Novel tryptophan derivative and use thereof

Abstract

The present invention addresses the problem of providing an inexpensive and simple means for evaluating dynamics of Trp and activity of Trp-metabolizing enzyme within a living organism. One aspect of the present invention relates to a compound represented by formula (I) (in the formula, R1, R2, R3, RN1, and RN2 have the same meanings as defined in the specification or claims), a salt thereof, or a solvate thereof. Another aspect of the present invention also relates to: a tryptophan-metabolizing enzyme activity measurement agent comprising the compound according to one aspect of the present invention, a salt thereof, or a solvate thereof; a tryptophan-metabolizing enzyme activity measurement kit comprising the tryptophan-metabolizing enzyme activity measurement agent; a composition comprising the compound according to one aspect of the present invention, a salt thereof, or a solvate thereof, and one or more components; a pharmaceutical composition comprising the compound according to one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable components; and a method for measuring tryptophan-metabolizing enzyme activity.

Description

Novel tryptophan derivatives and their applications

[0001] This invention relates to novel tryptophan derivatives and their uses.

[0002] The essential amino acid tryptophan (Trp) is used in the body to produce serotonin, kynurenic acid, and nicotinamide adenine dinucleotide (NAD). + It produces essential metabolites for life, such as ) and others. Furthermore, changes in the activity of tryptophan-metabolizing enzymes that produce these metabolites are said to be involved in various diseases, including cancer and mental illnesses (such as schizophrenia and depression).

[0003] A method for evaluating the dynamics of Trp in vivo and the activity of Trp metabolic enzymes is known, which involves using high-performance liquid chromatography-mass spectrometry to assess the concentrations of Trp and its metabolite, kynurenine, present in the body (Non-Patent Literature 1).

[0004] Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression, Samara J Brown, Katerina Christofides, Christin Weissleder, Xu-Feng Huang, Cynthia Shannon Weickert, Chai K Lim, Kelly A Newell, Neuropsychopharmacology. 2024 Feb; 49(3): 584-592.DOI: 10.1038 / s41386-023-01736-8, https: / / pubmed.ncbi.nlm.nih.gov / 37735504 /

[0005] As mentioned above, methods for evaluating the dynamics of Trp and the activity of Trp-metabolizing enzymes in vivo using mass spectrometry are known. However, mass spectrometry is not only expensive, but the measurement method is also complex. Therefore, there has been a need for a more inexpensive and simpler method to evaluate the dynamics of Trp and the activity of Trp-metabolizing enzymes in vivo.

[0006] Therefore, the present invention aims to provide a means for evaluating the dynamics of Trp and the activity of Trp metabolic enzymes in vivo by inexpensive and simple means.

[0007] The inventors investigated various means to solve the above-mentioned problems. The inventors created a novel Trp derivative by attaching a fluorescent labeling group to Trp. Furthermore, the inventors found that by using this novel Trp derivative as an in vivo probe, the dynamics of Trp and the activity of Trp metabolic enzymes in vivo can be evaluated inexpensively and simply. Based on the above findings, the inventors completed the present invention.

[0008] In other words, the present invention encompasses the following aspects and embodiments. (Embodiment 1) Formula (I): [In the formula, R 1 and R 2 At least one of the groups is a fluorescent labeling group, and the remaining group is H, R 3 R is an OH, a substituted or unsubstituted alkoxy, a substituted or unsubstituted cycloalkoxy, a substituted or unsubstituted heterocycloalkoxy, a substituted or unsubstituted aryloxy, a substituted or unsubstituted arylalkyloxy, a substituted or unsubstituted arylalkenyloxy, a substituted or unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, a substituted or unsubstituted acyloxy, or a substituted or unsubstituted amino. N1 and R N2 The compounds represented by ] or salts thereof, or solvates thereof. (Embodiment 2) R3 is OH, and R N1 and R N2 are both H, the compound or a salt thereof according to Embodiment 1, or a solvate thereof. (Embodiment 3) R 1 and R 2 one of which is a fluorescent labeling group and the other is H, the compound or a salt thereof according to Embodiment 1 or 2, or a solvate thereof. (Embodiment 4) R 1 is a fluorescent labeling group, and R 2 is H, the compound or a salt thereof according to any one of Embodiments 1 to 3, or a solvate thereof. (Embodiment 5) The fluorescent labeling group is of formula (F-1) or (F-2): (Embodiment 6) A compound or salt thereof, or a solvate thereof, that is a group represented by [wherein the formula, the asterisk indicates the binding position with the remainder.]. (Embodiment 7) A kit for measuring the activity of tryptophan metabolic enzymes, comprising the compound or salt thereof, or a solvate thereof, as described in any of Embodiments 1 to 5. (Embodiment 8) A composition comprising the compound or salt thereof, or a solvate thereof, as described in any of Embodiments 1 to 5, and one or more components. (Embodiment 9) A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as described in any of Embodiments 1 to 5, and one or more pharmaceutically acceptable components. (Embodiment 10) The pharmaceutical composition according to Embodiment 9, for use in the diagnosis, prevention or treatment of one or more symptoms, diseases or disorders related to tryptophan metabolism. (Embodiment 11) A method for measuring tryptophan metabolic enzyme activity, comprising a step of measuring tryptophan metabolic enzyme activity by adding the tryptophan metabolic enzyme activity measuring agent described in Embodiment 6 to a target and measuring the activity of the tryptophan metabolic enzyme. (Embodiment 12) The method according to Embodiment 11, used for screening tryptophan metabolic enzyme activity inhibitors. (Embodiment 13) A method for diagnosing, preventing or treating one or more symptoms, diseases and / or disorders related to tryptophan metabolism, comprising administering an effective amount of a compound described in any of Embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a subject in need of diagnosis, prevention or treatment of such symptoms, diseases and / or disorders. (Embodiment 14) A compound described in any of Embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the diagnosis, prevention or treatment of one or more symptoms, diseases and / or disorders related to tryptophan metabolism. (Embodiment 15) Use of any of the compounds described in Embodiments 1 to 5, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, in the manufacture of a pharmaceutical for the diagnosis, prevention or treatment of one or more symptoms, diseases and / or disorders related to tryptophan metabolism.(Embodiment 16) Use of any of the compounds described in Embodiments 1 to 5, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, for the diagnosis, prevention, or treatment of one or more symptoms, diseases and / or disorders related to tryptophan metabolism.

[0009] Each aspect of the present invention makes it possible to provide an inexpensive and simple means for evaluating the dynamics of Trp and the activity of Trp metabolic enzymes in vivo.

[0010] Other issues, configurations, and effects will be clarified by the following description of the embodiments.

[0011] This specification includes the content described in the specification and / or drawings of Japanese Patent Application No. 2025-024126, which forms the basis of the priority claim of this application.

[0012] This is a schematic diagram illustrating the overview of rat kidney microdialysis (MD) using a 5-FL-L-Trp probe. The diagram compares HPLC-fluorescence chromatograms of MD samples collected before Trp derivative administration (1.0-hour MD, collected over 30 minutes from 1.0 to 1.5 hours), after Trp derivative administration (2.0-hour MD, collected over 30 minutes from 2.0 to 2.5 hours), and after Trp derivative administration (8.0-8.5 hours MD, collected over 30 minutes). In the diagram, the horizontal axis represents retention time (minutes), and the vertical axis represents fluorescence intensity. This figure shows the results of comparing HPLC-fluorescence chromatograms of 2.0-hour MD samples (samples collected during the 30-minute period from 2.0 to 2.5 hours) obtained by administering a 25 μM Trp derivative using test (1) and 2.0-hour MD samples (samples collected during the 30-minute period from 2.0 to 2.5 hours) obtained by administering a 5 μM Trp derivative using test (2). In the figure, the horizontal axis represents retention time (minutes) and the vertical axis represents fluorescence intensity. This is a comparison of HPLC-fluorescence chromatograms of samples obtained in the pharmacological study of Trp derivatives, specifically the 2.0-hour MD sample (collected during the 30-minute period from 2.0 to 2.5 hours) from the sample administered alone with 5 μM Trp derivative (single-administration group) in test (2) and the 2.0-hour MD sample (collected during the 30-minute period from 2.0 to 2.5 hours) from the sample administered in combination with 5 μM Trp derivative and 50 μM 1-methyl-D-Trp (combination-administration group) in test (3). In the figure, the horizontal axis represents retention time (minutes), and the vertical axis represents fluorescence intensity. This is the LC-MS / MS chromatogram obtained in test (1) in the pharmacological study of Trp derivatives. In the figure, the upper panel shows the LC-MS / MS chromatogram of a precursor ion with m / z 459 and a product ion with m / z 217, while the lower panel shows the LC-MS / MS chromatogram of a precursor ion with m / z 463 and a product ion with m / z 221. The horizontal axis represents retention time (minutes), and the vertical axis represents ionic intensity.

[0013] Preferred embodiments of the present invention will be described in detail below.

[0014] <1. Compounds> In this specification, "alkyl" means a linear or branched saturated aliphatic hydrocarbon group containing a specific number of carbon atoms. For example, "C1-C6 alkyl" means a linear or branched saturated aliphatic hydrocarbon group containing at least one and at most six carbon atoms. Preferred alkyls are not limited to, but examples include linear or branched C1-C6 alkyls such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.

[0015] In this specification, "alkenyl" means a group in which one or more single C2-C6 bonds of the alkyl group are replaced by double bonds. Suitable alkenyls are not limited to, but include, for example, linear or branched C2-C6 alkenyls such as vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-pentenyl, and 1-hexenyl.

