Derivatives of borono-phenylalanine

Abstract

The present invention provides a novel compound which can have the property of being specifically taken into cancer cells. Produced in the present invention is a novel 4-borono-phenylalanine derivative, a borono-phenylalanine derivative having a heterocyclic skeleton, a borono-phenylalanine derivative having a condensed ring structure, or a pharmaceutically acceptable salt of any of these. In an evaluation of LAT1- and LAT2-specific intake, these compounds are LAT1-specifically taken in, and thus have the property of being easily specifically taken into cancer cells and can be used favorably in neutron capture therapy and the like.　Representatively, provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.　

Description

Technical Field

[0001] The present invention relates to derivatives of boronophenylalanine.

Background Art

[0002] As a method for treating cancer, there is boron neutron capture therapy (BNCT). Boron neutron capture therapy is a treatment method in which a boron compound containing boron-10 isotope ( 10 10B) is incorporated into cancer cells, and low-energy neutron rays (for example, thermal neutrons) are irradiated to locally destroy cancer cells by a nuclear reaction occurring in the cells. In this treatment method, 10 selectively accumulating a boron compound containing 10B in the cells of cancer tissue is important for enhancing the treatment effect, so it is necessary to develop a boron compound that is selectively incorporated into cancer cells.

[0003] Derivatives of 4-boronophenylalanine in which a boron atom or a boron atomic group is introduced into the basic skeleton have been synthesized as drugs used in BNCT. Drugs actually used in clinical practice include derivatives of 4-boronophenylalanine (L-BPA) and mercaptoundecahydrododecaborate (BSH). 4-Boronophenylalanine is incorporated into LAT1 (L-type Amino acid Transporter 1), which is a kind of amino acid transporter, as a mimic of phenylalanine. Since the expression of LAT1 is enhanced in cancer cells, L-BPA is likely to accumulate, and its properties are utilized for the treatment of cancer (for example, see Patent Document 1).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] There is a need for further development of new compounds having the property of being specifically taken up by cancer cells.

[0006] An object of the present invention is to provide a derivative of borono-phenylalanine.

Means for Solving the Problems

[0007] As a result of intensive studies to solve the above problems, the present inventors have found a new derivative of borono-phenylalanine and have completed the present invention.

[0008] That is, the present invention provides the following compound. [1] A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[10] a compound represented by the following formula (IV) or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

Advantages of the Invention

[0009] The novel compounds of the present invention are excellent in uptake into LAT1 and can be advantageously used in boron neutron capture therapy.

Modes for Carrying Out the Invention

[0010] In this specification, when representing a compound having an asymmetric carbon, unless otherwise specified, the compound may be either a racemate, an R-form, or an S-form.

[0011] [Derivatives of 4-boronophenylalanine] In one aspect of the present invention, the derivative of borono-phenylalanine is a derivative of 4-boronophenylalanine and is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

Chemical formula

[0012] In this specification, halogen may be any of F, Cl, Br, I, but is particularly preferably F, Cl, Br.

[0013] As used herein, C1-C6 alkyl refers to a straight-chain or branched C1-C6 saturated hydrocarbon group. This definition also includes cases where it is used in alkoxy, alkoxyalkyl, and haloalkyl. Examples of C1-6 alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. Preferably, it is a straight-chain or branched C1-C4 alkyl group, and non-limiting examples include a methyl group, an ethyl group, an isopropyl group, a butyl group, and the like.

[0014] As used herein, C1-C6 haloalkyl refers to a C1-C6 alkyl group having one or more halogen substituents. The haloalkyl group is preferably represented by C2X5, CH2X, CHX2, or CX3 (where X represents Cl, F, Br, or I), and non-limiting examples include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0015] As used herein, C1-C6 alkoxy refers to a group having a straight-chain or branched C1-C6 alkyl group and an oxygen molecule. C1-C6 alkoxy preferably has a straight-chain or branched C1-C4 alkyl, and non-limiting examples include methoxy, ethoxy, isopropoxy, butoxy, and the like.

[0016] As used herein, C1-6 alkoxy C1-6 alkyl includes, without limitation, methoxyethyl, ethoxyethyl, and the like.

[0017] As used herein, C1-C6 alkylaminocarbonyl (CONR 8 R 9 (R 8 、R 9 each independently represents H or C1-6 alkyl)) includes, without limitation, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, i-propylaminocarbonyl, and the like.

[0018] In this specification, examples of C1-C6 alkylcarbonyl include, but are not limited to, methylcarbonyl, ethylcarbonyl, and the like.

[0019] In this specification, examples of C1-C6 alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like.

[0020] In this specification, COOR 10 (R 10 is H or C1-6 alkyl, amino, alkylamino (NR 11 R 12 (R 11 R 12 each independently represents H or C1-6 alkyl)) include, but are not limited to, methyloxycarbonyl, aminooxycarbonyl, and the like.

[0021] In this specification, examples of haloalkylsulfanyl, haloalkylsulfinyl, and haloalkylsulfonyl include, but are not limited to, trifluoromethylsulfanyl, trifluoromethylsulfinyl group, or trifluoromethylsulfonyl, and the like.

[0022] In this specification, examples of C1-C6 alkylthio include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, and the like.

[0023] In this specification, examples of C1-C6 alkylsulfinyl include, but are not limited to, methylsulfinyl, ethylsulfinyl, and the like.

[0024] In this specification, examples of C1-C6 alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.

[0025] In the derivative of the present invention, R 7 represents any one of a boronic acid (—B(OH)2), a boronic acid ester, or a boronic acid amide group. Examples of the boronic acid ester or boronic acid amide group in this definition include, at the position of R 7 , a group having a chain structure such as —B(NR 41 )2 or —B(OR 41 )2, or a group having a cyclic structure together with atom B. Here, R 41 represents a linear or branched C1-C10 alkyl group. Here, when referring to a “linear or branched C1-C10 alkyl group,” it may be any alkyl group having 1 to 10 carbon atoms. Preferably, it is a linear or branched C1-C8 alkyl group, more preferably a linear or branched C1-C6 alkyl group. Examples of these groups include, but are not limited to, a methyl group, an ethyl group, an isopropyl group, a butyl group, and the like. Further, in the cyclic structure referred to here, not necessarily only an O atom intervenes, and an N atom may also intervene. Examples include, but are not limited to, esters or ester analogs composed of any one selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,6-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol and atom B. These include, but are not limited to, boronic acid pinacol ester, boronic acid MIDA ester, boronic acid 1,3-propanediol ester, boronic acid neopentyl glycol ester, boronic acid catechol ester, boronic acid pinandiol ester, boronic acid biscyclohexyldiol ester, boronic acid MPM ester, trifluoroborate salt, cyclic triol borate salt, a cyclic body of diaminonaphthalene amide and boron, and the like.

[0026] Among these, R7 Particularly, boric acid or a boronic acid ester having a chain or cyclic structure is preferable, and boric acid is most preferable.

[0027] Here, although the boron atom is not limited, the proportion of boron-10 is preferably 75% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and particularly preferably 95% by mass or more.

[0028] In natural boron (boron), boron-10 and boron-11 exist as isotopes, with boron-10 at 20% and boron-11 at 80%. Therefore, prior to the production of the derivative of 4-boronophenylalanine of the present invention, it is also preferable to concentrate boron having a mass number of 10 (boron-10). In the present invention, for example, commercially available products may be used as the boron atom source. As commercially available products, for example, 10B-enriched boric acid (manufactured by Stella Chemifa Corporation) can be used.

[0029] Here, as a method for measuring boron-10, it can be carried out by multi-type ICP emission spectrometry (ICP-OES) using Agilent 710 (manufactured by Agilent). The ICP-OES used for measurement is adjusted according to JISK0116.

[0030] In the said compound, although not limited, said R 1 , R 2 , R 3 , and R 4 Any one or two or more of them are independently particularly preferably Cl, F, C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, or CF3, C1-3 alkylthio.

[0031] In the said compound, although not limited, said R 5 particularly preferably represents H. However, at this time, all of R 1 , R 2 , R 3 , and R 4 shall not all be H.

[0032] Among the said compounds, although not limited, said R 6 particularly preferably represents methyl or ethyl.

[0033] Among the said compounds, although not limited, R 7 particularly preferably represents boric acid (B(OH)₂) or a pinacol ester of boric acid.

[0034] In one aspect of the present invention, among the said compounds, said R 1 , R 2 , R 3 , and R 4 any one or two or more of them are independently Cl or F, said R 5 represents H, said R 6 represents methyl, and said R 7 preferably represents boric acid (B(OH)₂).

[0035] In another aspect of the present invention, among the said compounds, said R 1 , R 2 , R 3 , and R 4 any one or two or more of them are independently CH₂F, CHF₂, or CF₃, said R 5 represents H, said R 6 represents methyl, and said R 7 preferably represents boric acid (B(OH)₂).

[0036] In yet another aspect of the present invention, among the said compounds, said R 1 , R 2 , R 3 , and R 4 any one or two or more of them are independently methyl or ethyl, said R 5 represents H, said R 6 represents methyl, and said R 7 preferably represents boric acid (B(OH)₂).

[0037] In yet another aspect of the present invention, among the said compounds, said R 1 , R 2 , R3 and R 4 any one or two or more of them are independently methoxy or ethoxy, and said R 5 represents H, said R 6 represents methyl, and said R 7 preferably represents boronic acid (B(OH)₂).

[0038] In yet another aspect of the present invention, in said compound, said R 1 , R 2 , R 3 , and R 4 any one or two or more of them are independently methylthio or ethylthio, and said R 5 represents H, said R 6 represents methyl, and said R 7 preferably represents boronic acid (B(OH)₂).

[0039] In yet another aspect of the present invention, in said compound, said R 1 , R 2 , R 3 , and R 4 all represent H, said R 5 represents H, said R 6 represents ethyl, and said R 7 preferably represents boronic acid (B(OH)₂).

[0040] The "pharmaceutically acceptable salts" in the present invention include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Preferred examples of salts with inorganic bases include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts, ammonium salts, etc. Preferred examples of salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Preferred examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferred examples of salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferred examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, etc., and preferred examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc.

[0041] [Derivatives of Borono-Phenylalanine Having a Heterocyclic Ring] Another aspect of the present invention relates to a compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof. [Chemical Formula] Here, in formula (III), R c is substituted by one group with any of boronic acid (—B(OH)2), boronic acid ester or boronic acid amide, and further optionally halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, benzyloxy, C1-6 alkoxy C1-6 alkyl, nitro, C1-6 haloalkyl, aminocarbonyl, C1-C6 alkylaminocarbonyl (CONR 8 R 9 (R 8 、R 9represents, independently, H or C1-6 alkyl)), C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR 10 (R 10 represents H or C1-6 alkyl, amino, alkylamino (NR 11 R 12 (R 11 R 12 each independently represents H or C1-6 alkyl)), haloalkylsulfanyl, haloalkylsulfinyl, haloalkylsulfonyl, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, sulfo, or sulfamoyl, and may be substituted at 1 to 3 positions with a heterocyclic ring, the heterocyclic ring is one selected from the group consisting of pyridine, pyrimidine, thiophene, triazine, pyrrole, pyrazine, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, and thiazole, R 5 represents H, hydroxy, C1-6 alkyl, or halogen; R 6 represents C1-6 alkyl. Here, conditions including the type of substituents, preferred examples, types of salts, etc. shall conform to the description in the section of [Derivatives of 4-borono-phenylalanine].

