PEG-modified cyclic dipeptides

Abstract

Novel PEG-modified cyclic dipeptide compounds are disclosed. The modified cyclic dipeptide compounds contain a cyclic dipeptide and a biocompatible polymer attached to the cyclic dipeptide. The cyclic dipeptide can be a proline-, hydroxyproline-, or histidine-containing cyclic dipeptide. In one embodiment, the cyclic dipeptide is cyclo(-his-pro). An exemplary modified cyclic dipeptide compound is represented by Formula A': JPEG2025532708000019.jpg37116

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 411,508, filed September 29, 2022, the contents of which are incorporated by reference in their entirety. The present disclosure is directed to novel modified cyclic dipeptide compounds. [Background technology]

[0002] Cyclic dipeptides are cyclic peptides containing a 2,5-diketopiperazine ring. Cyclic dipeptides have been reported to have advantageous structures and properties, including excellent hydrogen bond formation ability, structural rigidity, and enzymatic stability. Because two amino acids are linked at their terminal ends via an amide, cyclic peptides have higher lipid solubility than linear dipeptides (especially linear dipeptides with the same amino acid structure) that have exposed polar groups, such as terminal carboxyl and amino groups. Therefore, cyclic dipeptides may have superior permeability through the gastrointestinal tract and membranes compared to their corresponding linear dipeptides. For example, Cyclo(-His-Pro), C 11 H 14N4O2 is known as an anhydrodipeptide with CAS Registry Number 53109-32-3. cyclo(-His-Pro) is an endogenous cyclic dipeptide derived in vivo from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of hypothalamic thyrotropin-releasing hormone. cyclo(-His-Pro) can be completely synthesized ex vivo by conventional chemical methods. cyclo(-His-Pro) may be important in regulating the nature of glial cell contributions. Grotelli et al., The Role of Cyclo(His-Pro) in Neurodegeneration, Int J Mol Sci. 2016 Aug;17(8):1332. cyclo(-His-Pro) is ubiquitous in the central nervous system and is a major substrate for organic cation transporters that are strongly associated with neuroprotection. The cyclic dipeptides can also cross the blood-brain barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis.

[0003] Cyclo(Leu-Gly) has been reported to have memory function improving effects, and cyclo(Asp-Pro) has been reported to have an inhibitory effect on fat preference. It has been reported that cyclo(Trp-Pro) has anticancer activity, cyclo(His-Pro) and cyclo(Gly-Pro) have antibacterial activity, cyclo(Gly-Pro) has memory function improving activity, and cyclo(Tyr-Pro) and cyclo(Phe-Pro) have biological herbicidal activity. Alan D. Borthwick, Chem. Rev. 2012, 112, 7, 3641-3716. The present inventors have conducted research to improve the chemical and physical properties of cyclic dipeptide compounds, and therefore the present disclosure is directed to novel cyclic dipeptide conjugates with improved characteristics. Summary of the Invention

[0004] In one aspect, a cyclic dipeptide conjugate is disclosed, obtained by coupling a biocompatible polymer to a cyclic dipeptide. Throughout this disclosure, the terms "modified cyclic dipeptide" and "PEG-modified cyclic dipeptide" are used interchangeably unless otherwise specified. In some embodiments, the modified cyclic dipeptide compound can be represented by the following formula (A): (X1-X2)-(L1) p -O-(-CH2CH2O) n -(L2) q -R formula (A) (In the formula, X1-X2 is a cyclic dipeptide, L1 is C1-C6 alkyl, C1-C6 alkyl-C(O), -C(O)-, -S(O)-, -S(O)2-, -P(O)(O - )- or C(O)-C1-C6 alkyl; L2 is C1-C6 alkyl or C1-C6 alkyl-C(O); R is hydrogen, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, or C6-10 aryl; p is an integer of 0 or 1, q is an integer of 0 or 1, n is 1 to 500.

[0005] In some embodiments, the cyclic dipeptide X1-X2 can be a proline (Pro)-containing cyclic dipeptide, a hydroxyproline (Hyp)-containing cyclic dipeptide, or a histidine-containing cyclic dipeptide. In some embodiments, the proline-containing cyclic dipeptide, the hydroxyproline-containing cyclic dipeptide, or the histidine-containing cyclic dipeptide can be represented by X1-Pro, X1-Hyp, Pro-X2, Hyp-X2, X1-His, or His-X2-, where X1 and X2 are each independently arginine, lysine, histidine, phenylalanine, tyrosine, leucine, isoleucine, methionine, valine, alanine, glycine, proline, glutamic acid, glutamine, serine, threonine, aspartic acid, asparagine, tryptophan, or cysteine. In some embodiments, X1 and X2 are each independently glycine, phenylalanine, lysine, tryptophan, aspartic acid, tyrosine, leucine, histidine, proline, alanine, hydroxyproline, or arginine. In some embodiments, the cyclic dipeptide X1-X2 is cyclo(Gly-Pro), cyclo(Phe-Pro), cyclo(Pro-Trp), cyclo(Leu-Pro), cyclo(His-Pro), cyclo(Pro-Asp), cyclo(Pro-Lys), cyclo(Pro-Tyr), cyclo(Pro-Gly), cyclo(Pro-Hyp), cyclo(Pro-Ala), cyclo(Pro-Arg), cyclo(Pro-Leu), cyclo(Hyp-Gly), cyclo(His -Leu), cyclo(Vla-His), cyclo(Met-His), cyclo(Ile-His), cyclo(His-Tyr), cyclo(His-Phe), cyclo(Gln-His), cyclo(Ala-Leu), cyclo(Trp-His), cyclo(Gly-His), cyclo(Thr-His), cyclo(Asp-His), cyclo(Asn-His), cyclo(Arg-His), a salt thereof, or an isomer thereof, or a salt thereof, or an isomer thereof.

[0006] In an exemplary embodiment, the cyclic dipeptide can be cyclo(-His-Pro) or a salt thereof. In some aspects, the biocompatible polymer includes, but is not limited to, polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, or polyvinyl ethyl ether. In an exemplary embodiment, the biocompatible polymer is polyethylene glycol (PEG). In an exemplary embodiment, the PEG may have an average molecular weight ranging from about 200 Da to about 25,000 Da. In some embodiments, the PEG may have an average molecular weight ranging from about 200 Da to about 10,000 Da, from about 200 Da to about 7,500 Da, or from about 300 Da to 5,000 Da.

