Manganese chelate isomers

Abstract

To provide isomers of chelate compounds and their use as contrast agents in magnetic resonance imaging (MRI) procedures.SOLUTION: There is provided a compound of Formula IA or a salt or solvate thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to isomers of chelating compounds and contrast agents in magnetic resonance imaging (MRI) procedures. The present invention relates to the use of isomers of chelating compounds as chelates. [Background technology]

[0002] MRI is a medical imaging technique that visualizes areas of the body with the nuclei of selected atoms, specifically hydrogen nuclei. The MRI signal is generated by the environment surrounding the visualized nuclei and by the longitudinal and transverse relaxation times. The time depends on T1 and T2. Therefore, if the visualized nuclei are protons, However, MRI signal intensity depends on factors such as proton density and the chemical environment of the protons. Contrast agents can be used in MRI to improve image contrast. Contrast agents are T1, T2 and / or T2 * This causes relaxation time, which in turn increases the contrast of the image. It works by affecting the

[0003] Paramagnetic contrast agents are T1, T2 and / or T2 * You can change the relaxation time, and this effect is always It is known that magnetic metal chelates can be optimized by modifying their structure. The presence and residence time of water molecules bound to paramagnetic ions and the rotational correlation time of the contrast agent. The presence and residence time of water molecules bound to paramagnetic ions is The rotational correlation time can be adjusted by the choice of the fluorophore moiety. It can be adjusted by

[0004] When used as a contrast agent for MRI, it is administered to patients in relatively large doses, The solubility of the paramagnetic chelate in water is also an important factor. It requires only a small injection volume, making it easy to administer to patients and causing minimal discomfort. Soluble paramagnetic chelates, i.e., complexes of chelating agents with paramagnetic metal ions, are well known, e.g. For example, the commercially available gadolinium chelate Omniscan™ (GE Healthcare re), Dotarem(trademark)(Guerbet), Gadavist(trademark)(Ba (Bayer), and Magnevist™ (Bayer). Due to its molecular weight, when administered into the vascular system, it is distributed in the extracellular space (i.e., blood and interstitium). They are rapidly distributed and relatively quickly cleared from the body.

[0005] An important property of MRI chelates is that the paramagnetic ion is retained as long as possible within the chelate structure. In vivo, the paramagnetic ions released from the chelates are transported through biological pathways. This can interfere with the ion transport and potentially induce toxicity. The ability to achieve this (also referred to herein as stability) depends on the structural design of the cheland portion. Of particular interest is the kinetic stability, as well as the dissociation half-life. The measurements are performed with a 100% purity and are inert to the altered chemical environment (i.e., endogenous ions). tia) indicates the degree.

[0006] This is understandable given the availability of drugs on the market and the focus of the prior art. Gadolinium is the most widely used paramagnetic metal ion for MRI chelation. This is due to its favorable relaxivity properties. The concept of "relaxivity" of an MRI contrast agent is well known in the art. The term is well known to those skilled in the art and refers to the ability of a magnetic compound to enhance the relaxation rate of surrounding water proton spins. To improve the contrast of MR images and to identify tissue-specific areas where the contrast agent can diffuse better. Relaxivity is used to study the cellular environment or to perform functional MRI. The relaxivity of a contrast agent depends on the molecular structure and dynamics of the complex. Relaxivity varies with temperature, magnetic field strength, and It depends on the substance in which the contrast agent is dissolved.

[0007] When used as a contrast agent, the stability of the paramagnetic ion within the chelate structure is improved by gadolinium. Therefore, the level of stability is more favorable for the mucilagenase, especially in a physiological environment. There is a high demand to identify new gadolinium chelates.

[0008] The manganese(II) ion is a paramagnetic species with a high spin number and long electronic relaxation time. The potential of manganese(II)-based high relaxivity contrast agents has been reported in the literature (Toth, E, Adv ances in Inorganic Chemistry, 2009, 61 (09), 63-129). However, Certain manganese(II) chelates are significantly more soluble than the corresponding gadolinium chelates. For example, the manganese chelate of DOTA (MnDOTA) , which is several hundred times less stable than the corresponding gadolinium complex Gd-DOTA (Drahos, B; Inorganic Chemistry, 2012(12), 1975-1986).

[0009] International Publication No. 201 by Andreas Meijer, published on June 23, 2011 The brochure for No. 1 / 073371 states that the chelate has high stability and high relaxivity. This has led to the development of novel molecular designs that could be used as MRI contrast agents. This is very suitable for the example of WO 2011 / 073371. The compound has the structure:

[0010] [ka]

[0011] Published internationally on December 28, 2017 by Andreas Meijer et al. Brochure No. 2017 / 220610 states that it is suitable for use as a contrast agent, Manganese chelates that provide superior properties over other known manganese-based contrast agents are described. The manganese chelate in the pamphlet of International Publication No. 2017 / 220610 is , a compound of formula (I):

[0012] [ka] or a salt or solvate thereof, During the ceremony, Each R 1 is halo and -C(=O)-NH-C 1~6 hydroxyalkyl C optionally substituted with one or more substituents 1~20 Hydroxyalkyl, C1 ~6 Alkyl or C 3~6 independently selected from the group consisting of an aryl, an aryl, or a carbohydrate moiety; Is; Each R 2 is C 1~20 Hydroxyalkyl, C 1~6 From the group containing alkyl or hydrogen Independently selected; R 3 is C 1~3 Alkyl or -(CH2)m -C(=0)-NR 5 R 6 From the group containing where m is an integer from 2 to 5, and R 5 and R 6 are R 1 and R 2 As defined in; R 4 is hydroxy, C 1~6 Alkyl and C 1~6 From the group containing hydroxyalkyl represents 0 to 3 substituents selected from the following: Each n is an integer from 0 to 4; The compound of formula (I) is a compound or a salt thereof which contains at least two hydroxy groups. This includes solvates. Summary of the Invention

[0013] There is a need to develop a stable manganese contrast agent suitable for use as a contrast agent. There's more left.

[0014] The present invention relates to compounds of formula IA:

[0015] [ka] or a salt or solvate thereof. 1 Halo and -C (=O)-NH-C 1~6 hydroxyalkyl; Optionally substituted C 1~20 Hydroxyalkyl, C 1~6 Alkyl or C 3~ 6 aryl, or a carbohydrate moiety. 2 is C 1~20 Hydro C 1~6 R is independently selected from alkyl or hydrogen.3 is C 1~3 Alkyl or -(CH2) m -C(=0)-NR 5 R 6 wherein m is selected from 2 to 5 integers, where R 5 and R 6 from hydrogen, halo and -C(=O)-NH-C 1~6 C1 optionally substituted with one or more substituents selected from hydroxyalkyl ~20 Hydroxyalkyl, C 1~6 Alkyl or C 3~6 Aryl, or Carbohydrate R 4 is hydroxy, C 1~6 Alkyl and C 1~6 hydroxyalkyl; each n is an integer from 0 to 4. .

[0016] In one embodiment, the present invention relates to a compound of formula IA, or a salt or solvate thereof, and a pharma- ceutically acceptable excipient. In one embodiment, the composition comprises: Lacking detectable amounts of the compound of formula IB.

[0017] [ka] In the formula, each R 1 is halo and -C(=O)-NH-C 1~6 Selected from hydroxyalkyl C optionally substituted with one or more substituents selected from 1~20 Hydroxyalkyl , C 1~6 Alkyl or C 3~6 aryl, or carbohydrate moiety. Each R 2 is C 1~20Hydroxyalkyl, C 1~6 Independent of alkyl or hydrogen R 3 is C 1~3 Alkyl or -(CH2) m -C(=0)-NR 5 R 6 where m is an integer from 2 to 5, where R 5 and R 6 From hydrogen, halo and -C(=O)-NH-C 1~6 Hydroxyalkyl C optionally substituted with a substituent 1~20 Hydroxyalkyl, C 1~6 Alkyl or is C 3~6 R is independently selected from an aryl, an aryl, or a carbohydrate moiety. 4 is hydroxy , C 1~6 Alkyl and C 1~6 0 to 3 substituents selected from hydroxyalkyl Each n is an integer from 0 to 4.

