Novel guanidine derivative and method for producing same

Abstract

To provide a guanidine derivative (especially an amino acid compound having 4-guanidino group) which is produced at a low cost and hardly causes a waste liquid problem, to provide a method for producing the same, and to provide an intermediate used for the production.SOLUTION: A compound represented by formula (I), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to novel guanidine derivatives and the like. [Background technology]

[0002] Guanidino groups are known to form hydrogen bonds through electrostatic interactions with sulfate, carboxyl, and phosphate groups. Arginine is known as a natural amino acid that contains a guanidino group, and the guanidino group in arginine is known to play important roles in the body, such as interacting with cell membranes and intracellular transport. However, because arginine is a natural amino acid, it is susceptible to degradation by proteases, etc., and its use as a pharmaceutical can pose problems such as its short half-life in the blood. 4-Guanidinophenylalanine (F4G) is known as a substitute for arginine (J. Med. Chem 2012, 55, 10287-10291). This compound is trypsin-resistant (Chem. Pharm. Bull. 1986, 34(3), 1351-1354) and highly stable (J. Med. Chem. 2012, 55, 6294-6305), making it an important amino acid derivative for peptide pharmaceuticals. Currently, mercury- or silver-based reactions are known for F4G synthesis (Tetrahedron Letters 1996, 37, 48, 8711-8714). However, the use of heavy metals makes F4G expensive to produce and generates wastewater. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] J. Med. Chem.2012, 55, 10287-10291 [Non-patent document 2] Chem.Pharm.Bull. 1986,34(3),1351-1354 [Non-patent document 3] J.Med.Chem.2012,55,6294-6305 [Non-patent document 4] Tetrahedron Letters 1996,37,48,8711-8714 Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention is to provide a guanidine derivative (particularly an amino acid compound having a 4-guanidino group) which can be produced at low cost and which is less likely to cause waste liquid problems, a method for producing the same, and intermediates used in the production thereof. [Means for solving the problem]

[0005] The first aspect relates to a compound (novel guanidine compound) represented by the following formula (I), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof:

[0006] [ka] (In formula (I), -R 1 - is a C1-C alkyl group optionally having one or more substituents selected from group A. 10 an alkylene group, C which may have one or more substituents selected from group A; 6-10 arylene group, or -R 11 -R 12 - represents a group represented by Group A includes halogen atoms, amino groups, nitro groups, and C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, and C 1-3 is a halogenoalkyl group, -R 11 - is C which may have one or more substituents selected from group A 6-10 Represents an arylene group, -R 12The group represented by - represents a C1-C4 alkylene group which may have one or more substituents selected from Group A, R 2 and R 4 may be the same or different and represent a protecting group or a hydrogen atom, R 3 indicates a hydrogen atom, R 5 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, or C 1-3 R indicates a halogenoalkyl group. 5 ,-NR 1 C, which may contain an asymmetric carbon atom at the α-position together with - 5-7 Forming heterocyclic amines, R 6 and R 7 may be the same or different, and may be a protecting group, C 1-5 represents an alkyl group or a hydrogen atom, R 8 represents the protecting group of an amino acid, hydrogen atom, halogen atom, hydroxyl group, amino group, nitro group, C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenoalkyl group or -OR 13 - represents a group represented by R 13 The group represented by - is a protecting group for the oxygen atom, C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, or C 1-3 represents a halogenoalkyl group, -R 1 - represents a propylene group, and R 2 ~ and R 7 indicates a hydrogen atom, and R 8 But, those which show a hydroxyl group, and -R 1 -ga,-R 11 -R 12 - represents a group represented by -R 11- represents a 1,4-phenylene group, and -R 12 - indicates a methylene group, and R 2 ,R 4 ,R 5 ,R 6 , and R 7 However, both represent hydrogen atoms, and R 8 (Excluding those where indicates a hydroxyl group.)

[0007] A second aspect relates to a method for producing a peptide using the above-mentioned compound, its tautomer, its enantiomer, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate.

[0008] A third aspect relates to a method for producing a compound represented by formula (I), its tautomer, its enantiomer, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate, comprising a mixing step of mixing a compound represented by the following formula (II) with a compound represented by the following formula (III): [ka] (R 22 ,R 23 and R 24 are R 2 ,R 3 and R 4 is equivalent to [ka] (R 21 ,R 25 ,R 26 , and R 27 are R 1 ,R 5 ,R 6 , and R 7 is synonymous with R 28 ,-OR 33 - represents a group represented by R 33 The group represented by - indicates a protecting group for an oxygen atom. [Effects of the Invention]

[0009] According to this invention, by using a novel thiourea compound as an intermediate, it is possible to obtain guanidine derivatives (especially amino acid compounds having a 4-guanidino group) at low production costs and with little risk of waste liquid problems. DETAILED DESCRIPTION OF THE INVENTION

[0010] The following describes embodiments for carrying out the present invention. The present invention is not limited to the embodiments described below, and also includes appropriate modifications of the embodiments below within the scope obvious to those skilled in the art.