[0007] In exemplary embodiments, the PEG moiety can be directly attached to the nitrogen atom of a histidine in the cyclic dipeptide. In exemplary embodiments, the PEG moiety can be attached to the nitrogen atom of a histidine in the cyclic dipeptide via a linker. In these exemplary embodiments, the linker can be hydrolyzable so that the modified cyclic dipeptide can function as a prodrug and be converted to the active cyclic dipeptide upon ingestion, or the linker can be non-hydrolyzable so that the modified cyclic dipeptide can extend the half-life of the active cyclic dipeptide in the body. In non-limiting embodiments, the hydrolyzable group can be carboxy (-OC(O)- or -C(O)-O-) or alkylcarboxy. In another aspect, a method for preparing a modified cyclic dipeptide compound, isomer, or pharmaceutically acceptable salt of formula (A) is disclosed.

[0008] In embodiment 1, a compound of formula A' [ka] (In the formula, L1 is -C(O)-, -S(O)-, -S(O)2-, -P(O)(O -)-, -CHC(O)-, -C(O)CH-, -C(O)CHCH-, -CH-, -CHCH- or -CHCHCH-, wherein L1 is bonded to one of the two nitrogen atoms of the imidazole group; n is an integer from 1 to 500, R is hydrogen, linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy. or an isomer or a pharmaceutically acceptable salt thereof is disclosed.

[0009] In embodiment 2, the compound of formula A' is a compound of formula A-1. [ka] (wherein L1, n, and R have the same meanings as defined in embodiment 1).

[0010] In embodiment 3, n is 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 1 to 30, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 1 Disclosed are compounds according to embodiment 1 or 2, wherein the R is 0 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, or an isomer or a pharmaceutically acceptable salt thereof. In embodiment 4, a compound according to any one of embodiments 1 to 3, or an isomer or a pharmaceutically acceptable salt thereof is disclosed, wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 4, 48, 49, or 50. In embodiment 5, L1 is -C(O)-, -S(O)-, -S(O)2-, -P(O)(O - )-, -CH2-, or -CH2CH2-, or an isomer or pharmaceutically acceptable salt thereof.

[0011] In embodiment 6, a compound according to any one of embodiments 1 to 5, or an isomer or pharmaceutically acceptable salt thereof, is disclosed, wherein R is linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy. In embodiment 7, a composition comprising a compound according to any one of embodiments 1-6 is disclosed. In embodiment 8, a modified cyclic dipeptide compound is disclosed, represented by the following formula (A): (X1-X2)-(L1) p -O-(-CH2CH2O) n -(L2) q -R formula (A) (In the formula, X1-X2 is a cyclic dipeptide, L1 is C1-C6 alkyl, C1-C6 alkyl-C(O), -C(O)-, -S(O)-, -S(O)2-, -P(O)(O - )- or C(O)-C1-C6 alkyl; L2 is C1-C6 alkyl or C1-C6 alkyl-C(O); R is hydrogen, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, or C6-10 aryl; p is an integer of 0 or 1, q is an integer of 0 or 1, n is 1 to 500.

[0012] In embodiment 9, the modified cyclic dipeptide compounds of embodiment 8 are disclosed, wherein the cyclic dipeptide can be a proline-containing cyclic dipeptide, a hydroxyproline-containing cyclic dipeptide, or a histidine-containing cyclic dipeptide.

[0023] In embodiment 10, the modified cyclic dipeptide compounds of embodiment 8 or 9 are disclosed, wherein the proline-containing cyclic dipeptide, hydroxyproline-containing cyclic dipeptide, or histidine-containing cyclic dipeptide can be represented by X1-Pro, X1-Hyp, Pro-X2, Hyp-X2, X1-His, or His-X2-, where X1 and X2 are each independently arginine, lysine, histidine, phenylalanine, tyrosine, leucine, isoleucine, methionine, valine, alanine, glycine, proline, glutamic acid, glutamine, serine, threonine, aspartic acid, asparagine, tryptophan, or cysteine. In some embodiments, X1 and X2 are each independently glycine, phenylalanine, lysine, tryptophan, aspartic acid, tyrosine, leucine, histidine, proline, alanine, hydroxyproline, or arginine. In some embodiments, the cyclic dipeptides X1-X2 are cyclo(Gly-Pro), cyclo(Phe-Pro), cyclo(Pro-Trp), cyclo(Leu-Pro), cyclo(His-Pro), cyclo(Pro-Asp), cyclo(P ro-Lys), cyclo(Pro-Tyr), cyclo(Pro-Gly), cyclo(Pro-Hyp), cyclo(Pro-Ala), cyclo(Pro-Arg), cyclo(Pro-Leu), cyclo(Hyp-Gly), cyclo(His -Leu), cyclo(Vla-His), cyclo(Met-His), cyclo(Ile-His), cyclo(His-Tyr), cyclo(His-Phe), cyclo(Gln-His), cyclo(Ala-Leu), cyclo(Trp-His), cyclo(Gly-His), cyclo(Thr-His), cyclo(Asp-His), cyclo(Asn-His), cyclo(Arg-His), a salt thereof, or an isomer thereof, or a salt thereof, or an isomer thereof. [Brief explanation of the drawings]

[0013] [Figure 1]FIG. 1 illustrates an exemplary modified CHP compound (Compound 1) obtained in Example 2, in which PEG is attached to the nitrogen atom of the imidazole ring of CHP. [Figure 2] FIG. 1 illustrates an exemplary modified CHP compound (Compound 2) obtained in Example 3, in which PEG is attached to the nitrogen atom of the imidazole ring of CHP. [Figure 3] FIG. 1 shows the LC-MS spectrogram of modified CHP compound 1 obtained in Example 2. [Figure 4] FIG. 1 shows the LC-MS spectrogram of modified CHP compound 2 obtained in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0014] Various aspects and embodiments will now be fully described herein. However, these aspects and embodiments may be embodied in many different forms and should not be construed as limiting; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the present subject matter to those skilled in the art. All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. definition Unless otherwise defined, all terms and phrases used herein include the meaning that they have acquired in the art unless the contrary is clearly indicated or clearly apparent from the context in which the term or phrase is used. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, particular methods and materials are described below.