[0018] In one embodiment, the present invention provides a method of imaging a patient, comprising administering to a patient a contrast agent or After administering the composition, the method includes obtaining an MRI image of the patient.

[0019] In one embodiment, the present invention involves a method for producing the above-described imaging agent. , enantioselective synthesis or isomerization of a compound of formula (IB) to a compound of formula (IA) may be involved. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 shows the predicted stereoisomers of Mn-chelate-5. [Diagram 2]Figure 2 shows HPLC chromatographs of (a) Mn-chelate-5 synthesized without stereochemical control, (b) (R,S)-Mn-chelate-5, (c) (R,R)-Mn-chelate-5, (d) (S,S)-Mn-chelate-5, and (e) (S,R)-Mn-chelate-5. [Diagram 3] FIG. 3 shows the rate of dechelation of Mn-chelate-5 stereoisomers in human serum. [Figure 4] FIG. 4 shows the %Mn chelate-5 remaining as a function of time for (a) (R,R)-Mn chelate-5 (diamonds), (b) (S,S)-Mn chelate-5 (squares), (c) (S,R)-Mn chelate-5 (circles), and (d) (R,S)-Mn chelate-5 (triangles) when incubated in the presence of xs.ZnCl2 at pH 4 and 40 °C. [Diagram 5] FIG. 5 shows the %ID (injected amount) / organ 7 days after injection of a 0.62 mmol Mn-chelate-5 / kg dose containing approximately 30 μmol Mn-54 chelate-5, (a) synthesis with no stereochemical control (solid bars), (b) a 1:1 mixture of (R,R) and (S,S)-Mn-chelate-5 isomers (hashed bars), and (c) (R,S)-Mn-chelate-5 (checked bars). [Figure 6] FIG. 6 shows the structure of Mn-chelate-10. [Figure 7] FIG. 7 shows the structure of Mn chelate-15. [Figure 8] FIG. 8 shows the % Mn chelate remaining as a function of time for (R,S)-Mn chelate-5 (circles), a 1:1 mixture of (R,R and S,S)-Mn chelate-5 isomers (X), Mn chelate-10 isomer pool A (triangles), and Mn chelate-10 isomer pool B (diamonds). [Figure 9] FIG. 9 shows a synthetic route to isomerically pure chelates according to an embodiment of the present invention. [Figure 10] FIG. 10 is an example of a chromatogram showing the separation of manganese-containing proteins from intact chelates. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] In order to more clearly and concisely describe and point out the subject matter of the claimed invention, Definitions and exemplary embodiments for specific terms used throughout the claims are provided herein. Any examples of specific terms herein are to be considered as non-limiting examples. This should be taken into consideration.

[0022] The terms "comprise" and "comprise" have their accustomed meaning throughout this application and are intended to include, but are not limited to, the term "comprises" and "includes" or the composition must have the recited essential features or components, but may have other The term "comprising" means that further features or components may be present. A preferred subset includes the enumerated features in the absence of other features or features. This includes "consisting essentially of", which means that the composition has.

[0023] "Salts" according to the present invention include physiologically acceptable acid addition salts, e.g., hydrochloric acid, Acid addition salts derived from inorganic acids such as hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid; and for example, tartaric acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid. Acid, glycolic acid, gluconic acid, succinic acid, methanesulfonic acid and para-toluenesulfonic acid Examples of the acid addition salts include those derived from organic acids such as benzoic acid.

[0024] Suitable "solvates" according to the present invention include those containing ethanol, water, saline, physiological buffers, and and glycols.

[0025] The term “alkyl”, alone or in combination, refers to a group of the general formula C n H 2n+1 Direct It refers to a single chain or branched alkyl group. Examples of such groups are methyl, ethyl, and isopropyl.

[0026] The term "hydroxyl" refers to an OH group.

[0027] The term "hydroxyalkyl" refers to a group having one or more hydroxyl substituents as defined above. "alkyl" refers to an alkyl group as defined above, including any of the groups listed above.

[0028] The term "aryl" refers to a functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon. and examples include phenyl and pyridyl. The aryl group of the present invention contains between 0 and 3 heteroatoms selected from O, N and S. , an aromatic six-membered ring.

[0029] The term "halogen" or "halo" refers to an atom selected from fluorine, chlorine, bromine, or iodine. It means a substituent.

[0030] The term "hydroxy" refers to an OH group.

[0031] The term "chelating moiety" refers to a substituent that is a metal chelate, and the term "metal chelate" refers to a substituent that is a metal chelate. Coordination complexes, in which the metal ion is surrounded by an anion contained in a molecule or complex. A "key land" as used herein refers to a molecule that is linked to a sequence via two or more donor atoms. It is defined as an organic compound capable of forming a coordinate bond with a paramagnetic metal ion. A typical keyland has 2 to 6, preferably 4 to 6, metal donor atoms (metal donor atoms Having a non-coordinating backbone of either carbon atoms or non-coordinating heteroatoms linking the molecules The metal ions are arranged to give a 5- or 6-membered ring. Examples of suitable donor atom types that are amines, thiols, amides, oximes, and phosphine, hi one embodiment, the metal ion is manganese.

[0032] In one embodiment, the present invention provides a compound of formula IA:

[0033] [ka] or a salt or solvate thereof. 1 Halo and -C (=O)-NH-C 1~6 hydroxyalkyl; Optionally substituted C 1~20 Hydroxyalkyl, C 1~6 Alkyl or C 3~ 6 aryl, or carbohydrate moiety; each R 2 is C 1~20 Hydroxy Dialkyl, C 1~6 R is independently selected from alkyl or hydrogen; 3 is C 1~3 Al Kill or - (CH2) m -C(=0)-NR 5 R 6 where m is selected from 2 to 5. an integer, where R 5 and R 6 from hydrogen, halo and -C(=O)-NH-C 1~6 Hide C optionally substituted with one or more substituents selected from alkoxyalkyl 1~2 0 Hydroxyalkyl, C 1~6 Alkyl or C 3~6 Aryl, or carbohydrate moiety selected independently from the 4 is hydroxy, C 1~6 Alkyl and C1~6 Hydro and each n represents an integer from 0 to 4. be.

[0034] The next process involves the stereoselective synthesis of the (R,R) and (S,S) isomers of Mn-chelate-5. The synthesis is shown. (R,R)-Mn chelate-5 is converted to the deprotected two-arm cyclic chelate ( Compound III) to give (S)-5-benzyl 1-tert-butyl 2-(methylsulfonyl) It is synthesized by bis-alkylation with pentanediate (oxy) and protected. The protected (R,R)-Mn 2-arm C5 chelate (compound V) is then obtained. (R,R)-Mn 2-arm C5 chelate is deprotected under acidic conditions to chelate Mn Then, an amino alcohol (D-glucamine) was coupled to obtain the (R,R)-Mn chelate. The (S,S)-Mn chelate-5 is converted to the deprotected two-arm cyclic chelate ( From compound III), (R)-5-benzyl 1-tert-butyl 2-(methylsulfonyl) (peroxy) pentanedioate (pentanedioate) by bis-alkylation and protection The (S,S)-Mn 2-arm C5 chelate (compound VI) was obtained. The Mn 2-arm C5 chelate has been described for the synthesis of (R,R)-Mn chelate-5. Using the approach described above, the compound was converted to the (S,S)-Mn chelate-5.