[0016] In this specification, "alkynyl" means a group in which one or more C2-C6 single bonds of the alkyl group are replaced by triple bonds. Suitable alkynyls are, but are not limited to, linear or branched C2-C6 alkynyls such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, and 1-hexynyl.

[0017] In this specification, "cycloalkyl" means an alicyclic alkyl group containing a specific number of carbon atoms. For example, "C3-C6 cycloalkyl" means a cyclic hydrocarbon group containing at least three and at most six carbon atoms. Preferred cycloalkyls are not limited to, but include, for example, C3-C6 cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0018] In this specification, "cycloalkenyl" means a group in which one or more single CC bonds of the cycloalkyl group are substituted with double bonds. Preferred cycloalkenyls are not limited to, but include, for example, C4-C6 cycloalkenyls such as cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0019] In this specification, "cycloalkynyl" means a group in which one or more CC single bonds of the cycloalkyl group are substituted with triple bonds. Preferred cycloalkynyls are not limited to, but include C4-C6 cycloalkynyls such as cyclobutynyl, cyclopentynyl, and cyclohexynyl.

[0020] In this specification, "heterocycloalkyl" means a group in which one or more carbon atoms of the cycloalkyl, cycloalkenyl, or cycloalkynyl are independently substituted with one or more heteroatoms selected from nitrogen (N), sulfur (S), and oxygen (O). In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heterocycloalkyls are, but are not limited to, 3- to 6-membered heterocycloalkyls such as pyrrolidinyl, tetrahydrofuranil, dihydrofuranil, tetrahydrothienyl, tetrahydropyranil, dihydropyranil, tetrahydrothiopyranil, piperidinyl, morpholinil, thiomorpholinil, and piperazinyl.

[0021] In this specification, "cycloalkylalkyl" means a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is substituted with the cycloalkyl, cycloalkenyl, or cycloalkynyl. Preferred cycloalkylalkyls are not limited to, but include, for example, C3-C6 cycloalkyl-C1-C5 alkyls such as cyclohexylmethyl and cyclohexenylmethyl.

[0022] In this specification, "heterocycloalkylalkyl" means a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl group is substituted with the heterocycloalkyl group. Preferred heterocycloalkylalkyls are, but are not limited to, 3- to 6-membered heterocycloalkyl-C1-C6 alkyl groups.

[0023] In this specification, "alkoxy" and "alkoxyl" mean a group in which a hydrogen atom of hydroxyl is substituted with the alkyl, alkenyl, or alkynyl group. Suitable alkoxys and alkoxyls include, but are not limited to, C1-C6 alkoxys or C1-C6 alkoxyls such as methoxy or methoxyl, ethoxy or ethoxyl, propoxy or propoxyl, butoxy or butoxyl, pentoxy or pentoxyl, and hexoxy or hexoxyl.

[0024] In this specification, "cycloalkoxy" and "cycloalkoxyl" mean a group in which a hydrogen atom of hydroxyl is substituted with the cycloalkyl, cycloalkenyl, or cycloalkynyl group. Suitable cycloalkoxys and cycloalkoxyls are, but are not limited to, C3-C6 cycloalkoxys or C3-C6 cycloalkoxyls such as cyclopropoxy or cyclopropoxyl, cyclobutoxy or cyclobutoxyl, and cyclopentoxy or cyclopentoxyl.

[0025] In this specification, "heterocycloalkoxy" and "heterocycloalkoxyl" mean a group in which a hydrogen atom of hydroxyl is substituted with the heterocycloalkyl group. Suitable heterocycloalkoxys and heterocycloalkoxyls are, but are not limited to, 3- to 6-membered heterocycloalkoxys or 3- to 6-membered heterocycloalkoxyls.

[0026] In this specification, "aryl" means an aromatic ring group. Preferred aryls are, but are not limited to, C6-C6 aryls such as phenyl, biphenyl, terphenyl, naphthyl, and anthracenyl. 18 I can mention Ariel.

[0027] In this specification, "arylalkyl" means a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is substituted with the aryl group. Preferred arylalkyls are, but are not limited to, C6-C6 groups such as benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, terphenylmethyl, and styryl. 15 Aryl-C1 to C6 alkyl or C6 to C 15 Examples include aryl-C2 to C6 alkenyls.

[0028] In this specification, “heteroaryl” means a group in which one or more carbon atoms of the aryl are each independently substituted with one or more heteroatoms selected from N, S, and O. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heteroaryls are, but are not limited to, 5 to 15 member heteroaryls such as furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridadinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, and indolyl.

[0029] In this specification, "heteroarylalkyl" means a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is substituted with the heteroaryl. Preferred heteroarylalkyls are, but are not limited to, 5- to 15-membered heteroaryl-C1-C6 alkyls such as pyridylmethyl or 5- to 15-membered heteroaryl-C2-C6 alkenyls.

[0030] In this specification, "aryloxy" means a group in which a hydrogen atom of hydroxyl is substituted with the aryl group. Preferred aryloxys are, but are not limited to, C6-C6 groups such as phenoxy, biphenyloxy, naphthyloxy and anthryloxy (anthracenyloxy). 18 Aryloxys can be cited as an example.

[0031] In this specification, "arylalkyloxy" means a group in which a hydrogen atom of hydroxyl is substituted with the arylalkyl group. Preferred arylalkyloxys are, but are not limited to, C6-C6 groups such as benzyloxy, 1-phenethyloxy, 2-phenethyloxy, and styryloxy. 18 Aryl-C1-C6 alkyloxy or C6-C 18 Examples include aryl-C2 to C6 alkenyloxys.

[0032] In this specification, "heteroaryloxy" means a group in which a hydrogen atom of hydroxyl is substituted with the heteroaryl group. Suitable heteroaryloxys are, but are not limited to, 5 to 15 member heteroaryloxys such as furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridadinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy, and indolyloxy.

[0033] In this specification, "heteroarylalkyloxy" means a group in which a hydrogen atom of hydroxyl is substituted with the heteroarylalkyl group. Preferred heteroarylalkyloxys are, but are not limited to, 5- to 15-membered heteroaryl-C1-C6 alkyloxys or 5- to 15-membered heteroaryl-C2-C6 alkenyloxys.

[0034] In this specification, "acyl" means a group formed by linking a monovalent group selected from the groups described above with a carbonyl group. Preferred acyls are not limited to, but include, for example, C1-C6 aliphatic acyls such as formyl, acetyl and propionyl, and C7-C6 aliphatic acyls such as benzoyl. 20 C1-C containing aromatic acyls 20 Asil can be mentioned.

[0035] In this specification, "halogen" or "halo" means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0036] Each of the groups described above can be independently unsubstituted or further substituted by one or more of the monovalent groups described above.

[0037] One aspect of the present invention is formula (I): This specification relates to compounds represented by formula (I) or salts thereof, or solvates thereof. In this specification, compounds represented by formula (I) of this embodiment or salts thereof, or solvates thereof may be referred to as "tryptophan derivatives" or "Trp derivatives".

[0038] The inventors have created a novel Trp derivative by attaching a fluorescent labeling group to Trp. Furthermore, the inventors have found that by using this novel Trp derivative as an in vivo probe, the dynamics of Trp and the activity of Trp metabolic enzymes in vivo can be evaluated inexpensively and simply. Therefore, by using the compound represented by formula (I) of this embodiment, the dynamics of Trp and the activity of Trp metabolic enzymes in vivo can be evaluated inexpensively and simply.

[0039] In equation (I), R 1 and R 2 At least one of the groups is a fluorescent labeling group, and the remaining group is H. 1 and R 2 Preferably, one of the components is a fluorescent labeling group and the other is H; R 1 is a fluorescent labeling group, R 2 It is more preferable that R is H. 1 and R 2 When is one of the groups exemplified above, the compound represented by formula (I) in this embodiment can be used to inexpensively and easily evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo.

[0040] In each embodiment of the present invention, the fluorescent labeling group means a free group containing a fluorophore. In formula (I), the fluorescent labeling group is preferably a monovalent group containing a benzofurazan-type fluorophore, more preferably a group represented by formula (F-1) or (F-2), and even more preferably a group represented by formula (F-1). When the fluorescent labeling group is one of the groups exemplified above, the compound represented by formula (I) in this embodiment can be used to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo in an inexpensive and simple manner. [In the formula, the asterisk indicates the bond position with the remainder.]

[0041] In equation (I), R 3 R is an OH group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted cycloalkoxy group, a substituted or unsubstituted heterocycloalkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted arylalkyloxy group, a substituted or unsubstituted arylalkenyloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted heteroarylalkyloxy group, a substituted or unsubstituted acyloxy group, or a substituted or unsubstituted amino group. 3 This includes OH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 member heterocycloalkoxy, and substituted or unsubstituted C6-C6 alkoxy. 18 Aryloxy, substituted or unsubstituted C6-C 18 Aryl-C1 to C6 alkyloxy, substituted or unsubstituted C6 to C 18 Aryl-C2 to C6 alkenyloxys, substituted or unsubstituted 5 to 15-membered heteroaryloxys, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C6 alkyloxys, substituted or unsubstituted C1 to C 20 Preferably, it is an acyloxy, or a substituted or unsubstituted amino; OH, unsubstituted C1-C6 alkoxy, unsubstituted C3-C6 cycloalkoxy, unsubstituted 3-6 member heterocycloalkoxy, unsubstituted C6-C 18 Aryloxy, unsubstituted C6-C 18Aryl-C1 to C6 alkyloxy, unsubstituted C6 to C 18 Aryl-C2 to C6 alkenyloxys, unsubstituted 5 to 15-membered heteroaryloxys, unsubstituted 5 to 15-membered heteroaryl-C1 to C6 alkyloxys, unsubstituted C1 to C 20 It is more preferably an acyloxy or an unsubstituted amino; even more preferably an OH group. 3 When is one of the groups exemplified above, the compound represented by formula (I) in this embodiment can be used to inexpensively and easily evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo.