[0015] Unless otherwise specified, the use of individual numerical values ​​is designated as approximations, as if the value were preceded by the word "about" or "approximately." Similarly, numerical values ​​in various ranges specified in this specification, unless explicitly stated otherwise, are designated as approximations, as if both the minimum and maximum values ​​within the specified range were preceded by the word "about" or "approximately." In this manner, variations above and below the specified range can be used to achieve substantially the same results as values ​​within the range. As used herein, the terms "about" and "approximately," when referring to numerical values, have the obvious and ordinary meaning of those terms to one of ordinary skill in the art to which the disclosed subject matter most closely pertains or to which the range or element in question pertains. The amount by which the boundaries of the exact numbers are expanded depends on numerous factors. For example, some of the factors that may be considered include the importance of the element and / or the effect a given amount of variation has on the performance of the claimed subject matter, as well as other considerations known to those of ordinary skill in the art. As used herein, the use of different amounts of significant digits for different numerical values ​​does not imply a limitation on the extent to which the use of the word "about" or "approximately" extends a particular numerical value or range. Thus, as a general matter, "about" or "approximately" extends the numerical value. Also, the disclosure of ranges is intended as a continuous range that includes every value between the minimum and maximum values, plus the expanding range provided by the use of the term "about" or "approximately." Consequently, the recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. In certain embodiments, the word "about," when used in reference to a numerical value, is intended to include a variation of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that numerical value.

[0016] The term "active ingredient," as used herein, refers to any chemical substance that, when administered to a human or animal, induces a biochemical response. A drug may act as a substrate or product of a biochemical response, or a drug may interact with a cellular receptor to induce a physiological response, or a drug may bind to a receptor and block the receptor from inducing a physiological response. As used herein, the term "consisting essentially of," when referring to a composition or formulation, means that the composition or formulation contains the recited compound as the only active ingredient, and may additionally contain pharmaceutically acceptable inert additives, excipients, or carriers. Such inert additives, excipients, or carriers are known in the art. The term "pharmaceutically acceptable" excipient, diluent, or carrier as used herein includes those well known in the art. Generally, the nature of the carrier will depend on the particular mode of administration being employed. For example, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, or the like as a vehicle. For solid compositions (e.g., powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0017] Unless otherwise specified herein, examples of a "C1-C6 alkyl group" include methylethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, and 2-methylcyclopropyl. Examples of a "C1-C4 alkyl group" include methylethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, and cyclopropylmethyl.

[0018] As used herein, the term "conjugate" or "conjugated compound" generally refers to at least two covalently linked components, a first component and a second component. In this specification, unless otherwise specified, the term "alkoxyl group" refers to a group in which the above-mentioned "alkyl group" is substituted with an oxygen atom. An alkoxyl group is generally represented by RO- (R = alkyl group). Modified cyclic dipeptide compounds The modified cyclic dipeptide compound comprises a cyclic dipeptide and a biocompatible polymer attached to the cyclic dipeptide directly or via a linker (L1).

[0019] In non-limiting embodiments, the biocompatible polymer can be polyethylene glycol (PEG). In these embodiments, the modified cyclic dipeptide compound can be represented by the following formula (A): (X1-X2)-(L1) p -O-(-CH2CH2O) n -(L2) q -R formula (A) (In the formula, X1-X2 is a cyclic dipeptide, L1 is C1-C6 alkyl, C1-C6 alkyl-C(O), C(O), -S(O)-, -S(O)2-, -P(O)(O - )- or C(O)-C1-C6 alkyl; L2 is C1-C6 alkyl or C1-C6 alkyl-C(O); R is hydrogen, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, or C6-10 aryl; p is an integer of 0 or 1, q is an integer of 0 or 1, n is 1 to 500.

[0020] In some embodiments, L is C-C alkyl, C-C alkyl-C(O), C(O), —S(O)—, —S(O)—, —P(O)(O - )- or C(O)-C1-C4 alkyl. In some embodiments, L2 is C1-C4 alkyl or C1-C4 alkyl-C(O). In some embodiments, R is a straight or branched C1-C4 alkyl or a straight or branched C1-C4 alkoxy. The present disclosure includes, unless otherwise indicated, the isomers (enantiomers or diastereomers) or pharmaceutically acceptable salts of the compounds described herein.

[0021] In exemplary embodiments, X1-X2 can be a proline-containing cyclic dipeptide, a hydroxyproline-containing cyclic dipeptide, or a histidine-containing cyclic dipeptide. In some embodiments, the proline-containing cyclic dipeptide, the hydroxyproline-containing cyclic dipeptide, or the histidine-containing cyclic dipeptide can be represented by X1-Pro, X1-Hyp, Pro-X2, Hyp-X2, X1-His, or His-X2-, where X1 and X2 are each independently arginine, lysine, histidine, phenylalanine, tyrosine, leucine, isoleucine, methionine, valine, alanine, glycine, proline, glutamic acid, glutamine, serine, threonine, aspartic acid, asparagine, tryptophan, or cysteine. In some embodiments, X1 and X2 are each independently glycine, phenylalanine, lysine, tryptophan, aspartic acid, tyrosine, leucine, histidine, proline, alanine, hydroxyproline, or arginine. In some embodiments, the cyclic dipeptide X1-X2 is cyclo(Gly-Pro), cyclo(Phe-Pro), cyclo(Pro-Trp), cyclo(Leu-Pro), cyclo(His-Pro), cyclo(Pro-Asp), cyclo(Pro-Lys), cyclo(Pro-Tyr), cyclo(Pro-Gly), cyclo(Pro-Hyp), cyclo(Pro-Ala), cyclo(Pro-Arg), cyclo(Pro-Leu), cyclo(Hyp-Gly). ), cyclo(His-Leu), cyclo(Vla-His), cyclo(Met-His), cyclo(Ile-His), cyclo(His-Tyr), cyclo(His-Phe), cyclo(Gln-His), cyclo(Ala-Leu), cyclo(Trp-His), cyclo(Gly-His), cyclo(Thr-His), cyclo(Asp-His), cyclo(Asn-His), cyclo(Arg-His), a salt thereof, or an isomer thereof.

[0022] According to some embodiments, a compound of formula A' [ka] (In the formula, L1 is -C(O)-, -S(O)-, -S(O)2-, -P(O)(O - )-, -CHC(O)-, -C(O)CH-, -C(O)CHCH-, -CH-, -CHCH-, or -CHCHCH-, and L1 is bonded to one of the two nitrogen atoms of the imidazole group; n is an integer from 1 to 500, R is hydrogen, linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy. or an isomer or a pharmaceutically acceptable salt thereof is disclosed. The present disclosure includes, unless otherwise indicated, the isomers (enantiomers or diastereomers) or pharmaceutically acceptable salts of the compounds described herein.