[0035] The next process involves the stereoselective synthesis of the (S,R) and (R,S) isomers of Mn-chelate-5. The synthesis of (S,R)-Mn chelate-5 and (R,S)-Mn chelate-5 are described. From the deprotected two-arm cyclic chelate, (S)-5-benzyl 1-tert-butyl 2 -(Methylsulfonyloxy)pentanedioate and monoalkyl After polymerization, (R)-5-benzyl 1-tert-butyl 2-(methylsulfonyloxy) phenyl It is synthesized by alkylating with pentanedioate to obtain (R,S)- The Mn 2-arm C5 chelate (compound VII) is then prepared by the (R,S)-Mn 2-arm C5 chelate synthesis. The C5 chelate was deprotected under acidic conditions and Mn was chelated to give (S,R)-Mn A mixture of 2-arm C5 chelate and (R,S)-Mn2-arm C5 chelate was obtained. (S,R)-Mn 2-arm C5 chelate and (R,S)-Mn 2-arm C 5. The mixture of chelates was coupled with an amino alcohol (D-glucamine) As a result, a mixture of (S,R)-Mn chelate-5 and (R,S)-Mn chelate-5 was obtained. C 18 In addition, the (R,S)-Mn chelate-5 chelate was The C5 chelate is (S,R)-Mn 2-arm. The C5 chelate is (R,S)-Mn 2-arm. The (S,R)-Mn 2-arm C5 chelate and ( A mixture of the (R,S)-Mn 2-arm C5 chelate was heated at 90 °C and then )-Mn 2-arm C5 chelate coupled with amino alcohol (D-glucamine) The compound was synthesized by cycloaddition of the (R,S)-Mn chelate-5. The approach described for the stereoselective synthesis of isomers of Mn-chelate-5 is as follows: It is applicable to the stereoselective synthesis of compounds of formula IA and IB.

[0036] Mn-chelate-5 was synthesized without stereochemical control over the attachment site to the macrocycle. In the absence of chemical control, four isomers were predicted to exist, as shown in Figure 1. (S The (R,R) and (R,S) isomers can interact with each other via metal dechelation and rechelation. The R and S designations represent the stereochemistry at the points of attachment to the macrocycle.

[0037] Figure 2a shows the results of HPLC analysis of Mn-chelate-5 synthesized without stereochemical control. Subsequently, (S,S)-Mn chelate-5 and (R,R)-Mn chelate-5 are As illustrated in Figure 9, the (R,R)-Mn chelate-5 was synthesized enantioselectively. The results of HPLC analysis of (S,S)-Mn chelate-5 are shown in Fig. 2c and Fig. 2d. The enantiomers of (R,S)-Mn chelate-5 and (S,R)-Mn chelate-5 are shown in d. The thioselective synthesis was carried out as illustrated in Figure 9. H of (R,S)-Mn chelate-5 The results of the PLC analysis are shown in Figure 2b, and the results of the HPLC analysis of (S,R)-Mn chelate-5 are shown in Figure 2c. Shown in 2e.

[0038] The stability of Mn-chelate-5 against the metal exchange reaction with Zn was confirmed by a 100-fold excess of Zn(1 In the presence of 200 mM ZnCl2 in 5 mM ammonium formate, pH = 4, 40 °C The (R,R)-Mn complex was evaluated at pH 4 with 2 mM Mn chelate-5. Chelate-5 (diamond), (S,S)-Mn-chelate-5 (open square), (S,R) -Mn chelate-5 (circular), and (R,S)-Mn chelate-5 (triangle) The data in FIG. 3 shows the % Mn chelate-5 remaining as a function of time. The transmetallation rate of the (R,S)-Mn chelate-5 isomer is significantly slower, whereas the (S,R)-M The rate of transmetallation of the n-chelate-5 isomer was shown to be significantly faster, and the stereochemistry of the chelate was This suggests that the strength of Mn chelation varies depending on the function of the size exclusion chromium. Combined method for on-line detection of manganese-containing species by lithography and ICP-MS By using The stability of Mn-chelate-5 stereoisomers in mouse serum was evaluated in vitro. The percentage of dechelation over a total incubation time of 2 days at 100° C. is shown. The isomer of (S,R)-Mn chelate 5 (upper curve, least stable) and (R,S)-Mn The Zn transmetallation reaction between the n-chelate 5 isomers (lower curve, most stable) The difference is significant, similar to the results obtained in the previous study.

[0039] Mn released in vivo is known to be retained in the brain, bone, and liver. In vivo stability of the isomer pool 54 Biodistribution of Mn radioactive material was evaluated Mn chelate-5, synthesized without stereochemical control, (R,R)-Mn chelate-5 and (S,S)-Mn chelate-5 isomers in a 1:1 ratio, and (R,S For isomeric pool B of )-Mn chelate-5, the amount of 54 M The amount of Mn released in vivo was evaluated using the (R,R)-Mn labelled material. A 1:1 mixture of isomers of (S,S)-Mn chelate-5 and isomers of (S,S)-Mn chelate-5 was selected. The transmetallation rates of the two isomers are comparable, predicting similar stability. The rats were dosed with approximately 30 μCi 54 0.62m containing Mn chelate-5 The animals were sacrificed 7 days after injection and the organs of interest were and using a gamma counter to measure the amount of 54 Mn was measured. Figure 4 shows Approximately 30 μmol 54 Contains 0.62 mmol of Mn chelate-5 1 shows the %ID (injected dose) / organ 7 days after injection of 1 / kg dose. Bars with %ID represent %ID / organ below the detection limit of this study. Statistical ratio of %ID for each organ Comparison results were analyzed by one-way ANOVA-Howell comparison or two-way ANOVA, as appropriate for each organ. Results are summarized as p-values ​​using either a 2-way t-test.

[0040] Surprisingly, in brain and bone, (S,S)-Mn chelate-5 and (R,R)-Mn Mn-chelate-5 synthesized in a 1:1 mixture or without stereochemical control In comparison, the amount of Mn remaining in vivo was significantly reduced 7 days after injection of (R,S)-Mn chelate-5. The data in Figure 4 show that the Mn release was significantly lower in vivo. This is consistent with the Zn transmetallation data, and the strength of Mn chelation is This further supports the conclusion that the function of the (R,S)-Mn chelate stereochemistry is This is further supported by the fact that higher levels of Mn were detected in the kidney for t-5. , this may be due to the more complete passage of Mn chelate-5 through the kidney.

[0041] In addition to the two stereocenters α to the macrocycle, Mn-chelate-5 has an additional α-amino acid in the glucamine side chain. Racemic 3-amino-1,2-propanediol was used since it has 10 stereocenters. Mn-chelate-10 (Figure 5) was synthesized without stereochemical control using the18 Chromatography The Mn chelate-10 isomer pool A and Mn chelate-10a isomer pool B were obtained by the The Mn chelate-10 isomer pool A and Mn chelate-10a isomer pool B were The transmetallation of Zn was carried out under the above conditions (Figure 9). Sex pool A, (S,S)-Mn chelate-5, and (R,R)-Mn chelate-5 The metal exchange reaction occurs in the same proportion as Zn, resulting in the formation of Mn chelate-10 isomer pool B and (R,S ) Mn chelate-5 reacted with Zn in the same ratio as the Zn. This data is from the side arm. Both the identity of the and the stereochemistry of the side arm do not affect the strength of Mn chelation, whereas It was shown that the stereochemistry of the α-site to the macrocycle is the key to determining the stability of the Mn chelate. Based on the data presented above, (R,S) and / or (S,R) The stereochemistry α is different from the (R,R) and (S,S) stereochemistry α for the macrocycles. It is reasonable to consider the stability of the chelate as favorable.

