 10 · 3g (0. Imol). Carried out.

[0105] Next, after cooling to room temperature, 50 ml of 1M-NaOH aqueous solution was added and stirred for 24 hours. This solution was neutralized by passing through a cation exchange resin (Amberlite EG-4-HG: manufactured by Rohm and Haas, USA), and the solvent was distilled off under reduced pressure. Silica gel chromatodara residue Purified (Wakogell00C18 reverse-layer silica gel 63-212 m, manufactured by Wako Pure Chemical Industries, Ltd.) (solvent is pure water: methanol = 1: 1). The solvent was concentrated under reduced pressure to obtain 86.7 g (total yield 60%) of the target product Alio-4Gd-DTP A as a white glassy solid. It was confirmed by elemental analysis that it was the target product.

[0106] Elemental analysis values

(Calculated./o): C, 38.14; H, 5.85; Gd, 10.86; N, 8.70

(Actual value ⁰ / o): C, 38.43; H, 5.61; Gd, 10.23; N, 8.76

(Synthesis Example 2)

Except that the starting material was changed to altronolalatone in Synthesis Example 1, Exemplified Compound 8 10-40 (1-0 to 8) was obtained in the same manner as Synthesis Example 1. Total yield 54%.

[0107] Elemental analysis values

(Calculated./o): C, 38.14; H, 5.85; Gd, 10.86; N, 8.70

(Actual value ⁰ / o): C, 38.23; H, 5.71; Gd, 10.73; N, 8.73

(Synthesis Example 3)

Exemplified compound Man-4 Gd DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to mannolatone in Synthesis Example 1. Touta no yield 53%.

[0108] Elemental analysis values

(Calculated./o): C, 38.14; H, 5.85; Gd, 10.86; N, 8.70

(Actual value ⁰ / o): C, 38.13; H, 5.81; Gd, 10.79; N, 8.83

(Synthesis Example 4)

Exemplified compound Gulo-4Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to Guronorataton in Synthesis Example 1. Total yield 56%.

[0109] Elemental analysis values

(Calculated./o): C, 38.14; H, 5.85; Gd, 10.86; N, 8.70

(Actual value ⁰ / o): C, 38.13; H, 5.81; Gd, 10.53; N, 8.93

(Synthesis Example 5)

Exemplified compound Ido-4 Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to Idnorataton in Synthesis Example 1. Total yield 49%. [0110] Elemental analysis

(Calculated./o): C, 38.14; H, 5.85; Gd, 10.86; N, 8.70

(Actual value ⁰ / o): C, 38.23; H, 5.61; Gd, 10.77; N, 8.72

(Synthesis Example 6)

Exemplified compound Gala-4 Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to galactronolatatone in Synthesis Example 1. Total yield 64%.

[0111] Elemental analysis

(Calculated./o): C, 38.14; H, 5.85; Gd, 10.86; N, 8.70

(Actual value ⁰ / o): C, 38.28; H, 5.83; Gd, 10.77; N, 8.56

(Synthesis Example 7)

Exemplified compound Tal-4Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to Talonoratatone in Synthesis Example 1. Total yield 59%.

[0112] Elemental analysis

(Calculated./o): C, 38.14; H, 5.85; Gd, 10.86; N, 8.70

(Actual value ⁰ / o): C, 38.11; H, 5.67; Gd, 10.89; N, 8.69

(Synthesis Example 8)

Exemplified compound Libo-4 Gd-DTPA was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to Ribonolaton in Synthesis Example 1. Tota no yield 56%.

[0113] Elemental analysis values

(Calculated./o): C, 37.98; H, 5.77; Gd, 11.84; N, 9.49

(Actual value ⁰ / o): C, 37.73; H, 5.71; Gd, 11.73; N, 9.73

(Synthesis Example 9)

Except that the starting material was changed to arabinolatatone in Synthesis Example 1, Exemplified Compound 8 1 & 1 ^ 40 (1-0 to 8) was obtained in the same manner as Synthesis Example 1. Total yield 60%.

[0114] Elemental analysis

(Calculated./o): C, 37.98; H, 5.77; Gd, 11.84; N, 9.49

(Actual value ⁰ / o): C, 37.83; H, 5.76; Gd, 11.83; N, 9.53

(Synthesis Example 10) Exemplified compound Xyl-4 Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to xylonolatone in Synthesis Example 1. Total yield 58%.

[0115] Elemental analysis

(Calculated./o): C, 37.98; H, 5.77; Gd, 11.84; N, 9.49

(Actual value ⁰ / o): C, 37.84; H, 5.71; Gd, 11.83; N, 9.53

(Synthesis Example 11)

Exemplified compound Lix-4Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to Lixonoratatone in Synthesis Example 1. Total yield 65%.

[0116] Elemental analysis

(Calculated./o): C, 37.98; H, 5.77; Gd, 11.84; N, 9.49

(Actual value ⁰ / o): C, 37.84; H, 5.75; Gd, 11.83; N, 9.63

(Synthesis Example 12)

Exemplified compound Erithro-4-Gd-DTPA was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to erythronolatatone in Synthetic Example 1. Total yield 62%.

[0117] Elemental analysis

(Calculated value./o): C, 37.77; H, 5.67; Gd, 13.01; N, 10.43

(Actual value ⁰ / o): C, 37.73; H, 5.71; Gd, 13.23; N, 10.53

(Synthesis Example 13)

Exemplified compound Threo-4 Gd DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material in Synthetic Example 1 was changed to threronoratatone. Total yield 63%.

[0118] Elemental analysis

(Calculated value./o): C, 37.77; H, 5.67; Gd, 13.01; N, 10.43

(Actual value ⁰ / o): C, 37.63; H, 5.61; Gd, 13.13; N, 10.47

(Synthesis Example 14)

In Synthesis Example 1, Exemplified compounds ₆ 11 ₀ 1 ^ —40 (1-0 to 8) were obtained in the same manner as Synthesis Example 1 except that the starting material was changed to cellovinolaton. Total yield 61%.

[0119] Elemental analysis values

(Calculated value ⁰ / o): C, 40.09; H, 5.96; Gd, 7.50; N, 6.01 (Measured value ⁰ / o): C, 40.00; H, 5.81; Gd, 7.43; N, 6.23

(Synthesis Example 15)

Exemplified compound Malto-4 Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to maltonolatone in Synthesis Example 1. Tota no yield 55%.

[0120] Elemental analysis values

(Calculated value ⁰ / o): C, 40.09; H, 5.96; Gd, 7.50; N, 6.01

(Measured value ⁰ / o): C, 40.01; H, 5.83; Gd, 7.53; N, 6.03

(Synthesis Example 16)

Exemplified compound Lacto 4 Gd-DTPA was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to lactonolatatone in Synthetic Example 1. Touta no yield 65%.

[0121] Elemental analysis values

(Calculated value ⁰ / o): C, 40.09; H, 5.96; Gd, 7.50; N, 6.01

(Actual value ⁰ / o): C, 40.03; H, 5.91; Gd, 7.53; N, 6.13

(Synthesis Example 17)

Exemplified compound Maltrio-4 Gd-DTP A was obtained in the same manner as in Synthetic Example 1, except that the starting material was changed to maltrionolatatone in Synthetic Example 1. Total yield 61%.

[0122] Elemental analysis

(Calculated value./o): C, 41.09; H, 6.09; Gd, 5.72; N, 4.59

(Actual value ⁰ / o): C, 41.00; H, 6. ll; Gd, 7.63; N, 4.43

(Synthesis Example 18)

Exemplified compound Allo-12-Gd-DTPA was synthesized according to the following scheme (Scheme 2).

