Method for producing kakeromycin and its derivatives

Abstract

The present invention provides a method for producing kakeromycin and its derivatives by chemical synthesis, which show antifungal activity and cytotoxicity and are expected to be novel antifungal agents and anticancer agents. The present invention relates to a method for producing a compound represented by formula (1) or a salt thereof, which comprises: subjecting a compound represented by formula (2) or a salt thereof to an oxidation reaction. [In formula (2), R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and n represents 0 or 1. ][In formula (1), R and n have the same meaning as above. ].

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201680020805.X (application date: February 26, 2016, invention name: Method for producing kakeromycin and its derivatives). Technical Field

[0002] The present invention relates to a method for producing kakeromycin and its derivatives. Background Art

[0003] In recent years, the increase in the number of elderly people, the development of advanced medical care, and the immunodeficiency of patients with advanced cancer are causing infections caused by fungi. These infections can cause serious consequences and often even lead to death. Existing antifungal drugs are lacking in variety and have high toxicity, so it is expected that a new antifungal agent that is different from the drugs used so far will emerge. In addition, the use of antifungal drugs will cause an increase in the emergence of resistant bacteria, so it is urgent to develop new drugs. In addition, Candin antifungal agents have low toxicity, but their molecular weight is large and their reactivity with serum becomes a problem. Azole antifungal drugs have the problem of being difficult to achieve high concentration administration due to their toxicity. Therefore, there is a strong demand for the emergence of an effective compound with low molecular weight, low reactivity with serum, and low toxicity.

[0004] In the past, the search for medicinal seed compounds from microbial metabolites mainly collected terrestrial separation sources, which have been gradually used for microbial separation. Among the microbial metabolites discovered so far, a large number of antibiotics and anticancer agents headed by penicillin and doxorubicin have been found, which have gradually been used as therapeutic drugs for infections, cancer, etc. However, as a result of long-term continuous exploration, almost all microbial metabolites obtained from terrestrial areas are known compounds, and it is difficult to obtain secondary metabolites that can become candidates for new drugs. Therefore, the new drug development of natural medicine creation companies has shrunk rapidly. In order to break this situation, screening using chemical libraries (natural products and synthetic compounds) has been carried out worldwide. However, the results are contrary to expectations, and no promising new drug candidate compounds have been obtained from chemical libraries. Based on these circumstances, obtaining new drug candidate compounds has fallen into an extremely difficult situation.

[0005] In view of the above-mentioned current situation of the exploration of new drug candidate compounds, marine microbial resources have attracted attention. Marine microbial resources have been almost unexploited so far, and there is a high possibility of discovering new secondary metabolites.

[0006] Recently, a new compound represented by the following formula was discovered from microorganisms collected from seabed sand around Kakeromashima Island in the Amami Islands of Kagoshima Prefecture and was named "Kakeromycin".

[0007] [Chemical formula 1]

[0008]

[0009] This "Kakeromycin" shows antifungal activity, especially strong antibacterial activity against pathogens of candidiasis. It is very likely to achieve antibacterial activity with a new action different from existing antifungal agents, and further research and development can be expected in the future. In addition, since this "Kakeromycin" shows cytotoxicity against HepG2 liver cancer cells and PANC-1 pancreatic cancer cells, it is expected to be developed as an anticancer agent. Summary of the invention

[0010] Problem that the invention aims to solve

[0011] The object of the present invention is to provide a method for producing kakeromycin and its derivatives by chemical synthesis.

[0012] Solutions to the problem

[0013] The present inventors have conducted intensive studies to solve the above-mentioned problems and, as a result, have found a method for producing kakeromycin represented by the following formula (1) and its derivatives by chemical synthesis, thereby completing the present invention.

[0014] That is, the present invention is as follows.

[0015] [1] A method for producing a compound represented by formula (1) or a salt thereof, comprising: subjecting a compound represented by formula (2) or a salt thereof to an oxidation reaction.

[0016] [Chemical formula 2]

[0017]

[0018] [Wherein,

[0019] R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0020] n represents 0 or 1. ]

[0021] [Chemical formula 3]

[0022]

[0023] [Wherein, R and n have the same meanings as above.]

[0024] [2] The production method described in [1] above, further comprising the step of subjecting the compound represented by formula (3) or a salt thereof to an intramolecular dehydration condensation reaction to produce the compound represented by formula (2) or a salt thereof.

[0025] [Chemical formula 4]

[0026]

[0027] [Wherein, R and n are the same as defined in [1].]

[0028] [3] The production method described in [2] above, further comprising the step of subjecting the compound represented by formula (4) or a salt thereof to an intramolecular addition reaction to produce the compound represented by formula (3) or a salt thereof.

[0029] [Chemical formula 5]

[0030]

[0031] [Wherein, R and n are the same as defined in [1].]

[0032] [4] The method according to the above [3], further comprising the step of subjecting the compound represented by formula (5) or its salt to a deprotection reaction of the acyl protecting group of the amino group to produce the compound represented by formula (4) or its salt.

[0033] [Chemical formula 6]

[0034]

[0035] [Where R 4 represents an optionally substituted hydrocarbon group or an optionally substituted hydrocarbonoxy group, and R and n are the same as defined in [1].

[0036] [5] The production method described in [4] above, further comprising: subjecting the compound represented by formula (6) or a salt thereof to a reduction reaction to produce the compound represented by formula (5) or a salt thereof.

[0037] [Chemical formula 7]

[0038]

[0039] [wherein, R and n are the same as defined in [1], R 4 Same as defined in [4].]

[0040] [6] The method of the above-mentioned [5] further comprises a step of subjecting the compound represented by formula (7) or its salt to a cycloaddition reaction with the compound represented by formula (8) or its salt to produce the compound represented by formula (6) or its salt.