[0042] The following Examples 1-8 describe the preparation of precursors to the present invention. Examples 9-23 Illustrates compounds according to various embodiments of the present invention.

[0043] [Example 1] N,N'-((methylazanediyl)bis(ethane-2,1-diyl))bis(4-methylazanediyl) Synthesis of ethylbenzenesulfonamide (Compound I).

[0044] [ka]

[0045] In a 1 L round bottom flask equipped with a magnetic stir bar, add N-tosylaziridine (4 9 g, 248 mmol) and AcN (450 mL). Solution (12 mL, 121 mmol) was added and stirred at ambient temperature for 36 hours. A second aliquot of diethyl ether (1.7 g, 8.62 mmol) was added and the mixture was incubated at ambient temperature for an additional 48 hours. The solvent was removed in vacuo and the crude residue was recrystallized from EtOH to give 45 g (8 7%) of the desired product was obtained as a white solid. 1H NMR (400 MHz, DMSO-D6, δ) 7.68 (4H , m), 7.36 (6H, m), 2.75 (4H, t), 2.38 (6H, s), 2.22 (4H, t), 1.93 (3H, s).

[0046] [Example 2] Synthesis of protected cyclic 2-arm chelates (compound II).

[0047] [ka]

[0048] In a 12 L, 3-neck round-bottom flask equipped with a reflux condenser and a mechanical stirrer, add N, N'-((methylazanediyl)bis(ethane-2,1-diyl))bis(4-methylbenzyl) Charge benzenesulfonamide (93 g, 218.5 mmol) and AcN (8.3 L). 2,6-bis(chloromethyl)pyridine (38.5 g, 218.5 mmol) was added. The resulting solution was heated at 80° for 16 h. The reaction mixture was cooled to ambient temperature and crystalline The solvent was removed in vacuo until polymerization began. The resulting crystals were collected by vacuum filtration and were then eluted with 8 6.9 g (75%) of the desired product was obtained as a white solid (ESI: m / z=530 (M +H)+ ).

[0049] [Example 3] Synthesis of the deprotected two-arm cyclic chelate (compound III).

[0050] [ka]

[0051] A 1 L 3-neck round-bottom flask equipped with a mechanical stirrer was fitted with a protected circular 2-arm Charge the chelate (150 g, 284 mmol) and concentrated sulfuric acid (250 mL, 4.69 mol). The solution was poured onto ice and 50% by weight of NaOH aqueous solution was added. The pH was adjusted to 7.4 by adding AcN (200 mL) to form a white solid. ) was added and the white solid was removed by vacuum filtration. The filtrate was evaporated to dryness to give a brown foam. was dissolved in water (200 mL) and purified with Amberlite A26 resin in the hydroxide form to give 6 Obtained 1 g (98%) of the desired product as a tan solid. 1H NMR (400 MHz, AcN-D3, δ) 7.56 (1H, m), 7.03 (2H, m), 3.76 (4H, s), 2.47 (4H, m), 2.19 (3H, s), 1.95 (4H, s).

[0052] [Example 4] Synthesis of protected Mn 2-arm C5 chelate (compound IV).

[0053] [ka]

[0054] In a 500 mL round-bottom flask equipped with a magnetic stir bar, add the deprotected 2Ar The mixture was charged with cyclic chelate (20.0 g, 90.8 mmol) and AcN (160 mL). Diisopropylethylamine (38.7 mL, 217 mmol) and 2-bromophenyl Dimethyl benzoate (47.7 g, 199.7 mmol) was added and the resulting solution was heated to 65° C. The mixture was stirred at rt for 20 h. Diisopropylethylamine (9.75 mL, 54.6 mmol) and dimethyl 2-bromopentanedioate (11.8 g, 49.4 mmol) were added to the resulting The resulting solution was stirred at 65° C. for an additional 19 h. The solvent was removed in vacuo to leave a red oil. The oil was then dissolved in water (300 mL) and washed with EtOAc (300 mL). The EtOAc layer was then extracted with water (2x50 mL) and combined with the first aqueous layer. Removed in vacuo to leave a red oil which was used without further purification.

[0055] [Example 5] Synthesis of protected (R,R)-Mn 2-arm C5 chelate (compound V).

[0056] [ka]

[0057] In a 50 mL round bottom flask equipped with a magnetic stir bar, add the deprotected 2-arm cyclic ethyl acetate (1.01g, 4.58mmol), potassium carbonate (1.58g, 11.5mmol (S)-5-benzyl 1-tert-butyl 2-(Methylsulfonyloxy)pentanedioate (Levy, SG et al. al Org. Proc. Res. Dev. 2009, 13, 535-542) (2.60 g, 6.98 mmol) After dissolving in CN (2 mL), it was added to the stirred suspension. This mixture was incubated at 50 °C for 21 h. An additional amount of (S)-5-benzyl 1-tert-butyl 2-(methylsulfonyl) Sulfonyloxy)pentanedioate (1.71g, 4.59mmol 1, in 2 mL of AcN) and potassium carbonate (317 mg, 2.29 mmol) were added, Heating was continued for an additional 47 hours, after which the reaction was cooled to room temperature and 0.45 μm PTFE The solid was rinsed with acetonitrile (5x5mL) and then The filtrate was concentrated under reduced pressure to give a red oil which was used without further purification (ESI : m / z=774(M+H) + ). Specific rotation: [α] 27 D= +12.1°(c=0.0 0404, acetonitrile); 1 H NMR (CDCl3, 500 MHz) δ 1.40-1.45 (m, 10H), 1.49 (s, 9H), 1.55-1.64 (m, 1H), 1.65-1.73 (m, 1H), 1.85-1.95 (m, 2H), 1.95-2.04 (m, 1H), 2.04-2.10 (m, 2H), 2.83-2.87 (m, 3H), 2.93-2.98 (m, 1H), 3.05-3.28 (m, 7H) , 3.57 (d, J = 17.4 Hz, 1H), 3.70 (d, J = 16.9 Hz, 1H), 4.00 (d, J = 16.9 Hz, 1 H), 4.03-4.14 (m, 2H), 4.25 (d, J = 17.6 Hz, 1H), 4.84-4.98 (m, 4H), 6.93 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 7.15-7.20 (m, 2H), 7.20-7.23 (m, 2H), 7.28-7.34 (m, 6H), 7.49 (t, J = 7.6 Hz, 1H), 11.45 (bs, 1H); 13 C NMR (CDCl3, 125 MHz) δ 25.5, 26.6, 28.3, 28.4, 30.4, 30.6, 33.9, 46.7, 52.9, 53.6, 54.3, 54.7, 57.7, 66.3, 66.5, 66.8, 67.9, 82.5, 82.6, 120.2, 120.6, 126.0, 128.5, 128.6, 12 8.7, 135.7, 135.8, 138.5, 159.8, 160.9, 170.7, 171.3, 172.1, 172.2.

[0058] [Example 6] Synthesis of protected (S,S)-Mn 2-arm C5 chelate (compound VI).

[0059] [ka]

[0060] In a 10 mL round-bottom flask equipped with a magnetic stir bar, add the deprotected 2-arm Cyclic chelate (0.210 g, 0.953 mmol), potassium carbonate (0.329 g, 2 (R)-5-benzyl 1-tert-butyl 2-methyl-2-propanediol (1.38 mmol) and AcN (6 mL) were charged. t-Butyl 2-(methylsulfonyloxy)pentanedioate (D -Prepared from glutamic acid: Levy, SG et al Org. Proc.Res. Dev. 2009, 13, 535-542) (0.888 g, 2.38 mmol) was dissolved in AcN (2 mL) and then added to the stirred suspension. The mixture was heated in an oil bath at 50° C. for 67 hours. The reaction was then cooled to room temperature. The residue was partitioned between water and dichloromethane (20 mL each). After separation, the aqueous layer was extracted with dichloromethane (2x10 mL). (2x20mL) and dried over anhydrous sodium sulfate. The layer was filtered through a 0.45 μm PTFE filter, and the filtrate was concentrated under reduced pressure to give a yellow oil. The resulting product was used without further purification (ESI: m / z=774 (M+H) + ).