[0011] Guanidine Derivatives The novel guanidine derivative of the present invention relates to a compound represented by the following formula (I), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof:

[0012] [ka]

[0013] -R 1 - is a C1-C alkyl group optionally having one or more substituents selected from group A. 10 an alkylene group, C which may have one or more substituents selected from group A; 6-10 arylene group, or -R 11 -R 12 - represents a group represented by the symbol -. Group A includes halogen atoms, amino groups, nitro groups, and C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, and C 1-3 It is a halogenoalkyl group. -R 11 - is C which may have one or more substituents selected from group A 6-10 This represents an arylene group. -R 12 The group represented by - represents a C1-C4 alkylene group which may have one or more substituents selected from Group A.

[0014] R 2 and R 4 may be the same or different and represent a protecting group or a hydrogen atom, R 3 indicates a hydrogen atom.

[0015] R 5 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, or C 1-3 R represents a halogenoalkyl group. 5 ,-NR 1 C, which may contain an asymmetric carbon atom at the α-position together with - 5-7 Heterocyclic amines may also be formed.

[0016] R 6 and R 7 may be the same or different, and may be a protecting group, C 1-5 It represents an alkyl group or a hydrogen atom.

[0017] R 8 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenoalkyl group or -OR 13 - represents a group represented by R 8 may be a protecting group for an amino acid.

[0018] R 13 The group represented by - is a protecting group for the oxygen atom, C 1-5 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, or C 1-3 This represents a halogenoalkyl group.

[0019] Most of the compounds represented by formula (I) -R 1 - represents a propylene group, and R 2 ~ and R 7 indicates a hydrogen atom, and R 8However, those that exhibit a hydroxyl group (arginine), and -R 1 -ga,-R 11 -R 12 - represents a group represented by -R 11 - represents a 1,4-phenylene group, and -R 12 - indicates a methylene group, and R 2 ,R 4 ,R 5 ,R 6 , and R 7 However, both represent hydrogen atoms, and R 8 represents a hydroxyl group (F4G) is excluded from the guanidine derivatives of the present invention.

[0020] The tautomer means a tautomer of the compound represented by formula (I). The tautomer means an isomer that undergoes rapid conversion between two isomers and can reach an equilibrium state in which both isomers coexist.

[0021] The enantiomer refers to the enantiomer of the compound represented by formula (I). Enantiomers refer to two molecules that are chiral (mirror images) and cannot be superimposed.

[0022] The pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt of the compound represented by formula (I). Examples of pharmacologically acceptable salts include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halide ions, etc., and internal salts. Examples of inorganic bases include alkali metals (Na, K, etc.) and alkaline earth metals (Ca, Mg, etc.). Examples of organic bases include trimethylamine, triethylamine, choline, procaine, ethanolamine, dicyclohexylamine, cyclohexylamine, cinchonidine, pyridine, lutidine, triethylenediamine, etc. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, etc. Examples of organic acids include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and maleic acid, etc. Examples of basic amino acids include lysine, arginine, ornithine, and histidine, etc.

[0023] The pharmaceutically acceptable solvate means a pharmaceutically acceptable solvate of the compound represented by formula (I). An example of a solvate is a hydrate. The compound of the present invention may absorb moisture present in the atmosphere during storage and become a hydrate. The present invention includes such hydrates. The pharmaceutically acceptable solvate may be a solvate of a pharmaceutically acceptable salt of the compound represented by formula (I).

[0024] Preferred examples of compounds of formula (I) include -R 1 -ga, -R 11 -R 12 - represents a group represented by the formula: In this example, -R 11 - represents a 1,3-phenylene group or a 1,4-phenylene group which may have one or more substituents selected from Group A, and -R 12 - is a group represented by C 1-4 represents an alkylene group. In this example, -R 11 - represents a 1,3-phenylene group or a 1,4-phenylene group, -R 12 - is a group represented by C 1-4 Those which represent an alkylene group are even more preferred.

[0025] In the above example, R 5 ,R 6 ,R 7 , and R 8 is preferably the following group: R 5 represents a hydrogen atom, a methyl group, or an ethyl group. R 6 indicates the Fmoc group (9-fluorenylmethyloxycarbonyl group). R 7 indicates a hydrogen atom. R 8 is a hydroxyl group or -OR 13 - represents a group represented by R 13 The group represented by - represents a protecting group for an oxygen atom, a methyl group, or an ethyl group.

[0026] Another preferred example of the compound of formula (I) is -R 1 - represents a C3-C6 alkylene group. 1 A preferred example is a compound represented by formula (I) in which -R represents a C4 alkylene group. 1 - represents a C4 alkylene group, and R 2 indicates a protecting group (e.g., Rbf-), and R 3 indicates a hydrogen atom, and R 4 indicates a protecting group (e.g., Sub-), and R 5 indicates a methyl group, and R 6 indicates the Fmoc group, and R 7 indicates a hydrogen atom, and R 8 exhibits a hydroxyl group (for example, N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(N'-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)-N6-methyl-L-lysine).

[0027] In formula (I), -R 1 - represents a C3-C6 alkylene group, R 5 ,R 6 ,R 7 , and R 8 is preferably the following group: R 5 represents a hydrogen atom, a methyl group, or an ethyl group. R 6 indicates the Fmoc group (9-fluorenylmethyloxycarbonyl group). R 7 represents a hydrogen atom, a methyl group, or an ethyl group. R 8 is a hydroxyl group or -OR 13 - represents a group represented by R 13 The group represented by - represents a protecting group for an oxygen atom, a methyl group, or an ethyl group.