[0042] [Derivatives of Borono-phenylalanine Having a Condensed Ring] Another aspect of the present invention relates to a compound represented by the following formula (IV) or a pharmaceutically acceptable salt thereof. [Chemical formula] Here, in formula (IV), R 20 independently represents H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, benzyloxy, C1-6 alkoxy C1-6 alkyl, nitro, C1-6 haloalkyl, aminocarbonyl, C1-C6 alkylaminocarbonyl (CONR 8 R 9 (R 8 and R9 each independently represents H or C1-6 alkyl)), C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR 10 (R 10 represents H or C1-6 alkyl, amino, alkylamino (NR 11 R 12 (R 11 R 12 each independently represents H or C1-6 alkyl)), haloalkylsulfanyl, haloalkylsulfinyl, haloalkylsulfonyl, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, sulfo, or sulfamoyl; R 7 represents either boronic acid (-B(OH)2), boronic ester or boronic amide; R 40 and R 60 together represent a ring structure in the form of being condensed to a benzene ring, where the ring structure represents unsubstituted C5-7 cycloalkyl or unsubstituted C6-7 cycloalkenyl; s represents an integer of any one of 1 to 3 (provided that

Chemical formula

[0043] Here, among such compounds, particularly preferably, it can be a compound represented by the following chemical formula.

Chemical formula

Chemical formula

[0044] In this specification, the halogen may be any of F, Cl, Br, I, but particularly preferably F, Cl, Br.

[0045] In this specification, C1-C6 alkyl refers to a linear or branched C1-C6 saturated hydrocarbon group. This definition also includes cases where it is used in alkoxy, alkoxyalkyl, and haloalkyl. Examples of the C1-6 alkyl group include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc. Preferably, it is a linear or branched C1-C4 alkyl group, and non-limiting examples include a methyl group, an ethyl group, an isopropyl group, a butyl group, etc.

[0046] As used herein, C1-C6 haloalkyl refers to a C1-C6 alkyl group having one or more halogen substituents. The haloalkyl group is preferably represented by C2X5, CH2X, CHX2, or CX3 (where X represents Cl, F, Br, or I), and includes, but is not limited to, for example, CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc.

[0047] As used herein, C1-C6 alkoxy represents a group having a linear or branched C1-C6 alkyl group and an oxygen molecule. C1-C6 alkoxy preferably has a linear or branched C1-C4 alkyl, and includes, but is not limited to, for example, methoxy, ethoxy, isopropoxy, butoxy, etc.

[0048] As used herein, C1-6 alkoxy C1-6 alkyl includes, but is not limited to, methoxyethyl, ethoxyethyl, etc.

[0049] As used herein, C1-C6 alkylaminocarbonyl (CONR 8 R 9 (R 8 、R 9 each independently represents H or C1-6 alkyl)) includes, but is not limited to, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, i-propylaminocarbonyl, etc.

[0050] As used herein, C1-C6 alkylcarbonyl includes, but is not limited to, methylcarbonyl, ethylcarbonyl, etc.

[0051] As used herein, C1-C6 alkoxycarbonyl includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.

[0052] In this specification, COOR 10 (R 10 is, but is not limited to, H or C1-6 alkyl, amino, alkylamino (NR 11 R 12 (R 11 R 12 each independently represents H or C1-6 alkyl)), include, but are not limited to, methyloxycarbonyl, aminooxycarbonyl, etc.).

[0053] In this specification, haloalkylsulfanyl, haloalkylsulfinyl, and haloalkylsulfonyl include, but are not limited to, trifluoromethylsulfanyl, trifluoromethylsulfinyl group, or trifluoromethylsulfonyl, etc.).

[0054] In this specification, C1-C6 alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc.).

[0055] In this specification, C1-C6 alkylsulfinyl includes, but is not limited to, methylsulfinyl, ethylsulfinyl, etc.).

[0056] In this specification, C1-C6 alkylsulfonyl includes, but is not limited to, methylsulfonyl, ethylsulfonyl, etc.).

[0057] In this specification, unsubstituted C5-7 cycloalkyl or examples include cyclopentyl, cyclohexyl, cycloheptyl, etc.).

[0058] In this specification, unsubstituted C6-7 cycloalkenyl examples include cyclohexenyl, cycloheptenyl, etc.).

[0059] In the derivative of the present invention, R 7represents any of a boronic acid (—B(OH)2), boronic ester, or boronic amide group. Examples of the boronic ester or boronic amide group in this definition include, at the position of R 7 , a group having a chain structure such as —B(NR 41 )2 or —B(OR 41 )2, or a group having a cyclic structure together with atom B. Here, R 41 represents a linear or branched C1-C10 alkyl group. Here, when referring to a “linear or branched C1-C10 alkyl group,” any alkyl group having 1 to 10 carbon atoms may be used. Preferably, it is a linear or branched C1-C8 alkyl group, more preferably a linear or branched C1-C6 alkyl group. Examples of these groups include, but are not limited to, a methyl group, an ethyl group, an isopropyl group, a butyl group, etc. Further, in the cyclic structure referred to here, not necessarily only an O atom intervenes, and an N atom may also intervene. Examples include, but are not limited to, esters or ester analogs composed of any one selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,6-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol and atom B. Examples of these include, but are not limited to, pinacol boronic ester, MIDA boronic ester, 1,3-propanediol boronic ester, neopentyl glycol boronic ester, catechol boronic ester, pinandiol boronic ester, bicyclohexanediol boronic ester, MPM boronic ester, trifluoroborate salt, cyclic triol borate salt, a cyclic body of diaminonaphthalene amide and boron, etc.

[0060] Among these, R 7 is particularly preferably a boronic acid or a boronic ester having a chain or cyclic structure, and most preferably a boronic acid.

[0061] Here, the boron atom, although not limited, preferably has a boron-10 ratio of 75% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and particularly preferably 95% by mass or more.

[0062] Natural boron (boron) contains boron-10 and boron-11 as isotopes, with boron-10 present at a ratio of 20% and boron-11 at 80%. Therefore, prior to the production of the derivative of 4-boronophenylalanine of the present invention, it is also preferable to concentrate boron having a mass number of 10 (boron-10). In the present invention, for example, commercially available products may be used as the boron atom source. As a commercially available product, for example, 10B enriched boric acid (manufactured by Stella Chemifa Corporation) can be used.

[0063] Here, as a method for measuring boron-10, it can be carried out by multi-type ICP emission spectrometry (ICP-OES) using Agilent 710 (manufactured by Agilent). The ICP-OES used for the measurement is adjusted according to JIS K0116.

[0064] In the said compound, although not limited, the said R 20 Any 1 to 3 of them are independently particularly preferably H, Cl, F, C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, or CF3, C1-3 alkylthio.

[0065] In the said compound, although not limited, R 7 is particularly preferably boric acid (B(OH)2) or a pinacol ester of boric acid.

[0066] In one aspect of the present invention, in the said compound, any 1 to 3 of the said R 20 are independently Cl or F, x is 1 to 3, and the said R 7 preferably represents boric acid (B(OH)2).

[0067] In another aspect of the present invention, in the said compound, the said R 20Any one to three of them are independently CH2F, CHF2, or CF3, x is from 1 to 2, and R 7 preferably represents boronic acid (B(OH)2).

[0068] In yet another aspect of the present invention, in the compound, any one to three of the R 20 are independently methyl or ethyl, x is from 1 to 2, and R 7 preferably represents boronic acid (B(OH)2).

[0069] In yet another aspect of the present invention, in the compound, any one or two or more of R 1 R 2 R 3 and R 4 are independently methoxy or ethoxy, R 5 represents H, R 6 represents methyl, and R 7 preferably represents boronic acid (B(OH)2).

[0070] In yet another aspect of the present invention, in the compound, any one to three of the R 20 are independently methylthio or ethylthio, x is from 1 to 3, and R 7 preferably represents boronic acid (B(OH)2).

[0071] The "pharmaceutically acceptable salts" in the present invention include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of salts with inorganic bases include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts, ammonium salts, and the like. Preferable examples of salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Preferable examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferable examples of salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and the like, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like.

[0072] [Particularly Preferred Compounds of the Present Invention] Among the derivatives of borono-phenylalanine of the present invention, particularly preferred is one selected from the group consisting of the following compounds or a salt thereof. (S)-2-Amino-3-(4-borono-2-fluorophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-methylphenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-methylphenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-(trifluoromethyl)phenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-(trifluoromethyl)phenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-methoxyphenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-methoxyphenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-chlorophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-chlorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2,6-difluorophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2,6-difluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-5-chloro-2-fluorophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-5-chloro-2-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2,3-difluorophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2,3-difluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-3-fluorophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-3-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-3-methylphenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-3-methylphenyl)-2-methylpropanoic acid; (S)-2-Amino-2-(4-boronobenzyl)butanoic acid; (R)-2-Amino-2-(4-boronobenzyl)butanoic acid; (S)-2-Amino-3-(4-borono-2-cyanophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-chloro-5-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-chloro-5-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-nitrophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-3-nitrophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(3-amino-4-boronophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(2-amino-4-boronophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-(methylthio)phenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-(difluoromethyl)phenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-(difluoromethyl)phenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-3-chlorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(5-boronopyridin-2-yl)propanoic acid; (S)-2-Amino-3-(5-borono-3-fluoropyridin-2-yl)propanoic acid; (S)-2-Amino-3-(5-borono-3-methylpyridin-2-yl)propanoic acid; (S)-2-Amino-3-(5-borono-3-chloropyridin-2-yl)propanoic acid; or (S)-2-Amino-3-(5-borono-4-methylpyridin-2-yl)propanoic acid.

[0073] [Process for producing derivatives of 4-boronophenylalanine] In the present invention, the process for producing novel derivatives of 4-boronophenylalanine is not limited, and ordinary amino acid synthesis methods are used. Although not limited, particularly preferred methods can be, for example, the following methods. First, a protected amino acid is reacted with an organic halide represented by the following general formula (II) in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst.

[0074]

Chemical formula

[0075] Here, as the organic halide represented by formula (II), a compound prepared by a known method can be used as it is, or a commercially available product can also be used.