[0123] [Chemical 62]

98ε d9ε8ζ80ps> εΟ 0::.--.,-

[0124] Aronolatataton (1) 17 · 8g (0. Imol) and diethylenetriamine (2) 10 · 3g (0. Imol) were added to Tetrahedron Lett., 41 (2000) page 8486 until the seventh step. Carried out.

Next, after cooling to room temperature, 60 ml of 1M NaOH aqueous solution was added and stirred for 24 hours. This solution was added to a cation exchange resin (Amberlite EG-4—HG: manufactured by Rohm and Haas, USA). ) Neutralized by passing through, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (WakogellOOC18 reverse layer silica gel 63-212 m, manufactured by Wako Pure Chemical Industries, Ltd.) (solvent: pure water: methanol = 1: 2). The solvent was concentrated under reduced pressure to obtain 86.7 g (total yield: 38%) of the target product Alio-12-Gd-DTPA as a white plate-like solid. It was confirmed by elemental analysis that it was the target product.

[0126] Elemental analysis values

(Calculated value./o): C, 42.37; H, 6.59; Gd, 4.08; N, 8.36

(Measured value ⁰ / o): C, 42.30; H, 6.51; Gd, 4.23; N, 8.33

(Synthesis Example 19)

Exemplified compound Altro-12-Gd-DTPA was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to altronolalatone in Synthesis Example 18. Total yield 38%.

[0127] Elemental analysis values

(Calculated value./o): C, 42.37; H, 6.59; Gd, 4.08; N, 8.36

(Measured value ⁰ / o): C, 42.35; H, 6.54; Gd, 4.03; N, 8.35

(Synthesis Example 20)

In Synthesis Example 18, the exemplified compound Man-12-Gd-DTP A was obtained in the same manner as in Synthesis Example 18 except that the starting material was changed to mannolaton. Total yield 48%.

[0128] Elemental analysis values

(Calculated value./o): C, 42.37; H, 6.59; Gd, 4.08; N, 8.36

(Measured value ⁰ / o): C, 42.36; H, 6.55; Gd, 4.13; N, 8.38

(Synthesis Example 21)

Exemplified compound Gulo-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to Guronorataton in Synthesis Example 18. Total yield 31%.

[0129] Elemental analysis values

(Calculated value./o): C, 42.37; H, 6.59; Gd, 4.08; N, 8.36

(Actual value ⁰ / o): C, 42.25; H, 6.49; Gd, 4.12; N, 8.38

(Synthesis Example 22)

In Synthesis Example 18, the same procedure as in Synthesis Example 18 except that the starting material was changed to Idnorataton. Thus, exemplary compound Ido-12-Gd-DTP A was obtained. Total yield 42%.

[0130] Elemental analysis

(Calculated value./o): C, 42.37; H, 6.59; Gd, 4.08; N, 8.36

(Measured value ⁰ / o): C, 42.25; H, 6.55; Gd, 4.02; N, 8.45

(Synthesis Example 23)

Exemplified compound Gala-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to galactronolatatone in Synthesis Example 18. Total yield 45%.

[0131] Elemental analysis

(Calculated value./o): C, 42.37; H, 6.59; Gd, 4.08; N, 8.36

(Actual value ⁰ / o): C, 42.45; H, 6.64; Gd, 4.13; N, 8.38

(Synthesis Example 24)

Exemplified compound Tal-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to Talonoratatone in Synthesis Example 18. Total yield 42%.

[0132] Elemental analysis

(Calculated value./o): C, 42.37; H, 6.59; Gd, 4.08; N, 8.36

(Actual value ⁰ / o): C, 42.15; H, 6.59; Gd, 4.13; N, 8.29

(Synthesis Example 25)

Exemplified compound Libo-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to Ribonolatone in Synthesis Example 18. Total yield 39%.

[0133] Elemental analysis values

(Calculated value ⁰ / o): C, 42.62; H, 6.58; Gd, 4.50; N, 9.22

(Actual value ⁰ / o): C, 42.55; H, 6.53; Gd, 4.53; N, 9.35

(Synthesis Example 26)

In Synthesis Example 18, Exemplified Compound 8 1 & 1 ^ 12-0 (1-0 C? 8) was obtained in the same manner as Synthesis Example 18 except that the starting material was changed to arabinolatatone. Total yield 40%.

[0134] Elemental analysis values

(Calc ^{0 / o): C, 42.62} ; H, 6.58; Gd, 4.50; N, 9.22

(Found ^{0 / o): C, 42.65} ; H, 6.57; Gd, 4.50; N, 9.33 (Synthesis Example 27)

Exemplified compound Xyl-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to xylonolatone in Synthesis Example 18. Total yield 39%.

[0135] Elemental analysis values

(Calculated value ⁰ / o): C, 42.62; H, 6.58; Gd, 4.50; N, 9.22

(Actual value ⁰ / o): C, 42.65; H, 6.57; Gd, 4.51; N, 9.25

(Synthesis Example 28)

Exemplified compound Lix-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to Lixonoratatone in Synthesis Example 18. Total yield 38%.

[0136] Elemental analysis values

(Calculated value ⁰ / o): C, 42.62; H, 6.58; Gd, 4.50; N, 9.22

(Actual value ⁰ / o): C, 42.52; H, 6.52; Gd, 4.52; N, 9.32

(Synthesis Example 29)

Exemplified compound Erithro-12-Gd-DTPA was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to erythronolatatone in Synthesis Example 18. Total yield 33%.

[0137] Elemental analysis values

(Calculated value ⁰ / o): C, 42.92; H, 6.56; Gd, 5.50; N, 10.28

(Actual value ⁰ / o): C, 42.85; H, 6.53; Gd, 5.53; N, 10.35

(Synthesis Example 30)

Exemplified compound Threo-12-Gd-DTPA was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to Threoronolatathone in Synthetic Example 18. Total yield 37%.

[0138] Elemental analysis values

(Calculated value ⁰ / o): C, 42.92; H, 6.56; Gd, 5.50; N, 10.28

(Actual value ⁰ / o): C, 42.84; H, 6.52; Gd, 5.53; N, 10.31

(Synthesis Example 31)

Exemplified compound Cellobi-12-Gd-DTPA was obtained in the same manner as in Synthesis Example 18, except that the starting material was changed to cellovinolaton in Synthesis Example 18. Total yield 43%.

[0139] Elemental analysis values (Calculated value ⁰ / o): C, 43.07; H, 6.46; Gd, 2.71; N, 5.55

(Actual value ⁰ / o): C, 43.05; H, 6.43; Gd, 2.63; N, 5.45

(Synthesis Example 32)

Except that the starting material was changed to maltonolatatone in Synthesis Example 18, Exemplified Compound ^ ½ 0-12-0 (1-0 C? 8) was obtained in the same manner as Synthesis Example 18. Total yield 33%.

[0140] Elemental analysis values

(Calc ^{0 / o): C, 43.07} ; H, 6.46; Gd, 2.71; N, 5.55

(Actual value ⁰ / o): C, 43.06; H, 6.46; Gd, 2.66; N, 5.46

(Synthesis Example 33)

Exemplified compound Lacto-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to a lactolonatone derivative in Synthetic Example 18. Total yield 34%.