[0023] In some embodiments, the modified cyclic dipeptide compound is a compound of formula A-1 [ka] (In the formula, L1 is -C(O)-, -S(O)-, -S(O)2-, -P(O)(O -)-, -CHC(O)-, -C(O)CH-, -C(O)CHCH-, -CH-, -CHCH-, or -CHCHCH-, where n is an integer from 1 to 500, 5 to 500, 5 to 400, 5 to 300, 5 to 200, 5 to 100, 1 to 100, or 1 to 50, and R is hydrogen, linear or branched C-C alkyl, or linear or branched C-C alkoxy. In some embodiments, n is about 1 to 50, 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 1 to 30, 2 to 30, 3 to 30 , 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 10 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10 or 9 to 10. In some specific embodiments, in the above compounds, R is a linear or branched C1-C4 alkyl or a linear or branched C1-C4 alkoxy, and n is 1 to 500, 5 to 500, 5 to 400, 5 to 300, 5 to 200, 5 to 100, 1 to 50, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 2 to 30, 3 to 30, 4 to 3 0, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 10 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, or 7 to 8. In some embodiments, n can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, or 100.

[0024] In some embodiments, the modified cyclic dipeptide compound comprises: [ka] (wherein R is hydrogen, linear or branched C1-C6 alkyl, or linear or branched C1-C6 alkoxy, and n is 1 to 500), or an isomer or pharmaceutically acceptable salt thereof. In some embodiments, n is about 1 to 500, 5 to 500, 5 to 400, 5 to 300, 5 to 200, 5 to 100, 1 to 100, 1 to 50, 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40 , 10 to 40, 1 to 30, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 10 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, or 9 to 10. In some specific embodiments, in the above compounds, R is a linear or branched C1-C4 alkyl or a linear or branched C1-C4 alkoxy, and n is 1 to 500, 5 to 500, 5 to 400, 5 to 300, 5 to 200, 5 to 100, 1 to 100, 1 to 50, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 10 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, or 7 to 8. In some embodiments, n can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, or 100.

[0025] In some embodiments, the modified cyclic dipeptide compound comprises: [ka] (wherein n is 1 to 500), or an isomer or pharmaceutically acceptable salt thereof. In some embodiments, n is about 1 to 500, 5 to 500, 5 to 400, 5 to 300, 5 to 200, 5 to 100, 1 to 100, 1 to 50, 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 1 to 30, 2 to 30, 3 to 30, 4 to 30 , 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 10 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8 or 7 to 8. In some embodiments, n can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, or 100. In some embodiments, the modified cyclic dipeptide compound can be a dimer comprising two cyclic dipeptides linked to either end of a polyethylene glycol, which can be the same or different. An exemplary embodiment of such a dimer is:

[0026] [ka] wherein all symbols are the same as defined above, but are not limited to:

[0027] Without wishing to be bound by theory, modified cyclic dipeptides according to the present disclosure are expected to have improved in vivo stability, stronger biological activity, longer half-life and reduced frequency of drug treatment, reduced enzymatic degradation, better solubility, enhanced permeability, and improved metabolic clearance profiles. For example, modified cyclic dipeptides (e.g., Compound 1 or Compound 5) having a hydrolyzable ester (e.g., -C(O)O-) between the polymer and the cyclic dipeptide can function as a prodrug and, upon administration to a subject, can release the active cyclic dipeptide through enzymatic cleavage in the body. On the other hand, modified cyclic dipeptides without a hydrolyzable bond in the molecule (e.g., Compound 3) cannot be cleaved in the body and may function as new chemical entities, potentially exhibiting additional or novel physiological activities.

[0028] Modified cyclic dipeptide compounds can be prepared by linking a biocompatible polymer to a cyclic dipeptide either directly or via a linker (L1). The biocompatible polymer can have a reactive group (or activating group) for covalent attachment to the cyclic dipeptide, as described below. In certain embodiments, biocompatible polymers suitable for modifying cyclic dipeptides can be functionalized with reactive groups at one or both ends. The reactive group can be a carboxylic acid (e.g., polyethylene glycol diacid (i.e., PEG with carboxylic acids at both ends), which can be used to prepare dimers), a tosyl group, an aldehyde group, a propionaldehyde group, a butyraldehyde group, a maleimide group, succinimidyl propionate, succinimidyl carboxymethyl, hydroxysuccinimidyl, or succinimidyl carbonate. As described below, in one embodiment, a cyclic dipeptide and mPEG-OH can be reacted in the presence of phosgene and a base known in the art to provide the desired PEG-modified cyclic dipeptide (see Example 2). In another embodiment, when tosyl-PEG is utilized to PEGylate a cyclic dipeptide, the tosyl-PEG and cyclic dipeptide are reacted in the presence of a base such as carbonic acid, preferably cesium carbonate, to afford the desired PEG-modified cyclic dipeptide (see Example 3).

[0029] Cyclic dipeptides In exemplary embodiments, the cyclic dipeptide can be a proline-containing, hydroxyproline-containing, or histidine-containing cyclic dipeptide. In some embodiments, the proline-containing, hydroxyproline-containing, or histidine-containing cyclic dipeptide can be represented by X1-Pro, X1-Hyp, Pro-X2, Hyp-X2, X1-His, or His-X2-, where X1 and X2 are each independently arginine, lysine, histidine, phenylalanine, tyrosine, leucine, isoleucine, methionine, valine, alanine, glycine, proline, glutamic acid, glutamine, serine, threonine, aspartic acid, asparagine, tryptophan, or cysteine. In some embodiments, X1 and X2 are each independently glycine, phenylalanine, lysine, tryptophan, aspartic acid, tyrosine, leucine, histidine, proline, alanine, hydroxyproline, or arginine. In some embodiments, the cyclic dipeptide X1-X2 is cyclo(Gly-Pro), cyclo(Phe-Pro), cyclo(Pro-Trp), cyclo(Leu-Pro), cyclo(His-Pro), cyclo(Pro-Asp), cyclo(Pro-Lys), cyclo(Pro-Tyr), cyclo(Pro-Gly), cyclo(Pro-Hyp), cyclo(Pro-Ala), cyclo(Pro-Arg), cyclo(Pro-Leu), cyclo(Hyp-Gly). , cyclo(His-Leu), cyclo(Vla-His), cyclo(Met-His), cyclo(Ile-His), cyclo(His-Tyr), cyclo(His-Phe), cyclo(Gln-His), cyclo(Ala-Leu), cyclo(Trp-His), cyclo(Gly-His), cyclo(Thr-His), cyclo(Asp-His), cyclo(Asn-His), cyclo(Arg-His), a salt thereof, or an isomer thereof. In some embodiments, the cyclic dipeptide can be cyclo(his-pro) (CHP) or a salt thereof.Cyclic dipeptides can be prepared by known methods, exemplified but not limited to, the method described in Japanese Patent No. 6826359.