[0041] [Chemical formula 8]

[0042]

[0043] [where n is the same as defined in [1], R4 Same as defined in [4]. ]:

[0044] [Chemical formula 9]

[0045]

[0046] [Wherein, R has the same definition as in [1].]

[0047] [7] The production method described in any one of [1] to [6] above, further comprising: a step of subjecting the hydroxyl group of the compound represented by formula (1) or its salt to a protection reaction to produce the compound represented by formula (1-1) or its salt.

[0048] [Chemical formula 10]

[0049]

[0050] [Where R 3 represents an optionally substituted hydrocarbon group or an optionally substituted acyl group, and R and n are the same as defined in [1].

[0051] [8] The production method according to any one of [1] to [7] above, wherein R is a group represented by formula (A).

[0052] [Chemical formula 11]

[0053]

[0054] [Where R 1 and R 2 are the same or different and represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.]

[0055] [9] The method according to any one of [1] to [8] above, wherein n is 1;

[0056]

[10] A compound represented by formula (1) or a salt thereof.

[0057] [Chemical formula 12]

[0058]

[0059] [Wherein,

[0060] R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0061] n represents 0 or 1. ]

[0062]

[11] The compound or a salt thereof according to the above

[10] , wherein R is a group represented by formula (A).

[0063] [Chemical formula 13]

[0064]

[0065] [Where R 1 and R 2 are the same or different and represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.]

[0066]

[12] A compound represented by formula (2) or a salt thereof.

[0067] [Chemical formula 14]

[0068]

[0069] [Wherein,

[0070] R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0071] n represents 0 or 1. ]

[0072]

[13] A compound represented by formula (3) or a salt thereof.

[0073] [Chemical formula 15]

[0074]

[0075] [Wherein,

[0076] R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0077] n represents 0 or 1. ]

[0078]

[14] A compound represented by formula (4) or a salt thereof.

[0079] [Chemical formula 16]

[0080]

[0081] [Wherein,

[0082] R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0083] n represents 0 or 1. ]

[0084]

[15] A compound represented by formula (5) or a salt thereof.

[0085] [Chemical formula 17]

[0086]

[0087] [Wherein,

[0088] R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0089] R 4 represents an optionally substituted hydrocarbon group or an optionally substituted hydrocarbonoxy group;

[0090] n represents 0 or 1. ]

[0091]

[16] A compound represented by formula (6) or a salt thereof.

[0092] [Chemical formula 18]

[0093]

[0094] [Wherein,

[0095] R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0096] R 4 represents an optionally substituted hydrocarbon group or an optionally substituted hydrocarbonoxy group;

[0097] n represents 0 or 1. ]

[0098] Effects of the Invention

[0099] According to the production method of the present invention, kakeromycin and its derivatives which show antifungal activity and cytotoxicity and are expected to serve as novel antifungal agents and anticancer agents can be produced by chemical synthesis. DETAILED DESCRIPTION

[0100] Hereinafter, the definition of each group used in the structural formula in this specification will be described in detail.

[0101] R, R 1 and R 2 and respectively represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.

[0102] R 3 represents an optionally substituted hydrocarbon group or an optionally substituted acyl group.

[0103] R 4 represents an optionally substituted hydrocarbon group or an optionally substituted hydrocarbonoxy group.

[0104] Examples of the "hydrocarbon" of the "optionally substituted hydrocarbon" and the "hydrocarbon" (hydrocarbon part) of the "optionally substituted hydrocarbonoxy" include: 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, C 6-20 Aryl, C 7-20Aralkyl.

[0105] As "C 1-20 The "alkyl group" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

[0106] As "C 2-20 The term "alkenyl" includes, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

[0107] As "C 2-20 The term "alkynyl" includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

[0108] As "C 3-20 The “cycloalkyl group” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0109] As "C 3-20 The "cycloalkenyl group" includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0110] As "C 6-20 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0111] As "C 7-20 The "aralkyl group" includes, for example, benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0112] Examples of the "heterocyclic group" of the "optionally substituted heterocyclic group" include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered heterobridged ring groups each containing, as ring-constituting atoms in addition to carbon atoms, 1 to 4 hetero atoms selected from nitrogen atoms, sulfur atoms and oxygen atoms.

[0113] Examples of the “aromatic heterocyclic group” include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing 1 to 4 hetero atoms selected from nitrogen atoms, sulfur atoms and oxygen atoms as ring-constituting atoms in addition to carbon atoms.

[0114] Preferred examples of the "aromatic heterocyclic group" include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Azolyl, iso Azolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- Oxazolyl, 1,3,4- 5-6 membered monocyclic aromatic heterocyclic groups such as oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.;

[0115] Benzothiphenyl, benzofuranyl, benzimidazolyl, benzo Azolyl, benzyl oxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazine, naphtho[2,3-b]thienyl, phenoxy Thiol, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenanthridinyl, 8-14-membered condensed polycyclic (preferably 2- or 3-ring) aromatic heterocyclic groups such as oxazinyl.

[0116] Examples of the “non-aromatic heterocyclic group” include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing 1 to 4 hetero atoms selected from nitrogen atoms, sulfur atoms and oxygen atoms as ring-constituting atoms in addition to carbon atoms.

[0117] Preferred examples of the "non-aromatic heterocyclic group" include aziridine, oxiranyl, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, Oxazoline, oxazolidinyl, pyrazolyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydro Azolyl, tetrahydroisoxazine 3-8 membered monocyclic non-aromatic heterocyclic groups such as oxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepinyl, azooctanyl, and diazaoctanyl;

[0118] Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzo oxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, dihydroindolyl, isoindolyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenanthridinyl 9-14 membered condensed polycyclic (preferably 2- or 3-ring) non-aromatic heterocyclic groups such as oxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl and octahydroisoquinolinyl.