[0141] Elemental analysis values

(Calculated value ⁰ / o): C, 43.07; H, 6.46; Gd, 2.71; N, 5.55

(Found ^{0 / o): C, 43.02} ; H, 6.42; Gd, 2.65; N, 5.47

(Synthesis Example 34)

Exemplified compound Maltrio-12-Gd-DTP A was obtained in the same manner as in Synthetic Example 18, except that the starting material was changed to maltrionolatatone in Synthesis Example 18. Total yield 38%.

[0142] Elemental analysis values

(Calculated./o): C, 43.41; H, 6.40; Gd, 2.03; N, 4.16

(Actual value ⁰ / o): C, 43.45; H, 6.43; Gd, 2.13; N, 4.25

(Synthesis Example 35)

Exemplified compound Alio-2- o-Gd-DTP A was synthesized according to the following scheme (Scheme 3).

[0143] [Chemical 63]

Tetrahedron Lett., 41 (2000) page 8486, caDTPA 35.7 g (0. It was suitable over 30 minutes. After stirring as it was for 3 hours, 35.6 g (0.2 mol) of alonolatatone (1) was added, and the mixture was heated and stirred at 65 ° C. for 12 hours. The reaction solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain 83.7 g (yield 97%) of white crystals of (6). Then ½) 8 · 6g ( 0. Olmol) was dissolved in 50 ml of distilled water, 3.71 g (0. Olmol) of salt and gadolinium hexahydrate were added, and the mixture was heated and stirred at 90 ° C. for 8 hours. After cooling, the solution was neutralized by passing through a cation exchange resin (Amberlite EG-4-HG: manufactured by Rohm and Haas, USA), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (WakogellOOC18 reverse-layer silica gel 63-212 m, manufactured by Wako Pure Chemical Industries, Ltd.) (solvent: pure water: methanol = 2: 1). The solvent was concentrated under reduced pressure to obtain 8.28 g (yield 80%) of the target product Alio-2-o-Gd-DTPA as a white candy-like solid. Total yield 78%. Elemental analysis confirmed the target product.

[0145] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.15; H, 5.43; Gd, 15.13; N, 6.55

(Synthesis Example 36)

Exemplified compound Altro-2-o-Gd-DTP A was obtained in the same manner as in Synthesis Example 35, except that in Example 35, Aralonelataton (1) was changed to Altronolaton. Total yield 78%.

[0146] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.14; H, 5.44; Gd, 15.16; N, 6.65

(Synthesis Example 37)

Exemplified compound Glu-2-o-Gd-DTPA was obtained in the same manner as in Synthetic Example 35, except that in Example 35, Aralonelataton (1) was changed to Darconolataton. Total yield 78%.

[0147] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.13; H, 5.45; Gd, 15.17; N, 6.75

(Synthesis Example 38)

Exemplified compound ^ ½1 2-0—0 (1-0 to 0? 8) was obtained in the same manner as in Synthetic Example 35, except that valonolatatone (1) was changed to mannolatatone in Synthesis Example 35. Total yield 78%.

[0148] Elemental analysis

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76 (Actual value ⁰ / o): C, 37.13; H, 5.45; Gd, 15.17; N, 6.75

(Synthesis Example 39)

Exemplified compound Gulo-2-o-Gd-DTP A was obtained in the same manner as in Synthesis Example 35, except that, in Synthesis Example 35, Aralonelataton (1) was changed to Guronorataton. Total yield 71%.

[0149] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.11; H, 5.65; Gd, 15.21; N, 6.69

(Synthesis Example 40)

In Synthesis Example 35, Aronorataton (1) was replaced with Idonorataton in the same manner as in Synthesis Example 35 Exemplified Compound 1 (10 2 ₀ -? 0 (1-0 Ding give the eight total yield 72% .

[0150] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Found ^{0 / o): C, 37.21} ; H, 5.55; Gd, 15.11; N, 6.68

(Synthesis Example 41)

Exemplified compound Gala-2-o-Gd-DTP A was obtained in the same manner as in Synthetic Example 35, except that in Example 35, Aralonelataton (1) was changed to Galactronorataton. Total yield 75%

Yes

[0151] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.11; H, 5.45; Gd, 15.14; N, 6.78

(Synthesis Example 42)

Exemplified compound Tal-2-o-Gd-DTP A was obtained in the same manner as in Synthetic Example 35, except that in Example 35, Aralonelataton (1) was changed to Talonorataton. Total yield 72%.

[0152] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.13; H, 5.47; Gd, 15.18; N, 6.77

(Synthesis Example 43)

In Synthesis Example 35, except that Aronolataton (1) was changed to Ribonolaton, Synthesis Example 35 and Similarly, the exemplified compound Libo-2-o-Gd-DTPA was obtained. Total yield 69%.

[0153] Elemental analysis values

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.88; H, 5.33; Gd, 16.13; N, 7.25

(Synthesis Example 44)

Exemplified compound 8 1 & 1 ^ — 2—0—0 (1—0 ?? 8) was obtained in the same manner as in Synthesis example 35, except that in the synthesis example 35, valonolatatone (1) was changed to arabinolatatone, the total yield was 70%. .

[0154] Elemental analysis values

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.98; H, 5.35; Gd, 16.12; N, 7.23

(Synthesis Example 45)

Exemplified compound Xyl-2-o-Gd-DTPA was obtained in the same manner as in Synthesis Example 35, except that in Example 35, Aralonelataton (1) was changed to Xylonolataton. Total yield 69%.

[0155] Elemental analysis values

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.93; H, 5.33; Gd, 16.13; N, 7.21

(Synthesis Example 46)

Exemplified compound Lix-2-o-Gd-DTP A was obtained in the same manner as in Synthesis Example 35, except that in Example 35, Aralonelataton (1) was changed to Lixonorataton. Total yield 68%.

[0156] Elemental analysis values

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.91; H, 5.31; Gd, 16.11; N, 7.20

(Synthesis Example 47)

Exemplified compound Erithro-2-O-Gd-DTP A was obtained in the same manner as in Synthesis Example 35, except that in Example 35, Aralonelataton (1) was changed to Erythronolatone. Total yield 63

%.

[0157] Elemental analysis values

(Calculated./o): C, 36.72; H, 5.28; Gd, 17.17; N, 7.65 (Actual value ⁰ / o): C, 36.80; H, 5.30; Gd, 17.15; N, 7.62

(Synthesis Example 48)

Exemplified compound 1¾ 0—2—0—0 (1—0 ?? 8) was obtained in the same manner as in Synthesis Example 35, except that aronoratatone (1) was changed to threlonoratatone in Synthesis Example 35. Tota nore yield 67 %.

[0158] Elemental analysis values

(Calculated./o): C, 36.72; H, 5.28; Gd, 17.17; N, 7.65

(Actual value ⁰ / o): C, 36.81; H, 5.31; Gd, 17.11; N, 7.66

(Synthesis Example 49)

In Compound Example 35, Exemplified Compound ₆ 11 ₀ 1 ^ — 2—0—0 (1—0 ?? 8) was obtained in the same manner as in Synthesis Example 35, except that valonolatatone (1) was changed to cellovinolaton. The rate is 73%.

[0159] Elemental analysis values

(Calculated./o): C, 38.85; H, 5.63; Gd, 11.56; N, 5.15

(Actual value ⁰ / o): C, 38.91; H, 5.43; Gd, 11.63; N, 5.25

(Synthesis Example 50)

Exemplified compound ^ ½ 0−2−0−0 (1−0 ?? 8) was obtained in the same manner as in Synthesis Example 35, except that in Example 35, allolanataton (1) was changed to maltonolatone. 63%.