[0028] R 5But,-NR 1 C, which may contain an asymmetric carbon atom at the α-position together with - 5-7 Examples of compounds that form heterocyclic amines are: [ka]

[0029] In the compound represented by formula (I), another preferred example is R 7 is a hydrogen atom, and R 8 is a protecting group (amino acid protecting group), C 1-5 It is a compound in which the alkyl group is a hydrogen atom (a peptoid, a compound having a piperazine ring).

[0030] In this specification, "C m―n " means that the number of carbon atoms is any one of m to n.

[0031] An alkyl group is a monovalent group formed by the loss of one hydrogen atom from a straight-chain or branched-chain aliphatic hydrocarbon. 1―5 Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and neopentyl. Examples of C1-C4 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0032] An alkoxy group is a monovalent group formed by the loss of a hydrogen atom from the hydroxyl group of a straight-chain or branched-chain alcohol. 1-3 Examples of alkoxy groups are methoxy, ethoxy, propoxy, and isopropoxy groups.

[0033] An alkylthio group is an alkoxy group in which the oxygen is replaced by sulfur. 1-3 Examples of alkylthio groups are methylthio, ethylthio, propylthio, and isopropylthio groups.

[0034] A halogenoalkyl group is a monovalent group in which one or more hydrogen atoms of an alkyl group are substituted with halogen atoms. 1-3 Examples of halogenoalkyl groups are trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, and 4-fluorobutyl groups.

[0035] An alkylene group is a divalent group formed by the loss of two hydrogen atoms from a straight-chain or branched-chain aliphatic hydrocarbon. 1-10 Examples of alkylene groups include methylene, methylmethylene, ethylene, propylene, trimethylene, 1-methylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene The alkylene groups are ethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 5-methylheptamethylene, 2-ethylhexamethylene, 2-ethyl-3-methylpentamethylene, and 3-ethyl-2-methylpentamethylene. 1-4 Alkylene groups are preferred, C 1-2 An alkylene group is more preferred.

[0036] An arylene group is a divalent group formed by removing two hydrogen atoms from an aromatic hydrocarbon ring. 6-10 Examples of the ring constituting the arylene group include a benzene ring and a naphthalene ring.

[0037] Examples of halogen atoms are fluorine, chlorine, bromine, and iodine.

[0038] Examples of protecting groups include 10,11-dihydro-5H-dibenzo-[a,d][7]annulen-5-yl (Sub), diphenylmethyl (Bzh), 4-methoxyphenylmethyl (PMB), tert-butyl (tBu), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), tosyl (Tos), nitro (NO), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), 2,2,5,7,8- Pentamethylchroman-6-sulfonyl group (Pmc), 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl group (Pbf), benzyloxycarbonyl group (Z), 2-chlorobenzyloxycarbonyl group (Cl·Z), 3-nitro-2-pyridinesulfenyl group (Npys), phenacyl group (Pac), benzyloxymethyl group (Bom), dinitrophenyl group (Dmp), trityl group (Trt), benzyl group (Bzl), 4-methoxybenzyl group (MBzl), 4-methylbenzyl group (4-MeBzl), acetamidomethyl group (Acm), tertiary-butylthio group (tBuS), 2, They are 6-dichlorobenzyl group (Cl2·Bzl), formyl group (CHO), benzyl ester group (OBzl), tertiary butyl ester group (OtBu), cyclohexyl ester group (OcHex), phenacyl ester group (OPac), and xanthyl group (Xan).

[0039] Method for producing peptides Next, a method for producing a peptide using the above-mentioned compound, its tautomer, its enantiomer, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate will be described. The guanidine derivative of the present invention has a guanidino group, and peptides and proteins can be synthesized by binding the guanidino group. Furthermore, peptides can be obtained by mixing and reacting the above-mentioned compound with amino acids.

[0040] Thiourea compounds A novel thiourea compound, which is an intermediate used for producing a guanidine derivative, is a compound represented by the following formula (II).

[0041] [ka]

[0042] R 22 and R 24 may be the same or different and represent a protecting group or a hydrogen atom. Examples of protecting groups are Pbf, Pmc, or Sub. Among these, R 22 and R 24 are preferably Pbf and Sub, respectively. R 23 indicates a hydrogen atom.

[0043] Specific examples of the compound represented by formula (II) are compounds represented by the following formula (VI) or (V).

[0044] [ka]

[0045] [ka]

[0046] Specific compounds represented by formula (I) are as follows: i. 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid; ii. 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid; iii. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(N'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl-L-lysine; iv. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-(3-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)glycine; v. 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(N'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)piperidin-4-yl)propanoic acid; vi. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(N'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)-N6-methyl-L-lysine; vii. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-Nw'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-Nd-methyl-Nw-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-L-arginine; viii. 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(N'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)piperidine-4-carboxylic acid; ix. 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(1-(N'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)piperidin-4-yl)acetic acid; x. 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)butanoic acid; xi. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(N-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N'-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)-N6-methyl-D-lysine; xii. 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(3-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidinophenyl)propanoic acid; xiii. 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(3-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid; and xiv. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-Nw-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-Nd-methyl-Nw'-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-D-arginine.