[0119] Preferred examples of the "7- to 10-membered heterobridged ring group" include a quinuclidine ring group and a 7-azabicyclo[2.2.1]heptyl group.

[0120] Examples of the "acyl group" of the "optionally substituted acyl group" include formyl, carboxyl, C 1-6 Alkyl-carbonyl, C 2-6 Alkenyl-carbonyl, C 3-10 Cycloalkyl-carbonyl, C 3-10 Cycloalkenyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, aromatic heterocyclic-carbonyl, non-aromatic heterocyclic-carbonyl, C 1-6 Alkoxy-carbonyl, C 6-14 Aryloxy-carbonyl, C 7-16 Aralkyloxy-carbonyl, carbamoyl.

[0121] As "C 1-6 Examples of the "alkyl-carbonyl group" include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, hexanoyl and heptanoyl.

[0122] As "C 2-6The “alkenyl-carbonyl” includes, for example, vinylcarbonyl, 1-propenylcarbonyl, 2-propenylcarbonyl, 2-methyl-1-propenylcarbonyl, 1-butenylcarbonyl, 2-butenylcarbonyl, 3-butenylcarbonyl, 3-methyl-2-butenylcarbonyl, 1-pentenylcarbonyl, 2-pentenylcarbonyl, 3-pentenylcarbonyl, 4-pentenylcarbonyl, 4-methyl-3-pentenylcarbonyl, 1-hexenylcarbonyl, 3-hexenylcarbonyl and 5-hexenylcarbonyl.

[0123] As "C 3-20 The "cycloalkyl-carbonyl" group includes, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, bicyclo[2.2.1]heptylcarbonyl, bicyclo[2.2.2]octylcarbonyl, bicyclo[3.2.1]octylcarbonyl and adamantylcarbonyl.

[0124] As "C 3-20 The "cycloalkenyl-carbonyl group" includes, for example, a cyclopropenylcarbonyl group, a cyclobutenylcarbonyl group, a cyclopentenylcarbonyl group, a cyclohexenylcarbonyl group, a cycloheptenylcarbonyl group and a cyclooctenylcarbonyl group.

[0125] As "C 6-14 Examples of the "aryl-carbonyl" include benzoyl, 1-naphthoyl and 2-naphthoyl.

[0126] As "C 7-16 Examples of the "aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl.

[0127] Examples of the "aromatic heterocyclic-carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0128] Examples of the "non-aromatic heterocyclic-carbonyl group" include a morpholinylcarbonyl group, a piperidinylcarbonyl group, and a pyrrolidinylcarbonyl group.

[0129] As "C 1-6 The "alkoxy-carbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

[0130] As "C 6-14 Examples of the "aryloxy-carbonyl group" include phenoxycarbonyl, 1-naphthoxycarbonyl and 2-naphthoxycarbonyl.

[0131] As "C 7-16 Examples of the "aralkyloxy-carbonyl group" include benzyloxycarbonyl and phenethoxycarbonyl.

[0132] Examples of the "substituent" of the "optionally substituted hydrocarbon group", "optionally substituted hydrocarbonoxy group", "optionally substituted heterocyclic group" and "optionally substituted acyl group" include the following.

[0133] (1) Halogen atoms,

[0134] (2) Nitro,

[0135] (3) Cyano,

[0136] (4) Oxo group,

[0137] (5) Hydroxyl,

[0138] (6) Optionally substituted C 1-6 Alkoxy,

[0139] (7) Optionally substituted C 6-14 aryloxy,

[0140] (8) Optionally substituted C 7-16 Aralkyloxy,

[0141] (9) an optionally substituted aromatic heterocyclic-oxy ​​group,

[0142] (10) an optionally substituted non-aromatic heterocyclic-oxy ​​group,

[0143] (11) optionally substituted C 1-6 Alkyl-carbonyloxy,

[0144] (12) optionally substituted C 6-14 Aryl-carbonyloxy,

[0145] (13) Optionally substituted C 1-6 Alkoxy-carbonyloxy,

[0146] (14) optionally substituted mono- or di-C 1-6 Alkyl-carbamoyloxy,

[0147] (15) optionally substituted C 6-14 Aryl-carbamoyloxy,

[0148] (16) an optionally substituted 5- to 14-membered aromatic heterocyclic-carbonyloxy group,

[0149] (17) an optionally substituted 3- to 14-membered non-aromatic heterocyclic-carbonyloxy group,

[0150] (18) Optionally substituted C 1-6 Alkylsulfonyloxy,

[0151] (19) optionally substituted C 6-14 Arylsulfonyloxy,

[0152] (20) optionally substituted C 1-6 Alkylthio,

[0153] (21) an optionally substituted 5- to 14-membered aromatic heterocyclic group,

[0154] (22) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group,

[0155] (23) Formyl,

[0156] (24) Carboxyl,

[0157] (25) optionally substituted C 1-6 Alkyl-carbonyl,

[0158] (26) optionally substituted C 6-14 Aryl-carbonyl,

[0159] (27) an optionally substituted 5- to 14-membered aromatic heterocyclic-carbonyl group,

[0160] (28) an optionally substituted 3- to 14-membered non-aromatic heterocyclic-carbonyl group,

[0161] (29) optionally substituted C 1-6 Alkoxy-carbonyl,

[0162] (30) optionally substituted C 6-14 Aryloxy-carbonyl,

[0163] (31) optionally substituted C 7-16 Aralkyloxy-carbonyl,

[0164] (32) Carbamoyl,

[0165] (33) thiocarbamoyl,

[0166] (34) optionally substituted mono- or di-C 1-6 Alkyl-carbamoyl,

[0167] (35) optionally substituted C 6-14 Aryl-carbamoyl,

[0168] (36) an optionally substituted 5- to 14-membered aromatic heterocyclic carbamoyl group,