[0061] [Example 7] Synthesis of protected (R,S)-Mn 2-arm C5 chelate (compound VII).

[0062] [ka]

[0063] In a 10 mL round-bottom flask equipped with a magnetic stir bar and nitrogen inlet, add the deprotected The two-arm cyclic chelate (278 mg, 1.26 mmol) and isopropanol (4 ml Diisopropylethylamine (522 μL, 3.07 mmol) was added. followed by (S)-5-benzyl 1-tert-butyl 2-(methylsulfonyloxy)phenyl pentanedioate (prepared from L-glutamic acid. Levy, SG et al. Or g. Proc.Res. Dev. 2009, 13, 535-542) (407 mg, 0.87 mmol) and additional isopropanol (1 mL) was added. The resulting solution was placed under nitrogen and heated at 50 °C for 48 h. The mixture was heated in an oil bath for 1 h. An additional amount of (S)-5-benzyl 1-tert-butyl 2-(methyl Sulfonyloxy)pentanedioate (222 mg, 0.596 m mol) and diisopropylethylamine (215 μL, 1.26 mmol), Heating was continued for an additional 21 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane. The mixture was diluted with 15 mL of dichloromethane and 30 mL of water. The layers were separated and the aqueous layer was diluted with 15 mL of dichloromethane. The combined organics were washed with 30 mL of water and then dried over sodium sulfate. The dried organics were filtered through a #1 filter and the filtrate was concentrated under reduced pressure. Use gradient elution (AcN / 2 mM HCl, 10:90 to 80:20) for C 1 8 The residual material was purified by column chromatography to give 260 mg (43%) of the (R)-monoalkylated intermediate. Obtained (ESI:m / z=497(M+H) + ). Magnetic stir bar and nitrogen introduction Add the monoalkylated intermediate (260 mg, 0.524 mm) to a 10 mL round-bottom flask equipped with a neck. The mixture was charged with potassium carbonate (219 mg, 1.58 ml) and acetonitrile (5 mL). mol) was added, followed by (R)-5-benzyl 1-tert-butyl 2-(methylsulfonyl) (nyloxy)pentanedioate (prepared from D-glutamic acid. Levy, SG et al Org. Proc.Res. Dev. 2009, 13, 535-542) (252 mg, 0.676 mmol) was added. The resulting solution was placed under nitrogen and heated in an oil bath at 50° C. for 48 hours. An additional amount of (R)- 5-Benzyl 1-tert-butyl 2-(methylsulfonyloxy)pentanedioate (pentanedioate) (97 mg, 0.260 mmol) was added and heating was continued for an additional 48 hours. The reaction was cooled to room temperature, diluted with acetonitrile, and filtered through a 0.45 μm filter. The yellow filtrate was concentrated under reduced pressure. The residue was diluted with 1:1 acetonitrile:water (4 ml L) and gradient elution (AcN / 2 mM HCl, 10:90 to 80:20) Using C 18 Column purification yielded 310 mg (76%, 32%, in two steps) The desired product was obtained (ESI: m / z=774 (M+H) + ); Specific rotation: [α] 24 D= +1.9° (c=0.044, acetonitrile); 1 H NMR (CDCl3, 500 MHz) δ 1. 38 (s, 18H), 1.37-1.45 (m, 2H), 1.69-1.80 (m, 4H), 1.80-1.89 (m, 2H), 2.63 (bs, 3H), 2.89-3.02 (m, 4H), 3.03-3.08 (m, 2H), 3.08-3.14 (m, 2H), 3.47 (d, J = 17.5 Hz, 2H), 3.96 (bs, 2H), 4.15 (d, J = 17.5 Hz, 2H), 4.79 (s, 4H), 6.90 (d, J = 7 .5 Hz, 2H), 7.03-7.08 (m, 4H), 7.14-7.19 (m, 6H), 7.41 (t, J = 7.5 Hz, 1H), 11.8 3 (bs, 1H); 13 C NMR (CDCl3, 125 MHz) δ 26.1, 27.8, 28.0, 30.0, 52.1, 52.7, 53,4 , 66.0, 67.4, 82.0, 119.8, 128.2, 128.3, 135.3, 138.6, 160.4, 170.9, 171.8.

[0064] [Example 8] Synthesis of deprotected (R,R)-Mn 2-arm C5 chelate (compound VIII).

[0065] [ka]

[0066] A 100 mL round-bottom flask equipped with a magnetic stir bar, reflux condenser, and nitrogen inlet To Lasco, the protected (R,R)-Mn 2-arm C5 chelate (3.64 g, 4.7 1 mmol) and dioxane (20 mL). 0.0 mmol) was added and the mixture was placed under a nitrogen atmosphere and heated to 50°C. After 5 days, the concentrated salt Aqueous acid was added (1.7 mL, 20.4 mmol) and heating was continued. After 3 days, the reaction was stirred at room temperature. The solution was cooled to room temperature and extracted with ethyl acetate (2x25 mL). The pH of the resulting aqueous layer was adjusted to K The pH was adjusted to approximately 8 with OH(s) and the solution was concentrated under reduced pressure. L) was added and the mixture was stirred. The resulting slurry was passed through a 0.45 μm PTFE filter. The filtrate was concentrated under reduced pressure to give a brown foam which was carried on without further purification. I used it.

[0067] [Example 9] Synthesis of deprotected (S,S)-Mn-2 arm C5 chelate (compound IX).

[0068] [ka]

[0069] A 100 mL round-bottom flask equipped with a magnetic stir bar, reflux condenser, and nitrogen inlet Lasco received the protected (S,S)-Mn 2-arm C5 chelate (0.713 g, 0. 922 mmol) and dioxane (5 mL). Water (3.75 mL) was added. Then, concentrated HCl (1.25 mL, 15.0 mmol) was added and the mixture was placed under a nitrogen atmosphere. The reaction was cooled to room temperature and the solution was diluted with ethyl acetate (2x1 The combined organic extracts were back-extracted with water (10 mL). The pH of the solution was adjusted to about 8 with KOH pellets and the solution was concentrated under reduced pressure. Porphyrin (25 mL) was added and the mixture was stirred. The resulting slurry was diluted with 0.45 μm P The mixture was filtered through a TFE filter. The filtrate was concentrated under reduced pressure to give the desired product. Used without purification (ESI: m / z=481 (M+H) + ).

[0070] [Example 10] Synthesis of deprotected (R,S)-Mn 2-arm C5 chelate (compound X).

[0071] [ka]

[0072] A 10 mL round-bottom flask equipped with a magnetic stir bar, reflux condenser, and nitrogen inlet The protected (R,S)-Mn 2-arm C5 chelate (189 mg, 0.24 5 mmol) and dioxane (2.5 mL). Water (1.25 mL) was added. Afterwards, concentrated HCl (1.25 mL) was added and the mixture was placed under a nitrogen atmosphere and incubated at 50° C. for 40 h. The reaction was cooled to room temperature and the solution was diluted with water (15 mL) and ethyl acetate (10 mL). The mixture was diluted with ethyl acetate (2x10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x10 mL). The pH of the aqueous layer was adjusted to about 7 with KOH(s) and the solution was concentrated under reduced pressure. Phenol (25 mL) was added and the mixture was stirred. The resulting slurry was diluted with 0.45 μm The filtrate was concentrated under reduced pressure to give the deprotected chelate. Used without further purification (ESI: m / z=481 (M+H) + ).