[0160] Elemental analysis values

(Calculated./o): C, 38.85; H, 5.63; Gd, 11.56; N, 5.15

(Actual value ⁰ / o): C, 38.90; H, 5.53; Gd, 11.53; N, 5.18

(Synthesis Example 51)

Exemplified compound Lacto-2-o-Gd-DTPA was obtained in the same manner as in Synthesis Example 35, except that in Example 35, Aralonelatatone (1) was changed to lactonolataton. Total yield 64%.

[0161] Elemental analysis values

(Calculated./o): C, 38.85; H, 5.63; Gd, 11.56; N, 5.15

(Actual value ⁰ / o): C, 38.80; H, 5.63; Gd, 11.55; N, 5.16

(Synthesis Example 52)

Exemplified compound Maltrio-2-o-Gd-DTP A was obtained in the same manner as in Synthesis Example 35, except that in Example 35, alonolatatatone (1) was changed to maltrionolatatone. Tota no yield 68 %.

[0162] Elemental analysis values

(Calculated./o): C, 38.85; H, 5.63; Gd, 11.56; N, 5.15

(Actual value ⁰ / o): C, 38.81; H, 5.61; Gd, 11.57; N, 5.17

(Synthesis Example 53)

Exemplified compound Alio-2-n-Gd-DTP A was synthesized according to the following scheme (Scheme 4).

[0163] [Chemical 64]

Tetrahedron Lett., 41 (2000) Page 8486, caDTPA35.7 g (0. It took over 40 minutes. After stirring as it was for 5 hours, 30 ml of 1M NaOH was added and reacted at 40 ° C for 3 hours. After neutralizing the reaction solution, the precipitated crystals are collected by mouth, and methanol is sufficient. Washing and drying gave intermediate (7) in 42. Og (88% yield). Next, 4.81 g (0.01 mol) of (7) and 3.72 g (0.02 mol) of alonolatatone (1) were heated and stirred at 45 ° C for 9 hours in 30 ml of DMF. The reaction solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain 7.9 g (yield 95%) of (8) white crystals. Next, 8.33 g (0. Olmol) of (8) was dissolved in 50 ml of distilled water, 3.71 g (0. Olmol) of gadolinium chloride hexahydrate was added, and the mixture was stirred with heating at 90 ° C. for 12 hours. After cooling, the solution was neutralized by passing through a cation exchange resin (Amberlite EG-4-HG: manufactured by Rumand Haas, USA), and the solvent was distilled off under reduced pressure. The residue was purified by silica genore chromatography 0 ^ & 1 «3861100 18 reverse layer silica genore 63-212〃111 (manufactured by Rokko Junyaku Co., Ltd.) (solvent is pure water: methanol = 2: 3). The solvent was concentrated under reduced pressure to obtain 8.28 g (yield 80%) of the target product Alio — 2-n — Gd — DTPA as a white glassy solid. Total yield 78%. Elemental analysis confirmed the desired product.

[0165] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.15; H, 5.43; Gd, 15.13; N, 6.55

(Synthesis Example 54)

Exemplified compound Altro-2-n-Gd-DTP A was obtained in the same manner as in Synthetic Example 53, except that in Example 53, Aralonelataton (1) was changed to Altronolatone. Tota no yield 78%.

[0166] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.14; H, 5.44; Gd, 15.16; N, 6.65

(Synthesis Example 55)

Exemplified compound 0111-2-1-0 (1-0 ?? 8) was obtained in the same manner as in Synthetic Example 53, except that Aronolatataton (1) was changed to Darconolatatone in Synthesis Example 53. Total yield was 78%.

[0167] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Found ^{0 / o): C, 37.13} ; H, 5.45; Gd, 15.17; N, 6.75

(Synthesis Example 56)

In Synthesis Example 53, except that Aronolataton (1) was changed to Mannolataton, Similarly, the exemplified compound Man-2-n-Gd-DTP A was obtained. Total yield 78%.

[0168] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.13; H, 5.45; Gd, 15.17; N, 6.75

(Synthesis Example 57)

Exemplified compound Gulo-2-n-Gd-DTP A was obtained in the same manner as in Synthetic Example 53, except that in Example 53, alonolatataton (1) was changed to guronolaton. Total yield 71%.

[0169] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.11; H, 5.65; Gd, 15.21; N, 6.69

(Synthesis Example 58)

Exemplified compound Ido-2-n-Gd-DTP A was obtained in the same manner as in Synthetic Example 53 except that, in Synthesis Example 53, valonolatatone (1) was changed to idonorataton. Total yield 72%.

[0170] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.21; H, 5.55; Gd, 15.11; N, 6.68

(Synthesis Example 59)

Exemplified compound Gala-2-n-Gd-DTP A was obtained in the same manner as in Synthetic Example 53, except that in Example 53, alalonelatatone (1) was changed to galactronolatone. Total yield 75%

Yes

[0171] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76

(Actual value ⁰ / o): C, 37.11; H, 5.45; Gd, 15.14; N, 6.78

(Synthesis Example 60)

Exemplified compound Tal-2-n-Gd-DTP A was obtained in the same manner as in Synthetic Example 53, except that in Example 53, alonolatatone (1) was changed to talonolataton. Total yield 72%.

[0172] Elemental analysis values

(Calculated./o): C, 37.10; H, 5.45; Gd, 15.18; N, 6.76 (Actual value ⁰ / o): C, 37.13; H, 5.47; Gd, 15.18; N, 6.77

(Synthesis Example 61)

Exemplified compound Libo-2-n-Gd-DTPA was obtained in the same manner as in Synthetic Example 53, except that in Example 53, Aranolatatone (1) was changed to Ribonolaton. Total yield 69%.

[0173] Elemental analysis values

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.88; H, 5.33; Gd, 16.13; N, 7.25

(Synthesis Example 62)

Exemplified compound Alabi-2-n-Gd-DTPA was obtained in the same manner as in Synthetic Example 53 except that in Example 53, alonolatatone (1) was changed to arabinolatatone. Total yield 70%.

[0174] Elemental analysis

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.98; H, 5.35; Gd, 16.12; N, 7.23

(Synthesis Example 63)

Exemplified compound Xyl-2-n-Gd-DTP A was obtained in the same manner as in Synthetic Example 53, except that in Example 53, Aralonelataton (1) was changed to Xylonolataton. Total yield 69%.

[0175] Elemental analysis

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.93; H, 5.33; Gd, 16.13; N, 7.21

(Synthesis Example 64)

Exemplified compound Lix-2-n-Gd-DTP A was obtained in the same manner as in Synthetic Example 53, except that in Example 53, Aralonelataton (1) was changed to Lixonorataton. Total yield 68%.