[0169] (37) an optionally substituted 3- to 14-membered non-aromatic heterocyclic carbamoyl group,

[0170] (38) optionally substituted C 1-6 Alkylsulfonyl,

[0171] (39) optionally substituted C 6-14Arylsulfonyl,

[0172] (40) an optionally substituted 5- to 14-membered aromatic heterocyclic-sulfonyl group,

[0173] (41) optionally substituted C 1-6 Alkylsulfinyl,

[0174] (42) optionally substituted C 6-14 Arylsulfinyl,

[0175] (43) an optionally substituted 5- to 14-membered aromatic heterocyclic-sulfinyl group,

[0176] (44) Amino group,

[0177] (45) optionally substituted mono- or di-C 1-6 Alkylamino,

[0178] (46) optionally substituted mono- or di-C 6-14 Arylamino,

[0179] (47) an optionally substituted 5- to 14-membered aromatic heterocyclic amino group,

[0180] (48) optionally substituted C 7-16 Aralkylamino,

[0181] (49) formylamino,

[0182] (50) optionally substituted C 1-6 Alkyl-carbonylamino,

[0183] (51) optionally substituted (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino,

[0184] (52) optionally substituted C 6-14 Aryl-carbonylamino,

[0185] (53) optionally substituted C 1-6 Alkoxy-carbonylamino,

[0186] (54) optionally substituted C 7-16 Aralkyloxy-carbonylamino,

[0187] (55) optionally substituted C 1-6 Alkylsulfonylamino,

[0188] (56) optionally substituted C 6-14 Arylsulfonylamino,

[0189] (57) optionally substituted C 1-6 alkyl,

[0190] (58) optionally substituted C 2-6 Alkenyl,

[0191] (59) optionally substituted C 2-6 Alkynyl,

[0192] (60) optionally substituted C 3-10 Cycloalkyl,

[0193] (61) optionally substituted C 3-10 Cycloalkenyl, and

[0194] (62) Optionally substituted C 6-14 Aryl.

[0195] The number of the "substituents" in the "optionally substituted hydrocarbon group", "optionally substituted hydrocarbonoxy group", "optionally substituted heterocyclic group" and "optionally substituted acyl group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

[0196] R is preferably an optionally substituted C 2-20 Alkenyl (e.g. vinyl), more preferably a group represented by formula (A),

[0197] [Chemical formula 19]

[0198]

[0199] [Where R 1 and R 2 are the same or different and represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.]

[0200] More preferably, R 1 and R 2 The same or different optionally substituted C 1-20 Alkyl (eg methyl) or optionally substituted C 7-20 The group represented by the formula (A) of an aralkyl group (for example, a benzyl group) is particularly preferably R 1 and R 2 Same or different as C 1-20 Alkyl (eg methyl) or C 7-20 A group represented by the formula (A) is an aralkyl group (for example, benzyl group).

[0201] In another embodiment of the present invention, R is preferably an optionally substituted C 2-20 Alkenyl (e.g., vinyl), optionally substituted C 1-20 Alkyl (e.g. heptyl), optionally substituted C 6-20Aryl (e.g., phenyl, naphthyl) or optionally substituted C 7-20 Arylalkyl (e.g., phenylethyl), more preferably a group represented by formula (A), an optionally substituted C 1-20 Alkyl (e.g. heptyl), optionally substituted C 6-20 Aryl (e.g., phenyl, naphthyl) or optionally substituted C 7-20 Aralkyl (e.g. phenylethyl),

[0202] [Chemical formula 20]

[0203]

[0204] [Where R 1 and R 2 are the same or different and represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.]

[0205] More preferably, R 1 and R 2 The same or different optionally substituted C 1-20 Alkyl (e.g. methyl), optionally substituted C 6-20 Aryl (e.g. phenyl) or optionally substituted C 7-20 A group represented by the formula (A) of an aralkyl group (e.g., benzyl, phenylethyl), an optionally substituted C 1-20 Alkyl (e.g. heptyl), optionally substituted C 6-20 Aryl (e.g., phenyl, naphthyl) or optionally substituted C 7-20 Arylalkyl (e.g. phenylethyl), particularly preferably R 1 and R 2 The same or different may be optionally C 1-20 Alkyl (e.g. methyl) or halogen (e.g. chlorine) substituted C 6-20 Aryl (e.g. phenyl) or C 7-20 Aralkyl (e.g., benzyl, phenylethyl) group represented by formula (A), C 1-20 Alkyl (e.g. heptyl), C 6-20 Aryl (e.g. phenyl, naphthyl) or C 7-20 Aralkyl (eg phenylethyl).

[0206] R 3 Preferably, optionally substituted C 1-20 Alkyl (eg methyl) or optionally substituted C 1-6 Alkyl-carbonyl (e.g. acetyl), more preferably C 1-20 Alkyl (eg methyl) or C 1-6 The alkyl-carbonyl group (eg, acetyl group) is more preferably a methyl group or an acetyl group.

[0207] R 4 Preferably, optionally substituted C 1-20 Alkyl (e.g. methyl), optionally substituted C 6-20 Aryl (e.g. phenyl), optionally substituted C 1-20 Alkyl-oxy (eg tert-butoxy) or optionally substituted C 7-20 Aralkyl-oxy (e.g. benzyloxy), more preferably C 1-20 Alkyl (e.g. methyl), C 6-20 Aryl (e.g. phenyl), C 1-20 Alkyl-oxy (e.g. tert-butoxy) or C 7-20 The aralkyl-oxy group (eg benzyloxy group) is further preferably a methyl group, a phenyl group, a tert-butoxy group or a benzyloxy group, and particularly preferably a tert-butoxy group.