[0042] In equation (I), R N1 and R N2 These are, independently of each other, H, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heterocycloalkylalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroarylalkyl, or a substituted or unsubstituted acyl. N1 and R N2 These are, independently of each other, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted 3-6 member heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, substituted or unsubstituted 3-6 member heterocycloalkyl-C1-C6 alkyl, and substituted or unsubstituted C6-C 18 Aryl, substituted, or unsubstituted C6-C 18Aryl-C1 to C6 alkyl, substituted or unsubstituted 5 to 15-membered heteroaryl, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C6 alkyl, or substituted or unsubstituted C1 to C 20 Preferably acyl; independently of each other, H, unsubstituted C1-C6 alkyl, unsubstituted C2-C6 alkenyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C3-C6 cycloalkenyl, unsubstituted C3-C6 cycloalkynyl, unsubstituted 3-6 member heterocycloalkyl, unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, unsubstituted 3-6 member heterocycloalkyl-C1-C6 alkyl, unsubstituted C6-C 18 Aryl and unsubstituted C6-C 18 Aryl-C1 to C6 alkyl, unsubstituted 5 to 15-membered heteroaryl, unsubstituted 5 to 15-membered heteroaryl-C1 to C6 alkyl, or unsubstituted C1 to C 20 It is more preferable that they be acyl; it is even more preferable that they are H. N1 and R N2 When is one of the groups exemplified above, the compound represented by formula (I) in this embodiment can be used to inexpensively and easily evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo.

[0043] In formula (I), if the group is substituted, each substituent is independently a halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or Preferably, it is at least one monovalent group selected from the group consisting of unsubstituted heteroarylalkyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, substituted or unsubstituted alkylsulfanyl, and substituted or unsubstituted amino; halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxy, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 member heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 member heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted, or unsubstituted C6-C 15Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 member heteroaryl, substituted or unsubstituted 5-15 member heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 member heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 member heteroaryloxy, substituted or unsubstituted 5-15 member heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted C1-C 20 Acyl, substituted, or unsubstituted C1-C 20 It is more preferable that the monovalent group is at least one monovalent group selected from the group consisting of acyloxy, substituted or unsubstituted C1-C9 alkylsulfanyls, and substituted or unsubstituted aminos; it is even more preferable that the monovalent group is at least one monovalent group selected from the group consisting of halogens (fluorine, chlorine, bromine, or iodine), unsubstituted C1-C5 alkyls, unsubstituted C1-C9 alkylsulfanyls, and unsubstituted aminos. If the monovalent group is substituted, the substituent can be further selected from the monovalent group.

[0044] The compound represented by formula (I) is R as exemplified above. 1 , R 2 , R 3 , R N1 and R N2 It can encompass compounds defined by any combination of the following.

[0045] Preferably, the compound represented by formula (I) is R 1 and R 2 In this case, one side is a fluorescent labeling group and the other side is H; R 3 This includes OH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 member heterocycloalkoxy, and substituted or unsubstituted C6-C6 alkoxy.18 Aryloxy, substituted or unsubstituted C6-C 18 Aryl-C1 to C6 alkyloxy, substituted or unsubstituted C6 to C 18 Aryl-C2 to C6 alkenyloxys, substituted or unsubstituted 5 to 15-membered heteroaryloxys, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C6 alkyloxys, substituted or unsubstituted C1 to C 20 Acyloxy, or substituted or unsubstituted amino; R N1 and R N2 These are, independently of each other, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted 3-6 member heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, substituted or unsubstituted 3-6 member heterocycloalkyl-C1-C6 alkyl, and substituted or unsubstituted C6-C 18 Aryl, substituted, or unsubstituted C6-C 18 Aryl-C1 to C6 alkyl, substituted or unsubstituted 5 to 15-membered heteroaryl, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C6 alkyl, or substituted or unsubstituted C1 to C 20 It is an acyl; if the group is substituted, the substituents are, each independently, a halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxy, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15Aryl, substituted or unsubstituted C6-C 15 aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 member heteroaryl, substituted or unsubstituted 5-15 member heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 member heterocycloalkoxy, substituted or unsubstituted C6-C 15 aryloxy, substituted or unsubstituted C6-C 15 aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 member heteroaryloxy, substituted or unsubstituted 5-15 member heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted C1-C 20 acyl, substituted or unsubstituted C1-C 20 acyloxy, substituted or unsubstituted C1-C9 alkylsulfanyl, and at least one monovalent group selected from the group consisting of substituted or unsubstituted amino.

[0046] More preferably, the compound represented by formula (I) is R 1 and R 2 is a fluorescent labeling group which is a monovalent group containing a benzofurazan type fluorophore on one hand and H on the other hand; R 3 is OH, unsubstituted C1-C6 alkoxy, unsubstituted C3-C6 cycloalkoxy, unsubstituted 3-6 member heterocycloalkoxy, unsubstituted C6-C 18 aryloxy, unsubstituted C6-C 18 aryl-C1-C6 alkyloxy, unsubstituted C6-C 18 aryl-C2-C6 alkenyloxy, unsubstituted 5-15 member heteroaryloxy, unsubstituted 5-15 member heteroaryl-C1-C6 alkyloxy, unsubstituted C1-C 20 acyloxy, or unsubstituted amino; R N1 and R N2are, independently of each other, H, unsubstituted C1-C6 alkyl, unsubstituted C2-C6 alkenyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C3-C6 cycloalkenyl, unsubstituted C3-C6 cycloalkynyl, unsubstituted 3-6 membered heterocycloalkyl, unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, unsubstituted 3-6 membered heterocycloalkyl-C1-C6 alkyl, unsubstituted C6-C 18 aryl, unsubstituted C6-C 18 aryl-C1-C6 alkyl, unsubstituted 5-15 membered heteroaryl, unsubstituted 5-15 membered heteroaryl-C1-C6 alkyl, or unsubstituted C1-C 20 acyl.

[0047] More preferably, in the compound represented by formula (I), R 1 and R 2 is a fluorescent labeling group which is a monovalent group containing a benzofurazan type fluorophore, and the other is H; R 3 is OH; R N1 and R N2 are both H.

[0048] Even more preferably, in the compound represented by formula (I), R 1 and R 2 is a fluorescent labeling group which is a group represented by formula (F-1) or (F-2), and the other is H; R 3 is OH; R N1 and R N2 are both H.

[0049] Particularly preferably, in the compound represented by formula (I), R 1 is a fluorescent labeling group which is a group represented by formula (F-1) or (F-2), R 2 is H; R 3 is OH; R N1 and R N2 are both H.

[0050] Especially particularly preferably, in the compound represented by formula (I), R 1 is a fluorescent labeling group which is a group represented by formula (F-1), R2 H is; R 3 is OH; R N1 and R N2 All of these are H.

[0051] The compounds represented by formula (I) that are particularly preferred are: (S)-2-amino-3-(5-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (5-FL-L-Trp); and (S)-2-amino-3-(7-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (7-FL-L-Trp).

[0052] When the compound represented by formula (I) in this embodiment is the aforementioned compound, it can be used to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo in a particularly inexpensive and simple manner.

[0053] The compound represented by formula (I) includes not only the compound itself but also its salts. While not limited to, salts of the compound represented by formula (I) are preferably salts with cations such as sodium ions, potassium ions, calcium ions, magnesium ions, or substituted or unsubstituted ammonium ions; or salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid; or salts with organic acid anions such as formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid. Even when the compound represented by formula (I) is in the form of the aforementioned salt, it can be used to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo in an inexpensive and simple manner.

[0054] The compound represented by formula (I) includes not only the compound itself but also solvates of the compound or its salt. While not limited to, solvents that can form a solvate with the compound or its salt are preferred, for example, water, or organic solvents such as lower alcohols (e.g., methanol, ethanol, or 2-propanol (isopropyl alcohol) having 1 to 6 carbon atoms), higher alcohols (e.g., 1-heptanol or 1-octanol having 7 or more carbon atoms), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, or ethyl acetate. Even when the compound represented by formula (I) or its salt is in the form of a solvate with the aforementioned solvent, it can be used inexpensively and easily to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo.

[0055] The compound represented by formula (I) includes not only the compound itself but also its protected forms. In this specification, “protected form” means a form in which a protecting group is introduced to one or more functional groups (e.g., an amino group or a carboxylic acid group). In this specification, the protected forms of the compounds represented by each of the above formulas may be described as protected derivatives of the compounds represented by each of the above formulas. In this specification, “protecting group” means a group introduced to a specific functional group in order to prevent the progress of an undesirable reaction, which is quantitatively removed under specific reaction conditions and is substantially stable, i.e., reaction-inactive, under other reaction conditions. The protecting groups that can form the protected form of the above compound are not limited to, but for example, in the case of an amino group protecting group, t-butoxycarbonyl (Boc), 2-bromobenzyloxycarbonyl (BrZ), or 9-fluorenylmethoxycarbonyl (Fmoc) are preferred; in the case of a hydroxyl group protecting group, silyl (e.g., t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), or tert-butyldiphenylsilyl (TBDPS)), or alkoxy (e.g., methoxymethoxy (MOM) or methoxy (Me)) are preferred; and in the case of a carboxylic acid group protecting group, alkyl esters (e.g., methyl, ethyl, or isopropyl esters), arylalkyl esters (e.g., benzyl esters), or amides (e.g., amides with oxazolidinones) are preferred. Protection and deprotection with the above protecting groups can be carried out as appropriate by those skilled in the art based on known reaction conditions. Even when the compound represented by formula (I) is in the protected form with the above protecting group, it may be used to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo in an inexpensive and simple manner.