[0176] Elemental analysis values

(Calculated./o): C, 36.92; H, 5.37; Gd, 16.11; N, 7.18

(Actual value ⁰ / o): C, 36.91; H, 5.31; Gd, 16.11; N, 7.20

(Synthesis Example 65)

Exemplified compound Erithro-2-n-Gd-DTP A was obtained in the same manner as in Synthesis Example 53, except that in Example 53, Aralonelataton (1) was changed to Erythranolataton. Total yield 63 [0177] Elemental analysis

(Calculated./o): C 36.72; H 5.28; Gd 17.17; N 7.65

(Actual value ⁰ / o): C 36.80; H 5.30; Gd 17.15; N 7.62

(Synthesis Example 66)

Exemplified compounds 1¾ 0-2-10 (1-0 to 8? 8) were obtained in the same manner as in Synthetic Example 53, except that in Example 53, alonolatataton (1) was changed to threlonoratatone. 67%

[0178] Elemental analysis

(Calculated./o): C 36.72; H 5.28; Gd 17.17; N 7.65

(Found ^{0 / o): C 36.81;} H 5.31; Gd 17.11; N 7.66

(Synthesis Example 67)

In Synthesis Example 53, Exemplary Compound Ji ₆ 11 ₀ 1 ^ except for changing Aronorataton (1) to the Serobinorataton in the same manner as in Synthesis Example 53 -?. To give 2 1 0 (1-0 chome eight total yield 73%

[0179] Elemental analysis

(Calculated./o): C 38.85; H 5.63; Gd 11.56; N 5.15

(Actual value ⁰ / o): C 38.91; H 5.43; Gd 11.63; N 5.25

(Synthesis Example 68)

Exemplified compound ^ ½ 0—2—10 (1-0 to 8) was obtained in the same manner as in Synthetic Example 53, except that in Example 53, alonolatataton (1) was changed to maltonolatone, total yield 63 % [0180] Elemental analysis

(Calculated./o): C 38.85; H 5.63; Gd 11.56; N 5.15

(Actual value ⁰ / o): C 38.90; H 5.53; Gd 11.53; N 5.18

(Synthesis Example 69)

Exemplified compound Maltrio-2-n-Gd-DTP A was obtained in the same manner as in Synthesis Example 53, except that in Example 53, alonolatatone (1) was changed to maltrionolatatone. Tota no yield 68 [0181] Elemental analysis values

(Calculated./o): C, 38.85; H, 5.63; Gd, 11.56; N, 5.15

(Actual value ⁰ / o): C, 38.81; H, 5.61; Gd, 11.57; N, 5.17

(Synthesis Example 70)

Exemplified compound Allo-6-Gd-DTPA was synthesized according to the following scheme (Scheme 5).

[0182] [Chemical 65]

[0183] Using 17.8 g (0. Imol) of valonolactone (1) and 16.2 g (0. Imol) of N- (tert-butoxycarbonyl) 1 1 2-diaminoethane (9)! According to the method described in Tetrahedron Lett. 41 (2000) 8486, the process up to the sixth step was performed.

[0184] Next, after cooling to room temperature, 40 ml of 1M-NaOH aqueous solution was added and stirred for 24 hours. this The solution was neutralized by passing through a cation exchange resin (Amberlite EG-4-HG: manufactured by Rohm and Haas, USA), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (Wakogell00C18 reverse layer silica gel 63-212 m, manufactured by Wako Pure Chemical Industries, Ltd.) (solvent: pure water: methanol = 1: 2). The solvent was concentrated under reduced pressure to obtain 121. lg (total yield 48%) of the target product Alio-6-Gd-DTP A as a white glassy solid. Elemental analysis confirmed the target product.

[0185] Elemental analysis values

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Actual value ⁰ / o): C, 41.88; H, 6.61; Gd, 6.23; N, 9.76

(Synthesis Example 71)

Exemplified compound Altro-6-Gd-DTP A was obtained in the same manner as in Synthetic Example 70, except that the starting material was changed to altronolalatone in Synthesis Example 70. Total yield 44%.

[0186] Elemental analysis

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Actual value ⁰ / o): C, 41.89; H, 6.51; Gd, 6.25; N, 9.56

(Synthesis Example 72)

Exemplified compound Glu-6-Gd-DTP A was obtained in the same manner as in Synthetic Example 70, except that the starting material was changed to dalconolatatone in Synthesis Example 70. Total yield 48%.

[0187] Elemental analysis

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Actual value ⁰ / o): C, 41.88; H, 6.41; Gd, 6.35; N, 9.58

(Synthesis Example 73)

In Synthesis Example 70, Exemplified compound Man-6-Gd-DTPA was obtained in the same manner as Synthesis Example 70 except that the starting material was changed to mannolaton. Tota no yield 55%.

[0188] Elemental analysis values

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Actual value ⁰ / o): C, 41.78; H, 6.55; Gd, 6.33; N, 9.66

(Synthesis Example 74) Exemplified compound Gulo-6-Gd-DTP A was obtained in the same manner as in Synthetic Example 70 except that the starting material was changed to Guronorataton in Synthesis Example 70. Total yield 55%.

[0189] Elemental analysis

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Actual value ⁰ / o): C, 41.84; H, 6.56; Gd, 6.12; N, 9.72

(Synthesis Example 75)

Exemplified compound Ido-6-Gd-DTP A was obtained in the same manner as in Synthetic Example 70 except that the starting material was changed to Idnorataton in Synthesis Example 70. Total yield 48%.

[0190] Elemental analysis values

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Actual value ⁰ / o): C, 41.79; H, 6.53; Gd, 6.22; N, 9.50

(Synthesis Example 76)

Exemplified compound Gala-6-Gd-DTPA was obtained in the same manner as in Synthetic Example 70, except that in Synthesis Example 70, the starting material was changed to galactronolatone. Total yield 54%.

[0191] Elemental analysis values

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Actual value ⁰ / o): C, 41.82; H, 6.43; Gd, 6.25; N, 9.52

(Synthesis Example 77)

Exemplified compound Tal-6-Gd-DTP A was obtained in the same manner as in Synthetic Example 70, except that the starting material was changed to Talonoratatone in Synthetic Example 70. Total yield 49%.

[0192] Elemental analysis values

(Calculated value./o): C, 41.82; H, 6.46; Gd, 6.22; N, 9.42

(Found ^{0 / o): C, 41.89} ; H, 6.43; Gd, 6.25; N, 9.55

(Synthesis Example 78)

Exemplified compound Libo-6-Gd-DTPA was obtained in the same manner as in Synthetic Example 71 except that the starting material was changed to Ribonolaton in Synthesis Example 71. Total yield 50%.

[0193] Elemental analysis values

(Calculated value./o): C, 41.96; H, 6.44; Gd, 6.70; N, 10-14 (Measured value ⁰ / o): C, 41.73; H, 6.51; Gd, 6.73; N, 10.13

(Synthesis Example 79)

In Synthesis Example 70, Exemplified Compound 8 1 & 1 ^ -6-0 (1-0 C? 8) was obtained in the same manner as Synthesis Example 70 except that the starting material was changed to arabinolatatone. Total yield 50%.

[0194] Elemental analysis values

(Calculated value./o): C, 41.96; H, 6.44; Gd, 6.70; N, 10-14

(Actual value ⁰ / o): C, 41.83; H, 6.50; Gd, 6.70; N, 10.10

(Synthesis Example 80)

Exemplified compound 16-0 (1-0 ?? 8) was obtained in the same manner as in Synthetic Example 70, except that the starting material was changed to xylonolatone in Synthesis Example 70. The total yield was 48%.

[0195] Elemental analysis

(Calculated value./o): C, 41.96; H, 6.44; Gd, 6.70; N, 10-14

(Actual value ⁰ / o): C, 41.83; H, 6.45; Gd, 6.79; N, 10.19

(Synthesis Example 81)

Exemplified compound Lix-6-Gd-DTPA was obtained in the same manner as in Synthetic Example 70 except that the starting material was changed to Lixonoratatone in Synthetic Example 70. Total yield 45%.

[0196] Elemental analysis values

(Calculated value./o): C, 41.96; H, 6.44; Gd, 6.70; N, 10-14

(Actual value ⁰ / o): C, 41.79; H, 6.54; Gd, 6.63; N, 10.18

(Synthesis Example 82)

Exemplified compound Erithro-6-Gd-DTPA was obtained in the same manner as in Synthetic Example 70, except that the starting material in Synthetic Example 70 was changed to erythronolatatone. Total yield 52%.