[0073] [Example 11] Synthesis of Mn 2-arm C5 chelate (Compound XI).

[0074] [ka]

[0075] In a 1 L round bottom flask equipped with a magnetic stir bar, place a protected Mn 2 arm C5 chelate (48.7 g, 90.8 mmol) and water (450 mL) were charged. Sodium hydroxide (29.1 g, 726 mmol) was added and stirred at ambient temperature for 2 hours. The reaction mixture was washed with EtOAc (250 mL) and the layers were separated. The aqueous layer was diluted with EtOAc ( The aqueous solution was washed again with 100 mL of manganese chloride tetrahydrate (19. The pH was adjusted to 7.1 with 6M NaOH and the mixture was stirred at ambient temperature for 1 The mixture was stirred for 7 hours, then at 90° C. for 2.5 hours. After cooling to ambient temperature, 50% by weight of NaO The pH was adjusted to 10.1 with aqueous H2O, forming a fine brown precipitate. The residue was removed by centrifugation at rcf for 20 min and the supernatant was collected and evaporated to dryness in vacuo. The material was triturated with MeOH (127 mL) at 40° C. for 1.5 h. An insoluble white solid was obtained. The supernatant was evaporated to dryness in a vacuum. An off-white solid was obtained, which was 18 Purify on silica gel (3% AcN in water) 36.8 g (75%) of the desired product was obtained as an off-white solid (ESI: m / z =534(M+H) + ).

[0076] [Example 12] Synthesis of (R,R)-Mn 2-arm C5 chelate (compound XII).

[0077] [ka]

[0078] In a 25 mL round-bottom flask equipped with a magnetic stir bar, add the deprotected (R,R )-Mn 2-arm C5 chelate (2.98 g, 4.71 mmol) and water (12 m Manganese chloride tetrahydrate (1.41 g, 7.12 mmol) was added to the aqueous solution. The pH was adjusted to 6.5 with 50% aqueous KOH and the mixture was stirred at ambient temperature for 5 hours. The pH was adjusted to 10 with (s) and the mixture was stirred overnight. The brown suspension was filtered through a PTFE filter (4.9 cm2 x 1.8 cm). The pH was adjusted to 7.3 with cHCl (20 μL) and the material was concentrated under reduced pressure. Methanol (25 mL) was added and stirred. The resulting slurry was mixed with 0.45 μm PTFE The solid was filtered and rinsed several times with methanol. The filtrate was concentrated under reduced pressure to give a residue. The residue is treated as C 18 Purification by column (AcN / water) gave 1.09 g (43%) of the desired product. Obtained (ESI:m / z=534(M+H) + ).

[0079] [Example 13] Synthesis of (S,S)-Mn 2-arm C5 chelate (compound XIII).

[0080] [ka]

[0081] The (S,S)-Mn 2-arm C5 chelate (0 0.092 g, 0.17 mmol) yielded 0.101 g (68%) of the expected product (ESI: m / z=860 (M+H) + ). Specific rotation: [α] 24 D= -3.0°( c=0.018, water).

[0082] [Example 14] Synthesis of (R,S)-Mn 2-arm C5 chelate (compound XIV).

[0083] [ka]

[0084] In a 5 mL round-bottom flask equipped with a magnetic stir bar, add the deprotected (R,S) -Mn 2-arm C5 chelate (180 mg, 0.284 mmol) and water (4 mL Manganese chloride tetrahydrate (115 mg, 0.581 mmol) was added to the aqueous solution. The pH of the solution was adjusted to 6.0-6.4 with 50% KOH aqueous solution and stirred at ambient temperature for 4 days. The pH was adjusted to 10 with KOH(s) and the mixture was stirred overnight. 0.45μm PTFE filter (4.9cm 2 Filter the brown suspension through a 1.8 cm filter. The pH of the filtrate was adjusted to 7.2 with cHCl (8 μL) and the material was concentrated under reduced pressure. Methanol (25 mL) was added to the remaining material and stirred. The resulting slurry was diluted with 0.45 mL of methanol. The solid was filtered through a .mu.m PTFE filter and the solid was rinsed several times with methanol. The filtrate was concentrated under reduced pressure. After concentration, the remaining material was 18 Purify on a column and elute with water to give 94 g (62%) of the desired product. The product was obtained (ESI: m / z=534 (M+H) + ).

[0085] [Example 15] Synthesis of Mn chelate-5 (compound XV).

[0086] [ka]

[0087] Add D-glucamine (0.5 mL) to a 50 mL two-neck flask equipped with a magnetic stir bar. The mixture was charged with 1.0 M HCl (713 g, 3.94 mmol) and water (19.7 mL). The pH of the resulting solution was adjusted to 7.4, and Mn 2-arm C5 chelate (1.00 g, 1.87 mmol) was added, followed by EDCI-HCl (0.848 g, 4.42 mmol). ) and HOBt hydrate (0.121 g, 0.787 mmol) were added. Add 1.0M HCl or 1.0M NaOH as needed while stirring for 2 hours. The pH was maintained at 6. D-glucamine (0.359 g, 1.98 mmol) and ED CI-HCl (0.433 g, 2.26 mmol)) was added and stirred at ambient temperature for 16 h. The reaction solution was evaporated to dryness in vacuo to give the crude product, which was then eluted with C18 silica gel. Purify on gel (100% water to 20% AcN in water) to obtain 0.782 g (48%) of the desired product. The product was obtained as a pale yellow solid (ESI: m / z=860 (M+H) + ).

[0088] [Example 16] Synthesis of (R,R)-Mn chelate-5 (compound XVI).

[0089] [ka]

[0090] Place (R,R)-Mn 2-arm in a 25 mL flask equipped with a magnetic stir bar. C5 chelate (1.06 g, 2.04 mmol), D-glucamine (0.833 g, 4 .60 mmol), HOBt hydrate (0.016 g, 0.10 mmol) and water (8. The pH of the resulting solution was adjusted to 6.2 with concentrated HCl. Cl (0.924 g, 4.82 mmol) was added and stirred at ambient temperature for 23 h. The pH was maintained at 6-6.5 by adding concentrated HCl as needed. The reaction solution was diluted with water (30 mL). Dilute and run on an IR-120 (Na) ion exchange column followed by an IR-400 (Cl) ion exchange column. The solution was passed through a column to purify it. 18 Silica gel (2% AcN in water ~ 50% AcN in water) to give 1.42 g (81%) of the desired product as a pale yellow foam (ESI: m / z = 860 (M+H)+). Specific rotation: [α]26D = -19 .7°(c=0.0129, water).

[0091] [Example 17] Synthesis of (S,S)-Mn chelate-5 (compound XVII).

[0092] [ka]

[0093] The (S,S)-Mn 2-arm C5 chelate (0 0.092 g, 0.17 mmol) yielded 0.101 g (68%) of the expected product (ESI: m / z=860 (M+H) + ). Specific optical rotation: [α]24D=-3.0°( c=0.018, water).

[0094] [Example 18] Synthesis of (R,S)-Mn chelate-5 (compound XVIII).