[0076] Among these, for example, 4-iodobenzyl bromide and 4-bromo-2-fluorobenzyl bromide are available from Tokyo Chemical Industry Co., Ltd. and Combi-Blocks. 4-Bromo-3-fluorobenzyl bromide, 1-bromo-4-(bromomethyl)-2,3-difluorobenzene, 4-bromo-1-(bromomethyl)-2-methoxybenzene, 4-bromo-1-(bromomethyl)-2-nitrobenzene, 4-bromo-1-(bromomethyl)-2-chlorobenzene, 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene, 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene, 1-bromo-4-(bromomethyl)-2-methylbenzene are available from Combi-Blocks. 4-Bromo-1-(bromomethyl)-2-methylbenzene and 4-bromo-2,6-difluorobenzyl bromide are available from Fluorochem Ltd.

[0077] 5-Bromo-2-(bromomethyl)benzonitrile can be prepared, for example, from 5-bromo-2-methylbenzonitrile available from Tokyo Chemical Industry Co., Ltd. 1-Bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene can be prepared from 4-bromo-5-chloro-2-fluorotoluene available from Combi-Blocks. 4-Bromo-1-(bromomethyl)-2-(methylthio)benzene can be prepared from 5-bromo-2-methylthioanisole available from Combi-Blocks. These compounds can be prepared, for example, by reacting N-bromosuccinimide with commercially available compounds in the presence of 2,2'-azobis(isobutyronitrile).

[0078] 4-(Bromomethyl)-1-iodo-2-nitrobenzene can be prepared, for example, by brominating (4-iodo-3-nitro-phenyl)-methanol available from Combi-Blocks with hydrobromic acid.

[0079] Other benzyl bromides are available from commercial sources. Those that are not available can be prepared, for example, by reacting N-bromosuccinimide with toluene having the corresponding substituent in the presence of 2,2'-azobis(isobutyronitrile), or by reducing benzaldehyde or methyl benzoate having the corresponding substituent with sodium borohydride or lithium aluminum hydride to obtain benzyl alcohol and then brominating it with hydrobromic acid or phosphorus tribromide.

[0080] The reaction between the organic halide represented by formula (II) and the protected amino acid can proceed in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst. Examples of the protected amino acid include p-chlorobenzaldehyde imine or benzophenone imine. Preferably, it can be p-chlorobenzaldehyde imine having the following structure. [Chemical formula]

[0081] Here, the organic solvent to be used is not limited, but preferably includes toluene, benzene, xylene, mesitylene, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, methyl t-butyl ether, and the like.

[0082] The basic aqueous solution is preferably an aqueous solution of calcium hydroxide, cesium hydroxide, potassium hydroxide, or the like.

[0083] The correlation transfer catalyst can be, for example, the Maruoka reagent. The Maruoka reagent includes, but is not limited to, preferably (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, etc. can be used.

[0084] The reaction temperature at this time is preferably between -20°C and 10°C, and the reaction time can be about 1 hour to 60 hours.

[0085] After the reaction is completed, it can be extracted with an organic solvent such as toluene and appropriately subjected to washing, drying, and filtration processes.

[0086] Next, a solvent is added to such a reaction product and reacted with an acid. Here, it is preferable to use an ether-based solvent as the solvent. Here, examples of the ether-based solvent include, but are not limited to, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, glyme, diglyme, etc. In the present invention, tetrahydrofuran is particularly preferably used.

[0087] Examples of the acid include organic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, methanesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

[0088] The reaction is carried out at a temperature in the range of 0°C to 50°C.

[0089] The reaction time is about 1 to 10 hours, more preferably 2 to 8 hours, and even more preferably 3 to 6 hours.

[0090] The amino group of the obtained compound is protected by a conventional method. The protecting group is not limited, but for example, carbamate protecting groups, amide protecting groups, and alkyl protecting groups are preferably used. Examples of such carbamate protecting groups include tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl group (Fmoc), 2,2,2-trichloroethoxycarbonyl group (Troc), etc. Examples of amide protecting groups include acetyl group, benzoyl group, etc. Examples of alkyl protecting groups include benzyl group, etc.

[0091] Next, the obtained compound is reacted with a boron compound in a solvent in the presence of a palladium catalyst, an organic phosphorus compound, and a base.

[0092] Here, the palladium catalyst is not limited, and examples thereof include palladium(II) acetate, palladium(II) chloride, and tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), etc.

[0093] The organic phosphorus compound is not limited, and examples thereof include triphenylphosphine, tricyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, etc.

[0094] Examples of the base include, but are not limited to, potassium acetate, sodium acetate, sodium carbonate, cesium carbonate, potassium carbonate, and sodium hydrogen carbonate.

[0095] Examples of the boron compound include a borate ester or a boric acid amide, and preferably, a compound represented by B(OR)3, B(NR)3, B(OR)2(NR), (RO)2B-B(OR)2, or B(OR)(NR)2 (R is a linear or branched C1-C10 alkyl group, a phenyl group, or a benzyl group). Further, among these, a compound represented by (RO)2B-B(OR)2 is particularly preferably used. Here, when referring to the "linear or branched C1-C10 alkyl group", any alkyl group having 1 to 10 carbon atoms may be used, but preferably, a linear or branched C1-C8 alkyl group, more preferably, a linear or branched C1-C6 alkyl group. Examples of these groups include, but are not limited to, a methyl group, an ethyl group, an isopropyl group, and a butyl group. Representative examples of the boron compound include, but are not limited to, bis(pinacolato)diboron.

[0096] Examples of the solvent include, but are not limited to, ether solvents such as 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; hydrocarbon solvents such as toluene; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is dimethyl sulfoxide. The reaction temperature is, for example, from 20°C to 160°C, preferably from 60°C to 120°C.

[0097] Next, the obtained compound can be deprotected sequentially to produce the target compound. The deprotection is carried out according to a conventional method, and can be carried out, for example, by hydrolysis, catalytic hydrogenation, decarboxylation, or oxidation.

[0098] In each step of the production method, purification is carried out according to a conventional method and can be appropriately modified.

[0099] Particularly when the compound is a racemate, it can be used as it is, or for example, in order to obtain a preferable compound for use in boron neutron capture therapy, the optical purity of the R-form or S-form can also be enhanced.

[0100] Optical resolution may appropriately use known methods. For example, in addition to the method of optical resolution (using, for example, α-chymotrypsin) through a hydrolysis step and an esterification step, a simplified method including a simplified step of using acylase through a hydrolysis step can also be adopted.

[0101] [Production method of derivative of borono-phenylalanine having a condensed ring] In the present invention, the production method of the derivative of borono-phenylalanine having a novel condensed ring is not limited, and ordinary amino acid synthesis methods are used. The production method conforms to the production method of the above-mentioned derivative of 4-borono-phenylalanine. First, for example, a protected amino acid is reacted with an organic halide represented by the following general formula (V) in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst.

[0102] [Chemical formula]

[0103] In formula (V), x can be any integer from 1 to 3. X 3 represents a halogen. Also, the amino group or the hydroxyl group may be appropriately protected. These are available from commercial products. For example, 2-amino-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid hydrochloride is available from Enamine.

[0104] Those that are not available from other cyclic amino acids can be prepared by the Strecker reaction from indene or tetranone having the corresponding substituents. For example, for the corresponding indene or tetranone, potassium cyanide and ammonium carbonate are used to form hydantoin, and then it can be prepared by hydrolysis with sodium hydroxide followed by decarboxylation with hydrochloric acid.

[0105] [LAT1 (L-type Amino acid Transporter 1) Selective Agent] The derivative of 4-boronophenylalanine of the present invention can be used as an LAT1 selective agent in the form of the above compound or a pharmaceutically acceptable salt thereof as it is, or in a formulation known to those skilled in the art by mixing with a pharmaceutically acceptable carrier, or in a form such as encapsulation in micro / nanoparticles. Here, an LAT1 selective agent means that it is easily taken up by cells expressing LAT1 and hardly taken up by normal cells expressing LAT2. LAT1 is highly expressed in cancer cells, and the more selective a compound is for LAT1 over LAT2, which is also expressed on the surface of normal cells, the higher the effect of boron neutron capture therapy and the more damage to normal cells can be minimized. The derivative of 4-boronophenylalanine of the present invention preferably has a ratio of uptake into cells expressing LAT1 / uptake into cells expressing LAT2 of 2-fold or more, more preferably 5-fold or more, and even more preferably 10-fold or more.

[0106] [Agent for BNCT (Boron Neutron Capture Therapy)] The derivative of boronophenylalanine of the present invention can be advantageously used for BNCT in the form of the above compound or a pharmaceutically acceptable salt thereof as it is, or in a formulation known to those skilled in the art by mixing with a pharmaceutically acceptable carrier, or in a form such as encapsulation in micro / nanoparticles.

[0107] Treatment using the derivative preparation of borono-phenylalanine of the present invention is carried out by administering, via any suitable route of administration, in such a way that the derivative of borono-phenylalanine accumulates in the target tumor. The derivative of borono-phenylalanine preferably accumulates in the tumor before radiation exposure, and the tumor:blood ratio before radiation exposure is at least 1.5 or more:1, preferably 2 or more:1. The derivative of borono-phenylalanine can be administered once or continuously. In some cases, it can also be administered separately. After the compound has desirably accumulated in the tumor, the site is irradiated with an effective amount of low-energy neutron rays (e.g., epithermal neutron rays). The site can be irradiated through the skin, or the site can be completely or partially exposed before irradiation. Administration of the derivative of borono-phenylalanine and subsequent radiation exposure can be repeated as necessary. If desired, in order to surgically reduce the tumor to a possible extent, treatment using the derivative of borono-phenylalanine can be performed, and then a surgical procedure can be carried out. Alternatively, after a surgical procedure, the remaining tumor can be destroyed using the derivative of borono-phenylalanine of the present invention. As another aspect, an appropriate amount of the derivative of borono-phenylalanine is administered to the patient and irradiated with an effective amount of 252 Californium, a naturally occurring neutron emitter. This is preferably inserted into the tumor and removed at an appropriate time.

[0108] Here, the type of tumor is not particularly limited, but brain tumors including glioblastoma and malignant glioma, etc., other head and neck cancers, malignant melanoma, breast cancer, or prostate cancer, etc. can be particularly suitable targets. In addition, epithelial cell cancers such as lung cancer, uterine cancer, kidney cancer, liver cancer, etc., various sarcomas, etc. can also be targets.

[0109] Administration of the derivative of borono-phenylalanine of the present invention can be carried out orally and parenterally. In the case of parenteral administration, it can be carried out intraarterially (e.g., via the carotid artery), intramuscularly, subcutaneously, intramedullary, intrathecal, intraventricularly, intravenously, intraperitoneally, or intranasally.