[0056] If a compound represented by formula (I) has one or more tautomers, the compound also includes the individual tautomer forms of the compound.

[0057] Furthermore, if the compound represented by formula (I) has one or more stereocenters (chiral centers), the compound also includes individual enantiomers and diastereomers of the compound, as well as mixtures thereof such as racemates.

[0058] Having the aforementioned features, the compound represented by formula (I) in this embodiment can be used to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo in an inexpensive and simple manner.

[0059] <2. Method for Producing Novel Compounds> Another aspect of the present invention relates to a method for producing a compound represented by formula (I) in an aspect of the present invention. The method in this aspect includes at least a tryptophan precursor formation step, a fluorescent labeling group introduction step, and a tryptophan derivative formation step. Each step will be described in detail below.

[0060] [2-1. Tryptophan Precursor Formation Process] This process involves formula (XI): A compound represented by or a protected derivative thereof, or a salt or solvate thereof, is reacted with serine to obtain formula (XII): This includes forming a compound represented by or a protected derivative thereof, or a salt or solvate thereof.

[0061] In equations (XI) and (XII), R 1' and R 2' At least one of the groups is a reactive group that can react with the fluorescent labeling group introduction reagent, and the remaining group is H. In the method of this embodiment, R 1 When obtaining a compound represented by formula (I) in which R is a fluorescent labeling group, 1' R is a reactive group that can react with a fluorescent labeling group introduction reagent. In the method of this embodiment, R 2 When obtaining a compound represented by formula (I) in which R is a fluorescent labeling group, 2' This is a reactive group that can react with fluorescent labeling reagents.

[0062] The reactive group that can react with the fluorescent labeling reagent can be appropriately selected depending on the fluorescent labeling reagent described below. For example, if the fluorescent labeling reagent is a compound represented by formula (F-11) or (F-12) described below, the reactive group that can react with the fluorescent labeling reagent is preferably a group having an amino group, more preferably an aminoalkyl group, and even more preferably an aminomethyl group. In this embodiment, the amino group may be in a free form or a protected form.

[0063] The reaction in this step can be carried out, for example, by reacting a compound represented by formula (XI) or its protected derivative, or a salt or solvate thereof, with serine in glacial acetic acid in the presence of a base catalyst and acetic anhydride. Examples of base catalysts include N,N-dimethylaminopyridine and 9-azajuroridine.

[0064] The indole compound and serine used in this process may be prepared by purchasing pre-prepared compounds, or they may be prepared by the user based on reaction conditions known in the art.

[0065] [2-2. Fluorescent Labeling Group Introduction Step] This step involves reacting a compound represented by formula (XII) or its protected derivative, or a salt or solvate thereof, with a fluorescent labeling group introduction reagent to produce formula (XIV): This includes forming a compound represented by or a protected derivative thereof, or a salt or solvate thereof.

[0066] In equation (XIV), R 1 and R 2 This is equivalent to equation (I).

[0067] The fluorescent labeling group introduction reagent used in this process is preferably a benzoflazan-type fluorophore having a monovalent leaving group, more preferably a compound represented by formula (F-11) or (F-12), and even more preferably a compound represented by formula (F-11). In the method of this embodiment, R 1 or R 2If the group is represented by formula (F-1), the fluorescent labeling group introduction reagent is a compound represented by formula (F-11), and R 1 or R 2 If the group is represented by formula (F-2), the fluorescent labeling reagent is the compound represented by formula (F-12).

[0068] In formulas (F-11) and (F-12), Hal is a halogen. Hal is preferably F, Cl, Br, or I, and more preferably F.

[0069] The reaction in this step can be carried out, for example, by reacting a compound represented by formula (XII) or its protected derivative, or a salt or solvate thereof, with a fluorescent labeling group introduction reagent in the presence of a base catalyst. Examples of base catalysts include triethylamine and N,N-dimethylaminopyridine.

[0070] The fluorescent labeling group introduction reagent used in this process may be prepared by purchasing a pre-prepared compound, or it may be prepared by the user based on reaction conditions known in the art.

[0071] [2-3. Tryptophan Derivative Formation Step] This step includes hydrolyzing a compound represented by formula (XIV) or its protected derivative, or a salt or solvate thereof, with acylase to form a compound represented by formula (I) or its protected derivative, or a salt or solvate thereof.

[0072] The method according to this embodiment makes it possible to provide a large quantity of a compound represented by formula (I) according to one embodiment of the present invention, which can be used to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo in an inexpensive and simple manner, at high purity and low cost.

[0073] <3. Pharmaceutical and Other Uses> The compound represented by formula (I) in one aspect of the present invention can be used to evaluate the activity of Trp metabolic enzymes inexpensively and easily. Therefore, another aspect of the present invention relates to an activity meter for Trp metabolic enzymes comprising the compound represented by formula (I) in one aspect of the present invention, a salt thereof, or a solvate thereof. Another aspect of the present invention relates to an activity meter for Trp metabolic enzymes comprising the activity meter for Trp metabolic enzymes in one aspect of the present invention. Furthermore, another aspect of the present invention relates to a composition comprising the compound represented by formula (I) in one aspect of the present invention, a salt thereof, or a solvate thereof, and one or more components.

[0074] A Trp metabolic enzyme activity analyzer, Trp metabolic enzyme activity analyzer kit, and composition according to one aspect of the present invention may be used in vitro or in vivo. By using a Trp metabolic enzyme activity analyzer, Trp metabolic enzyme activity analyzer kit, and composition according to one aspect of the present invention in vitro, the activity of Trp metabolic enzymes can be evaluated inexpensively and easily.

[0075] A Trp metabolic enzyme activity measurement kit according to one aspect of the present invention may include one or more components in addition to the Trp metabolic enzyme activity measurement agent according to one aspect of the present invention. Examples of one or more components include instructions explaining how to use the kit and reagents used for measuring the activity of Trp metabolic enzymes.

[0076] Examples of one or more components included in a composition according to one embodiment of the present invention include various components included in the pharmaceutical composition described below.

[0077] Another aspect of the present invention relates to a method for measuring Trp metabolic enzyme activity using a Trp metabolic enzyme activity measuring agent according to an aspect of the present invention. The method according to this aspect includes a Trp metabolic enzyme activity measurement step of adding the Trp metabolic enzyme activity measuring agent according to an aspect of the present invention to a target and measuring the activity of the Trp metabolic enzyme.

[0078] In the method of this embodiment, the subject is preferably the subject itself as described below, or a biological sample obtained therefrom (for example, blood, body fluids, cells, tissues or organs, or separated fractions thereof).

[0079] The method according to this embodiment allows for inexpensive and simple evaluation of the activity of Trp metabolic enzymes. Therefore, the method according to this embodiment can be used to screen for inhibitors of Trp metabolic enzyme activity. By implementing the method according to this embodiment, inhibitors of Trp metabolic enzyme activity can be found inexpensively and simply.

[0080] One example of a method for measuring or evaluating the activity of Trp metabolic enzymes using the Trp metabolic enzyme activity measuring agent, Trp metabolic enzyme activity measuring kit, and composition according to one aspect of the present invention is high-performance liquid chromatography (HPLC-fluorescence detection method) connected to a fluorescence detector. In the HPLC-fluorescence detection method, the separation conditions of the HPLC and the detection conditions of the fluorescence detector can be appropriately set by those skilled in the art based on the physicochemical properties of the compound represented by formula (I) according to one aspect of the present invention. By using the method exemplified above, the activity of Trp metabolic enzymes can be evaluated inexpensively and simply.

[0081] A compound represented by formula (I) in one aspect of the present invention can be used to inexpensively and easily evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo. Therefore, another aspect of the present invention relates to a pharmaceutical or pharmaceutical composition comprising a compound represented by formula (I) in one aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable components.

[0082] When applying a compound represented by formula (I) to a pharmaceutical application, the compound represented by formula (I) includes not only the compound itself, but also pharmaceutically acceptable salts of the compound and pharmaceutically acceptable solvates thereof. The pharmaceutically acceptable salts of the compound represented by formula (I) and their pharmaceutically acceptable solvates are, but are not limited to, the salts or solvates exemplified above, which are preferred. When the compound represented by formula (I) is in the form of a pharmaceutically acceptable salt or pharmaceutically acceptable solvate, the compound can be applied to the desired pharmaceutical application without substantially reducing the ability to evaluate the dynamics of Trp in vivo and the activity of Trp metabolic enzymes.

[0083] When a compound represented by formula (I) is applied to pharmaceutical use, the compound represented by formula (I) includes not only the compound itself but also its prodrug form. In this specification, "prodrug" means a compound that is converted to a parent drug in vivo. Examples of the prodrug form of the compound are, but are not limited to, an amide of an amino group and any carboxylic acid if an amino group is present, or an ester of a carboxylic acid group and any alcohol, and an amide of a carboxylic acid group and any amine if a carboxylic acid group is present. When the compound represented by formula (I) is in the aforementioned prodrug form, the pharmacokinetics of the prodrug form administered to the target can be improved without substantially reducing the ability to evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo of the parent drug represented by formula (I).