[0095] [ka]

[0096] In a 5 mL flask equipped with a magnetic stir bar, add the (R,S)-Mn chelate 1a (60 mg, 0.112 mmol), D-glucamine (50 mg, 0.276 mmol) 1), HOBt hydrate (4.6 mg, 0.030 mmol) and water (3 mL) were charged. The pH of the resulting solution was adjusted to 6 with concentrated HCl (40 μL). 2 mg, 0.271 mmol) was added and the mixture was stirred at ambient temperature. After 6 hours (44 mg, 0.230 mmol), after 24 hours (40 mg, 0.209 mmol), After 30 hours (50 mg, 0.261 mmol), the reaction solution was diluted with water (3 mL) and then loaded onto an IR-120(Na) ion exchange column followed by an IR-400(C l) The solution was purified by passing it through an ion exchange column in sequence. Gradient elution (AcN / water , 0:100~10:90) and C 18 The crude product was purified by column chromatography to give 23 mg of (S,R)-Mn chelate-5 (24%, 42%de) and 40 mg of (R,S )-Mn chelate-5 (42%, 91% de) was obtained (ESI: m / z = 860 (M +H)+ ).

[0097] [Example 19] (S,R)-Mn 2-arm C5 chelate to (R,S)-Mn 2-arm C5 Isomerization. (R,S)-Mn chelate-1a and (S,R)-Mn chelate-1a (59 mg, A mixture of 0.111 mmol) was dissolved in water (1 mL). The mixture was sealed in a flask and heated at 90°C for 42 hours. After this period of heating, the two peaks merged into one. HPLC showed that the peak decayed to 1.0 (ESI: m / z=534 (M+H) + ) .

[0098] [Example 20] (R,S)-M prepared from isomerized (S,R)-Mn 2-arm C5 chelate Synthesis of n-chelate-5. (R,S)-Mn chelate-1a (59 mg, 0.111 mmol) and water (1 mL) The HPLC vial contained D-glucamine (49 mg, 0.270 mmol) and HO. Bt hydrate (5 mg, 0.032 mmol) was added. Concentrated HCl (35 μL) was added to obtain The pH of the resulting solution was adjusted to 5.7. EDCI-HCl (53 mg, 0.276 mmol) was added and the mixture was stirred at ambient temperature for 22 h. (mmol) was added and the reaction was stirred for an additional 42 h. The reaction solution was diluted with water (3 mL). , IR-120(Na) ion exchange column, followed by IR-400(Cl) ion exchange column. The solution was passed through a column of 100 ml ... :90) using C 18 The crude product was purified by column to give 12 mg (37%, 74% d The desired (R,S) isomer of .e.) was obtained as an off-white solid (ESI: m / z = 860(M+H) + ).

[0099] [Example 21] Synthesis of Mn chelate-10 (compound XIX).

[0100] [ka]

[0101] rac-3-aminopropane-1,2-diol (0.190 g, 2.08 mmol) The solution was placed in a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar and a pH probe. The solution was adjusted to pH 7 with 1.0 M HCl. The mixture was adjusted to 0.1, Mn chelate-1a (0.603 g, 0.996 mmol) was added, and EDCI-HCl (0.473g, 2.47mmol), HOBt hydrate (0.063g 0.466 mmol) was added in that order. The mixture was stirred at ambient temperature for 7.5 hours while stirring as needed. The pH was maintained at 6 by adding 1.0 M HCl or 1.0 M NaOH. 3-Aminopropane-1,2-diol (0.095 g, 1.04 mmol) and ED CI-HCl (0.453 g, 2.36 mmol) was added and the mixture was stirred at ambient temperature for 15 h. The pH was maintained at 6. The reaction solution was evaporated to dryness in vacuum, and the crude product was 18 Silicage The resulting mixture was purified by elution with 100% water to 20% AcN in water to give 0.280 g (41%) of the desired product. The product was obtained as a pale yellow solid (ESI: m / z=680 (M+H) + ).

[0102] [Example 22] Synthesis of Mn-chelate-10 isomer pool A and isomer pool B. Mn-chelate-10 was synthesized as above, the two isomeric pools were separated, and C 18 Silica gel (100% water ~20% AcN in water) as a pale yellow solid (ESI: m / z = 680 (M+H ) + ).

[0103] [Example 23] Synthesis of Mn chelate-15 (compound XX).

[0104] [ka]

[0105] Ethanolamine (5.153 g, 84.4 mmol) was placed on a magnetic stirrer. of HO (50 mL) in a 250 mL three-neck round-bottom flask equipped with a pH probe Mn chelate-1a (20.107 g, 37.7 mmol) was added, followed by HOBt hydrate (0.289 g, 1.89 mmol) was added. The pH was adjusted to 6.3 with concentrated HCl. The mixture was adjusted to 0.5°C and then EDCI-HCl (16.966 g, 88.5 mmol) was added. The reaction solution was stirred at room temperature for 2.5 hours while maintaining the pH between 6.0 and 6.5. The solution was diluted with 280 mL of IR-120(Na) ion exchange column, followed by IR-400 The solution was purified by sequentially passing it through a (Cl) ion exchange column. The resulting crude material was then purified using C 18 Purify with silica gel (5% AcN in water to 20% AcN in water) to obtain 16.05 g (69 %) of the desired product was obtained as a pale yellow solid (ESI: m / z=620 (M+H) + ) .

[0106] [Example 24] Synthesis of Mn-chelate-15 isomer pool A and isomer pool B. Mn-chelate-15 was synthesized as above, the two isomeric pools were separated, and C 18 Silica gel (5% in water HCl to 20% AcN in water) as a pale yellow solid (ESI: m / z = 620 (M +H) + ).

[0107] [Example 25] A general method for measuring r1 relaxivity and r2 relaxivity. The compounds were dissolved in water at concentrations ranging from 1 M to 1 Mn and then analyzed in a Bruker mq60 relaxometer. The T1 and T2 relaxation times were measured at 60 MHz and 40°C using a 300 MHz oscilloscope. Linear fit of 1 / T1 or 1 / T2 as a number (R 2 >0.99) , we obtained values ​​of r1 or r2, respectively.

[0108] [Table 1]

[0109] A method to evaluate the transmetallation reaction with Zn. 200 mM ZnCl2 and 15 mM formate were used. The Mn chelate was dissolved in an aqueous solution containing ammonium at pH = 4, and the Mn chelate concentration was adjusted to approximately The resulting solution was incubated at 40°C with mixing and aliquots were periodically The percentage of Mn-containing chelate remaining in solution was determined by HPLC at 265 nm. and measured.

[0110] Method for preparation of Mn-54 labeled chelates for biodistribution studies. Magnetic stir bar In a 3 mL glass vial equipped with a 500 sieve, add the manganese-containing chelate (1 mg) and 1.0 M ammonium formate. 0.5 mL of 1.0 M HCl (approximately 500 μCi) was then added. ) in 54 MnCl2 was added and the resulting solution was heated at 40 °C for 16 h. The resulting solution was purified by preparative HPLC to remove unreacted Mn. The solution was collected and evaporated to dryness in vacuum. The radioactive residue was absorbed into the 0.620 mmol Mn / kg and was formulated to give an injection volume of 2 mL / kg.

[0111] General methods for Mn-54 biodistribution studies. Experimental procedures and animal care and use. The study was conducted in accordance with guidelines for use in the study and approved by the Institutional Animal Care and Use Committee. Dawley rats (130–150 g) were housed in standard cages and fed standard commercial chow and They were kept in a temperature- and humidity-controlled room with free access to water and a 12-h light-dark cycle. Before injecting the Mn-54 labeled chelate, the mice were fed with inhaled 3% isoflurane (EZ Anesthesia Systems) The rats were anesthetized via intravenous infusion. The injection site was prepared with alcohol wipes and a temporary 27Ga A catheter was placed in the tail vein. Approximately 30 μCi of 100 μg ... non-radioactive Mn chelate was administered. The Mn-54 labeled chelate was administered at 2 ml at 0.620 mmol of non-radioactive Mn chelate / kg. The dose was administered in an infusion volume of 1 L / kg and injected at a rate of 1 mL / min. After injection, the first urine was excreted. The animals were individually housed in wire-bottom cages lined with filter paper until urine was collected. The rats were housed together in standard long-term cages. Seven days after injection, the animals were immersed in CO2. The animals were then sacrificed and the organs and tissues of interest were removed and counted using a Wizard 2480 gamma counter. The radioactivity was assayed using the following method (Table 2).