[0110] The preparation can be in any form such as powder, granule, fine granule, dry syrup, tablet, capsule, injection, liquid preparation, etc. Further, depending on the dosage form, it can be mixed with appropriate additives and / or pharmaceutically acceptable carriers by pharmaceutically known methods and administered to patients alone or in combination with other drugs. Additives include, for example, excipients; disintegrants; binders; lubricants; diluents; buffers such as phosphoric acid, citric acid, succinic acid, acetic acid, and other organic acids or their salts; tonicity agents; preservatives; wetting agents; emulsifiers; dispersants; stabilizers; solubilizing agents; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides (e.g., polyarginine or tripeptide); proteins (e.g., serum albumin, gelatin, or immunoglobulin); hydrophilic polymers (e.g., polyvinylpyrrolidone); amino acids (e.g., glycine, glutamic acid, aspartic acid, or arginine); monosaccharides, disaccharides and other carbohydrates (including cellulose or its derivatives, glucose, mannose, or dextrin); chelating agents (e.g., EDTA); sugar alcohols (e.g., mannitol or sorbitol); counter ions (e.g., sodium); and / or nonionic surfactants (e.g., polysorbate, poloxamer), etc. These pharmaceutical additives can be formulated by appropriately mixing or diluting / dissolving them. Preferred carriers that can be used include, but are not limited to, pharmaceutically inert aqueous carriers. Such carriers include physiological saline, buffered physiological saline, dextrose, and water, etc. In one embodiment of the present invention, the pharmaceutically acceptable carrier is pharmaceutically inert. Appropriate additives and / or pharmaceutically acceptable carriers are non-toxic to the recipient at the dosage and concentration used. Particularly preferred in the preparation are injections prepared with an aqueous carrier.

[0111] Techniques for formulation and administration are described, for example, in the latest edition and latest supplement of the Japanese Pharmacopoeia, and the final edition of "REMINGTON’S PHARMACEUTICAL SCIENCES" (Maack Publishing Co. Easton, PA).

[0112] The preparation of the derivative of borono-phenylalanine of the present invention is a medicament containing an effective amount for the intended drug to achieve the intended purpose, and the "therapeutically effective amount" or "pharmacologically effective amount" is well recognized by those skilled in the art and refers to the amount of the drug effective to produce pharmacological results. The determination of the therapeutically effective dosage is well known to those skilled in the art.

[0113] The therapeutically effective amount herein refers to the amount of the drug that reduces the disease state by radiation irradiation after administration. The therapeutic effect and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell culture or experimental animals. The dosage is preferably within a range of circulating concentration including ED 50 This dosage varies within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration. As an example, the dosage can be appropriately selected according to the age and other patient conditions, the type of disease, the type of complex used, etc. The preferred dosage can be, but is not limited to, 5 to 1000 mg / kg for a single treatment. In particular, it can also be 5 to 500 mg, more preferably 6 to 480 mg of the derivative per kg of the body weight of the subject to be treated.

[0114] [Diagnostic agent containing radioisotope] The derivative of borono-phenylalanine of the present invention can also be prepared as a medicament containing a radioisotope. When prepared as a medicament containing radioisotope radioactivity, typically, as the F atom contained in the compound, 18 F is used, as the I atom contained in the compound, 131 I, 123 I is used, or as the C atom contained in the compound 11 C can be used. These radioisotopes are typically R 1 ~R 4can be introduced. The compound thus obtained can be used, for example, in RI tests and nuclear medicine tests. These include, but are not limited to, tomography for scintigraphy, agents for SPECT (Single Photon Emission Computed Tomography), and PET (Positron Emission Tomography). That is, a derivative of 4-boronophenylalanine of the present invention containing radioactivity is administered to a subject as an agent for PET or SPECT, an image is acquired before treatment, and information such as the in vivo accumulation distribution of the derivative and the tumor tissue / normal tissue presence ratio (T / N ratio) can be obtained. Based on this information, it is also possible to predict the therapeutic effect of BNCT in advance and formulate a research or treatment plan. The administration mode and others shall conform to the content described in the section of [Agents for BNCT (Boron Neutron Capture Therapy)].

Examples

[0115] The present invention will be described in more detail by the following examples, but the invention is not limited thereto.

[0116] In the following examples, the analysis, separation, and purification of the compound were carried out using the following models and reagents.

[0117] ·NMR spectrum: (JEOL RESONANCE / JNM-ECZ500R / 500 MHz)

[0118] ·LC / MS data: (Waters XEVO G2-XS QTof / UPLC) What is shown in the LC / MS spectrum of the compound of the present invention was measured by the following method, and the retention time (unit: minute) and [M + H] + or [M + Na] + are shown. Column: Waters ACQUITY UPLC BEH C18 1.7 μm, 2.1 x 50 mm column Flow rate: 0.8 mL / min Mobile phase: A; 0.1% aqueous formic acid solution, B; acetonitrile Gradient: 5% (B, 0 min), 100% B, 3.50 min, linear gradient), 100% (B, 6.00 min), 5% (B, 7.00 min, linear gradient) MS tune: Capilary (kV); 3.00, Sampling Cone; 40, Source Offset; 80, temperature Source; 150, Desolvation; 20, Cone Gas (L / h); 50, Desolvation Gas (L / h); 1200.

[0119] (Example 1) (S)-2-Amino-3-(4-borono-2-fluorophenyl)-2-methylpropanoic acid synthesis

Chemical formula

[0120] Step 1 Synthesis of tert-butyl (S)-2-amino-3-(4-bromo-2-fluorophenyl)-2-methylpropanoate To a toluene (56 mL) solution of tert-butyl 2-((4-chlorobenzylidene)amino)propanoate (7.16 g, 26.7 mmol), 4-bromo-1-(bromomethyl)-2-fluorobenzene (8.64 g, 32.3 mmol), and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide (19.9 mg, 26.6 μmol) was added dropwise an 80% aqueous cesium hydroxide solution (24.9 g) at 5 °C or lower, and the mixture was stirred at -5 °C for 42 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted twice with toluene (50 mL). The organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a concentrate. This concentrate was used in the next step without purification.

[0121] The obtained concentrate was dissolved in tetrahydrofuran (50 mL), 25% aqueous citric acid solution (203 g) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, tetrahydrofuran was distilled off under reduced pressure, and the resulting residue was washed with ethyl acetate (100 mL). Then, the pH of the aqueous phase was adjusted to 8 or higher with potassium carbonate. The aqueous phase was extracted twice with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 (v / v)) to obtain tert-butyl (S)-2-amino-3-(4-bromo-2-fluorophenyl)-2-methylpropanoate (6.17 g, yield 70%). 1 1H NMR (CDCl3); 1.44 (s, 9H, t-Bu), 2.80 (dd, J = 9.5, 14.0 Hz, 1H, β-H), 3.15 (dd, J = 6.0, 14.0 Hz, 1H, β-H), 3.66 (dd, J = 5.5, 9.0 Hz, 1H, α-H), 7.12 (d, J = 8.0 Hz, 1H, ArH), 7.42 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 7.99 (d, J = 2.0 Hz, 1H, ArH).

[0122] Step 2 Synthesis of tert-butyl (S)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)-2-methylpropanoate Dissolve tert-butyl (S)-2-amino-3-(4-bromo-2-fluorophenyl)-2-methylpropanoate (5.00 g, 15.1 mmol) obtained in Step 1 in acetonitrile (50 mL), and further add an aqueous solution of sodium carbonate (3.20 g, 30.2 mmol) dissolved in water (50 mL) and Boc2O (3.93 g, 18.0 mmol). Stir at room temperature overnight. After the reaction, concentrate the acetonitrile under reduced pressure. Extract the resulting aqueous phase with ethyl acetate (50 mL). Dry the obtained organic phase over anhydrous magnesium sulfate and then concentrate the solvent under reduced pressure. Powderize the obtained residue with n-hexane, filter, and wash with n-hexane to obtain tert-butyl (S)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (4.90 g, yield 75%). 1 1H NMR (CDCl3); 1.46 (s, 21H, t-Bu×2+α-Me), 3.26 - 3.34 (m, 2H, β-H), 5.11 (brs, 1H, amide), 7.04 (t, J = 8.0 Hz, 1H, ArH), 7.17 - 7.20 (m, 2H, ArH).

[0123] Step 3 Preparation of (S)-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-2-methyl-3-oxopropyl)-3-fluorophenyl)boronic acid To DMSO (49 mL), Pd(dba)2 (325 mg, 0.565 mmol) and tricyclohexylphosphine (222 mg, 0.791 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Then, bis(pinacolato)diboron (3.44 g, 13.6 mmol), potassium acetate (1.66 g, 17.0 mmol), and tert-butyl (S)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (4.90 g, 11.3 mmol) were added, and the mixture was stirred at 80 °C for 18 hours. After cooling the reaction mixture, ethyl acetate (49 mL) and distilled water (25 mL) were added. After stirring for about 5 minutes, the mixture was filtered through celite, and the resulting filtrate was transferred to a separatory funnel. The aqueous phase was further extracted with ethyl acetate (25 mL), and the combined organic phases were washed with saturated brine (49 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain the intermediate.

[0124] An acetone solution (245 mL) of the obtained intermediate was added to a mixture of sodium periodate (6.04 g, 28.3 mmol) and ammonium acetate (2.18 g, 28.3 mmol) in water (245 mL). The mixture was stirred at room temperature for 2 days. The acetone in the reaction mixture was distilled off under reduced pressure, and the resulting aqueous solution was extracted twice with ethyl acetate (123 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain (S)-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-2-methyl-3-oxopropyl)-3-fluorophenyl)boronic acid (2.38 g, yield 53%). 11H NMR (DMSO-d6); 1.08 (s, 3H, α-Me), 1.37 (s, 9H, t-Bu), 1.41 (s, 9H, t-Bu), 2.95 (d, J = 13.5 Hz, 1H, β-H), 3.27 (d, J = 13.5 Hz, 1H, β-H), 6.95 (brs, 1H, amide), 7.07 (t, J = 7.5 Hz, 1H, ArH), 7.44 - 7.50 (m, 2H, ArH), 8.17 (s, 2H, B(OH)2).

[0125] Step 4 Production of (S)-2-Amino-3-(4-boronon-2-fluorophenyl)-2-methylpropanoic acid (S)-(4-(3-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)-2-methyl-3-oxopropyl)-3-fluorophenyl)boronic acid (1.00 g, 2.52 mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, a small amount of distilled water was added, and it was neutralized with sodium carbonate. The precipitated precipitate was collected by filtration and washed with cold water to obtain (S)-2-amino-3-(4-boronon-2-fluorophenyl)-2-methylpropanoic acid (0.36 g, yield 59%). 1 1H NMR (3.5% DCl in D2O); 1.68 (s, 3H, α-Me), 3.34 (s, 2H, β-H), 7.35 (t, J = 7.5 Hz, 1H, ArH), 7.45 - 7.54 (m, 2H, ArH).

[0126] (Example 2) In the same manner as in Example 1, except that (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical] (R)-2-Amino-3-(4-borono-2-fluorophenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.68 (s, 3H, α-Me), 3.34 (s, 2H, β-H), 7.35 (t, J = 7.5 Hz, 1H, ArH), 7.45 - 7.54 (m, 2H, ArH).