[0084] When a compound represented by formula (I) is applied to a pharmaceutical use, the compound may be used alone or in combination with one or more pharmaceutically acceptable components. The pharmaceuticals of this embodiment can be formulated into various dosage forms commonly used in the art, depending on the desired method of administration. Therefore, the pharmaceuticals of this embodiment may also be provided in the form of a pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable components. Examples of one or more pharmaceutically acceptable components include one or more pharmaceutically acceptable media (e.g., solvents such as sterile water or solutions such as physiological saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, analgesics, antioxidants, sweeteners, and flavoring agents.

[0085] The dosage form of a pharmaceutical product containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is not particularly limited and may be a preparation for parenteral administration or a preparation for oral administration. Furthermore, the dosage form of the pharmaceutical product in this embodiment may be a single-dose preparation or a preparation in multiple dose forms. Examples of preparations for parenteral administration include injectable preparations such as sterile solutions or suspensions with water or other pharmaceutically acceptable media. The components that can be mixed with the injectable preparation are, but are not limited to, those that can be mixed with the injectable preparation, such as a vehicle (e.g., Ringer's solution) such as an isotonic solution containing physiological saline, glucose, or other adjuvants (e.g., D-sorbitol, D-mannitol, D-mannose, or sodium chloride), solubilizers such as alcohol (e.g., ethanol or benzyl alcohol), polyalcohol (e.g., propylene glycol or polyethylene glycol), or esters (e.g., benzyl benzoate), nonionic surfactants such as polysorbate 80 (trademark) or polyoxyethylene hydrogenated castor oil, oily solutions such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, analgesics such as benzalkonium chloride or procaine hydrochloride, stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants. The prepared injectable preparation is usually filled into a suitable vial (e.g., ampoule) and stored in a suitable environment until use.

[0086] Examples of formulations for oral administration include tablets, pills, powders, capsules, soft capsules, microcapsules, elixirs, liquids, syrups, slurries, and suspensions. Tablets may, if desired, be formulated as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, orally disintegrating tablets (OD tablets), or film-coated tablets, or as double or multi-layer tablets.

[0087] The ingredients that can be mixed into tablets or capsules are not limited to, but include, for example, water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, gelatin, corn starch, tragacanth gum or gum arabic as binders; crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or silicic acid as excipients; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, monoglyceride stearate. Examples of ingredients include: disintegrants such as starch, lactose, or polyvinylpyrrolidone; disintegration inhibitors such as sucrose, stearin cocoa butter, or hydrogenated oil; leavening agents such as corn starch, gelatin, or alginic acid; lubricants such as magnesium stearate; absorption enhancers such as quaternary ammonium salts or sodium lauryl sulfate; humectants such as glycerin or starch; adsorbents such as starch, lactose, kaolin, bentonite, or colloidal silicic acid; lubricants such as refined talc, stearate (e.g., magnesium stearate), boric acid powder, or polyethylene glycol; sweeteners such as sucrose, lactose, or saccharin; and flavoring agents such as peppermint, red ginger oil, or cherry. If the formulation is in capsule form, it may further contain a liquid carrier such as oil or fat.

[0088] A pharmaceutical product containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient can also be formulated as a depot formulation. In this case, the pharmaceutical product of this embodiment in depot formulation form can be administered, for example, by subcutaneous or intramuscular implantation, or by intramuscular injection. By applying the pharmaceutical product of this embodiment to a depot formulation, the ability of the compound represented by formula (I) to evaluate the kinetics of Trp in vivo and the activity of Trp metabolic enzymes can be sustainably expressed over a long period of time.

[0089] A pharmaceutical product containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as an active ingredient may be used in combination with one or more other pharmaceutically useful agents. Examples of other agents used in combination include, but are not limited to, Trp metabolic enzyme inhibitors (e.g., 1-methyl-D-tryptophan (indoximod) or epacadostat, which are indoleamine 2,3-dioxygenase (IDO) inhibitors), cyclooxygenase-2 (COX-2) inhibitors (e.g., celecoxib or piroxicam), and anticancer agents (e.g., docetaxel). In this case, the pharmaceutical product of this embodiment takes the form of a combination pharmaceutical product comprising the active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more of the aforementioned other agents. The combination drug may be in the form of a pharmaceutical composition comprising a compound represented by formula (I) as an active ingredient, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more of the other drugs, or it may be in the form of a pharmaceutical composition used in combination with one or more of the other drugs, which contains a compound represented by formula (I) as an active ingredient, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. When the drug of this embodiment is in the form of a combination drug as described above, it may be provided in the form of a single formulation containing a compound represented by formula (I) as an active ingredient, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more of the other drugs, or it may be provided in the form of a combination drug or kit containing multiple formulations in which one or more of the other drugs are formulated separately. In the form of a combination drug or kit, each formulation can be administered simultaneously or separately (for example, sequentially).

[0090] The compound represented by formula (I) can be used to inexpensively and easily evaluate the dynamics of Trp and the activity of Trp metabolic enzymes in vivo. Therefore, the pharmaceutical product of this embodiment is preferably used for the diagnosis, prevention, or treatment of one or more symptoms, diseases, or disorders related to Trp metabolism, and more preferably for the diagnosis of one or more symptoms, diseases, or disorders related to Trp metabolism.

[0091] One or more symptoms, diseases, or disorders related to Trp metabolism include, but are not limited to, cancer, schizophrenia, and major depressive disorder. The aforementioned symptoms, diseases, and / or disorders are preferably one or more selected from the group consisting of, for example, cancer, schizophrenia, and major depressive disorder, and are more preferably cancer or schizophrenia. By administering the pharmaceutical agent of this embodiment to a subject who requires diagnosis, prevention, or treatment of the aforementioned one or more symptoms, diseases, and / or disorders, the aforementioned diseases, symptoms, or disorders can be diagnosed, prevented, or treated.

[0092] A pharmaceutical product containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as an active ingredient can be applied to a variety of subjects requiring the diagnosis, prevention, or treatment of one or more of the aforementioned symptoms, diseases, and / or disorders. The subject is preferably a human or non-human mammal (e.g., a warm-blooded animal such as a pig, dog, cattle, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon, or chimpanzee). By administering the pharmaceutical product according to this embodiment to the subject, one or more of the aforementioned symptoms, diseases, and / or disorders present in the subject can be diagnosed, prevented, or treated.

[0093] In this specification, “diagnosis” means identifying the onset or manifestation of symptoms, diseases and / or disorders or the likelihood thereof. In this specification, “prevention” means substantially preventing the onset or manifestation of symptoms, diseases and / or disorders. In this specification, “treatment” means suppressing (e.g., inhibiting progression), alleviating, restoring, and / or curing symptoms, diseases and / or disorders that have occurred or manifested.

[0094] The compound represented by formula (I) can be used in the diagnosis, prevention, or treatment of one or more of the symptoms, diseases, and / or disorders in subjects having said one or more symptoms, diseases, and / or disorders. Therefore, the pharmaceutical product of this embodiment is preferably a pharmaceutical product for use in the diagnosis, prevention, or treatment of one or more symptoms, diseases, and / or disorders selected from the group consisting of cancer, schizophrenia, and major depressive disorder, and more preferably a pharmaceutical product for use in the diagnosis, prevention, or treatment of cancer or schizophrenia. By using the pharmaceutical product of this embodiment for the diagnosis, prevention, or treatment of one or more of the symptoms, diseases, and / or disorders, said symptoms, diseases, and / or disorders can be diagnosed, prevented, or treated inexpensively and easily.

[0095] The compound represented by formula (I) can be used in the diagnosis, prevention, or treatment of the symptoms, diseases, and / or disorders in subjects having one or more of the aforementioned symptoms, diseases, and / or disorders. Therefore, another aspect of the present invention is a method for diagnosing, preventing, or treating the symptoms, diseases, and / or disorders in subjects requiring diagnosis, prevention, or treatment of the aforementioned symptoms, diseases, and / or disorders, comprising administering an effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a subject requiring diagnosis, prevention, or treatment of the aforementioned symptoms, diseases, and / or disorders. The one or more symptoms, diseases, and / or disorders are preferably one or more selected from the group consisting of cancer, schizophrenia, and major depressive disorder as described above, and more preferably cancer or schizophrenia. By administering the compound represented by formula (I) or the pharmacopoeia of this aspect to a subject requiring diagnosis, prevention, or treatment of the aforementioned symptoms, diseases, and / or disorders, the symptoms, diseases, and / or disorders can be diagnosed, prevented, or treated inexpensively and easily.

[0096] Another aspect of the present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the diagnosis, prevention, or treatment of one or more symptoms, diseases and / or disorders. Another aspect of the present invention is the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the diagnosis, prevention, or treatment of one or more symptoms, diseases and / or disorders. Yet another aspect of the present invention is the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the diagnosis, prevention, or treatment of one or more symptoms, diseases and / or disorders. The one or more symptoms, diseases and / or disorders are preferably one or more symptoms, diseases and / or disorders selected from the group consisting of cancer, schizophrenia, and major depressive disorder as described above, and more preferably cancer or schizophrenia. By using a compound represented by formula (I) or a pharmaceutical product according to this embodiment to diagnose, prevent, or treat one or more of the symptoms, diseases, and / or disorders, the symptoms, diseases, and / or disorders can be diagnosed, prevented, or treated inexpensively and easily.