[0030] Biocompatible Polymers The biocompatible polymer used to modify the cyclic dipeptides according to the present disclosure can be a polyalkylene glycol (e.g., polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol), polyvinyl alcohol, polysaccharide, dextran, or polyvinyl ethyl ether. In exemplary embodiments, the biocompatible polymer is a polyalkylene glycol derivative. In certain exemplary embodiments, the polyalkylene glycol can be a polyethylene glycol (PEG) derivative. A variety of PEGs can be used to modify (e.g., PEGylate) the cyclic dipeptide. Any suitable reactive PEG reagent can be used. In some embodiments, the reactive PEG reagent is coupled to the cyclic dipeptide at a nitrogen or carbon atom of the cyclic dipeptide, resulting in the formation of a carbamate or amide bond.

[0031] In an exemplary embodiment, when the polymer is PEG, for example, it may be preferable to use a form of PEG, typically linear, methoxy-PEG (commonly referred to as mPEG), in which one end of the polymer is a methoxy (-OCH3) group, while the other end is a hydroxyl or other functional group that can be chemically modified. The structure of mPEG is shown below. CH3O-(CH2CH2O)n-CH2CH2- where the values ​​of (n) are as described herein. Cyclic dipeptides according to the present disclosure can be modified with a monofunctionally activated hydroxyPEG (e.g., a single terminus activated hydroxyPEG, including reactive esters of hydroxyPEG-monocarboxylic acid, hydroxyPEG-monoaldehyde, hydroxyPEG-monoamine, hydroxyPEG-monohydrazide, hydroxyPEG-monocarbazic acid, hydroxyPEG-monoiodoacetamide, hydroxyPEG-monomaleimide, hydroxyPEG-monoorthopyridyl disulfide, hydroxyPEG-monoxime, hydroxyPEG-monophenylcarbonate, hydroxyPEG-monophenylglyoxal, hydroxyPEG-monothiazolidine-2-thione, hydroxyPEG-monothioester, hydroxyPEG-tosylestoer, hydroxyPEG-monothiol, hydroxyPEG-monotriazine, and hydroxyPEG-monovinylsulfone) to prepare modified cyclic dipeptides of Formula (I).

[0032] In other exemplary embodiments, mPEG-oTS, mPEG2-NHS, mPEG2-ALD, multi-arm PEG, mPEG(MAL)2, mPEG2(MAL), mPEG-NH2, MPEG-SPA, mPEG-SBA, mPEG-thioester, mPEG-double ester, mPEG-BTC, mPEG-butyl ALD, MPEG-ACET, heterofunctional PEG (e.g., NH2-PEG-COOH, Boc-PEG-NHS, Fmoc-PEG-NHS, NHS-PEG-VS, NHS -PEG-MAL), PEG acrylate (ACRL-PEG-NHS), PEG-phospholipid (e.g., mPEG-DSPE), carboxyl-PEG, carboxyl-PEG-carboxyl, p-NP-PEG, tosyl-PEG, tresyl-PEG, aldehyde PEG, acetal-PEG, amino-PEG, thiol-PEG, maleimide-PEG, amino-PEG-COOH, succinimidyl-PEG, carboxylic anhydride-type PEG, functionalized PEG-phospholipid, and the like can be used.

[0033] According to the embodiments discussed herein, linear and branched PEGs of various sizes are suitable, including those having average molecular weights (excluding the mass of activating or reactive groups) ranging from about 44 Da to about 50,000 Da, about 200 Da to about 50,000 Da, or about 200 Da to about 22,000 Da. Suitable ranges of average molecular weight include about 100 Da to about 25,000 Da, about 100 Da to about 10,000 Da, about 100 Da to about 8,000 Da, about 100 Da to about 7,000 Da, about 150 Da to about 6,000 Da, about 200 Da to about 5,000 Da, about 250 Da or about 5,000 Da, about 250 Da to about 4,500 Da, and about 250 Da, about 5,000 Da, about 250 Da, ...250 Da, about 250 Da, about 250 Da, about 250 Da, about 250 Da, about 250 Da, about 250 Da, about 250 Da, about 250 Da, about 250 Da, about 250 Da, about 2 Examples of suitable PEGs include, but are not limited to, 300 Da, about 350 Da, about 400 Da, about 450 Da, about 500 Da, about 750 Da, about 1000 Da, about 1500 Da, about 2000 Da, about 3000 Da, about 4000 Da, about 5000 Da, about 6000 Da, about 7000 Da, about 8000 Da, about 9000 Da, or about 10000 Da. For linear PEGs, a molecular weight range of about 50 Da to about 25000 Da corresponds to a degree of polymerization (n) of formula (I) ranging from about 1 to about 500 monomer units of ethylene oxide. Commercially available PEG derivatives can be used. For example, PEG200 having an average molecular weight of 190 to 210 Da (n is approximately 4.2), PEG1000 having an average molecular weight of 900 to 1000 Da (n is approximately 22.3), PEG2000 having an average molecular weight of 1800 to 2200 Da (n = 40 to 50), PEG4000 having an average molecular weight of 3000 to 4800 Da (n = 69 to 84), or PEG4000 having an average molecular weight of 3600 to 4400 Da (n = 26 to 32) can be used.

[0034] In some embodiments, the degree of polymerization (n) of Formula (I) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500, or about 1 to 500, 5 to 500, 5 to 400, 5 to 300, 5 to 200, 5 to 100, The range may be 1 to 50, 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 1 to 30, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 10 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, or 7 to 10. Compositions and Uses The modified cyclic dipeptide compounds of formula (I) can be included in compositions as active ingredients for controlling or lowering blood glucose levels in a subject, or alleviating or treating diabetes, for anti-obesity, anti-inflammatory, and / or antioxidant effects. The modified cyclic dipeptide compounds of formula (I) of the present disclosure can also be used in therapeutically effective amounts to treat various diseases and disorders, such as metabolic diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, acute kidney injury (AKI), chronic kidney disease (CKD), pulmonary fibrosis, renal fibrosis, etc., to provide cytoprotection against oxidative damage, to suppress inflammatory responses in PC12 cell lines, and as appetite suppressants.