[0127] (Example 3) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-methylbenzene, the following compound was synthesized. [Chemical] (S)-2-Amino-3-(4-borono-2-methylphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.66 (s, 3H, α-Me), 2.34 (s, 3H, Ar-Me), 3.33 - 3.34 (m, 2H, β-H), 7.24 (d, J = 7.5 Hz, 2H, ArH), 7.56 (d, J = 7.5 Hz, 1H, ArH), 7.62 (s, 1H, ArH).

[0128] (Example 4) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-methylbenzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemistry] (R)-2-Amino-3-(4-borono-2-methylphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.66 (s, 3H, α-Me), 2.34 (s, 3H, Ar-Me), 3.33 - 3.34 (m, 2H, β-H), 7.24 (d, J = 7.5 Hz, 2H, ArH), 7.56 (d, J = 7.5 Hz, 1H, ArH), 7.62 (s, 1H, ArH).

[0129] (Example 5) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene, the following compound was synthesized. [Chemistry] (S)-2-Amino-3-(4-borono-2-(trifluoromethyl)phenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.71 (s, 3H, α-Me), 3.50 (d, J = 4.0 Hz, 2H, β-H), 7.48 (d, J = 7.0 Hz, 2H, ArH), 7.92 (d, J = 7.5 Hz, 1H, ArH), 8.08 (s, 1H, ArH).

[0130] (Example 6) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-borono-2-(trifluoromethyl)phenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.71 (s, 3H, α-Me), 3.50 (d, J = 4.0 Hz, 2H, β-H), 7.48 (d, J = 7.0 Hz, 2H, ArH), 7.92 (d, J = 7.5 Hz, 1H, ArH), 8.08 (s, 1H, ArH).

[0131] (Example 7) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-methoxybenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-borono-2-methoxyphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.67 (s, 3H, α-Me), 3.28 (s, 2H, β-H), 3.85 (s, 3H, OMe), 7.26 (d, J = 7.5 Hz, 1H, ArH), 7.34 (d, J = 8.0 Hz, 1H, ArH), 7.35 (s, 1H, ArH).

[0132] (Example 8) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-methoxybenzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-borono-2-methoxyphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.67 (s, 3H, α-Me), 3.28 (s, 2H, β-H), 3.85 (s, 3H, OMe), 7.26 (d, J = 7.5 Hz, 1H, ArH), 7.34 (d, J = 8.0 Hz, 1H, ArH), 7.35 (s, 1H, ArH).

[0133] (Example 9) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-chlorobenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-borono-2-chlorophenyl)-2-methylpropanoic acid 11H NMR (3.5% DCl in D2O); 1.67 (s, 3H, α-Me), 3.38 (d, J = 14.5 Hz, 1H, β-H), 3.48 (d, J = 14.0 Hz, 1H, β-H), 7.34 (d, J = 8.0 Hz, 1H, ArH), 7.61 (dd, J = 1.0, 7.5 Hz, 1H, ArH), 7.74 (d, J = 1.5 Hz, 1H, ArH).

[0134] (Example 10) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-chlorobenzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-boron-2-chlorophenyl)-2-methylpropanoic acid 1 1H NMR (3.5% DCl in D2O); 1.67 (s, 3H, α-Me), 3.38 (d, J = 14.5 Hz, 1H, β-H), 3.48 (d, J = 14.0 Hz, 1H, β-H), 7.34 (d, J = 8.0 Hz, 1H, ArH), 7.61 (dd, J = 1.0, 7.5 Hz, 1H, ArH), 7.74 (d, J = 1.5 Hz, 1H, ArH).

[0135] (Example 11) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 5-bromo-2-(bromomethyl)-1,3-difluorobenzene, the following compound was synthesized.

Chem.

[0136] (Example 12) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 5-bromo-2-(bromomethyl)-1,3-difluorobenzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, the following compound was synthesized.

Chem.

[0137] (Example 13) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene, the following compound was synthesized.

Chem.

[0138] (Example 14) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2,3-difluorobenzene, the following compound was synthesized.

Chemical formula

[0139] (Example 15) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-fluorobenzene, the following compound was synthesized.

Chemical formula

[0140] (Example 16) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-fluorobenzene, and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-boronono-3-fluorophenyl)-2-methylpropanoic acid 1 1H NMR (3.5% DCl in D2O); 1.76 (s, 3H, α-Me), 3.23 (d, J = 14.0 Hz, 1H, β-H), 3.23 (d, J = 14.0 Hz, 1H, β-H), 7.05 (d, J = 9.5 Hz, 1H, ArH), 7.16 (dd, J = 1.0, 8.0 Hz, 1H, ArH), 7.68 (t, J = 7.0 Hz, 1H, ArH).

[0141] (Example 17) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-methylbenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-boronono-3-methylphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.69 (s, 3H, α-Me), 2.45 (s, 3H, Me), 3.08 (d, J = 14.0 Hz, 1H, β-H), 3.32 (d, J = 14.0 Hz, 1H, β-H), 7.08-7.10 (m, 2H, ArH), 7.49 (d, J = 6.0 Hz, 1H, ArH).

[0142] (Example 18) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was replaced with 1-bromo-4-(bromomethyl)-2-methylbenzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was replaced with (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-boronono-3-methylphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.69 (s, 3H, α-Me), 2.45 (s, 3H, Me), 3.08 (d, J = 14.0 Hz, 1H, β-H), 3.32 (d, J = 14.0 Hz, 1H, β-H), 7.08-7.10 (m, 2H, ArH), 7.49 (d, J = 6.0 Hz, 1H, ArH).

[0143] (Example 19) In the same manner as in Example 1, except that tert-butyl 2-((4-chlorobenzylidene)amino)propanoate was changed to tert-butyl 2-((4-chlorobenzylidene)amino)butanoate, 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-iodobenzyl bromide, the following compound was synthesized. [Chemical formula] (S)-2-Amino-2-(4-boronobenzyl)butanoic acid 1 H NMR (3.5% DCl in D2O); 1.04 (t, J = 7.5 Hz, 3H, α-CH2 CH 3), 1.97 - 2.01 (m, 1H, α- CH 2CH3), 2.15 - 2.19 (m, 1H, α- CH 2CH3), 3.17 (d, J = 14.0 Hz, 1H, β-H), 3.42 (d, J = 14.0 Hz, 1H, β-H), 7.32 (d, J = 8.0 Hz, 1H, ArH), 7.76 (d, J = 8.0 Hz, 1H, ArH).

[0144] (Example 20) In the same manner as in Example 1, except that tert-butyl 2-((4-chlorobenzylidene)amino)propanoate was changed to tert-butyl 2-((4-chlorobenzylidene)amino)butanoate, 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-iodobenzyl bromide, and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-2-(4-boronobenzyl)butanoic acid 1 1H NMR (3.5% DCl in D2O); 1.04 (t, J = 7.5 Hz, 3H, α-CH2 CH 3), 1.97 - 2.01 (m, 1H, α- CH 2CH3), 2.15 - 2.19 (m, 1H, α- CH 2CH3), 3.17 (d, J = 14.0 Hz, 1H, β-H), 3.42 (d, J = 14.0 Hz, 1H, β-H), 7.32 (d, J = 8.0 Hz, 1H, ArH), 7.76 (d, J = 8.0 Hz, 1H, ArH).

[0145] (Example 21) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 5-bromo-2-(bromomethyl)benzonitrile, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-boron-2-cyanophenyl)-2-methylpropanoic acid 1 1H NMR (3.5% DCl in D2O); 8.26 (d, J = 1.5 Hz, 1H, ArH), 8.03 (dd, J = 1.5, 7.5 Hz, 1H, ArH), 7.49 (d, J = 7.5 Hz, 1H, ArH), 3.50 (d, J = 16.5 Hz, 1H, CH2), 3.30 (d, J = 16.5 Hz, 1H, CH2), 2.09 (s, 3H, CH3), 1.71 (s, 3H, CH3).

[0146] (Example 22) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-borono-5-chloro-2-fluorophenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.66 (s, 3H, α-Me), 3.29 (s, 2H, β-H), 7.28 (dd, J = 2.0, 10.0 Hz, 1H, ArH), 7.34 (d, J = 5.0 Hz, 1H, ArH).

[0147] (Example 23) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-borono-2-chloro-5-fluorophenyl)-2-methylpropanoic acid 11H NMR (TFA in D2O); 7.65 (dd, J = 3.5, 6.0 Hz, 1H, ArH), 7.10 (dd, J = 2.5, 9.5 Hz, 1H, ArH), 3.47 (d, J = 15.0 Hz, 1H, CH2), 3.38 (d, J = 15.0 Hz, 1H, CH2), 1.68 (s, 3H, CH3).

[0148] (Example 24) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2,3-difluorobenzene, (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-borono-2,3-difluorophenyl)-2-methylpropanoic acid 1 1H NMR (TFA in D2O); 1.67 (s, 3H, α-Me), 3.36 (s, 2H, β-H), 7.11 (t, J = 7.0 Hz, 1H, ArH), 7.36 (t, J = 7.0 Hz, 1H, ArH).

[0149] (Example 25) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-nitrobenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-borono-2-nitrophenyl)-2-methylpropanoic acid 1 1H NMR (TFA in D2O); 8.33 (d, J = 1.5 Hz, 1H, ArH), 7.98 (d, J = 8.0 Hz, 1H, ArH), 7.50 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 3.76 (d, J = 14.0 Hz, 1H, CH2), 3.53 (d, J = 14.0 Hz, 1H, CH2), 1.67 (s, 3H, CH3).

[0150] (Example 26) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-(bromomethyl)-1-iodo-2-nitrobenzene, the following compound was synthesized.

Chemical formula

[0151] (Example 27) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-(bromomethyl)-1-iodo-2-nitrobenzene, the following compound was synthesized.

Chemical formula

[0152] (Example 28) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-nitrobenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(2-amino-4-boronophenyl)-2-methylpropanoic acid 1 1H NMR (3.5% DCl in D2O); 1.47 (s, 3H, α-Me), 3.22 (d, J = 15.5 Hz, 1H, β-H), 3.43 (d, J = 15.5 Hz, 1H, β-H), 7.27 (s, 1H, ArH), 7.33 (d, J = 7.5 Hz, 1H, ArH), 7.47 (d, J = 7.5 Hz, 1H, ArH).

[0153] (Example 29) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-boronato-2-chloro-5-fluorophenyl)-2-methylpropanoic acid 11H NMR (TFA in D2O); 7.65 (dd, J = 3.5, 6.0 Hz, 1H, ArH), 7.10 (dd, J = 2.5, 9.5 Hz, 1H, ArH), 3.47 (d, J = 15.0 Hz, 1H, CH2), 3.38 (d, J = 15.0 Hz, 1H, CH2), 1.68 (s, 3H, CH3).