[0097] When administering a pharmaceutical product containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as an active ingredient to a subject, particularly a human patient, the precise dosage and administration method (e.g., dose, frequency of administration, and / or route of administration) should be ultimately determined by the attending physician, taking into account many factors such as the subject's age, weight, and / or sex, the exact state (e.g., severity) of the symptoms, disease, and / or disorder to be diagnosed, prevented, or treated, and the route of administration, and considering the therapeutically effective dose, frequency of administration, and route of administration. Therefore, in the pharmaceutical product of this embodiment, the active ingredient, the compound represented by formula (I), is administered to the subject in a therapeutically effective amount and frequency. For example, when administering the pharmaceutical product of this embodiment to a human patient, the dose of the active ingredient, the compound represented by formula (I), is usually in the range of 0.001 to 100 mg / kg body weight per dose, typically in the range of 0.01 to 10 mg / kg body weight per dose, and particularly in the range of 0.1 to 10 mg / kg body weight per dose. Furthermore, the number of times the pharmaceutical agent of this embodiment is administered can be, for example, once or multiple times a day, or once every few days. The route of administration of the pharmaceutical agent of this embodiment is not particularly limited and may be administered orally, or parenterally (for example, rectally, transmucosa, intestine, intramuscularly, subcutaneously, intramedullarily, intrasacrally, directly into the ventricle, intravenously, intravitreously, intraperitoneally, intranasally, or intraocularly) as a single or multiple doses. By using the pharmaceutical agent of this embodiment in the above-described dosage and method of use, one or more of the above-described symptoms, diseases, and / or disorders can be diagnosed, prevented, or treated inexpensively and easily.

[0098] The present invention will be described in more detail below using examples. However, the technical scope of the present invention is not limited to these examples.

[0099] <I: Synthesis of Compounds> [I-1: Synthesis of (S)-2-amino-3-(5-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (5-FL-L-Trp)] tert-butyl((1H-indole-5-yl)methyl)carbamate (1H-indole-5-yl)methaneamine (1.00 mmol) was dissolved in 99.5% ethanol (2 mL). Di-t-butyl dicarbonate (1.50 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate (100 mL). This was transferred to a separatory funnel and washed with saturated sodium bicarbonate aqueous solution (50 mL). The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the solvent was removed by distillation. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 9:1), and the fraction containing the target substance was concentrated to dryness, yielding tert-butyl ((1H-indole-5-yl)methyl)carbamate as a white solid (0.75 mmol, 75%). m / z [M+H] 247.1510 (C 14 H 19 Calculated value for N2O2: 247.1441) 1 H-NMR (400 MHz, chloroform-D) δ 8.70 (s, 1H, indole-NH), 7.48 (s, 1H, ArH), 7.24 (d, J = 8.2 Hz, 1H, ArH), 7.09 (t, J = 2.7 Hz, 1H, ArH), 7.04 (d, J = 8.2 Hz, 1H, ArH), 6.44 (t, J = 2.1 Hz, 1H, ArH), 4.96 (s, 1H, CONH), 4.36 (d, J = 5.3 Hz, 2H, CH2), 1.48 (d, J = 8.2 Hz, 9H, tertBuH), 13 ¹¹C-NMR (10¹ MHz, chloroform-D) δ values: 155.9, 135.1, 129.6, 127.7, 124.8, 121.6, 119.4, 111.2, 101.9, 79.2, 45.1, 28.3.

[0100] 2-Acetamide-3-(5-(((tert-butoxycarbonyl)amino)methyl)-1H-indole-3-yl)propanoic acid 7.01 mmol of tert-butyl ((1H-indole-5-yl)methyl) carbamate, 14.0 mmol of DL-serine, a catalytic amount of N,N-dimethylaminopyridine, and 5 mL of acetic anhydride were dissolved in 50 mL of glacial acetic acid and heated and stirred for 1 hour at 80°C. The reaction solution was cooled to room temperature. The reaction solution was diluted with 50 mL of ethyl acetate. This was transferred to a separatory funnel, and the target substance was extracted into 100 mL of saturated sodium bicarbonate aqueous solution. The resulting aqueous layer was adjusted to approximately 1 pH using 35% hydrochloric acid. This was transferred to a separatory funnel and extracted with ethyl acetate (50 mL x 2 times). The organic layer was dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed by distillation. The residue was purified by chromatography (octadecylated silica gel, eluent: 0.1% acetic acid - [water / methanol 1:1]). When the fraction containing the target substance was concentrated, 2-acetamido-3-(5-(((tert-butoxycarbonyl)amino)methyl)-1H-indole-3-yl)propanoic acid was obtained (3.92 mmol, 56%). m / z [M+H] 367.1864(C 19 H 26 Calculated value for N3O5: 376.1867) 1 H-NMR (400 MHz, DMSO-D6) δ 10.70 (d, J = 1.8 Hz, 1H, indole-NH), 8.06 (d, J = 7.8 Hz, 1H, NH), 7.39 (s, 1H, NH), 7.25 (d, J = 8.5 Hz, 1H, ArH), 7.15 (t, J = 6.0 Hz, 1H, ArH), 7.10 (d, J = 2.1 Hz, 1H, ArH), 6.99 (dd, J = 8.5, 1.4 Hz, 1H, ArH), 4.46 (td, J = 8.2, 4.9 Hz, 1H, α-CH), 4.20 (d, J = 6.2 Hz, 2H, CH2), 3.19-3.13 (m, 1H, β-CH2), 2.98 (dd, J = 14.7, 8.9 Hz, 1H, β-CH2), 1.81 (s, 3H, AcH), 1.40 (s, 9H, tertBuH), 13C-NMR (101 MHz, DMSO-D6) δ 173.6, 169.3, 155.7, 135.2, 129.9, 127.1, 123.8, 120.8, 116.6, 111.1, 109.8, 77.5, 53.0, 44.2, 28.3, 27.1, 22.4.

[0101] 2-Acetamide-3-(5-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid 2-Acetamido-3-(5-(((tert-butoxycarbonyl)amino)methyl)-1H-indole-3-yl)propanoic acid (0.200 mmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. 99.5% ethanol (4 mL), triethylamine (0.4 mL), and 7-fluoro-N,N-dimethylbenzo[c][1,2,5]oxadiazole-4-sulfonamide (0.225 mmol) were added to the residue and stirred at room temperature under an argon atmosphere for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). This was transferred to a separatory funnel, and the target substance was extracted from the organic layer into an aqueous layer of saturated sodium bicarbonate aqueous solution (50 mL). The pH of the aqueous layer was adjusted to approximately 1 using 6 M hydrochloric acid. The aqueous layer was transferred to a separatory funnel and extracted with ethyl acetate (50 mL). The resulting organic layer was dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed by distillation. The residue was purified by chromatography (octadecylsilylated silica gel, eluent: water / methanol 1:1, followed by silica gel, eluent: ethyl acetate / methanol 2:1) to obtain 2-acetamido-3-(5-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid as a yellow solid (47.0 μmol, 24%). m / z [M+Na] 523.1216 (C 22 H 24 Calculated value for N6NaO6S: 523.1370), 1¹H-NMR (400 MHz, methanol-D4) δ 7.74 (d, J = 8.1 Hz, 1H, ArH), 7.64 (s, 1H, ArH), 7.27 (d, J = 8.2 Hz, 1H, ArH), 7.13-7.10 (m, 2H, ArH), 6.24 (d, J = 8.2 Hz, 1H, ArH), 4.63-4.58 (m, 3H, indole-5-CH2 and α-CH), 3.37-3.32 (m, overlap with solvent signal, β-CH2), 3.11 (dd, J = 14.7, 7.7 Hz, 1H, β-CH2), 2.67-2.78 (s, 6H, N(CH3)2), 1.82 (s, 3H, Acetyl H), 13 ¹¹C-NMR (10¹ MHz, methanol-D4) δ values: 172.7, 147.9, 145.9, 142.9, 141.6, 137.5, 129.4, 128.5, 125.1, 122.1, 118.8, 112.6, 112.0, 107.5, 100.4, 56.6, 49.8, 49.3, 38.2, 28.9, 22.8.

[0102] (S)-2-amino-3-(5-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (5-FL-L-Trp) 2-Acetamido-3-(5-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (0.237 mmol) was suspended in 50 mM phosphate buffer (pH 7.5) (50 mL). Cobalt chloride hexahydrate (catalytic amount) and acylase I (catalytic amount) were added, and the mixture was stirred at 45°C for 39 hours. Subsequently, the mixture was purified by chromatography (octadecylated silica gel, eluent: 0.1% acetate-[water / methanol 1:1]), and the fraction containing the target substance was concentrated. Recrystallization of the residue from hot water yielded (S)-2-amino-3-(5-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (5-FL-L-Trp) as a yellow solid (48.0 μmol, 41.8%). m / z [M+H] 459.1283 (C 20 H 23 Calculated value for N6O5S: 459.1445) 1 H-NMR (400 MHz, DMSO-D6) δ 10.92 (s, 1H, indole-NH), 9.03 (s, 1H, CH2NH), 7.75 (d, J = 8.1 Hz, 1H, ArH), 7.69 (s, 1H, ArH), 7.30 (d, J = 8.4 Hz, 1H, ArH), 7.19 (d, J = 1.5 Hz, 1H, ArH), 7.15 (d, J = 8.4 Hz, 1H, ArH), 6.35 (d, J = 8.1 Hz, 1H, ArH), 4.64 (s, 2H, CH2NH), 3.44 (dd, J = 9.0, 3.8 Hz, 1H, α-CH2), 3.30 (dd, J = 15.1, 3.5 Hz, 1H, β-CH2), 2.94 (dd, J = 15.1, 9.3 Hz, 1H, β-CH2), 2.64 (s, 6H, N(CH3)2), 13C-NMR (101 MHz, DMSO-D6) δ 169.8, 146.4, 144.4, 141.0, 140.5, 135.7, 127.4, 127.2, 124.7, 120.8, 117.9, 111.5, 109.6, 105.1, 99.5, 54.7, 47.0, 37.4, 27.1.