[0035] A composition according to the present disclosure may be a pharmaceutical composition. The pharmaceutical composition according to the present disclosure may further comprise a suitable carrier, excipient, or diluent conventionally used in the manufacture of pharmaceutical compositions. In this regard, the content of the modified cyclic dipeptide or a salt or fraction thereof contained in the composition may be preferably 0.0001 to 10% by mass, more preferably 0.001 to 1% by mass. However, the present disclosure is not particularly limited thereto. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that can be used pharmaceutically among substances having a cation and anion bound by electrostatic attraction. Typically, pharmaceutically acceptable salts include metal salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Examples of metal salts include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, barium salt, etc.), aluminum salts, etc.; examples of salts with organic bases include salts with triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.; examples of salts with inorganic acids include salts with hydrochloric acid, Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.; examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0036] The pharmaceutical composition can be administered orally or parenterally. For parenteral administration, extracorporeal or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection can be preferably selected. The pharmaceutical composition according to the present disclosure may further comprise commonly used excipients, disintegrants, sweeteners, lubricants, flavoring agents, etc. The disintegrant may be selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, chitosan, guar gum, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, and polacrilin potassium. Furthermore, the pharmaceutical composition according to the present disclosure may further comprise a pharmaceutically acceptable additive. In this regard, pharmaceutically acceptable excipients may include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, sugar, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, refined sugar, dextrose, sorbitol, talc, etc. The content of one or more pharmaceutically acceptable excipients according to the present disclosure may be in the range of 0.1 to 90 parts by weight relative to the total weight of the pharmaceutical composition.

[0037] In some embodiments, a composition comprises or consists essentially of a modified cyclic dipeptide of Formula (I), its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a composition comprises or consists essentially of a modified cyclic dipeptide of Formula (I), its isomer, or a pharmaceutically acceptable salt thereof, and zinc metal, an organic or inorganic salt of zinc, a zinc compound, or zinc ions as active ingredients. In some embodiments, the composition does not contain zinc metal, an organic or inorganic salt of zinc, a zinc compound, or zinc ions. In other embodiments, the composition may contain zinc metal, an organic or inorganic salt of zinc, a zinc compound, or zinc ions.

[0038] Solid formulations for oral administration include powders, granules, tablets, capsules, soft capsules, pills, etc. Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, sprays, etc. Liquid formulations may contain various excipients such as wetting agents, sweeteners, flavorings, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration can be formulated by conventional methods into the forms of powders, granules, tablets, capsules, sterile aqueous solutions, liquid preparations, non-aqueous solvents, suspensions, emulsions, syrups, topical preparations such as suppositories and sprays, and sterile injectable preparations. Preferably, topical skin preparations such as creams, gels, patches, sprays, ointments, alerts, lotions, liniments, pastes, or patches can be prepared, but are not limited to these. For non-aqueous preparations or suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. can be used, and witepsol, macrogol, Tween 61, cocoa butter, laurin butter, glycerogelatin, etc. can be used as suppository bases.

[0039] The preferred dose of the pharmaceutical composition according to the present disclosure varies depending on the degree of absorption of the active ingredient in the body, the rate of inactivation and excretion, the age, sex, and condition of the patient, and the severity of the disease being treated. The dose can be appropriately selected by those skilled in the art. However, to achieve the desired effect, in the case of oral administration, the pharmaceutical composition according to the present disclosure can generally be administered at a dose of 0.0001 to 100 mg / kg, preferably 0.001 to 100 mg / kg, per adult per day. Administration can be once a day or divided into several doses throughout the day. The dose does not limit the scope of the present disclosure in any way. The pharmaceutical composition according to the present disclosure has little toxicity or side effects and can be safely used even when taken over a long period of time. The composition according to the present disclosure may be a food product or a dietary supplement. The food product or dietary supplement contains the compound of formula (I) or its isomer or a food-acceptable salt. As used herein, the term "food-acceptable salt" refers to a salt that can be used as a food product among substances having a cation and an anion that are bound by electrostatic attraction. Specific examples of food-acceptable salts include the above examples of pharmaceutically acceptable salts.

[0040] Dietary supplements, sometimes called functional foods, health foods, or health supplements in some countries, refer to foods that have effective health-maintaining or health-promoting effects compared to general foods. Foods and / or dietary supplements can be prepared in various forms, such as tablets, capsules, powders, granules, liquids, and pills, to achieve beneficial effects. As used herein, the term "functional food" is the same as "food for specified health uses (FoSHU)." This food refers to a food with highly medical benefits, processed so that it can efficiently achieve biological control functions in addition to nutrition. As a specific example of such a health functional food, the above composition can be converted into a food having characteristics of an agricultural product, livestock product, or aquatic product to produce a processed food with good storage properties. It will be readily apparent to those skilled in the relevant art that other suitable modifications and adaptations of the methods and applications described herein can be made without departing from the scope of the present disclosure or any of its embodiments. The present disclosure will be more clearly understood with reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the present disclosure. [Example]

[0041] Abbreviation ACN: acetonitrile mPEG: methoxypolyethylene glycol MC: methylene chloride DCC: N,N'-dicyclohexylcarbodiimide DIEA or DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: dimethylformamide TEA: Triethanolamine THF: tetrahydrofuran Ts: Tosil

[0042] Reference Example 1: Preparation of methyl (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylate [ka] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(1H-imidazol-5-yl)propanoic acid (50.0 g, 196 mmol) and methyl (2S)-pyrrolidine-2-carboxylate (38.9 g, 235 mmol, HCl) in DMF (500 mL) was added DCC (44.5 g, 216 mmol, 43.6 mL), HOBt (29.1 g, 216 mmol), and DIEA (101 g, 784 mmol, 137 mL). The mixture was stirred at 25 °C for 12 h. TLC (CHCl / MeOH = 10 / 1, R f A pH of 0.2 indicated the reaction was complete. The reaction mixture was diluted with CHCl (500 mL) and washed with 500 mL of NHCl (250 mL × 2). It was then washed with NaHCO (250 mL × 2). It was then washed with 500 mL of brine (250 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, CHCl:MeOH = 1 / 0 to 10 / 1) to give methyl (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylate (43.0 g, 55.4% yield) as a white solid.

[0043] 1HNMR: 400 MHz, DMSO-d6δ 7.53 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 4.37-4.43 (m, 1H), 4.30-4.35 (m, 1H), 4.12 (s, 1H), 3.58-3.61 (m, 3H), 3.17 (s, 2H), 2.68-2.78 (m, 2H), 2.11-2.21 (m, 1H), 1.80-1.84 (m, 2H), 1.33 (s, 9H). LCMS: m / z=367.1 (M+H) + , Rt=0.406 min.