[0208] n represents 0 or 1. n is preferably 1.

[0209] Hereinafter, the production method of the present invention will be described.

[0210] The overall flow of the production method of the present invention is shown below.

[0211] [Chemical formula 21]

[0212]

[0213] [In the formula, each symbol has the same meaning as above.]

[0214] (Step 1: Production of Oxime 8)

[0215] Oxime (8) can be synthesized by a dehydration condensation reaction of aldehyde (9) with hydroxylamine prepared from hydroxylamine hydrochloride and a base. As the base, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, tertiary amines such as triethylamine, etc. can be used in an amount of usually 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents relative to hydroxylamine hydrochloride, and sodium bicarbonate is particularly preferred. Hydroxylamine hydrochloride can be used in an amount of usually 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents relative to aldehyde (9). The reaction temperature is usually in the range of 0 to 50°C, preferably 20 to 30°C, and the reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 1 to 48 hours, preferably 2 to 10 hours. As the reaction solvent, THF, water, acetonitrile, ethyl acetate, dichloromethane, or a mixed solvent thereof can be used, and a mixed solvent of THF-water is particularly preferred.

[0216] In addition, aldehyde (9) can be obtained as a commercial product, or can be produced by a method known per se or a method based on these methods.

[0217] (Step 2: dihydroiso Production of azoles 6A and 6B)

[0218] Dihydroiso Azoles (6A, 6B) can be synthesized by a (3+2) cycloaddition reaction of nitrile oxide prepared from oxime (8) and an aqueous sodium hypochlorite solution, or from oxime (8) and chloramine-T, and N-acylaminobutene (7A) or N-acylaminopropylene (7B). The aqueous sodium hypochlorite solution or chloramine-T can be used in an amount of usually 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to oxime 8. The oxime (8) can be used in an amount of usually 0.5 to 3 molar equivalents, preferably 0.8 to 1.2 molar equivalents, relative to N-acylaminobutene (7A) or N-acylaminopropylene (7B). The reaction temperature is usually in the range of 0 to 80°C, preferably 20 to 30°C, and the reaction time varies depending on the type of reagents, reaction temperature, etc., but is usually 1 to 48 hours, preferably 2 to 10 hours. As the reaction solvent, THF, ethyl acetate, dichloromethane, ethanol, methanol, acetonitrile or a mixed solvent thereof can be used.

[0219] N-acylaminobutene (7A) or N-acylaminopropene (7B) can be obtained as a commercial product, or can be produced by a method known per se or a method based thereon.

[0220] (Step 3: Production of N-acylaminohydroxyketone 5A, 5B)

[0221] N-acylaminohydroxyketones (5A, 5B) can be prepared by reacting dihydroisoxazole The synthesis is carried out by reducing the NO bond of oxazole (6A, 6B). As the reducing agent, hexacarbonyl molybdenum, octacarbonyl cobalt, iron, zinc, magnesium, etc. can be used. The amount used varies depending on the type of reagent, reaction temperature, etc., but is relatively small relative to dihydroisocyanate. The amount of oxazole (6A, 6B) is usually 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, and hexacarbonyl molybdenum is particularly preferred. The reaction temperature is usually in the range of 0 to 100°C, preferably 70 to 90°C, and the reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 1 to 24 hours, preferably 1 to 3 hours. As the reaction solvent, acetonitrile, propionitrile, water, THF, ethyl acetate, dichloromethane, dichloroethane, or a mixed solvent thereof can be used, and a mixed solvent of acetonitrile-water is particularly preferred.

[0222] (Step 4: Production of Aminohydroxyketones 4A and 4B)

[0223] Aminohydroxyketone (4A, 4B) can be synthesized by deprotecting the acyl protecting group of the amino group of N-acylaminohydroxyketone (5A, 5B). As a deprotecting agent, trifluoroacetic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, etc. can be used in an amount of usually 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents relative to N-acylaminohydroxyketone (5A, 5B), but trifluoroacetic acid is particularly preferred. The reaction temperature is usually in the range of 0 to 50°C, preferably 20 to 30°C, and the reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 1 to 24 hours, preferably 1 to 3 hours. As a reaction solvent, THF, ethyl acetate, dichloromethane, dichloroethane, or a mixed solvent thereof can be used, but dichloromethane and dichloroethane are particularly preferred.

[0224] (Step 5: Production of Cyclic Semiamine Aldehydes 3A and 3B)

[0225] Cyclic hemiamine aldehyde (3A, 3B) can be synthesized by intramolecular addition reaction of aminohydroxy ketone (4A, 4B). Intramolecular addition reaction may be carried out even without using a particular reactant, but when an acid catalyst is necessary, trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. can be used in an amount of usually 0.01 to 5 molar equivalents, preferably 0.01 to 1 molar equivalents relative to aminohydroxy ketone (4A, 4B). The reaction temperature is usually in the range of 0 to 100°C, preferably 30 to 50°C, and the reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 1 to 24 hours, preferably 1 to 6 hours. As a reaction solvent, THF, ethyl acetate, dichloromethane, dichloroethane, toluene, or a mixed solvent thereof can be used, but THF and dichloroethane are particularly preferred.

[0226] (Step 6: Production of Cyclic Imines 2A and 2B)

[0227] Cyclic imines (2A, 2B) can be synthesized by intramolecular dehydration condensation reaction of cyclic semiamine aldehydes (3A, 3B). As dehydrating agents, trifluoroacetic acid, acetic acid, molecular sieves, anhydrous sodium sulfate, etc. can be used. The amount used varies depending on the type of reagent, reaction temperature, etc., but is usually 0.01 to 100 molar equivalents, preferably 0.01 to 10 molar equivalents relative to the cyclic semiamine aldehyde (3A, 3B). The reaction temperature is usually in the range of 0 to 100°C, preferably 20 to 60°C. The reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 1 to 24 hours, preferably 3 to 12 hours. As reaction solvents, THF, ethyl acetate, dichloromethane, dichloroethane, toluene, or mixed solvents thereof can be used, but THF is particularly preferred.