[0047] Synthesis of thiourea compounds The novel thiourea compound of the present invention can be produced by the following scheme.

[0048] [ka]

[0049] R 2 and R 4 may be the same or different and represent a protecting group or a hydrogen atom. However, in Formula 1-1, Formula 1-3, and Formula 1-4, R 2 and R 4 R preferably represents a protecting group. 2 and R 4 Examples of are Pbf and Sub, respectively. R 3 represents a hydrogen atom. In Formula 1-2, X 1-1 is an alkali metal (e.g., Na, K) or alkaline earth metal (X depending on the valence of the cation) 1-1 The formula of SCN varies.

[0050] The compound represented by formula 1-1 is dissolved in an organic solvent (e.g., N,N-dimethylformamide: DMF). The compound represented by formula 1-2 is added to this solution, and the solution is stirred to obtain a solution containing the compound represented by formula 1-3. The molar ratio of the compounds represented by formula 1-1 and formula 1-2 may be 1:2 to 2:1, 2:3 to 3:2, or 4:5 to 5:4. The reaction temperature may be 10°C or higher and 60°C or lower, or 20°C or higher and 40°C or lower. The reaction time may be 10 minutes to 3 hours or lower, or 20 minutes to 1 hour or lower. A known catalyst may be added to the reaction system. The stirring speed may be adjusted appropriately.

[0051] The compound represented by formula 1-4 is dissolved in an organic solvent (e.g., DMF). A strong base (e.g., NaH) is added to this solution under cooling. The solution to which the strong base has been added is stirred to obtain a reaction liquid (e.g., a suspension). The molar ratio of the compounds represented by Formula 1-1 and Formula 1-4 may be 1:2 to 2:1, 2:3 to 3:2, or 4:5 to 5:4. The temperature of the solution when adding the strong base to the compound represented by Formula 1-4 is -20°C to 10°C, or may be -10°C to 5°C. The temperature of the solution during stirring may be 10°C to 60°C, or may be 20°C to 40°C. The reaction time may be 5 minutes to 2 hours, or 10 minutes to 1 hour. A known catalyst may be added to the reaction system. The stirring speed may be adjusted appropriately. In this manner, a solution containing the compound represented by Formula 1-4 is obtained.

[0052] A solution containing the compound represented by formula 1-3 is added to a solution containing the compound represented by formula 1-4, and the mixture is stirred to promote the reaction, thereby obtaining a solution containing the compound represented by formula 1-5. The temperature of the solution during stirring may be 10°C or higher and 60°C or lower, or 20°C or higher and 40°C or lower. The reaction time may be 10 minutes or higher and 4 hours or lower, or 30 minutes or higher and 2 hours or lower. To terminate this reaction, the solution is cooled and a strong acid (e.g., hydrochloric acid) is added. After the reaction is terminated, the compound represented by formula 1-5 can be obtained by purifying and drying using known purification and drying methods.

[0053] Synthesis of Guanidine Derivatives (1) The guanidine derivative of the present invention can be produced by the following scheme: This step utilizes the fact that, when the C-terminus of a side chain amino acid is not protected, a protecting group from a silylating agent protects the unprotected C-terminus of the side chain amino acid.

[0054] [ka]

[0055] R 1 ~R 8 has the same meaning as explained above. The compound of formula 2-2 is mixed with an organic solvent (e.g., tetrahydrofuran: THF), and the C-terminus is not protected (R 8 is a hydroxyl group), a silylating agent (e.g., MSA) is added and stirred. The molar ratio of the compound represented by formula 2-2 to the silylating agent may be 1:4 to 2:1, 1:3 to 1:1, or 1:2 to 1:1. The temperature of the solvent during stirring is 10°C to 90°C, or may be 20°C to 80°C. The stirring time may be 20 minutes to 3 hours, or 30 minutes to 2 hours.

[0056] The compound represented by formula 1-5 and a condensing agent are added to a solution containing the compound represented by formula 2-2, and the mixture is stirred. An organic base (e.g., TEA) may be added to this reaction system. The condensing agent may be a known condensing agent, such as dimethylaminopropylethylcarbodiimide hydrochloride (EDCI). The stirring time may be from 10 minutes to 2 hours, or from 20 minutes to 1 hour. To terminate the reaction, an acid (e.g., citric acid) may be added to the reaction solution. The molar ratio of the compounds represented by formula 2-1 and formula 1-5 may be 1:2 to 2:1, 2:3 to 3:2, or 4:5 to 5:4.

[0057] In this way, a liquid containing the compound represented by formula 2-3 can be obtained. From this liquid, extraction, purification, and drying treatments can be performed to obtain the compound represented by formula 2-3. The extraction treatment may also include treatments such as salt formation and purification.

[0058] Synthesis of Guanidine Derivatives (2) Group R in the compound represented by 2-3 2 , or R 4 When is a protecting group, the guanidine derivative of the present invention can be obtained by deprotecting it.