[0044] Reference Example 2: Preparation of methyl (2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylate [ka] To a solution of methyl (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylate (43.0 g, 117 mmol) in CHCl (400 mL) was added HCl / dioxane (4 M, 100 mL). The mixture was stirred at 25 °C for 2 h. TLC (CHCl / MeOH = 20 / 1, R f =0.3), indicating the reaction was complete. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylate (35.5 g, 91.7% yield, HCl) as a white solid.

[0045] 1HNMR: 400 MHz, CD3OD δ 8.97 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 4.69 (t, J = 6.8 Hz, 1H), 4.57 (dd, J = 9.2, 5.6 Hz, 1H), 3.79-3.86 (m, 2H), 3.76 (s, 3H), 3.66 (s, 5H), 3.47-3.52 (m, 1H), 3.42 (dd, J = 6.8, 1.6 Hz, 1H), 2.30-2.36 (m, 1H), 1.99-2.08 (m, 3H).

[0046] Reference Example 3: Preparation of (3S,8aS)-3-(1H-imidazol-5-ylmethyl)-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione [ka] A solution of methyl (2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylate (35.5 g, 117 mmol, HCl) and NaHCO3 (9.85 g, 117 mmol, 4.56 mL) in HO (3 L) was stirred at 130 °C for 2.5 h. TLC (CHCl / MeOH = 10 / 1, R f = 0.3) indicated the reaction was complete. After filtration through a paper spindle, methanol was added, followed by spinning again. The aqueous layer was concentrated to dryness under reduced pressure using column chromatography (SiO2, CHCl2 / MeOH = 1 / 0 to 10 / 1) to give (3S,8aS)-3-(1H-imidazol-5-ylmethyl)-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (25.5 g, 90.9% yield) as a colorless gum. LCMS: m / z=235.2 (M+H) + , Rt=0.273 min.

[0047] Example 1 Preparation of 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate [ka] To a solution of 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (4.0 g, 9.33 mmol) in CHCl (40 mL) was added TEA (2.83 g, 28.0 mmol, 3.90 mL), DMAP (114 mg, 933 μmol), and 4-methylbenzenesulfonyl chloride (2.67 g, 14.0 mmol). The mixture was stirred at 25 °C for 2 h. TLC (CHCl / MeOH = 10 / 1, R f = 0.4) indicated the reaction was complete. The reaction mixture was diluted with CHCl (50 mL) and washed with brine (25 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue as a yellow solid, which was purified by column chromatography (SiO, CHCl / MeOH = 1 / 0 to 10 / 1) to give 2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (4.2 g, 54.2% yield) as a yellow solid.

[0048] 1 HNMR (400 MHz, CD3OD) δ 7.76 (d, J=8.0 Hz, 2H), 7.41 (br d, J=8.0 Hz, 2H), 4.11 (t, J=4.4 Hz, 2H), 3.54-3.67 (m, 32H), 3.45-3.53 (m, 7H), 2.42 (s, 3H) LCMS: m / z=583.7 (M+H) + , Rt=1.218 minutes

[0049] Example 2 Preparation of Compound 1 [ka] To a solution of triphosgene (1.66 g, 5.60 mmol) in THF (15 mL) was added a solution of DIEA (1.81 g, 14.0 mmol, 2.44 mL) and 2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (3.00 g, 7.00 mmol) in THF (15 mL) dropwise at 0°C, and the mixture was stirred at 0°C for 30 min. Then, (3S,8aS)-3-(1H-imidazol-5-ylmethyl)-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1.64 g, 7.00 mmol) in DMF (15 mL) was added to the mixture. The final mixture was stirred at 25 °C for 10 h. TLC (CHCl / MeOH = 10:1, Rf = 0.3, I) showed the reaction was complete. The reaction mixture was quenched by adding H0 (50 mL) at 0 °C and extracted with CHCl (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: WELCH XTIMATE™ C18 150 * 40mm * Purification by HPLC (10 μm; mobile phase: [water-ACN]; B%: 0%-36%, 30 min) gave 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-[[(3S,8aS)-1,4-dioxo-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-3-yl]methyl]imidazole-1-carboxylate (Compound 1) (1.35 g, 72.75% yield, 97% purity) as a yellow oil.

[0050] 1HNMR: δ (d, J = 1.2 Hz, 1H), 7.91 (s, 1H), 7.39 (s, 1H), 4.47-4.49 (m, 2H), 4.30-4.35 (m, 1H), 4.17-4.22 (m, 1H), 3.73-3.76 (m, 2H), 3.56-3.59 (m, 2H), 3.48-3.51 (m, 30H), 3.41-3.43 (m, 2H), 3.23 (s, 3H), 3.15 (dd, J = 15.2 4.4 Hz, 1H), 2.73 (dd, J = 15.2, 7.6 Hz, 1H), 2.09-2.15 (m, 1H), 2.07 (s, 1H), 1.79-1.87 (m, 3H).

[0051] Example 3 Preparation of Compound 2 [ka] 3-1. Preparation of 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate To a solution of 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (4.0 g, 9.33 mmol) in CHCl (40 mL) was added TEA (2.83 g, 28.0 mmol, 3.90 mL), DMAP (114 mg, 933 μmol), and 4-methylbenzenesulfonyl chloride (2.67 g, 14.0 mmol). The mixture was stirred at 25 °C for 2 h. TLC (CHCl / MeOH = 10 / 1, R f= 0.4) indicated the reaction was complete. The reaction mixture was diluted with CHCl (50 mL) and washed with brine (25 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue as a yellow solid, which was purified by column chromatography (SiO, CHCl / MeOH = 1 / 0 to 10 / 1) to give 2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (4.2 g, 54.2% yield) as a yellow solid.

[0052] 1 HNMR (400 MHz, CD3OD) δ 7.76 (d, J=8.0 Hz, 2H), 7.41 (br d, J=8.0 Hz, 2H), 4.11 (t, J=4.4 Hz, 2H), 3.54-3.67 (m, 32H), 3.45-3.53 (m, 7H), 2.42 (s, 3H) LCMS: m / z=583.7 (M+H) + , Rt=1.218 minutes

[0053] 3-2. Preparation of (3S,8aS)-3-[[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]imidazol-4-yl]methyl]-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione To a solution of 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (4.20 g, 7.21 mmol) and (3S,8aS)-3-(1H-imidazol-5-ylmethyl)-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (2.03 g, 8.65 mmol) in DMF (40 mL) was added CsCO (7.05 g, 21.6 mmol). The mixture was stirred at 50 °C for 2 h. TLC (CHCl / MeOH = 20 / 1, R f =0.2) indicated the reaction was complete. The reaction mixture was diluted with CHCl (80 mL) and washed with 80 mL of brine (40 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: WELCH XTIMATE™ C18 150 * 30mm * Purification by HPLC using a 5 μm column chromatography (5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 0%-90%, 14 min) gave (3S,8aS)-3-[[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]imidazol-4-yl]methyl]-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (4.20 g, 89.2% yield, 98.67% purity) as a white solid. 1HNMR: 400 MHz, CD3OD δ 7.63 (s, 1H), 7.04 (s, 1H), 4.31-4.40 (m, 1H), 4.25 (t, J = 8.4 Hz, 1H), 4.15 (t, J = 4.8 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 3.60-3.64 (m, 32H), 3.52-3.55 (m, 2H), 3.35 (s, 3H), 3.27 (dd, J = 14.8, 4.0 Hz, 1H), 2.90 (dd, J = 14.8, 8.0 Hz, 1H), 2.23-2.34 (m, 1H), 1.88-2.03 (m, 3H).