[0197] Elemental analysis

(Calculated value ⁰ / o): C, 42.28; H, 6.07; Gd, 7.28; N, 11.03

(Actual value ⁰ / o): C, 42.33; H, 6.ll; Gd, 7.23; N, 11.13

(Synthesis Example 83)

Exemplified compound Threo-6-Gd-DTPA was obtained in the same manner as in Synthetic Example 70, except that the starting material was changed to threronoratatone in Synthesis Example 70. Total yield 43%. [0198] Elemental analysis values

(Calculated value ⁰ / o): C, 42.28; H, 6.07; Gd, 7.28; N, 11.03

(Measured value ⁰ / o): C, 42.23; H, 6.01; Gd, 7.25; N, 11.05

(Synthesis Example 84)

In Synthesis Example 70, the exemplified compound Cellobi-6-Gd-DTPA was obtained in the same manner as in Synthesis Example 70 except that the starting material was changed to cellobinolaton. Total yield 41%.

[0199] Elemental analysis values

(Calculated value./o): C, 42.57; H, 6.34; Gd, 4.49; N, 6.81

(Actual value ⁰ / o): C, 42.50; H, 6.31; Gd, 4.43; N, 6.73

(Synthesis Example 85)

Except that the starting material was changed to maltonolatone in Synthesis Example 70, Exemplified Compound ^ ½ 0-6-0 (1-0 to 8) was obtained in the same manner as Synthesis Example 70. Total yield 52%.

[0200] Elemental analysis values

(Calculated value./o): C, 42.57; H, 6.34; Gd, 4.49; N, 6.81

(Actual value ⁰ / o): C, 42.51; H, 6.32; Gd, 4.42; N, 6.75

(Synthesis Example 86)

Exemplified compound Lacto-6-Gd-DTP A was obtained in the same manner as in Synthetic Example 70, except that the starting material was changed to lactanolatatone in Synthesis Example 70. Total yield 45%.

[0201] Elemental analysis values

(Calculated value./o): C, 42.57; H, 6.34; Gd, 4.49; N, 6.81

(Actual value ⁰ / o): C, 42.51; H, 6.35; Gd, 4.45; N, 6.83

(Synthesis Example 87)

In Synthesis Example 70, an exemplary compound, Maltrio-6-Gd-DTPA, was obtained in the same manner as in Synthesis Example 70 except that the starting material was changed to maltrionolatatone. Total yield 41%.

[0202] Elemental analysis values

(Calculated value ⁰ / o): C, 42.72; H, 6.25; Gd, 4.11; N, 5.49

(Actual value ⁰ / o): C, 42.70; H, 6.19; Gd, 4.13; N, 5.43

(Synthesis Example 88) Exemplified compound Allo-8-Gd-DTPA was synthesized according to the following scheme (Scheme 6).

[0203] [Chem 66]

09 卜 ε0 U98

[0204] The target product Alio-8-Gd-DTP A was obtained in the same manner as in Synthesis Example 18 except that the intermediate (4) was changed to the intermediate (11) in Synthesis Example 18! . Total yield 42%.

[0205] Elemental analysis values (Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.70; H, 6.39; Gd, 5.63; N, 8.43

(Synthesis Example 89)

Exemplified compound Altro-8-Gd-DTPA was obtained in the same manner as in Synthetic Example 88, except that in Synthesis Example 88, the starting material was changed to altronolalatone. Total yield 39%.

[0206] Elemental analysis values

(Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.71; H, 6.44; Gd, 5.73; N, 8.53

(Synthesis Example 90)

Exemplified compound Glu-8-Gd-DTP A was obtained in the same manner as in Synthetic Example 88, except that in Synthesis Example 88, the starting material was changed to dalconolatone. Total yield 41%.

[0207] Elemental analysis values

(Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.70; H, 6.49; Gd, 5.73; N, 8.54

(Synthesis Example 91)

In Synthesis Example 88, the exemplified compound Man-8-Gd-DTP A was obtained in the same manner as in Synthesis Example 88 except that the starting material was changed to mannolaton. Total yield 42%.

[0208] Elemental analysis

(Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.71; H, 6.48; Gd, 5.63; N, 8.54

(Synthesis Example 92)

Exemplified compound Gulo-8-Gd-DTP A was obtained in the same manner as in Synthetic Example 88, except that the starting material was changed to Guronorataton in Synthesis Example 88. Total yield 38%.

[0209] Elemental analysis values

(Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.73; H, 6.44; Gd, 5.53; N, 8.64

(Synthesis Example 93)

In Synthesis Example 88, except that the starting material was changed to Idnorataton, it was the same as Synthesis Example 88. Thus, exemplary compound Ido-8-Gd-DTP A was obtained. Total yield 41%.

[0210] Elemental analysis values

(Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.70; H, 6.45; Gd, 5.65; N, 8.59

(Synthesis Example 94)

Exemplified compound Gala-8-Gd-DTP A was obtained in the same manner as in Synthetic Example 88, except that in Synthesis Example 88, the starting material was changed to galactronolatone. Total yield 40%.

[0211] Elemental analysis

(Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.71; H, 6.41; Gd, 5.63; N, 8.69

(Synthesis Example 95)

Exemplified compound Tal-8-Gd-DTP A was obtained in the same manner as in Synthetic Example 88, except that in Synthesis Example 88, the starting material was changed to Talonoratatone. Total yield 42%.

[0212] Elemental analysis

(Calculated value./o): C, 41.69; H, 6.41; Gd, 5.69; N, 8.61

(Actual value ⁰ / o): C, 41.71; H, 6.43; Gd, 5.67; N, 8.69

(Synthesis Example 96)

Exemplified compound Libo-8-Gd-DTPA was obtained in the same manner as in Synthetic Example 88, except that the starting material was changed to Ribonolaton in Synthesis Example 88. Total yield 38%.

[0213] Elemental analysis values

(Calculated value./o): C, 41.85; H, 6.39; Gd, 6.23; N, 9.43

(Actual value ⁰ / o): C, 41.75; H, 6.43; Gd, 6.33; N, 9.35

(Synthesis Example 97)

In Synthesis Example 88, Exemplified Compound 8 1 & 1 ^ 8-0 (1-0 C? 8) was obtained in the same manner as Synthesis Example 88 except that the starting material was changed to arabinolatatone. Total yield 40%.

[0214] Elemental analysis

(Calculated value./o): C, 41.85; H, 6.39; Gd, 6.23; N, 9.43

(Actual value ⁰ / o): C, 41.77; H, 6.33; Gd, 6.23; N, 9.45 (Synthesis Example 98)

Exemplified compound Xyl-8-Gd-DTP A was obtained in the same manner as in Synthetic Example 88, except that in Synthesis Example 88, the starting material was changed to xylonolatone. Total yield 37%.

[0215] Elemental analysis values

(Calculated value./o): C, 41.85; H, 6.39; Gd, 6.23; N, 9.43

(Actual value ⁰ / o): C, 41.85; H, 6.33; Gd, 6.23; N, 9.45

(Synthesis Example 99)

Exemplified compound Lix-8-Gd-DTPA was obtained in the same manner as in Synthetic Example 89 except that the starting material was changed to Lixonoratatone in Synthesis Example 89. Total yield 48%.