[0154] (Example 30) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 2-(benzyloxy)-4-bromo-1-(bromomethyl)benzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(2-(benzyloxy)-4-boronophenyl)-2-methylpropanoic acid 1 1H NMR (3.5% DCl in D2O); 1.77 (s, 3H, α-Me), 3.33 (d, J = 14.5 Hz, 1H, β-H), 3.45 (d, J = 14.0 Hz, 1H, β-H), 5.10 (d, J = 11.5 Hz, 1H, ArCH2), 5.16 (d, J = 12.0 Hz, 1H, ArCH2), 7.39 - 7.52 (m, 6H, ArH), 7.62 - 7.63 (m, 2H, ArH).

[0155] (Example 31) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 2-(benzyloxy)-4-bromo-1-(bromomethyl)benzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(2-(benzyloxy)-4-boronophenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.77 (s, 3H, α-Me), 3.32 (d, J = 14.0 Hz, 1H, β-H), 3.44 (d, J = 13.5 Hz, 1H, β-H), 5.10 (d, J = 12.0 Hz, 1H, ArCH2), 5.16 (d, J = 11.5 Hz, 1H, ArCH2), 7.39 - 7.52 (m, 6H, ArH), 7.60 - 7.62 (m, 2H, ArH).

[0156] (Example 32) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-methoxybenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-boronono-3-methoxyphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.74 (s, 3H, α-Me), 3.14 (d, J = 14.0 Hz, 1H, β-H), 3.38 (d, J = 14.0 Hz, 1H, β-H), 3.86 (s, 3H, OCH3), 6.87 (d, J = 2.0 Hz, 1H, ArH), 6.93 (d, J = 7.5 Hz, 1H, ArH), 7.00 (dd, J = 2.5, 8.0 Hz, 1H, ArH).

[0157] (Example 33) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-methoxybenzene, and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-borono-3-methoxyphenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.72 (s, 3H, α-Me), 3.11 (d, J = 14.5 Hz, 1H, β-H), 3.36 (d, J = 14.0 Hz, 1H, β-H), 3.84 (s, 3H, OCH3), 6.85 (s, 1H Ar), 6.91 (d, J = 8.5 Hz, 1H, ArH), 7.00 (dd, J = 2.0, 8.5 Hz, 1H, ArH).

[0158] (Example 34) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-3-methylthiobenzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-borono-2-(methylthio)phenyl)-2-methylpropanoic acid 11H NMR (3.5% DCl in D2O); 1.39 (s, 3H, α-Me), 2.18 (s, 3H, SCH3), 3.04 (d, J = 15.0 Hz, 1H, β-H), 3.14 (d, J = 15.0 Hz, 1H, β-H), 6.92 (d, J = 7.5 Hz, 1H, ArH), 7.26 (d, J = 7.5 Hz, 1H, ArH), 7.40 (s, 1H, ArH).

[0159] (Example 35) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-(difluoromethyl)benzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-borono-2-(difluoromethyl)phenyl)-2-methylpropanoic acid 1 1H NMR (3.5% DCl in D2O); 1.82 (s, 3H, α-Me), 3.54 - 3.55 (m, 2H, β-H), 6.92 - 7.14 (m, 1H, CHF2). 7.47 (d, J = 8.0 Hz, 1H, ArH), 7.96 (d, J = 7.5 Hz, 1H, ArH), 8.05 (s, 1H, ArH).

[0160] (Example 36) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-1-(bromomethyl)-2-(difluoromethyl)benzene and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemistry] (R)-2-Amino-3-(4-borono-2-(difluoromethyl)phenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.77 (s, 3H, α-Me), 3.49 - 3.50 (m, 2H, β-H), 6.92 - 7.13 (m, 1H, CHF2). 7.41 (d, J = 8.0 Hz, 1H, ArH), 7.89 (d, J = 7.5 Hz, 1H, ArH), 7.99 (s, 1H, ArH).

[0161] (Example 37) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-chlorobenzene, the following compound was synthesized. [Chemistry] (S)-2-Amino-3-(4-borono-3-chlorophenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.68 (s, 3H, α-Me), 3.13 (d, J = 14.0 Hz, 1H, β-H), 3.35 (d, J = 14.5 Hz, 1H, β-H), 7.20 (dd, J = 1.0, 7.5 Hz, 1H, ArH), 7.30 (d, J = 1.0 Hz, 1H, ArH), 7.52 (d, J = 7.5 Hz, 1H, ArH).

[0162] (Example 38) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-chlorobenzene, and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-boron-3-chlorophenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.69 (s, 3H, α-Me), 3.14 (d, J = 14.0 Hz, 1H, β-H), 3.36 (d, J = 14.0 Hz, 1H, β-H), 7.21 (d, J = 8.0 Hz, 1H, ArH), 7.30 (s, 1H, ArH), 7.53 (d, J = 7.5 Hz, 1H, ArH).

[0163] (Example 39) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-boron-3-(trifluoromethyl)phenyl)-2-methylpropanoic acid 11H NMR (3.5% DCl in D2O); 1.71 (s, 3H, α-Me), 3.24 (d, J = 14.5 Hz, 1H, β-H), 3.44 (d, J = 14.5 Hz, 1H, β-H), 7.51 (d, J = 8.0 Hz, 1H, ArH), 7.61 - 7.63 (m, 2H, ArH).

[0164] (Example 40) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene, (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-boronono-3-(trifluoromethyl)phenyl)-2-methylpropanoic acid 1 1H NMR (3.5% DCl in D2O); 1.69 (s, 3H, α-Me), 3.23 (d, J = 14.5 Hz, 1H, β-H), 3.44 (d, J = 14.5 Hz, 1H, β-H), 7.50 (d, J = 8.0 Hz, 1H, ArH), 7.60 - 7.61 (m, 2H, ArH).

[0165] (Example 41) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-2,5-difluorobenzene, (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide was changed to (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepinium bromide, the following compound was synthesized. [Chemical formula] (R)-2-Amino-3-(4-borono-2,5-difluorophenyl)-2-methylpropanoic acid 1 H NMR (3.5% DCl in D2O); 1.64 (s, 3H, α-Me), 3.36 (s, 2H, β-H), 7.31-7.33 (m, 2H, ArH).

[0166] (Example 42) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to tert-butyl 2-((4-chlorobenzylidene)amino)propanoate and tert-butyl-2-((4-chlorobenzylidene)amino)butanoate, the following compound was synthesized. [Chemical formula] (S)-2-Amino-2-(4-borono-2-fluorobenzyl)-2-butanoic acid 1 H NMR (3.5% DCl in D2O); 1.02 (t, J = 7.5 Hz, 3H, α-CH2 CH 3), 1.92-2.00 (m, 1H, α- CH 2CH3), 2.14-2.22 (m, 1H, α- CH2CH3), 3.35 (s, 2H, β-H), 7.36 (d, J = 7.5 Hz, 1H, ArH), 7.47 (d, J = 11.0 Hz, 1H, ArH), 7.53 (dd, J = 1.0, 7.0 Hz, 1H, ArH).

[0167] (Example 43) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 1-bromo-4-(bromomethyl)-3-methylthiobenzene, and it was oxidized with m-chloroperbenzoic acid before boronation to form a sulfone, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(4-boronato-2-(methylsulfonyl)phenyl)-2-methylpropanoic acid Retention time: 0.19 min HRMS(ESI,[M+H] + ), calcd for 302.0870; found: 302.1029.

[0168] (Example 44) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 5-bromo-2-(bromomethyl)pyridine, and tert-butyl 2-((4-chlorobenzylidene)amino)propanoate was changed to tert-butyl N-(diphenylmethylene)glycinate, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(5-boronatopyridin-2-yl)propanoic acid 11H NMR (D2O); 8.82 (brs, 1H, ArH), 8.73 (dd, J = 7.0, 9.5 Hz, 1H, ArH), 7.98 (d, J = 8.0 Hz, 1H, ArH), 4.49 (t, J = 7.5 Hz, 1H, CH), 3.65 (d, J = 7.5 Hz, 2H, CH2).

[0169] (Example 45) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 5-bromo-2-(bromomethyl)pyridine, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(5-boronopyridin-2-yl)-2-methylpropanoic acid 1 1H NMR (D2O); 8.87 (d, J = 3.5 Hz, 1H, ArH), 8.77 (dd, J = 2.5, 7.5 Hz, 1H, ArH), 7.96 (dd, J = 3.0, 7.5 Hz, 1H, ArH), 3.65 (d, J = 15.0 Hz, 1H, CH2), 3.61 (d, J = 15.0 Hz, 1H, CH2), 1.61 (s, 3H, CH3).

[0170] (Example 46) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 5-bromo-2-(bromomethyl)pyrimidine, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(5-boronopyrimidin-2-yl)propanoic acid Retention time: 0.19 minutes HRMS(ESI,[M+H] + ), calcd for 212.0843; found: 212.0982.

[0171] (Example 47) In the same manner as in Example 1, except that 4-bromo-1-(bromomethyl)-2-fluorobenzene was changed to 4-bromo-2-(bromomethyl)thiophene, the following compound was synthesized.

Chemical formula

[0172] (Example 48) Synthesis of (S)-2-amino-3-(5-boron-3-fluoropyridin-2-yl)propanoic acid

Chemical formula

[0173] Step 1 Synthesis of methyl (S)-3-(5-bromo-3-fluoropyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate Under a nitrogen atmosphere, methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (2.98 g, 9.05 mmol) was added to a mixed solution of zinc powder (710 mg, 10.9 mmol), N,N-dimethylformamide (12 mL), and trimethylsilyl chloride (98.3 mg, 0.905 mmol) under ice-cooling. After the exothermic reaction subsided, 2,5-dibromo-3-fluoropyridine (3.00 g, 11.8 mmol) and bis(triphenylphosphine)palladium(II) dichloride (318 mg, 0.453 mmol) were added, and the mixture was stirred at 80 °C for 1.5 hours. The reaction solution was cooled to room temperature, filtered through celite to remove the zinc residue, and the residue was washed with ethyl acetate (30 mL). Saturated aqueous ammonium chloride solution (10 mL) was added to the obtained filtrate, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8 / 1) to give methyl (S)-3-(5-bromo-3-fluoropyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (1.71 g, 4.55 mmol, 50%) as a yellow oil. Retention time: 2.52 min HRMS(ESI,[M+Na + ),calcd for 399.0332;found:399.0714.