[0228] (Step 7: Production of Bicyclic Oxaziridines 1A and 1B)

[0229] Bicyclic oxaziridine (1A, 1B) can be synthesized by oxidation reaction of cyclic imine (2A, 2B). As the oxidizing agent, m-chloroperbenzoic acid, peracetic acid, etc. can be used in an amount of usually 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents relative to the cyclic imine (2A, 2B), but m-chloroperbenzoic acid is particularly preferred. The reaction temperature is usually in the range of 0 to 50°C, preferably 10 to 30°C, and the reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 0.5 to 12 hours, preferably 1 to 2 hours. As the reaction solvent, THF, ethyl acetate, dichloromethane, dichloroethane, toluene, ethanol, methanol, acetonitrile or a mixed solvent thereof can be used, but THF and dichloromethane are particularly preferred.

[0230] (Step 8: Production of Bicyclic Oxaziridine Derivatives 1-1A and 1-1B)

[0231] The bicyclic oxaziridine derivatives (1-1A, 1-1B) can be synthesized by protecting the hydroxyl group of the bicyclic oxaziridine (1A, 1B).

[0232] R 3 In the case of an optionally substituted hydrocarbon group, the corresponding halide and base as a protecting agent can be used in an amount of usually 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to the bicyclic oxaziridine derivative (1-1A, 1-1B) for the protection reaction. As the halide, iodomethane is particularly preferred. As the base, sodium carbonate, potassium carbonate, sodium hydride, n-butyl lithium, etc. can be used, but sodium hydride is particularly preferred. The reaction temperature is usually in the range of 0 to 50°C, preferably 20 to 30°C, and the reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 0.5 to 24 hours, preferably 1 to 12 hours. As the reaction solvent, THF, dimethyl sulfoxide, dimethylformamide, acetonitrile, dichloromethane, dichloroethane, or a mixed solvent thereof can be used, but dimethyl sulfoxide and acetonitrile are particularly preferred.

[0233] R 3In the case of an acyl group that is optionally substituted, the corresponding acyl halide compound or acid anhydride as a protecting agent can be used in the presence of an amine base in an amount of usually 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to the bicyclic oxaziridine derivative (1-1A, 1-1B) for a protection reaction. As the acyl halide compound or acid anhydride, acetic anhydride is particularly preferred. As the amine base, a tertiary amine such as triethylamine, diisopropylethylamine, or a pyridine derivative such as pyridine or dimethylaminopyridine can be used in an amount of usually 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to the bicyclic oxaziridine derivative (1-1A, 1-1B), but triethylamine and dimethylaminopyridine are particularly preferred. The reaction temperature is usually in the range of 0 to 50°C, preferably 20 to 30°C, and the reaction time varies depending on the type of reagent, reaction temperature, etc., but is usually 0.5 to 24 hours, preferably 1 to 12 hours. As the reaction solvent, THF, ethyl acetate, acetonitrile, dichloromethane, dichloroethane, or a mixed solvent thereof can be used, and THF and dichloromethane are particularly preferred.

[0234] The kakeromycin derivatives (excluding kakeromycin) represented by formula (1) and (1-1) obtained by the production method of the present invention, and the synthetic intermediates thereof represented by formula (2), (3), (4), (5) and (6) are novel compounds.

[0235] Kakeromycin and its derivatives (bicyclic oxaziridine and its derivatives) and its synthetic intermediates obtained by the manufacture method of the present invention can also be salts. As such salts, for example, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or salts formed with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. can be cited. Among these salts, pharmaceutically acceptable salts are preferred.

[0236] Kakeromycin and its derivatives (bicyclic oxaziridine and its derivatives) obtained by the preparation method of the present invention show strong antifungal activity against a wide range of fungi and can be expected to be used as a novel antifungal agent. In addition, the kakeromycin and its derivatives show cytotoxicity to cancer cells. Therefore, compounds containing the kakeromycin and its derivatives as active ingredients can be used as medicines, pesticides, etc.

[0237] Examples of target fungi for antifungal drugs include Candida species (e.g. Candida albicans , Candida parapsilosis , Candida tropicalis , Candida krusei , Candida glabrata , Candida quilliermondii , Candida lusitania etc.), Aspergillus (e.g. Aspergillus smoked , Aspergillus flavus , Aspergillus niger , Aspergillus earthly etc.), Trichophyton spp. (e.g. Trichophyton red , Trichophyton Mentagrophytes , Trichophyton shaving , Microsporum dog , Microsporum gypsum , Trichophyton warty etc.), but are not limited to these. In addition, fungal diseases are not particularly limited, and deep skin fungal diseases, deep mycosis, mycetoma, or fungemia can be listed.

[0238] The target crops when using antifungal drugs as pesticides are not particularly limited, and examples thereof include: cereals (e.g., rice, barley, wheat, rye, oats, corn, sorghum, etc.), legumes (soybeans, adzuki beans, broad beans, peas, peanuts, etc.), fruit trees / fruits (apples, citrus fruits, pears, grapes, peaches, plums, cherries, walnuts, almonds, bananas, strawberries, etc.), vegetables (cabbage, tomatoes, spinach, broccoli, lettuce, onions, green peppers, etc.), root vegetables (carrots, potatoes, The present invention relates to plants such as potatoes, radishes, lotus roots, turnips, etc.), processing crops (cotton, hemp, paper mulberry, yellow daphne, rapeseed, sugar radish, hops, sugar cane, beets, olives, rubber, coffee, tobacco, tea, etc.), melons (pumpkin, cucumber, watermelon, honeydew melon, etc.), forage (duckgrass, sorghum, timothy, clover, alfalfa, etc.), zoysia grass (Korean grass, herb, etc.), spice crops (lavender, rosemary, thyme, parsley, pepper, ginger, etc.), flowers (chrysanthemum, rose, orchid, etc.). As for antifungal drugs, by treating the target crop and / or the seeds of the target crop with an effective amount thereof, they can be used to prevent and control diseases associated with the fungi as described above in the crop.