[0054] Example 4 [ka] Following the procedure of Example 2, except that PEG508 (average molecular weight 508), PEG2000 (n = 40.0-50.0, average molecular weight approximately 2000 Da), PEG3400 (average molecular weight 3400 Da), PEG6000 (average molecular weight 6000 Da), and PEG10000 (average molecular weight 10000 Da) are used instead of 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol, the corresponding PEG-modified 4-[[(3S,8aS)-1,4-dioxo-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-3-yl]methyl]imidazole-1-carboxylate is obtained.

[0055] Example 5 [ka] Tosyl-PEG1000, tosyl-PEG2000, tosyl-PEG3400, tosyl-PEG6000, tosyl-PEG10000, and tosyl-PEG2000 are prepared by following the procedure of Example 3-1. Then, by following the procedure of Example 3-2 except that tosyl-PEG1000, tosyl-PEG2000, tosyl-PEG3400, tosyl-PEG6000, tosyl-PEG10000, or tosyl-PEG2000 is used instead of 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate, the corresponding (3S,8aS)-3-PEG-imidazol-4-yl]methyl]-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione is obtained.

[0056] This invention is described herein with reference to specific embodiments thereof. The scope of this invention is not limited to the described embodiments, but rather is limited only by the claims and / or their equivalents. Those skilled in the art will readily recognize that other embodiments may be practiced without departing from the scope of this invention. All such variations are considered to be part of this invention.

Claims

1. Compound of Formula A' 【Chemical 1】 (In the formula, L 1 -C(O)-, -S(O)-, -S(O) 2 -, -P(O)(O - ) -, -CH 2 C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, and said L 1 is attached to one of the two nitrogen atoms of the imidazole group, n is an integer from 1 to 500, R is hydrogen, linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy. or an isomer or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound of formula A' is a compound of formula A-1. 【Chemistry 2】 (In the formula, L 1 , n, and R have the same meaning as defined in claim 1.

3. n is 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 1 to 30, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 1 3. The compound according to claim 1 or 2, wherein the ribonucleotides are 0 to 30, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, or 7 to 9, or an isomer or a pharmaceutically acceptable salt thereof.

4. 4. The compound according to any one of claims 1 to 3, wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or an isomer or pharmaceutically acceptable salt thereof.

5. L 1 is -C(O)-, -S(O)-, -S(O) 2 -, -P(O)(O - ) -, -CH 2 - or -CH 2 CH 2 The compound according to any one of claims 1 to 4, wherein -, or an isomer or a pharmaceutically acceptable salt thereof.

6. 6. The compound according to any one of claims 1 to 5, wherein R is linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy, or an isomer or a pharmaceutically acceptable salt thereof.

7. A composition comprising a compound according to any one of claims 1 to 6.

8. A modified cyclic dipeptide compound represented by the following formula (A): (X 1 - X 2 ) - (L 1 ) p - O - (-CH 2 CH 2 O) n - (L 2 ) q - R Formula (A) (In the formula, X 1 -X 2 is a cyclic dipeptide, L 1 is C1-C6 alkyl, C1-C6 alkyl-C(O), -C(O)-, -S(O)-, -S(O) 2 -, -P(O)(O - )- or C(O)-C1-C6 alkyl; L 2 is C1-C6 alkyl or C1-C6 alkyl-C(O), R is hydrogen, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, or C6-10 aryl; p is an integer of 0 or 1; q is an integer of 0 or 1; n is 1 to 500.

9. 9. The modified cyclic dipeptide compound of claim 8, wherein the cyclic dipeptide is a proline-containing cyclic dipeptide.

10. L 1 is C1-C4 alkyl, C1-C4 alkyl-C(O), —C(O)—, —S(O)—, —S(O) 2 -, -P(O)(O - 10. The modified cyclic dipeptide compound according to claim 8 or 9, wherein the aryl group is selected from C(O)- or C(O)-C1-C4 alkyl.

11. L 2 The modified cyclic dipeptide compound according to any one of claims 8 to 10, wherein is C1-C4 alkyl or C1-C4 alkyl-C(O).

12. Cyclic dipeptide X 1 -X 2 is X 1 - Pro, X 1 -Hyp, Pro-X 2 , Hyp-X 2 , X 1 -His, His-X 2 -, where X 1 and X 2 are each independently arginine, lysine, histidine, phenylalanine, tyrosine, leucine, isoleucine, methionine, valine, alanine, glycine, proline, glutamic acid, glutamine, serine, threonine, aspartic acid, asparagine, tryptophan, or cysteine.

13. Cyclic dipeptides are cyclo(Gly-Pro), cyclo(Phe-Pro), cyclo(Pro-Trp), cyclo(Leu -Pro), cyclo(His-Pro), cyclo(Pro-Asp), cyclo(Pro-Lys), cyclo(Pro-Ty r), cyclo(Pro-Gly), cyclo(Pro-Hyp), cyclo(Pro-Ala), cyclo(Pro-Arg) , cyclo(Pro-Leu), cyclo(Hyp-Gly), cyclo(His-Leu), cyclo(Vla-His), cy 13. The modified cyclic dipeptide compound according to any one of claims 8 to 12, wherein the modified cyclic dipeptide compound is selected from the group consisting of cyclo(Met-His), cyclo(Ile-His), cyclo(His-Tyr), cyclo(His-Phe), cyclo(Gln-His), cyclo(Ala-Leu), cyclo(Trp-His), cyclo(Gly-His), cyclo(Thr-His), cyclo(Asp-His), cyclo(Asn-His), cyclo(Arg-His), and combinations thereof, salts thereof, or isomers thereof.

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