[0174] Step 2 Methyl (S)-3-(5-bromo-3-fluoropyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (1.71 g, 4.55 mmol) was added with bis(pinacolato)diboron (2.08 g, 8.19 mmol), Pd(dba)2 (131 mg, 0.228 mmol), tricyclohexylphosphine (128 mg, 0.455 mmol), potassium acetate (1.34 g, 13.7 mmol), and 1,4-dioxane (30 mL), and stirred at 80 °C for 6 hours. The reaction mixture was filtered through celite to remove the palladium residue, and the residue was washed with ethyl acetate (30 mL). Water (10 mL) was added to the obtained filtrate, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was passed through alumina (neutral), and distilled with ethyl acetate for rough purification to obtain a crude product (2.85 g) containing methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propanoate as a yellow oil. Sodium periodate (6.82 g, 31.9 mmol) and ammonium acetate (2.46 g, 31.9 mmol) were added to an acetone / water (2 / 1, 30 mL) solution of the obtained crude product (2.85 g), and the mixture was stirred at room temperature for 15 hours. The insoluble matter was collected by filtration, and acetone in the obtained filtrate was distilled off under reduced pressure. The obtained residue was extracted twice with ethyl acetate (50 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was powdered with diisopropyl ether (5 mL) to obtain a crude product containing (S)-(6-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoropyridin-3-yl)boronic acid (300 mg) as a pale yellow powder. Concentrated hydrochloric acid (4.4 mL) was added to the obtained crude product (300 mg), and the mixture was stirred at 70 °C for 22 hours. Water (20 mL) was added to the reaction solution, and the aqueous phase was washed with dichloromethane (20 mL x 4). The aqueous phase was concentrated under reduced pressure to obtain the hydrochloride salt of (S)-2-amino-3-(5-borono-3-fluoropyridin-2-yl)propanoic acid (222 mg, 0.738 mmol, 16% for 3 steps) as a pale yellow solid. 1 1H NMR (D2O); 8.67 (s, 1H, ArH), 8.33 (d, J = 8.5 Hz, 1H, ArH), 4.39 (dd, J = 5.5, 8.0 Hz, 1H, CH), 3.65 (dd, J = 5.5, 15.0 Hz, 1H, CH2), 3.59 (dd, J = 8.0, 15.0 Hz, 1H, CH2).

[0175] (Example 49) In the same manner as in Example 48, except that 5-dibromo-3-fluoropyridine was changed to 5-bromo-2-iodo-3-methylpyridine, Pd(PPh3)2Cl2 was changed to Pd2(dba)3, and tri(ortho-tolyl)phosphine, the following compound was synthesized.

Chemical formula

[0176] (Example 50) In the same manner as in Example 48, except that 5-dibromo-3-fluoropyridine was changed to 2,5-dibromo-3-chloropyridine, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(5-borono-3-chloropyridin-2-yl)propanoic acid 1 H NMR (D2O); 8.72 (d, J = 1.5 Hz, 1H, ArH), 8.53 (d, J = 1.5 Hz, 1H, ArH), 4.42 (dd, J = 6.0, 8.5 Hz, 1H, CH), 3.71 (dd, J = 6.0, 15.0 Hz, 1H, CH2), 3.63 (dd, J = 8.5, 15.0 Hz, 1H, CH2).

[0177] (Example 51) In the same manner as in Example 48, except that 5-dibromo-3-fluoropyridine was changed to 5-bromo-2-iodo-4-methylpyridine, the following compound was synthesized. [Chemical formula] (S)-2-Amino-3-(5-borono-4-methylpyridin-2-yl)propanoic acid 1 H NMR (D2O); 8.56 (s, 1H, ArH), 7.77 (s, 1H, ArH), 4.43 (t, J = 7.5 Hz, 1H, CH), 3.55 (d, J = 7.5 Hz, 2H, CH2), 2.64 (s, 3H, CH3).

[0178] (Example 52) Production of 2-amino-5-borono-2,3-dihydro-1H-indene-2-carboxylic acid [Chemical formula]

[0179] (Step 1) [Chemical formula]

[0180] Production of Methyl 2-Amino-5-bromo-2,3-dihydro-1H-indene-2-carboxylate A mixture of 2-Amino-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid hydrochloride (0.5 g, 1.7 mmol), methanol (5 mL) and concentrated sulfuric acid (0.25 mL) was heated to reflux for 16 hours. The reaction solution was added to saturated sodium bicarbonate solution (100 mL), extracted with dichloromethane (50 mL × 2), and the organic phase was washed with semi-saturated brine (100 mL). After drying the organic phase over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain methyl 2-amino-5-bromo-2,3-dihydro-1H-indene-2-carboxylate (0.43 g, yield 93.6%) as a light brown oily substance. To a mixture of methyl 2-amino-5-bromo-2,3-dihydro-1H-indene-2-carboxylate (0.43 g, 1.6 mmol), dichloromethane (15 mL) and triethylamine (0.45 mL), a solution of di-tert-butyl dicarbonate (0.55 mL) in dichloromethane (3 mL) was added dropwise over 2 minutes under ice-cooling. After stirring the reaction solution at room temperature overnight, it was added to dichloromethane (100 mL) and washed with semi-saturated brine (100 mL × 2). After drying the organic phase over anhydrous sodium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 5-bromo-2-(tert-butoxycarbonyl)amino-2,3-dihydro-1H-indene-2-carboxylate (0.26 g, yield 43.9%) as a white solid. 1 H NMR (CDCl3); 1.42 (s, 9H), 3.04 - 3.51 (m, 4H), 3.76 (s, 3H), 5.07 (s, 1H), 6.97 - 7.33 (m, 4H).

[0181] (Step 2)

Chemical Structure

[0182] (Example 53) In the same manner as in Example 52, except that the hydrochloride salt of 2-amino-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid was changed to 2-amino-7-bromo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid, the following compound was synthesized.

Chemical Structure

[0183] [Uptake test] 1. Construction of an evaluation system for selective uptake of LAT1 and LAT2 (1) Preparation of human LAT1- and LAT2-overexpressing HEK293 cell lines According to the method described in the paper by Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol. 119, pp 368 - 380), HEK293 cells stably overexpressing human LAT1 and LAT2 were prepared respectively. Shuttle vector DNAs (LAT1: EX-H4509-M02, LAT2: EX-U0514-M02, manufactured by GeneCopoeia) having ampicillin and neomycin resistance markers and with the full-length cDNA of human LAT1 or LAT2 inserted under the promoter of CMV (cytomegalovirus) were constructed. This vector was introduced into HEK293 cells by the method using Lipofectamine (registered trademark) 2000 (Invitrogen) according to the manufacturer's instructions. Thereafter, stable expression cell clones of the introduced gene were selected by the limiting dilution method in the presence of 0.9 mg / mL Geneticin (registered trademark), and cell clones in which the uptake of L-boronophenylalanine (L-BPA) was enhanced by about 2 - 5 times compared with HEK293 cells before gene introduction were obtained. These cells were passaged and used for the evaluation of selective uptake of LAT1 and LAT2.

[0184] (2) Evaluation of selective uptake of LAT1 and LAT2 The method for evaluating cell uptake was the same as that described in the paper by Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol. 119, pp 368-380). Using each of the cells obtained in (1), the evaluation was carried out. However, radioisotopes were not used, a substrate concentration of 0.1 mM was used, 2 mM BCH (2-amino-2-norbornylcarboxylic acid) was used as an inhibitor of LAT1 and LAT2, and the concentration of the derivative of 4-boronophenylalanine in the cell lysate obtained by recovering the cells after the reaction with 0.05% Tween20 was determined. The quantification of the derivative of 4-boronophenylalanine in the cells was carried out according to the method described in the paper by Hattori, Y et al. (Sensors 2017, 17, 2436), using 2-(2-hydroxyphenyl)pyridine (boron sensor 5) as a boron sensor. When evaluating cell uptake, considering the variation between experiments, it was evaluated as the relative value (LAT1 selectivity) with respect to the uptake of L-BPA, which is the comparison target carried out on the same day. LAT1 selectivity = (quantification value of compound uptake in LAT1 cells / quantification value of control LBPA uptake in LAT1 cells) / (quantification value of compound uptake in LAT2 cells / quantification value of control LBPA uptake in LAT2 cells) That is, it is as follows. [Number]

[0185] As a result of the uptake evaluation of the compounds in the examples compared with L-BPA, a plurality of compounds showing high LAT1 selectivity values were found. Among them, in particular, the following compounds showed extremely high values of more than 2-fold. (S)-2-amino-3-(4-boronono-2-fluorophenyl)-2-methylpropanoic acid; (R)-2-amino-3-(4-boronono-2-fluorophenyl)-2-methylpropanoic acid; (S)‐2‐amino‐3‐(4‐boronono‐2‐methylphenyl)‐2‐methylpropanoic acid; (R)‐2‐amino‐3‐(4‐boronono‐2‐methylphenyl)‐2‐methylpropanoic acid (S)-2-Amino-3-(4-borono-2-(trifluoromethyl)phenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-(trifluoromethyl)phenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-methoxyphenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-chlorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2,6-difluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-5-chloro-2-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2,3-difluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-3-fluorophenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-3-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-chloro-5-fluorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-3-methylphenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-(methylthio)phenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-2-(difluoromethyl)phenyl)-2-methylpropanoic acid; (R)-2-Amino-3-(4-borono-2-(difluoromethyl)phenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(4-borono-3-chlorophenyl)-2-methylpropanoic acid; (S)-2-Amino-3-(5-boronopyridin-2-yl)propanoic acid; (S)-2-Amino-3-(5-borono-3-fluoropyridin-2-yl)propanoic acid; (S)-2-Amino-3-(5-borono-3-methylpyridin-2-yl)propanoic acid; (S)-2-Amino-3-(5-borono-3-chloropyridin-2-yl)propanoic acid; and (S)-2-Amino-3-(5-borono-4-methylpyridin-2-yl)propanoic acid.

[0186] [Uptake Test 2] Uptake evaluation test on tumor cells 1.5x10 6 Human tongue cancer cells (SAS cells), human glioma cells (A172 cells) or human breast cancer cells (MCF-7) at 1.5x10 are seeded in a 100 mm dish and pre-cultured for 24 hours at 37 °C in a 5% CO2 atmosphere. The culture medium is aspirated and removed, and a culture medium containing 1 mM of the drug of each Example or Reference Example is added, and exposure culture is performed for 3 hours at 37 °C in a 5% CO2 atmosphere. After the culture medium is aspirated and removed, the cells are washed once with PBS, then trypsinized, and the cells are collected. The number of collected cells is counted, packed by centrifugation, then HClO4 (60%, 0.3 ml) and H2O2 (31%, 0.6 mL) are added, and heated at 75 °C overnight to prepare an ashing solution. After the ashing solution is filled up to 5 mL with pure water, it is filtered using a 5C filter paper, and the boron concentration in the solution is measured using an Agilent 710 ICP-OES to determine the amount of boron (μg) per 10 7 cells. When evaluating cell uptake, considering the variation between experiments, it is evaluated as the relative value to the uptake of L-BPA of the Reference Example which is the comparison target performed on the same day.