[0216] Elemental analysis values

(Calculated value./o): C, 41.85; H, 6.39; Gd, 6.23; N, 9.43

(Actual value ⁰ / o): C, 41.87; H, 6.36; Gd, 6.25; N, 9.47

(Synthesis Example 100)

Exemplified compound Erithro-8-Gd-DTPA was obtained in the same manner as in Synthetic Example 88, except that in Synthesis Example 88, the starting material was changed to erythronolatatone. Total yield 33%.

[0217] Elemental analysis values

(Calculated value ⁰ / o): C, 42.04; H, 6.35; Gd, 6.88; N, 10.42

(Actual value ⁰ / o): C, 42.05; H, 6.43; Gd, 6.73; N, 10.35

(Synthesis Example 101)

Exemplified compound Threo-8-Gd-DTP A was obtained in the same manner as in Synthetic Example 88, except that in Synthesis Example 88, the starting material was changed to threonoratatone. Total yield 47%.

[0218] Elemental analysis values

(Calculated value ⁰ / o): C, 42.04; H, 6.35; Gd, 6.88; N, 10.42

(Actual value ⁰ / o): C, 42.07; H, 6.33; Gd, 6.83; N, 10.45

(Synthesis Example 102)

In Synthesis Example 88, the exemplified compound Cellobi-8-Gd-DTPA was obtained in the same manner as in Synthesis Example 88 except that the starting material was changed to cellobinolaton. Total yield 44%.

[0219] Elemental analysis (Calculated value ⁰ / o): C, 42.55; H, 6.35; Gd, 3.84; N, 5.82

(Actual value ⁰ / o): C, 42.45; H, 6.43; Gd, 3.73; N, 5.75

(Synthesis Example 103)

In Synthesis Example 88, except that the starting material was changed to maltonolatone, Exemplified Compound ^ ½ 0-8-0 (1-0 to 0? 8) was obtained in the same manner as Synthesis Example 88. Total yield 37%.

[0220] Elemental analysis

(Calculated value ⁰ / o): C, 42.55; H, 6.35; Gd, 3.84; N, 5.82

(Actual value ⁰ / o): C, 42.45; H, 6.43; Gd, 3.73; N, 5.75

(Synthesis Example 104)

Exemplified compound Lacto-8-Gd-DTP A was obtained in the same manner as in Synthetic Example 88, except that the starting material was changed to the lactonolatatone derivative in Synthetic Example 88. Total yield 37%.

[0221] Elemental analysis

(Calculated value ⁰ / o): C, 42.55; H, 6.35; Gd, 3.84; N, 5.82

(Actual value ⁰ / o): C, 42.55; H, 6.33; Gd, 3.83; N, 5.79

(Synthesis Example 105)

In Synthesis Example 88, except that the starting material was changed to maltrionolataton, Exemplified compound ^ ½1 ₀ — 8— 0 (1-0 to 8) was obtained in the same manner as Synthesis Example 88. Total yield 33% .

[0222] Elemental analysis

(Calculated value ⁰ / o): C, 43.02; H, 6.32; Gd, 2.93; N, 4.44

(Actual value ⁰ / o): C, 43.05; H, 6.33; Gd, 2.73; N, 4.65

Example 1

A 0.05 mM physiological saline solution of the present invention and the gadolinium compound of the following comparison was prepared, and the relaxation time was measured as follows.

[0223] [Chemical 67] Gd-

MS-

Glu -4-OH -Gd- DTPA (JP2004—307356 Figure 3)

C ₄₆ H ₈₇ GdW _s Q ₃₃

Mol. Wt .: 1451.47

DTPA (described in Tetrahedron Lett. 41 (2000) 8486p)

C ₈₆ H _{1Z7 GdN} ₉ 0 _S3

Mol. Wt .: 2292.21

Glu -12-OAc-Gd-DTPA (Tetrahedron Lett. 41 (2000) 8486p described}

9] -BGLUCA (Chem. Rev. 1999, 99, pages 2326)

C _2S H44GdN _s 0 ₂₁ ³

Mol. Wt .: 919.9 -BENGALAA (described in Chem. Rev. 1999, 99, 2326)

Mol. Wt .: 1006.0

C, 35.17; H, 4.99; Gd, 17.71; N, 7.89; 0, 34.24

Lacto— Gd— DTPA

C ₄₂ H ₇₄ GdM ₇ 0 ₃₁

ol. Wt: 1330.3

C, 37.92; H, 5.61; Gd, 11.82; N, 7.37; O, 37.28

Lacto -Am -DTPA

C ₄ 6H ₈ oGdN ₆ 0 ₂₉

Mo to Wt .: 1324.4

C, 41.72; H, S.09; Gd, 11.87; N, 5.29; O, 35.03

[0227] (Measurement of relaxation time)

1. The spin-lattice relaxation time (Tl) was measured using a 5T superconducting NMR imaging device (Magnetom SP, manufactured by Siemens) in combination with a transmitting / receiving knee-coil. Imaging conditions are spin echo system 歹 IJTR1 (ms) 2 3000, TR2 (ms) = 60, TE (ms) = 15, matrix = 256 X 192, F0 V (cm) = 16, NEX = 2. The measurement results are shown in Tables;