[0103] [I-2: Synthesis of (S)-2-amino-3-(7-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (7-FL-L-Trp)] tert-butyl((1H-indole-7-yl)methyl)carbamate (1H-indole-7-yl)methaneamine (18.9 mmol), triethylamine, and water (10 mL) were dissolved in tert-butanol (160 mL). Di-t-butyl dicarbonate (31.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 9:1). When the fraction containing the target substance was concentrated to dryness, tert-butyl ((1H-indole-7-yl)methyl)carbamate was obtained as a white solid (17.7 mmol, 94%). m / z [M+H] 247.1463(C 14 H 19 Calculated value for N2O2: 247.1441) 1 ¹H-NMR (400 MHz, chloroform-D) δ 9.94 (s, 1H, indole-NH), 7.60 (d, J = 7.8 Hz, 1H, ArH), 7.24-7.23 (m, 1H, ArH), 7.03-7.00 (m, 1H, ArH), 6.95 (d, J = 7.0 Hz, 1H, ArH), 6.55-6.54 (m, 1H, ArH), 5.09 (s, 1H, CONH), 4.53 (d, J = 6.9 Hz, 2H, CH2NH), 1.45 (s, 9H, tertBuH), 13¹¹C-NMR (10¹ MHz, chloroform-D) δ values: 157.5, 134.6, 128.2, 124.5, 122.4, 121.7, 120.7, 119.1, 102.2, 80.2, 42.4, 28.3.

[0104] 2-Acetamide-3-(7-(((tert-butoxycarbonyl)amino)methyl)-1H-indole-3-yl)propanoic acid 17.7 mmol of tert-butyl((1H-indole-7-yl)methyl)carbamate, 36.5 mmol of DL-serine, and 15 mL of acetic anhydride were dissolved in 50 mL of glacial acetic acid and heated and stirred for 2 hours (73°C). The reaction solution was cooled to room temperature. A 30% aqueous sodium hydroxide solution was added to adjust the pH to approximately 11. This was transferred to a separatory funnel, and the aqueous layer was washed with chloroform (100 mL). The resulting aqueous layer was adjusted to approximately 2 pH using 35% hydrochloric acid. This was transferred to a separatory funnel and extracted with ethyl acetate (100 mL x 4 times). The organic layer was dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed by distillation. The residue was purified by chromatography (octadecylated silica gel, eluent: 0.1% acetic acid - [water / methanol 1:1], then silica gel, eluent: ethyl acetate). The fraction containing the target substance was concentrated. The residue was suspended in hexane. The solid was filtered off and dried under reduced pressure to obtain 2-acetamido-3-(7-(((tert-butoxycarbonyl)amino)methyl)-1H-indole-3-yl)propanoic acid as a brownish-gray solid (10.8 mmol, 61%). m / z [MH] 347.1746 (C 19 H 24 Calculated value for N3O5: 374.1716) 1H-NMR (400 MHz, methanol-D4) δ 7.49 (q, J = 3.0 Hz, 1H, ArH), 7.10 (s, 1H, ArH), 6.98 (t, J = 2.8 Hz, 2H, ArH), 4.70 (dd, J = 7.9, 5.0 Hz, 1H, α-CH2), 4.42 (s, 2H, CH2NH), 3.36-3.32 (m, 1H, β-CH2), 3.14 (dd, J = 14.7, 8.0 Hz, 1H, β-CH2), 1.88 (s, 3H, COCH3), 1.39 (d, J = 39.4 Hz, 9H, tertBuH), 13 ¹¹C-NMR (10¹ MHz, methanol-D4) δ values: 175.3, 173.1, 159.0, 136.0, 129.1, 124.2, 123.6, 121.8, 119.9, 118.8, 111.7, 80.3, 54.9, 42.1, 28.8, 28.5, 22.4.

[0105] 2-Acetamide-3-(7-(((7-(((N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid 2-Acetamido-3-(7-(((tert-butoxycarbonyl)amino)methyl)-1H-indole-3-yl)propanoic acid (0.206 mmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Acetonitrile (10 mL), diisopropylethylamine (2 mmol), and 7-fluoro-N,N-dimethylbenzo[c][1,2,5]oxadiazole-4-sulfonamide (0.211 mmol) were added to the residue and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL). This was transferred to a separatory funnel, and the target substance was extracted from the organic layer into an aqueous layer of saturated sodium bicarbonate solution (50 mL x 4 times). The combined aqueous layer was adjusted to approximately 1 pH using 6 M hydrochloric acid. The aqueous layer was transferred to a separatory funnel and extracted with ethyl acetate (50 mL x 4 times). The resulting organic layer was dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed by distillation. The residue was purified by chromatography (silica gel, eluent: 0.1% acetate-[chloroform / methanol 4:1]) to obtain 2-acetamido-3-(7-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid as a yellow solid (0.185 mmol, 90%). m / z [MH] 499.1421 (C 22 H 23 Calculated value for N6O6S: 499.1400) 1H-NMR (400 MHz, methanol-D4) δ 7.75 (dd, J = 8.1, 0.6 Hz, 1H, ArH), 7.52 (d, J = 7.7 Hz, 1H, ArH), 7.14-7.12 (m, 2H, ArH), 6.98 (t, J = 7.6 Hz, 1H, ArH), 6.23 (d, J = 8.1 Hz, 1H, ArH), 4.82 (s, 2H, NHCH2), 4.65 (d, J = 5.0 Hz, 1H, α-CH), 3.35 (dd, J = 14.5, 4.4 Hz, 1H, β-CH2), 3.13 (dd, J = 14.5, 7.8Hz, 1H, β-CH2), 2.74 (s, 6H, N(CH3)2), 1.98 (s, 3H), 1.87 (s, 3H, acetyl-H), 13 ¹¹C-NMR (10¹ MHz, methanol-D4) δ values: 147.8, 145.8, 142.9, 141.3, 136.0, 129.7, 124.7, 121.8, 120.7, 119.9, 119.3, 112.3, 108.3, 100.6, 45.1, 38.1, 28.6, 22.6.

[0106] (S)-2-amino-3-(7-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (7-FL-L-Trp) 2-Acetamido-3-(7-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (0.185 mmol) was suspended in 50 mM phosphate buffer (pH 7.5) (50 mL). Cobalt chloride hexahydrate (109 mg) and acylase I (106 mg) were added, and the mixture was stirred at 37°C for 17 hours. The reaction mixture was adjusted to approximately 2 pH using 35% hydrochloric acid. This was transferred to a separatory funnel and extracted with ethyl acetate (100 mL x 3 times). The organic layer was dried over anhydrous sodium sulfate. After filtering off the drying agent and removing the solvent by distillation, a fraction containing (R)-2-acetamido-3-(7-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid was obtained. Subsequently, the aqueous layer was adjusted to a pH of approximately 6 using concentrated potassium hydroxide aqueous solution. After concentration, this was purified by chromatography (octadecylated silica gel, eluent: 0.1% acetate-[water / methanol 1:1]). The fraction containing the target substance was concentrated. Recrystallization of the residue from hot water yielded (S)-2-amino-3-(7-(((7-(N,N-dimethylsulfamoyl)benzo[c][1,2,5]oxadiazole-4-yl)amino)methyl)-1H-indole-3-yl)propanoic acid (7-FL-L-Trp) as a yellow solid (54.8 μmol, 59%). m / z [MH] 457.1336 (C 20 H 21 Calculated value for N6O5S: 457.1294) 1H-NMR (400 MHz, DMSO-D6) δ 11.24 (d, J = 0.6 Hz, 1H, インドール-NH), 8.90 (t, J = 6.1 Hz, 1H, NHCH2), 7.68 (d, J = 8.2 Hz, 1H, ArH), 7.44 (d, J = 7.9 Hz, 1H, ArH), 7.23 (d, J = 1.7 Hz, 1H, ArH), 7.09 (d, J = 7.1 Hz, 1H, ArH), 6.88 (t, J = 7.6 Hz, 1H, ArH), 6.24 (d, J = 8.2 Hz, 1H, ArH), 4.77 (d, J = 5.5Hz, 2H, NHCH2), 3.77-3.74 (m, 1H, α-CH2), 3.21 (dd, J = 14.9, 5.1 Hz, 1H, β-CH2), 3.07 (dd, J = 15.1, 7.3 Hz, 1H, β-CH2), 2.58 (s, 6H, N(CH3)2), 13 C-NMR (101 MHz, DMSO-D6) δ 170.6, 146.4, 144.4, 140.2, 134.4, 127.6, 124.7, 120.5, 120.0, 118.5, 117.9, 108.6, 105.8, 99.3, 53.6, 43.4, 37.4, 26.5, 17.8.