[0187] [Single-dose toxicity test] 17.6 mL of 1 mol / L NaOH was placed in a beaker, and 24 mL of water for injection was further added and mixed. 2.52 g of D-sorbitol was added thereto. After confirming complete dissolution, 17.1 mL of 1 mol / L hydrochloric acid was added to adjust the pH to 7.4 - 7.8. It was transferred to a volumetric cylinder, and the beaker was rinsed with water for injection, and the rinsing solution was transferred to the volumetric cylinder. This operation was repeated as much as possible, and the volume was made up to 80 mL while rinsing the beaker. It was sterilized by filtration using a filter (Millipore GV, pore size 0.22 μm, Merck KGaA, sterilized disposable product) to obtain a 3.15% D-sorbitol solution. On the other hand, 10.1 mL of 1 mol / L aqueous sodium hydroxide solution was placed in a beaker, and 13.8 mL of water for injection was further added and mixed. 2.30 g of the test substance and 1.45 g of D-sorbitol were added thereto. After confirming complete dissolution, 1.36 mL of 1 mol / L hydrochloric acid was added to adjust the pH to 7.4 - 7.8. It was transferred to a volumetric cylinder, and the beaker was rinsed with water for injection, and the rinsing solution was transferred to the volumetric cylinder. This operation was repeated as much as possible, and the volume was made up to 46 mL while rinsing the beaker. It was sterilized by filtration using a filter (Millipore GV, pore size 0.22 μm, Merck KGaA, sterilized disposable product) to obtain a solution with a concentration of 50 mg / mL. The animals were placed in a restraining device (Ballmann cage), and using a 10 mL polypropylene syringe filled with the administration solution and a 24-gauge indwelling needle (Surflo F&F, Terumo Corporation, both sterilized disposable products), they were injected into the tail vein at a rate of 1 mL / kg / min using a microprocessor single syringe pump (Pump11 Elite, Harvard Apparatus Inc.). The administration doses were 250, 500, and 1000 mg / kg, and the administration was carried out with 5 animals in each group. After the administration was completed, the animals were returned to the breeding cage. The observation period was 8 days including the dosing day. Taking the dosing day as Day1 and the day after dosing as Day2, subsequent days are represented. The observation frequency was 6 times on the dosing day (immediately before dosing, 5 minutes, 30 minutes, 60 minutes, 2 hours, and 4 hours after the end of dosing), once a day from the day after dosing, and individual observations were made from outside the cage. For animals suspected of having abnormalities, they were taken out of the cage for observation. The times for measuring body weight were Day1 (before dosing), Day4, and Day8.

[0188] As a result of this test, no severe changes attributable to the administration of the test substance were observed in any of the dosing groups for the compound (S)-2-amino-3-(4-boron-2-fluorophenyl)-2-methylpropanoic acid and the compound (S)-2-amino-3-(4-boron-2-chlorophenyl)-2-methylpropanoic acid throughout the entire observation period.

[0189] [Distribution Test Using Tumor-Bearing Mice] Human pancreatic cancer cells T3M-4 cells are cultured using HAM-F12 medium. The cells are detached with trypsin solution and recovered by centrifugation. The cells are suspended in PBS(-) to a concentration of 4x10 6 cells / 100 μL. The cell suspension is subcutaneously injected (100 μL / mouse) into the right hind limb of BALB / c nu / nu mice (male, 4 weeks old) using a 26G needle. Thereafter, the formed tumor size is visually confirmed at 3 - 4 weeks, and when the tumor size reaches about 4 mm - 10 mm, it is used for the distribution experiment. For the administered drug, it is prepared while corresponding according to the drug such as adding fructose or sorbitol, and the diluent used is physiological saline or PBS(-). With a sample concentration of 10 mg / mL as a guideline, 100 μL is administered to the tumor-bearing mice via the tail vein. The mice are sacrificed over time, dissected, and the organ weights are measured. The excised organs are ashed with nitric acid, and the boron content is quantified by ICP-MS or ICP-OES.

[0190] [Measurement of Km Value] The evaluation method of Km uses the cell uptake method described in the paper by Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol. 119, pp368 - 380), with the uptake time set to 2 - 3 minutes. However, radioactive isotopes are not used. Cells reacted at multiple substrate concentrations are collected with 0.05% Tween20, and the concentration of the boron compound in the obtained cell lysate is determined. The cells used are HEK293 cells stably expressing the Human LAT1 transporter or the Human LAT2 transporter established according to (Journal of Pharmacology Science, 2012, vol. 119, pp368 - 380). The quantification of the boron compound in the cells is carried out according to the method described in the paper by Hattori, Y et al. (Sensors 2017, 17, 2436), using 2-(2-hydroxyphenyl)pyridine (boron sensor 5) as the boron sensor. When evaluating Km, it is calculated using Lineweaver - Burk.

[0191] [Measurement of Efflux] Using LAT1 - overexpressing HEK293 cells, after allowing the substrate to be taken up, an efflux solution is added, and the boron compound taken up into the cells is measured. A substrate concentration of 0.1 mM, HBSS (Na+-Free) and 0.05 mM leucine as the LAT1 efflux solution are used, and the concentration of the boron compound in the cell lysate obtained by collecting the cells after the reaction with 0.05% Tween20 is determined. The efflux time is set to 1 - 10 minutes. The quantification of the boron compound in the cells is carried out according to the method described in the paper by Hattori, Y et al. (Sensors 2017, 17, 2436), using 2-(2-hydroxyphenyl)pyridine (boron sensor 5) as the boron sensor. When evaluating cell uptake, it is evaluated as the relative value with respect to the cell lysate before efflux, which is the comparison target.

[0192] [Evaluation of Water Solubility] Weigh an appropriate amount of the compound of each example and dissolve it in water. Dropwise add hydrochloric acid or an aqueous sodium hydroxide solution and adjust to neutral while checking with pH test paper. Analyze the prepared drug by ICP to calculate the boron concentration, which is taken as the sample concentration.

[0193] [Metabolic Stability Test] Using commercially available pooled human liver microsomes, react the target compound for a certain period of time, calculate the residual rate by comparing the reaction sample with the unreacted sample, and evaluate the degree of metabolism in the liver.

[0194] In 0.2 mL of buffer (50 mmol / L tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL of human liver microsomes, react at 37 °C for 0 or 30 minutes in the presence of 1 mmol / L NADPH (oxidative reaction). After the reaction, add 50 μL of the reaction solution to 100 μL of a methanol / acetonitrile = 1 / 1 (v / v) solution, mix, and centrifuge at 3000 rpm for 15 minutes. Quantify the test compound in the centrifuged supernatant by LC / MS-MS and calculate the remaining amount of the test compound after the reaction with the amount of the compound at 0 minutes of reaction set as 100%.

[0195] [Metabolic Stability Test] Using various commercially available cryopreserved hepatocytes, react the target compound for a certain period of time, calculate the residual rate by comparing the reaction sample with the unreacted sample, and evaluate the degree of metabolism in the liver.

[0196] In William's E medium containing 1.0x10 6 cells / mL, react at 37 °C for 0, 1, or 2 hours. After the reaction, add 120 μL of a methanol / acetonitrile = 1 / 1 (v / v) solution to 30 μL of the reaction solution, mix, and centrifuge at 3000 rpm for 15 minutes. Quantify the test compound in the centrifuged supernatant by LC / MS-MS and calculate the remaining amount of the test compound after the reaction with the amount of the compound at 0 minutes of reaction set as 100%.

[0197] [Protein Binding Test] Using various sera, the serum protein unbound fraction of the inventive compound is measured.

[0198] The reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37°C; concentration of the inventive compound, 2 μg / mL

[0199] The test solution is added to various sera and stirred to prepare a serum sample with the above compound concentration. The serum sample is added to one side of an equilibrium dialysis cell, and phosphate buffered saline (PBS) is added to the other side, followed by equilibrium dialysis at 37°C for 24 hours. The amount of the compound in the sample collected from each cell is measured by LC / MS-MS.

[0200] [Formulation Example] Injection The inventive compound is dissolved in water or a buffer to form an injection. If it is insoluble in water, an aqueous sodium hydroxide solution is added for dissolution, neutralized with hydrochloric acid, and made into an injection. Due to osmotic pressure relationships, it is also possible to add physiological saline, phosphate buffer, monosaccharides, disaccharides, and other carbohydrates.

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical Formula 1】 Here, in formula (I), R １ 、 R ２ 、 R ３ 、 and R ４ are, independently, H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, benzyloxy, C1-6 alkoxy C1-6 alkyl, nitro, C1-6 haloalkyl, aminocarbonyl, C1-C6 alkylaminocarbonyl (CONR ８ R ９ (R ８ 、 R ９ are, independently, H or C1-6 alkyl)), C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR １０ (R １０ is H or C1-6 alkyl, amino, alkylamino (NR １１ R １２ (R １１ R １２ are each independently H or C1-6 alkyl)), haloalkylsulfanyl, haloalkylsulfinyl, haloalkylsulfonyl, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, sulfo, or sulfamoyl, R ５ represents H, hydroxy, C1-6 alkyl, or halogen; R ６ represents C1-6 alkyl; R ７ represents any one of boric acid (—B(OH) ２ )), boronic acid ester or boronic acid amide (However, when R １ , R ２ , R ３ , and R ４ are all H, R ５ represents hydroxy or F, or when R １ , R ２ , R ３ , and R ４ are all H, R ６ represents C2-6 alkyl).

2. Said R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R represents methyl or ethyl.

3. Said R ７ represents boric acid (B(OH) ２ ), or a pinacol ester of boric acid, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. The aforementioned R ５ represents H, and is the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. Said R １ , R ２ , R ３ , and R ４ wherein any one or more of them are independently Cl, F, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, CH ２ X, CHX ２ , or CX ３ (wherein X represents F), the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. An LAT1 (L-type Amino acid Transporter 1) selective agent comprising the compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. An agent for BNCT comprising the compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. A diagnostic agent containing a radioisotope, comprising the compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt thereof.

9. A compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof: 【Chemical 2】 Here, in formula (III), R Ｃ is substituted at one position by any of boronic acid (—B(OH) ２ ), boronic ester or boronic amide, and further optionally by halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, benzyloxy, C1-6 alkoxyC1-6 alkyl, nitro, C1-6 haloalkyl, aminocarbonyl, C1-C6 alkylaminocarbonyl (CONR ８ R ９ (R ８ , R ９ each independently represents H or C1-6 alkyl)), C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR １０ (R １０ is H or C1-6 alkyl, amino, alkylamino (NR １１ R １２ (R １１ R １２ each independently represents H or C1-6 alkyl)), haloalkylsulfanyl, haloalkylsulfinyl, haloalkylsulfonyl, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, sulfo, or sulfamoyl, and may be substituted at 1 to 3 positions by a heterocyclic ring The heterocyclic ring is one selected from the group consisting of pyridine, pyrimidine, thiophene, triazine, pyrrole, pyrazine, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, and thiazole, R ５ represents H, hydroxy, C1-6 alkyl, or halogen; R ６ represents C1-6 alkyl.

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