[0059] Uses of guanidine derivatives The guanidine derivative of the present invention can be used for the following purposes. The guanidine derivatives (especially salts) of the present invention are used as protein denaturants because they easily form hydrogen bonds. The guanidine derivatives of the present invention are used as strong bases in organic synthesis. The guanidine derivative of the present invention has a guanidino group, and by binding the guanidino group, peptides and proteins can be synthesized. The guanidine derivative and peptide of the present invention have the property of permeating cell membranes, and are therefore also effective as carriers in drug delivery systems. [Example]

[0060] The present invention will be explained in more detail below by showing synthetic examples as reference examples, comparative examples and working examples, but the present invention is not limited to these examples. In this specification, when amino acids and the like are represented by abbreviations, each representation is based on the abbreviations established by the IUPAC-IUB Commission on Biochemical Nomenclature or on the abbreviations commonly used in the relevant field. The abbreviations used in the synthesis examples are as follows: Fmoc as 9-fluorenylmethyloxycarbonyl or 9-fluorenylmethoxycarbonyl; Pbf as 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; Pmc as 2,2,5,7,8-pentamethylchroman-6-sulfonyl; Sub as 10,11-dihydro-5H-dibenzo[A,D][7]annulen-5-yl; Bzh as benzhydryl; tBu as tertiary butyl; Pmb as para-methoxybenzyl; THF as tetrahydrofuran; MSA as N-methyl-N-trimethylsilylacetamide; TEA as triethylamine; EDCI as dimethylaminopropylethylcarbodiimide hydrochloride; DMF as N,N-dimethylformamide; DCM as dichloromethane; TIS as triisopropylsilane; DODT as 3,6-dioxa-1,8-octane-dithiol; milliliters (units) as mL; M as molar (unit: mol / L); mM as millimolar (unit); mm as millimeters (unit); nm as nanometer (unit); Angstroms (units) as Å; Minutes (units) as min; MS as mass spectrometry; mmol as millimoles (units); mg as milligrams (units); and Liquid chromatography-mass spectrometry: LC-MS or LC / MS.

[0061] Other abbreviations are as follows: F4G as 2-amino-3-(4-guanidinophenyl)propanoic acid; F3G as 2-amino-3-(3-guanidinophenyl)propanoic acid; Har as N6-carbamimidoyl-L-lysine; GpG as (3-guanidinopropyl)glycine; A4pG as 2-amino-3-(1-carbamimidoylpiperidin-4-yl)propanoic acid; HarMe as N6-carbamimidoyl-N6-methyl-L-lysine; RMe as Nd-methyl-L-arginine; A4pipG as 4-amino-1-carbamimidoylpiperidine-4-carboxylic acid; G4pipG as 2-amino-2-(1-carbamimidoylpiperidin-4-yl)acetic acid; Nar as 2-amino-4-guanidinobutanoic acid; N6-carbamimidoyl-D-lysine as dhar; dharMe as N6-carbamimidoyl-N6-methyl-D-lysine; (R)-df4G as 2-amino-3-(4-guanidinophenyl)propanoic acid; df3G as (R)-2-amino-3-(3-guanidinophenyl)propanoic acid; and drMe as Nd-methyl-D-arginine.

[0062] Unless otherwise specified, proton nuclear magnetic resonance (H NMR) spectra of the following synthesis examples were measured in deuterated chloroform or deuterated dimethyl sulfoxide using a JEOL JNM-ECP300, a JEOL JNM-ECX300, or a Bruker Ascend™500, and chemical shifts are shown as δ values ​​(ppm) using tetramethylsilane as the internal standard (0.0 ppm). In describing NMR spectra, "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "dd" means doublet of doublets, "dt" means doublet of triplets, "sept" means septet, "m" means multiplet, "br" means broad, "J" means coupling constant, "Hz" means Hertz, "CDCl3" means deuterated chloroform, and "DMSO-d6" means deuterated dimethyl sulfoxide. Unless otherwise specified, high-performance liquid chromatography / mass spectrometry was measured using either a Waters ACQUITY UPLC H-Class / QDa, a Waters ACQUITY UPLC H-Class / SQD2, or a Shimadzu LC-20AD / Triple Tof5600. In the description of HPLC / MS, ESI+ is the positive mode of electrospray ionization, M+H is the proton adduct, and M+Na is the sodium adduct. In the description of HPLC / MS, ESI- stands for negative mode of electrospray ionization, and MH stands for proton-deficient. The ratio of the raw material to the product was calculated from the peak area ratio obtained under the following analytical conditions in high performance liquid chromatography / mass spectrometry, and the structure of the obtained compound was confirmed by 1H NMR and LC / MS.

[0063] Analysis conditions A Column: Kinetex® EVO C18, 2.6 μm, 2.1 x 50 mm. Mobile phase A: 0.025% TFA in H2O Mobile phase B:0.025% TFA in CH3CN Column temperature: 60°C Gradient (%B): 5-95% over 2.1 min, then 95-95% over 0.75 min, flow rate: 0.6 mL / min Detection: UV 220nm. Analysis conditions B Column: Kinetex® EVO C18 100 Angstroms, 1.7 μm, 2.1 x 50 mm. Mobile phase A: 0.025% TFA in H2O Mobile phase B:0.025% TFA in CH3CN Column temperature: 60°C Gradient (%B): 5-95% over 2.1 min, then 95-95% over 0.75 min, flow rate: 0.6 mL / min Detection: UV 254nm.