[0239] The pesticide can be used in the following forms, usually together with adjuvants commonly used in the field of formulation. Kakeromycin and its derivatives obtained by the preparation method of the present invention can be formulated into, for example, emulsion stock solution, sprayable paste, sprayable or diluted solution, diluted emulsion, wettable powder, aqueous solvent, dust, granule, suspension, dry suspension, fumigant, fumigant, and capsule based on, for example, polymer substances by known methods.

[0240] As additives and carriers, when the goal is a solid preparation, plant powders such as soybean flour and wheat flour, mineral powders such as diatomaceous earth, apatite, gypsum, talc, bentonite, clay, and organic and inorganic compounds such as sodium benzoate, urea, and Glauber's salt can be used.

[0241] When a liquid dosage form is used as the target, vegetable oil, mineral oil, kerosene, aromatic hydrocarbons such as xylene and toluene, amides such as formamide and dimethylformamide, sulfoxides such as dimethyl sulfoxide, ketones such as methyl isobutyl ketone and acetone, trichloroethylene, water, etc. are used as solvents. In order to obtain a uniform and stable form, a surfactant may be added to these preparations as needed. The wettable powder, emulsion, aqueous solution, suspension, and dry suspension thus obtained may be diluted with water to a given concentration to prepare a suspension or emulsion for use, and the powder or granule may be used by directly spreading it on the soil or plants.

[0242] The content of the active ingredient in the pesticide containing kakeromycin and its derivatives obtained by the production method of the present invention and the application amount can be changed in a wide range depending on the formulation, the type of fungus to be applied, the target crop, and the like.

[0243] On the other hand, when an antifungal drug is used as a medicine, it can be administered to a treatment subject, such as a mammal (e.g., human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, etc.) by any administration route, either oral or parenteral (e.g., intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration).

[0244] When the antifungal drug is administered percutaneously, in addition to the above-mentioned active ingredients, an oily base, an emulsifier and an emulsion stabilizer, a solubilizing agent, a powder component, a polymer component, an adhesiveness improver, a film-forming agent, a pH adjuster, an antioxidant, a preservative, a preservative, a moisturizer, a skin protectant, a refreshing agent, a fragrance, a colorant, a chelating agent, a lubricant, a blood circulation promoter, a astringent, a tissue repair promoter, an antiperspirant, a plant extract component, an animal extract component, an anti-inflammatory agent, an antipruritic agent, etc. can be used as needed. These additives can be those generally used in preparations.

[0245] Antifungal drugs can be formulated into external medicines such as creams, liquids, lotions, emulsions, tinctures, ointments, aqueous gels, oily gels, sprays, powders, shampoos, soaps, or nail polishes for nail coating, etc., using methods commonly used in the field of pharmaceutical preparations, and then used.

[0246] When the antifungal drug is administered orally, it can be prepared into a dosage form suitable for oral administration such as capsules, tablets, granules, powders, pills, fine granules, lozenges, etc. These preparations can be prepared according to conventional methods using additives such as excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubility aids, preservatives, flavor correctors, analgesics, stabilizers, etc., which are usually used for oral preparations.

[0247] Target cells of anticancer agents include, but are not limited to, cancer cells such as HepG2 cells (liver cancer cells) and PANC1 cells (pancreatic cancer cells). In addition, cancers are not particularly limited and include brain tumors, skin cancer, leukemia, esophageal cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, rectal cancer, osteosarcoma, etc.

[0248] Example

[0249] The present invention will be further described in detail with reference to the following embodiments, but the present invention is not limited to these embodiments and may be modified without departing from the scope of the present invention.

[0250] 1 H and 13 C NMR spectra were measured using a nuclear magnetic resonance apparatus (Varian, 400MR and Mercury-300), and all δ values ​​are expressed in ppm. Mass spectra were measured using an HPLC-Chip / QTOF mass spectrometry system (Agilent Technologies) and are shown as m / z values.

[0251] Example 1

[0252] [Chemical formula 22]

[0253]

[0254] (Process 1)

[0255] Aldehyde 9a-01 (72 mg, 0.45 mmol) was dissolved in THF (3 mL), and hydroxylamine hydrochloride (47 mg, 0.68 mmol), sodium bicarbonate (57 mg, 0.68 mmol) and water (2 mL) were added at room temperature, and stirred at room temperature for 12 hours. Sodium sulfate (5 g) was added to remove water from the reaction system and filtered using cotton. The filtrate was concentrated using a rotary evaporator. The crude product was purified by silica gel column chromatography (solvent: hexane and ethyl acetate) to obtain oxime 8a-01 (75 mg, 0.43 mmol) (yield 95%) in the form of a colorless liquid.

[0256] 1H NMR (300MHz, CDCl3): δ1.85 (d, 3H, J = 7.5Hz), 3.70 (s, 2H), 6.01 (q, 1H, J = 7.5Hz), 7.04-7.32 (m, 5H), 7.75 (s, 1H).