[0107] <II. Pharmacological Tests of Trp Derivatives> [II-1: Rat Kidney Microdialysis Using 5-FL-L-Trp Probe] (1) Detection of Metabolites by Administration of Trp Derivatives Figure 1 shows an overview of rat kidney microdialysis (MD) using a 5-FL-L-Trp probe. A dialysis membrane was inserted into the left kidney of a male SD rat (9 weeks old). Ringer's solution (0–1.5 hours, 1.0 μL / min) was delivered to the dialysis membrane using a syringe pump. Subsequently, a 25 μM 5-FL-L-Trp probe (Trp derivative) dissolved in Ringer's solution (1.5–9.5 hours) was delivered to the dialysis membrane. Each dialysis solution was collected into a microtube every 30 minutes. The collected MD samples were measured by HPLC-fluorescence detection under the following measurement conditions. [HPLC-Fluorescence Detection Measurement Conditions] • Column: GL Sciences InertSustain C18 (5 μm, 4.6 × 250 mm) • Column Oven Temperature: 40°C • Flow Rate: 1.0 mL / min • Injection Sample: Collected MD sample (5-fold dilution with mobile phase A) • Injection Volume: 10 μL • Mobile Phase: A: 20 mM ammonium formate H2O / MeOH (90 / 10) solution B: MeOH • Gradient: B 20% (70 min) → B 100% (10 min) → B 20% (10 min) • Detection: Excitation Wavelength: 450 nm, Detection Wavelength: 560 nm

[0108] Figure 2 shows a comparison of HPLC-fluorescence chromatograms of MD samples taken before administration of the Trp derivative (1.0-hour MD sample, collected over 30 minutes from 1.0 to 1.5 hours), and MD samples taken after administration of the Trp derivative (2.0-hour MD sample, collected over 30 minutes from 2.0 to 2.5 hours), and 8.0-hour MD sample, collected over 30 minutes from 8.0 to 8.5 hours). In the figure, the horizontal axis represents retention time (minutes), and the vertical axis represents fluorescence intensity. As shown in Figure 2, multiple peaks of endogenous substances were confirmed even before administration of the Trp derivative (peaks marked with an asterisk). In addition to these peaks, after administration of the Trp derivative, peaks presumed to be metabolites of the Trp derivative (peaks indicated by black arrows, hereinafter simply referred to as metabolites) that were not detected before administration were detected. This suggests that the concentration of these peaks changes over time.

[0109] (2) Changes in the amount of metabolites produced due to changes in the administered concentration of the Trp derivative The test was carried out in the same procedure as above, except that the administered concentration of the Trp derivative was changed to 5.0 μM and the administration period was changed to 1.5 to 3.5 hours. The collected MD samples were measured under the same measurement conditions as above (1).

[0110] Figure 3 shows a comparison of HPLC-fluorescence chromatograms of a 2.0-hour MD sample (collected during the 30-minute period from 2.0 to 2.5 hours) obtained by administering a 25 μM Trp derivative in the test described in (1) above, and a 2.0-hour MD sample (collected during the 30-minute period from 2.0 to 2.5 hours) obtained by administering a 5.0 μM Trp derivative in this test. In the figure, the horizontal axis represents retention time (minutes), and the vertical axis represents fluorescence intensity. As shown in Figure 3, the magnitude of the metabolite peaks (peaks indicated by black arrows) changed in a concentration-dependent manner with respect to the administered Trp derivative.

[0111] (3) Changes in the amount of metabolites produced with concomitant administration of tryptophan metabolic enzyme inhibitors It is known that the kidney contains indoleamine 2,3-dioxygenase (IDO), a type of tryptophan metabolic enzyme. It is also known that 1-methyl-D-tryptophan (1-methyl-D-Trp) acts as an IDO inhibitor (Oncotarget. 2016 Mar 20;7(16):22928-22938. DOI: 10.18632 / oncotarget.8216). Therefore, we investigated the changes in the amount of metabolites produced by concomitant administration of a Trp derivative and an IDO inhibitor. The test was conducted in the same procedure as described in (2) above, except that 50 μM 1-methyl-D-Trp was delivered prior to the delivery of 5.0 μM Trp derivative (1.5 to 3.5 hours) (0 to 3.5 hours). This test was designated as the concomitant administration group. The collected MD samples were measured under the same measurement conditions as in (1) above.

[0112] Figure 4 shows a comparison of HPLC-fluorescence chromatograms of the 2.0-hour MD sample (collected during the 30-minute period from 2.0 to 2.5 hours) of the sample after administration of 5 μM Trp derivative alone (single-administration group) in the test described in (2) above, and the 2.0-hour MD sample (collected during the 30-minute period from 2.0 to 2.5 hours) of the sample after co-administration of 5.0 μM Trp derivative and 50 μM 1-methyl-D-Trp in this test (combination-administration group). In the figure, the horizontal axis represents retention time (minutes), and the vertical axis represents fluorescence intensity. As shown in Figure 4, the peak area of ​​the metabolite in the combination-administration group was reduced to approximately 22% compared to the single-administration group.

[0113] The results of the tests described in (1), (2), and (3) above show that the Trp derivative of the present invention is metabolized by IDO in rat kidneys, similar to Trp, and the resulting metabolites can be easily detected by HPLC-fluorescence detection.

[0114] (4) In the tryptophan metabolic pathway in the putative kidney produced by the administration of Trp derivatives, it is known that tryptophan is metabolized by IDO to produce kynurenine (KYN). Therefore, we investigated the possibility that KYN analogs are produced by the administration of Trp derivatives. The MD samples obtained in the above test (1) (samples collected within 30 minutes from 8.5 to 9.0 hours after administration of 25 μM Trp derivative) were subjected to LC-MS / MS under the following measurement conditions to detect Trp derivatives and metabolites in the samples. [LC-MS / MS Measurement Conditions] ・Column: GL Science InertSustain C18 (3 μm, 2.1 × 250 mm) ・Column Oven Temperature: 50℃ ・Flow Rate: 0.2 mL / min ・Injection Sample: MD sample recovered (5-fold dilution with mobile phase A) ・Injection Volume: 5.0 μL ・Mobile Phase: A: 20 mM ammonium formate H2O / MeOH (90 / 10) solution B: MeOH ・Gradient: B 20% (90 min) → B 100% (10 min) → B 20% (10 min) ・Detection Mode: Positive Ion Mode ・Mass Spectrometer Parameters (Detection of Trp Derivatives) Collision Energy: -15 V, Precursor Ion: m / z 459, Product Ion: m / z 217 (Detection of Metabolites) Collision Energy: -15 V, Precursor Ion: m / z 463, Product ion: m / z 221

[0115] Figure 5 shows the LC-MS / MS chromatograms obtained in the test described in (1) above. In the figure, the upper panel shows the LC-MS / MS chromatogram of the precursor ion: m / z 459, product ion: m / z 217, and the lower panel shows the LC-MS / MS chromatogram of the precursor ion: m / z 463, product ion: m / z 221. The horizontal axis represents retention time (minutes), and the vertical axis represents ionic intensity. As shown in Figure 5, the Trp derivative was detected at a retention time of approximately 31 minutes, and the metabolite at approximately 18 minutes. From the m / z values ​​of the precursor and product ions, it was indicated that the metabolite is a KYN analog (5-FL-KYN) having the structure shown in the figure. Furthermore, the detected fragment ions suggested that cleavage occurs at the sites indicated by the dotted lines in each structural formula in the figure.

[0116] It should be noted that the present invention is not limited to the embodiments described above, and various modifications are included. For example, the embodiments described above are described in detail for the purpose of clearly illustrating the present invention, and are not necessarily limited to those having all the configurations described. Furthermore, it is possible to add, delete, and / or replace some of the configurations in each embodiment with other configurations.

[0117] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

Claims

1. Equation (I): [In the formula, R 1 and R 2 At least one of the groups is a fluorescent labeling group, and the remaining group is H, R 3 R is an OH, a substituted or unsubstituted alkoxy, a substituted or unsubstituted cycloalkoxy, a substituted or unsubstituted heterocycloalkoxy, a substituted or unsubstituted aryloxy, a substituted or unsubstituted arylalkyloxy, a substituted or unsubstituted arylalkenyloxy, a substituted or unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, a substituted or unsubstituted acyloxy, or a substituted or unsubstituted amino. N1 and R N2 The compounds represented by [ ] or their salts, or solvates thereof, are independently of each other: H, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heterocycloalkylalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroarylalkyl, or a substituted or unsubstituted acyl.

2. R 3 is OH, and R N1 and R N2 The compound or salt thereof according to claim 1, or a solvate thereof, wherein all of the atoms are H.

3. R 1 and R 2 The compound or salt thereof according to claim 1, or a solvate thereof, wherein one of R 1 and R 2 is a fluorescent labeling group and the other is H.

4. R 1 is a fluorescent labeling group, R 2 The compound or salt thereof according to claim 1, or a solvate thereof, wherein is H.

5. The fluorescent labeling group is of formula (F-1) or (F-2): The compound or a salt thereof according to claim 1, or a solvate thereof, which is a group represented by [wherein the formula, the asterisk indicates the bond position with the remainder.].

6. An activity measuring agent for tryptophan metabolic enzymes, comprising the compound or salt thereof described in claim 1, or a solvate thereof.

7. A kit for measuring the activity of tryptophan metabolic enzymes, comprising the tryptophan metabolic enzyme activity measuring agent described in claim 6.

8. A composition comprising the compound or salt thereof described in claim 1, or a solvate thereof, and one or more components.

9. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable components.

10. The pharmaceutical composition according to claim 9, for use in the diagnosis, prevention, or treatment of one or more symptoms, diseases, or disorders related to tryptophan metabolism.

11. A method for measuring tryptophan metabolic enzyme activity, comprising a step of measuring tryptophan metabolic enzyme activity by adding the tryptophan metabolic enzyme activity measuring agent described in claim 6 to a target and measuring the activity of the tryptophan metabolic enzyme.

12. The method according to claim 11, used for screening inhibitors of tryptophan metabolic enzyme activity.

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