[0064] Synthesis of Pbf-Sub; N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5 sulfonamide

[0065] [ka]

[0066] Potassium thiocyanate (10.2 g, 105 mmol) was added to 5-chloro-10,11-dihydro-5H-dibenzo-[a,d][7]annulene (22.87 g, 100 mmol) dissolved in 200 mL of DMF, and the mixture was stirred at room temperature for 30 minutes to obtain a reaction solution. Sodium hydride (4.20 g, 105 mmol) was added to 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (26.9 g, 100 mmol) dissolved in 200 mL of DMF at 0°C, and the mixture was stirred at room temperature for 15 minutes. After cooling this suspension to 0°C, the reaction solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, quenched with 1M aqueous hydrochloric acid (110 mL), and then added to 1000 mL of water. The resulting solid was collected by filtration and dried under reduced pressure at 60°C overnight. The resulting solid was suspended in ethyl acetate / heptane (1 / 2, 300 mL), collected by filtration, and dried under reduced pressure to give the title compound (42.5 g, 82 mmol, 82% yield). The structure was confirmed by 1H NMR and LC / MS. Analysis condition A: Retention time = 2.25 min, ESI-MS(+) Observed value m / z = 521.3 (M+H)+ Theoretical value m / z = 520.2 [Example]

[0067] Synthesis of Fmoc-F4G(Pbf, Sub)-OH;(S,Z)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid

[0068] [ka]

[0069] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-aminophenyl)propanoic acid (0.6 g, 1.49 mmol) was suspended in 7.5 mL of THF, and N-methyl-N-trimethylsilylacetamide (MSA; 0.31 mL, 1.94 mmol) was added, followed by stirring at room temperature for 30 minutes. Triethylamine (TEA; 0.17 g, 1.64 mmol), N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (0.78 g, 1.49 mmol) obtained in Example 1, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.286 g, 1.49 mmol) were added and stirred for 60 minutes. The reaction solution was diluted with 15 mL of ethyl acetate and quenched with 1 M aqueous sulfuric acid solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed four times with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (5 mL), heptane (30 mL) was added, and the mixture was stirred for 18 hours. The resulting pale yellow solid was collected by filtration and washed with heptane to give the title compound. Its structure was confirmed by 1H NMR and LC / MS. Analysis condition A: Retention time = 2.24 min, ESI-MS(+) Observed value m / z = 889.5 (M+H)+ Theoretical value m / z = 888.4 [Example]

[0070] The effect of the type of protecting group on the deprotection efficiency was investigated. (1) Deprotection of Pbf and Sub of Fmoc-F4G(Pbf, Sub)-Met; (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)methylpropanoate [ka]

[0071] The title compound was obtained in the same manner as in Example 2, except that N-Fmoc-4-amino-L-phenylalanine methyl; (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-aminophenyl)propanoate methyl was used and MSA treatment was not performed. The obtained compound was added to TFA / TIS / DODT / HO=92.5:2.5:2.5:2.5 and stirred at room temperature for 60 minutes. The deprotection status was confirmed by LC / MS. Fmoc-F4G-Met; (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoate methyl was produced (LC / MS area 79.9%).

[0072] Analysis conditions for Fmoc-F4G-Met; (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoic acid methyl ester: LC / MS conditions were the same as in Example 2 Retention time = 1.35 min, ESI-MS(+) observed m / z = 459.3 (M+H)+ theoretical m / z = 458.2

[0073] (2) Synthesis and Deprotection of Fmoc-F4G(Pbf, tBu)-OH; (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid

[0074] [ka]

[0075] The product was synthesized and purified by a known method to obtain the title compound. The product was confirmed by 1H NMR. The title compound was deprotected in the same manner as in (1). After 60 minutes of deprotection, the formation of Fmoc-F4G-OH;(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoic acid was confirmed by LC / MS (analysis condition A). However, the Fmoc-F4G-OH peak accounted for only 4.61% of the total LC / MS area, and a peak with a mass (observed m / z = 501.6) nearly equivalent to that of Fmoc-F4G(H,tBu)-OH;(S,E)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyl)guanidino)phenyl)propanoic acid, in which tBu was not deprotected, accounted for 76.8% of the LC / MS area, indicating that deprotection was not complete.

[0076] (3) Synthesis and Deprotection of Fmoc-F4G(Pbf,PMB)-Met; (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(4-methoxybenzyl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)methylpropanoate

[0077] [ka]

[0078] The product was synthesized and purified by a known method to obtain the title compound. The product was confirmed by 1H NMR. The title compound obtained was deprotected in the same manner as in (1). After 60 minutes of deprotection, the formation of Fmoc-F4G-Met; (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoate methyl ester was confirmed by LC / MS (analysis condition A). The Fmoc-F4G-Met peak was barely observed, accounting for 1.32% of the total (LC / MS area). The completely undeprotected title compound accounted for 14.3% of the LC / MS area, and PMB was the undeprotected Fmoc- A peak showing a mass (observed value m / z = 579.6) almost equivalent to that of F4G(H,PMB)-Met;(S,E)-methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(4-methoxybenzyl)guanidino)phenyl)propanoate remained at 71.6% area in LC / MS, indicating that deprotection had not been completed.