[0228] [Table 1] Sample No. Gadolinium Compound 1 / T1 (1 / S) Remarks

1 Gd-OTPA 4.3 Comparison

2 MS— 325 8.5 Compare

3 19.5 Comparison

4 Glu-4 ~ 0Ac-Gd-DTPA 3.5 Comparison

5 Glu-12-OAc-Gd-DTPA 2.7 Comparison

6 DTPA-BGLUCA 10.1 Comparison

7 DTPA-BENGALLA 11.1 Comparison

8 Gal— Am— DTPA 11.5 Comparison

9 Lac to -Gd-DTPA 15.5 Comparison

10 Lacto— Am— Gd— DTPA 12.5 Comparison

·

11 Al | o-4-Gd-0TPA 40.5 The present invention

12 Altro— 4— Gd— DTPA 40.5 The present invention

13 Man— 4— Gd— DTPA 48.5 The present invention

14 Gulo-4 o-e Gd-DTPA 44.5 The present invention

15 ldo-4-Gd-DTPA 45.5 The present invention

16 Gala-4-Gd-DTPA 48.5 The present invention

17 Tal-4-Gd-DTPA 40.5

. The present invention

18 ibo— 4— Gd— DTPA 42.5 The present invention

19 Alabi— 4— Gd— DTPA 44.5 The present invention

20 Xyl-4-Gd-DTPA 43.5 The present invention

21 Lix-4-Gd-DTPA 43.5 The present invention

22 Erithro-4-Gd-DTPA 38.5 The present invention

23 ΤϊΐΓθθ-4-Gd-DTPA 38,5 The present invention

24 Cel iobi-4-Gd-DTPA 35.5 The present invention

25 Ma o— 4— Gd— DTPA 37.5 The present invention

26 Lacto-4-Gd-DTPA 34.5 The present invention

27 ialtrio-4-Gd-DTPA 38.5 Present invention

28 At 10—12— Gd— DTPA 30.5 The present invention

29 30.5 The present invention

30 Man— 12— Gd— DTPA 35.5 The present invention

31 Guio-12-Gd-DTPA 31.5 The present invention

32 ldo-12-Gd-DTPA 32.5 The present invention

33 Gala— 12— Gd— DTPA 35.5 The present invention

34 Tal-12-Gd-0TPA 28.5 The present invention

35 U bo— 12— Gd— DTPA 30.5 The present invention

36 Alabi— 12— Gd— OTPA 30.5 The present invention

37 Xyl-12-Gd ~ DTPA 30.5 The present invention

38 Lix-12-Gd ~ DTPA 29.5 The present invention

39 Erithro-12-Gd-0TPA 22.5 The present invention

40 Threo— 12— Gd— DTPA 25.5 The present invention

41 Cel lobi -12- Gd-DTPA 24.5 The present invention

42 alto— 12— Gd— DTPA 23.5 The present invention

43 27.5 The present invention

44 Ma rio— 12— Gd— DTPA 27.5 The present invention

45 Al lo— 2— o— Gd— DTPA 24.5 The present invention

46 Altro— 2— 0— Gd— DTPA 25.5 The present invention

47 Glu-2-o-Gd-DTPA 29.5 The present invention

48 Man— 2— 0— Gd— DTPA 29.5 The present invention

49 Gulo-2-o-Gd-DTPA 28.5 The present invention

50 Ido— 2— o— Gd— DTPA 25.5 The present invention Sample No. Gadolinium Compound 1 / T1 (1 / _S ) Remarks

51 Gala-2-o-Gd-DTPA 29.5 The present invention

52 Tal-2-o-Gd-DTPA 26.5 The present invention

53 Libo-2-o-Gd-DTPA 25.5 The present invention

54 Alabi-2-o-Gd-DTPA 25.5 The present invention

55 Xyl-2-o-Gd-DTPA 25.5 The present invention

56 Lix-2-o-Gd-DTPA 25.5 The present invention

57 Erithro-2-o-Gd-OTPA 19.5 The present invention

58 Threo-2-o-Gd-OTPA 19.0 The present invention

59 Cellobi-2-o-Gd-DTPA 20.5 The present invention

60 Malto-2-o-Gd-OTPA 20.5 The present invention

61 21.5 The present invention

62 22.5 The present invention

63 Alio— 2— π— Gd— DTPA 23.5 The present invention

64 Altro-2-n-Gd-DTPA 24.5 The present invention

65 Glu— 2— n— Gd— DTPA 30.5 The present invention

66 Man— 2— n— Gd— DTPA 29.5 The present invention

67 Gulo-2-n-Gd-DTPA 28.5 The present invention

68 Ido-Z-n-Gd-D. T. PA 25.5 The present invention

69 Gala— 2— n— Gd— DTPA 29.5 The present invention

70 Tal— 2— n— Gd— DTPA 25.5 The present invention

71 Libo-2-n-Gd-DTPA 25.5 The present invention

72 Alabi-2-n-Gd-DTPA 24.5 The present invention

73 Xyl-2-n-Gd-DTPA 25.5 The present invention

74 Lix-2-n-Gd-DTPA 25.5 The present invention

75 Erithro-2-n-Gd-DTPA 19.0 The present invention

76 Threo-2-n-Gd-DTPA 20.5 The present invention

77 Cel lobi-2-n-Gd-DTPA 20.5 The present invention

78 Halto-2-n-Gd-DTPA 24.5 The present invention

79 Mai trio— 2— n— Gd— DTPA 23.5 The present invention

80 Al lo-6-Gd-0TPA 37.5 The present invention

81 Altro-6-Gd-0TPA 34.5 The present invention

82 Glu— 6— Gd— DTPA 38.5 The present invention

83 Han— 6— Gd— DTPA 38.5 The present invention

84 Gulo-6-Cd-DTPA 35.5 The present invention

85 ldo-6-Gd-DTPA 35.5 The present invention

86 Gala-6-Gd-DTPA 38.5 The present invention

87 Tal— 6— Gd— DTPA 34.5 The present invention

88 Libo-6-Gd-DTPA 35.5 The present invention

89 Alabi-6-Gd-DTPA 34.5 The present invention

90 Xyl 1 6— Gd— DTPA 35.5 The present invention

91 LiK-6-Gd-DTPA 35.5 The present invention

92 Erithro-6-Gd-DTPA 30.5 The present invention

93 Threo— 6— Gd— DTPA 30.5 The present invention

94 Cel 1 obi -6- Gd-OTPA 31.5 The present invention

95 Mai to— 6— Gd— DTPA 31.5 The present invention

96 Lacto-6-Gd-DTPA 35.5 The present invention

97 Mai trio— 6— Gd— DTPA 34.5 The present invention

98 Al Ιο-8-Gd-DTPA 36.5 The present invention

99 Altro-8-Gd-0TPA 34.5 The present invention

100 Glu— 8— Gd— DTPA 39.5 The present invention (Sample No. Gadolinium Compound 1 / TUl / s) Remarks

101 Han-8-Gd-DTPA 39.5 The present invention

102 Gulo-8-Gd-DTPA 35.5 The present invention

103 ldo-8-Gd-DTPA 35.5 The present invention

104 Gala-8-Gd-DTPA 39.5 The present invention

105 Tal -8-Gd-DTPA 34.5 The present invention

106 Libo-8-Gd-DTPA 34.5 The present invention

107 Alabi-8-Gd-DTPA 36.5 The present invention

108 Xyl-8-Gd-DTPA 35.5 The present invention

109 Lix-8-Gd-DTPA 35.5 The present invention

110 Erithro-8-Gd-DTPA 31.5 The present invention

111 Threo-8-Gd-DTPA 30.5 The present invention

112 Ce! Lobi-8-Gd-0TPA 29.5 The present invention

113 lalto-8-Gd-DTPA 31.5 The present invention

114 Lacto-8-Gd-DTPA 35.5 The present invention

115 altrio-8-Gd-DTPA 33.5 The present invention

[0231] From Tables:! To 3, it was found that the gadolinium compound of the present invention shortened the T1 value at a higher rate than the comparative compound. This means that the signal enhancement effect as a contrast agent is high, suggesting that even a small dose and dose can be imaged with high sensitivity.

[0232] Example 2

The gadolinium compound of the present invention and the comparative gadolinium compound used in Example 1 were dissolved in physiological saline, and an MRI contrast medium was prepared at a dose of 0.3 mrC0.05 mmol / kg per mouse weighing 30 g.

[0233] The intra-tissue distribution of the contrast medium was evaluated by administering this contrast medium from the tail vein of ddy mice. After the injection, the concentration of gadolinium in the liver, spleen, and blood was measured for 5 minutes, 30 minutes, 2 hours, and 24 hours with an inductively coupled plasma emission spectrometer (SPS3000, manufactured by Seiko Instruments Inc.). Tables 4 to 7 show the average results obtained with 20 specimens.

[0234] [Table 4]

[] ¾a0325

[] ¾s0362

[] D0237

[0238] From Table 47, the contrast agent of the present invention is superior to the comparative contrast agent in systemic blood vessel and liver imaging and superior visceral imaging, and further increases outside the body within 24 hours. It can be seen that the part is safe to be excreted.

[0239] This application is based on Japanese Patent Application No. 2006-274710 filed on Oct. 6, 2006, the disclosure of which is incorporated by reference in its entirety.

Claims

The scope of the claims

[1] A gadolinium compound represented by the following general formula (1):

[Chemical 1

— 1

[2] A gadolinium compound represented by the following general formula (2):

[Chemical 2]

General

(In the formula, G represents a residue obtained by reacting a sugar rataton with an amino group, and the sugar of the sugar rataton is a malose.

2

, Anoletrose, mannose, gurose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, cellobiose, manoleose, latatoose or maltriose. )

[3] A gadolinium compound represented by the following general formula (3):

[Chemical 3] 1)