[0112] [Table 2]

[0113] [Example 26] To measure the dissociation of manganese from manganese chelates in human serum, the following method was used. Used.

[0114] Human serum (Sigma-Aldrich, 1900 μL) obtained from clotted blood Then, an aqueous solution of manganese chelate (2 mM, 100 μL) was added. The mixture was incubated at 37° C. At specific time points, aliquots of 200 μL of the test sample were diluted with saline (400 μL ) and then subjected to size exclusion chromatography (separation range 5000-500 000 Daltons). Manganese-containing species were analyzed by metal-free HPLC with a 1000mM column and ICP-SF-MS. The dechelation rate was analyzed by combining with on-line detection. The area percentage of the solid fraction was measured. At regular intervals, EDTA solution was poured into the system, and the The human serum was diluted with Mn(acetate) to ensure low levels of background metal ions. II) and injecting, Mn binding in the high molecular weight region of the chromatogram The locations of the components were identified.

[0115] Figure 10 shows the relative abundance of the manganese chelate in the slower eluting low molecular weight fraction. 1 shows chromatographic separation of protein-bound manganese.

[0116] In this assay, four different stereoisomers of Mn-chelate-5 (RR, SS, SR, and Table 3 shows the protein concentrations at 3, 24, and 49 hours after the start of the experiment. The percentage of dechelation was measured by quantitative detection of substrate-bound manganese. .

[0117] [Table 3]

Claims

1. Compound of formula IA: 【Chemistry 1】 or a salt or solvate thereof, During the ceremony, Each R １ is halo and -C(=O)-NH-C １～６ hydroxyalkyl C optionally substituted with one or more substituents １～２０ Hydroxyalkyl, C １ ～６ Alkyl or C ３～６ aryl, or carbohydrate moiety; Each R ２ is C １～２０ Hydroxyalkyl, C １～６ Independently from alkyl or hydrogen Selected; R ３ is C １～３ Alkyl or -(CH ２ ) ｍ -C(=0)-NR ５ R ６ Selected from where m is an integer from 2 to 5, and R ５ and R ６ from hydrogen, halo and -C(=O )-NH-C １～６ Optionally, one or more substituents selected from hydroxyalkyl; C replaced with alternative １～２０ Hydroxyalkyl, C １～６ Alkyl or C ３～６ Ants a cyclic or cyclic ether moiety; R ４ is hydroxy, C １～６ Alkyl and C １～６ Hydroxyalkyl represents 0 to 3 substituents that may be A compound or a salt or solvate thereof, wherein each n is an integer from 0 to 4.

2. The compound of claim 1 comprising at least two hydroxy groups.

3. 2. The compound of claim 1 which is a compound of formula IA.

4. A compound of formula IA, Each R １ is C １～２０ is hydroxyalkyl; R3 is methyl; R2 and R4 are hydrogen; and The compound of claim 1 , wherein n is 2.

5. Each R １ is C １～２０ The compound of claim 1 which is a hydroxyalkyl.

6. R ３ The compound of claim 1 , wherein is methyl.

7. R ２ and R ４ The compound of claim 1 , wherein is hydrogen.

8. The compound of claim 1 , wherein n is 2.

9. Each R １ is independently C ３～９ The compound of claim 1 which is a hydroxyalkyl.

10. Each R １ is independently C ３～６ The compound of claim 1 which is a hydroxyalkyl.

11. Compound of formula IA: 【Chemistry 2】 or a salt or solvate thereof, and a pharma- ceutically acceptable excipient. 、 During the ceremony, Each R １ is halo and -C(=O)-NH-C １～６ hydroxyalkyl C optionally substituted with one or more substituents １～２０ Hydroxyalkyl, C １ ～６ Alkyl or C ３～６ aryl, or carbohydrate moiety; Each R ２ is C １～２０ Hydroxyalkyl, C １～６ Independently from alkyl or hydrogen Selected; R ３ is C １～３ Alkyl or -(CH ２ ) ｍ -C(=0)-NR ５ R ６ Selected from where m is an integer from 2 to 5, and R ５ and R ６ from hydrogen, halo and -C(=O )-NH-C １～６ Optionally, one or more substituents selected from hydroxyalkyl; C replaced with alternative １～２０ Hydroxyalkyl, C １～６ Alkyl or C ３～６ Ants a cyclic or cyclic ether moiety; R ４ is hydroxy, C １～６ Alkyl and C １～６ Hydroxyalkyl represents 0 to 3 substituents that may be The composition wherein each n is an integer from 0 to 4.

12. The compound of formula IA comprises at least two hydroxy groups. Composition.

13. The compound comprises a detectable amount of a compound of formula (IB): 【Chemistry 3】 12. The composition of claim 11, wherein the composition is devoid of any of the salts or solvates thereof.

14. 10. The compound according to claim 1, further comprising Mn chelates having (R,R) and (S,S) stereochemistry.

1. The composition described in 1.

15. Each R １ is C １～２０ The composition of claim 11 which is a hydroxyalkyl.

16. R ３ The composition of claim 11 , wherein is methyl.

17. R ２ and R ４ The composition of claim 11 , wherein is hydrogen.

18. The composition of claim 11 , wherein n is 2.

19. Each R １ is independently C ３～９ The composition of claim 11 which is a hydroxyalkyl.

20. Each R １ is independently C ３～６ The composition of claim 11 which is a hydroxyalkyl.

21. A method of imaging a patient, comprising administering to a patient in need thereof a compound according to claim 1. obtaining an MRI image of the patient after administering the

22. A method of imaging a patient, comprising administering to a patient in need thereof the composition of claim 11. After administration, the method includes obtaining an MRI image of the patient.

23. A process for the enantioselective synthesis of a compound of formula (IA) according to claim 1, comprising: (a) 5-benzyl 1-tert-butyl 2-(methylsulfonyloxy)pentanediol Using the first enantiomer of the pentanedioate, a compound of formula (III) and monoalkylating 【Chemistry 4】 (b) followed by the opposite of the first enantiomer, 5-benzyl 1-tert-butyl The second enanthate of 2-(methylsulfonyloxy)pentanedioate alkylating the compound from step (a) using a thiomer; (c) reacting the product of step (b) with Mn; (d) reacting the product of step (c) with an amino alcohol; The method includes:

24. A method for the enantioselective synthesis of a composition comprising a compound of formula (IA) according to claim 11. There was, (a) 5-benzyl 1-tert-butyl 2-(methylsulfonyloxy)pentanediol Using the first enantiomer of the pentanedioate, a compound of formula (III) and monoalkylating 【Chemistry 5】 (b) followed by the opposite of the first enantiomer, 5-benzyl 1-tert-butyl The second enanthate of 2-(methylsulfonyloxy)pentanedioate alkylating the compound from step (a) using a thiomer; (c) reacting the product of step (b) with Mn; (d) reacting the product of step (c) with an amino alcohol; The method includes:

25. 25. The method of claim 24, wherein the method results in a composition comprising a compound of formula (IA). Composition.

26. A method for producing the composition of claim 11, comprising the steps of: Compound of formula (IB): 【Chemistry 6】 or a salt or solvate thereof, wherein the heating step converts the compound of formula (IB) substantially into a compound of formula (IA). The process is carried out for a time and at a temperature sufficient to convert all of the

27. 27. The composition obtained is devoid of detectable amounts of a compound of formula (IB). The method according to

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