[0079] (4) Synthesis and Deprotection of Fmoc-F4G(Pbf,Bzh)-Met;(S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-benzhydryl-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)methylpropanoate [ka]

[0080] The title compound was obtained by synthesis and purification using a known method. The product was confirmed by 1H NMR. The obtained title compound was deprotected in the same manner as in (1). After 60 minutes of deprotection, the formation of Fmoc-F4G-Met;(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoate was confirmed by LC / MS (analysis condition A). The Fmoc-F4G-Met peak accounted for 22.3%, while the title compound, which had not been deprotected, accounted for 12.0% in terms of LC / MS area. A peak showing a mass (observed value m / z = 625.4) nearly equivalent to that of Fmoc-F4G(H,Bzh)-Met;(S,E)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-benzhydrylguanidino)phenyl)propanoate, in which Bzh had not been deprotected, accounted for 57.6% in terms of LC / MS area, indicating that deprotection was not complete.

[0081] These results demonstrate that the compound Fmoc-F4G(Pbf, Sub)-Met;(S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)methylpropanoate can be deprotected with significantly higher efficiency than the Fmoc-F4G(Pbf) compound synthesized by known methods using other protecting groups. [Example]

[0082] Synthesis of Fmoc-F3G(Pbf, Sub)-OH; (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid

[0083] [ka]

[0084] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-aminophenyl)propanoic acid (1000 mg, 2.49 mmol) was suspended in THF (15 mL), and MSA (0.516 mL, 3.23 mmol) was added at room temperature and stirred for 1 hour to dissolve. To the reaction mixture was added TEA (0.381 mL, 2.73 mmol), followed by N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (1307 mg, 2.510 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (476 mg, 2.49 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with 0.5N aqueous citric acid and extracted with ethyl acetate. The organic layer was washed twice with water and then dried over sodium sulfate. After filtration, it was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and a nine-fold volume of hexane was added and stirred overnight. The resulting precipitate was collected by filtration and dried to give the title compound (2.1 g, 2.362 mmol, 95% yield) as a pale yellow solid. Its structure was confirmed by 1H NMR and LC / MS.

[0085] Analysis condition B: Retention time = 2.24 min, ESI-MS (+) Observed value m / z = 889.5 (M+H) + Theoretical value m / z = 888.4 [Example]

[0086] Synthesis of Fmoc-Har(Pbf,Sub)-OH;(Z)-N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(N'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl-L-lysine

[0087] [ka]

[0088] N-Fmoc-L-lysine hydrochloride (1.00 g, 2.47 mmol) was suspended in 10 mL of THF, and MSA (0.99 mL, 6.17 mmol) was added. The mixture was stirred at room temperature for 30 minutes. N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (1.29 g, 2.47 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (497 mg, 2.59 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with 10% aqueous citric acid and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and heptane was added. The resulting white solid was collected by filtration and washed with ethyl acetate / hexane (15 / 85) to obtain the title compound (1.73 g, 2.03 mmol, 82% yield). The structure was confirmed by H NMR and LC / MS. Analysis condition B: Retention time = 2.29 min, ESI-MS(+) Observed value m / z = 855.6 (M+H)+ Theoretical value m / z = 854.37 [Example]

[0089] Synthesis of Fmoc-GpG(Pbf,Sub)-OH; (Z)-N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-(3-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)glycine

[0090] [ka]

[0091] N-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N-(3-aminopropyl)glycine hydrochloride (3.91 g, 10.0 mmol) was placed in a 100 mL round-bottom flask equipped with a three-way stopcock fitted with a stirrer and a nitrogen-filled balloon. 95 mL of THF and MSA (3.82 mL, 23.81 mmol) were added to the flask at room temperature and stirred for 30 minutes. To the reaction mixture, N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (4.96 g, 9.52 mmol) obtained in Example 1 and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (1.92 g, 10.00 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched at room temperature with a saturated aqueous citric acid solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was suspended and washed with hexane / ethyl acetate (60 mL / 30 mL) to obtain the title compound (8.28 g, 9.84 mmol, 103% yield). The structure was confirmed by 1H NMR and LC / MS. Analysis condition B: Retention time = 2.23 min, ESI-MS(+) Observed value m / z = 841.5 (M+H)+ Theoretical value m / z = 840.36 [Example]

[0092] Synthesis of Fmoc-A4pG(Pbf,Sub)-OH;(S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(N'-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)piperidin-4-yl)propanoic acid

[0093] [ka]

[0094] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(piperidin-4-yl)propanoic acid hydrochloride (2.16 g, 5.00 mmol) was suspended in 25 mL of THF, and MSA (2.81 mL, 17.50 mmol) was added, followed by stirring at 0° C. for 15 minutes. N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (2.47 g, 4.75 mmol) obtained in Example 1 and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (959 mg, 5.00 mmol) were added to the reaction mixture, followed by stirring at room temperature for 2 hours. After dilution with ethyl acetate, the reaction was quenched with 1N aqueous hydrochloric acid and extracted twice with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfar HC Duo 50 g; mobile phase: hexane, 30% to 100% ethyl acetate gradient) to give the title compound (3.76 g, 4.00 mmol, 80% yield) as a white solid. The structure was confirmed by 1H NMR and LC / MS. Analysis condition B: Retention time = 2.34 min, ESI-MS(+) Observed value m / z = 881.9 (M+H)+ Theoretical value m / z = 880.39 [Example]

[0095] Synthesis of Fmoc-F4G(Pbf, Sub)-OH;(S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid

[0096] [ka]

[0097] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-aminophenyl)propanoic acid (15.0 g, 37.3 mmol) was suspended in 199 mL of THF, and MSA (7.8 mL, 48.5 mmol) was added dropwise in a water bath (internal temperature: 20.1 °C to 21.4 °C), followed by stirring in the water bath for 30 minutes. To the reaction mixture, N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (19.4 g, 37.3 mmol) obtained in Example 1 was added in a water bath. Subsequently, a suspension prepared by adding 50 mL of dichloromethane to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added dropwise in a water bath over 15 minutes (internal temperature: 20.3°C to 22.4°C). The reaction mixture was stirred in a water bath for 30 minutes, then quenched with 10% aqueous citric acid solution and extracted twice with ethyl acetate. The resulting organic layer was washed twice with water and once with 10% brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 300 mL of hexane was added to the resulting residue, and the mixture was stirred at 50°C for 1 hour, then gradually cooled to room temperature with stirring. The resulting pale yellow solid was collected by filtration and washed with hexane to obtain the title compound (35.1 g, 36.7 mmol, 98% yield). The structure was confirmed by H NMR and LC / MS. Analysis condition B: Retention time = 2.16 min, ESI-MS(+) Observed value m / z = 889.5 (M+H)+ Theoretical value m / z = 888.4 [Example]

[0098] Synthesis of Fmoc-F3G(Pbf, Sub)-OH;(S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)phenyl)propanoic acid

[0099] [ka]

[0100] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-aminophenyl)propanoic acid (15.0 g, 37.3 mmol) was suspended in 199 mL of THF, and MSA (7.77 mL, 48.5 mmol) was added dropwise thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added N-((10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)carbamothioyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (19.4 g, 37.3 mmol) obtained in Example 1, followed by the dropwise addition over 15 minutes of a suspension prepared by adding 49.7 mL of dichloromethane to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.15 g, 37.3 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then quenched with 10% aqueous citric acid and extracted with ethyl acetate. The resulting organic layer was washed twice with water and once with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 200 mL of hexane was added to the resulting residue, and the mixture was stirred at 50°C for 1 hour and then gradually cooled to room temperature while stirring. The resulting light brown solid was collected by filtration and washed with hexane to obtain the title compound (35.0 g, 39.4 mmol, 106% yield). The structure was confirmed by 1H NMR and LC / MS. Analysis condition B: Retention time = 2.18 min, ESI-MS(+) Observed value m / z = 889.5 (M+H)+ Theoretical value m / z = 888.4 [Example]

[0101] The following compounds were synthesized in the same manner as in Examples 5 to 9. The synthesized compounds are shown in Table 1. The structures of the synthesized compounds were confirmed by 1HNMR and LC / MS (analysis condition B).

[0102] [Table 1] TIFF2026027427000024.tif145166 [Industrial Applicability]

[0103] The present invention relates to guanidine derivatives and the like, and can be used in the fields of chemistry, biochemistry, medicine, and polymer chemistry.

Claims

[Claim 1] A compound represented by the following formula (I), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof: 【Chemistry 1】 (In formula (I), -R １ - is C which may have one or more substituents selected from group A １ -C １０ an alkylene group, C optionally having one or more substituents selected from Group A; ６－１０ an arylene group, or —R １１ -R １２ represents a group represented by -, Group A includes halogen atoms, amino groups, nitro groups, C １－５ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio groups, and C １－３ is a halogenoalkyl group, -R １１ - is C which may have one or more substituents selected from group A ６－１０ represents an arylene group, -R １２ The group represented by - is C which may have one or more substituents selected from group A. １ -C ４ represents an alkylene group, R ２ and R ４ may be the same or different and represent a protecting group of an amino acid or a hydrogen atom, R ３ indicates a hydrogen atom, R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, C １－５ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, or C １－３ indicates a halogenoalkyl group or R ５ is -N-R １ -, together with -, may contain an asymmetric carbon atom at the α-position ５－７ forming a heterocyclic amine, R ６ and R ７ may be the same or different, and are the protecting groups of amino acids, C １－５ represents an alkyl group or a hydrogen atom, R ８ represents the protecting group of an amino acid, a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, C １－５ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ halogenoalkyl group or -O-R １３ represents a group represented by -, R １３ The group represented by - is a protecting group for an oxygen atom, C １－５ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, or C １－３ represents a halogenoalkyl group, -R １ - represents a propylene group, and R ２ ~ and R ７ represents a hydrogen atom, and R ８ But those that show a hydroxyl group (arginine), and -R １ -ga, -R １１ -R １２ represents a group represented by -, -R １１ - represents a 1,4-phenylene group, and -R １２ - represents a methylene group, and R ２ , R ４ , R ５ , R ６ , and R ７ Both represent hydrogen atoms, and R ８ (Excluding those where indicates a hydroxyl group.)

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