[0257] (Process 2)

[0258] Oxime 8a-01 (52 mg, 0.30 mmol) and N-Boc-aminobutene 7A-01 (62 mg, 0.36 mmol) were dissolved in THF (5 mL), and an aqueous sodium hypochlorite solution (5%, 2 mL) was added at 0°C, and stirred at room temperature for 12 hours. Sodium sulfate (5 g) was added, and the water in the reaction system was removed and filtered using cotton. The filtrate was concentrated using a rotary evaporator. The crude product was purified by silica gel column chromatography (solvent: hexane and ethyl acetate) to obtain dihydroisocyanate in the form of a colorless liquid. Ole 6Aa-001 (120 mg, 0.35 mmol) (yield 86%).

[0259] 1 H NMR (300MHz, CDCl3): δ1.41 (s, 9H), 1.72-1.86 (m, 2H), 1.87 (d, 3H, J = 7.5Hz), 2.75 (dd, 1H, J = 8.1, 16.2Hz), 3.18 (dd, 1H, J = 10 .2,16.2Hz),3.15-3.30(m,2H),3.80(s,2H),4.55-4.68(m,1H),4.68-4.98(br,1H),5.95(q,1H,J=7.5Hz),7.05-7.28(m,5H).

[0260] 13 C NMR (75MHz, CDCl3): δ14.4,28.3,32.6,35.2,37.6,39.8,79.1,79.6,125.8,128.2,128.4,131.5,131.7,139.6,156.0,158.8.

[0261] (Process 3)

[0262] Dihydroiso Azole 6Aa-001 (110 mg, 0.32 mmol) and molybdenum hexacarbonyl (170 mg, 0.64 mmol) were dissolved in acetonitrile (3 mL), water (0.5 mL) was added, and the mixture was stirred at 85 ° C for 2 hours. Ethyl acetate (5 mL) was added and stirred at room temperature for 24 hours. The resulting mixture was filtered through diatomaceous earth using ethyl acetate, and the filtrate was concentrated using a rotary evaporator. The crude product was purified by silica gel column chromatography (solvent: hexane and ethyl acetate) to obtain N-Boc aminohydroxy ketone 5Aa-001 (83 mg, 0.24 mmol) (yield 75%) in the form of a colorless liquid.

[0263] 1 H NMR (300MHz, CDCl3): δ1.20-1.62(m,2H),1.43(s,9H),1.96(d,3H,J=7.5Hz),2.78-2.83(m,2H),3.10-3. 41(m,2H),3.68(s,2H),4.16-4.28(m,1H),4.75-5.10(br,1H),6.94(q,1H,J=7.5Hz),7.08-7.24(m,5H).

[0264] (Process 4 and 5)

[0265] N-Boc aminohydroxy ketone 5Aa-001 (50 mg, 0.14 mmol) was dissolved in dichloroethane (3 mL), and trifluoroacetic acid (0.5 mL) was added, and stirred at room temperature for 1 hour. The reaction solution was concentrated using a rotary evaporator to obtain a mixture of aminohydroxy ketone 4Aa-001 and cyclic semiamine aldehyde 3Aa-001 (31 mg, 0.13 mol) in the form of a yellow liquid (yield 87%).

[0266] 1 H NMR (300MHz, CDCl3): δ1.20-1.64(m,2H),1.95(d,3H,J=7.5Hz),2.76-2.96(m, 4H), 3.67 (s, 2H), 4.12-4.28 (m, 1H), 6.92 (q, 1H, J = 7.5Hz), 7.08-7.24 (m, 5H).

[0267] (Process 6)

[0268] A mixture of aminohydroxyketone 4Aa-001 and cyclic semiamine aldehyde 3Aa-001 (30 mg, 0.12 mmol) was dissolved in THF (3 mL), 4A-molecular sieves (100 mg) were added, and stirred at room temperature for 12 hours. The reaction solution was filtered through diatomaceous earth using ethyl acetate as a solvent, and then concentrated using a rotary evaporator to obtain cyclic imine 2Aa-001 (24 mg, 0.10 mmol) as a yellow liquid (yield 83%).

[0269] (Process 7)

[0270] Cyclic imine 2Aa-001 (9 mg, 0.039 mmol) was dissolved in THF (3 mL), m-chloroperbenzoic acid (11 mg) was added, and stirred at room temperature for 3 hours. The reaction solution was concentrated using a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (solvent: hexane and ethyl acetate) to obtain bicyclic oxaziridine 1Aa-001 (3 mg, 0.012 mmol) (yield 31%) in the form of a yellow liquid.

[0271] 1 H NMR (400MHz, CDCl3): δ1.16-1.36 (m, 1H), 1.69 (d, 3H, J = 7.6Hz), 1.80-1.98 (m, 1H), 1.99 (dd, 1H, J = 6.9, 15.1Hz), 2.35 (ddd, 1H,J=1.3,6.2,15.1Hz),3.15-3.25(m,1H),3.36-3.60(m,3H),3.75-3.84(m,1H),5.91(q,1H,J=6.9Hz),7.05-7.28(m,5H).

[0272] MS: m / z 246([M+1],C 15 H 19 NO2)

[0273] Example 2

[0274] [Chemical formula 23]

[0275]

[0276] (Process 2)

[0277] In the same manner as in step 2 of Example 1, octyl aldoxime 8A-01 and N-Boc-aminobutene 7A-01 were used as substrates to obtain dihydroisobutene in the form of a colorless liquid. Ole 6A-01 (yield 75%).

[0278] 1H NMR (300MHz, CDCl3): δ0.82(t,3H,J=7.5Hz),1.16-1.80(m,12H),1.39(s,9H),2.20-2.36(m,2H),2.56(dd,1 H, J=8.1, 16.2Hz), 2.98 (dd, 1H, J=10.2, 16.2Hz), 3.10-3.24 (m, 2H), 4.48-4.60 (m, 1H), 4.92-5.00 (br, 1H).

[0279] (Process 3)

[0280] In the same manner as in step 3 of Example 1, dihydroisoquinoline Using oxazole 6A-01 as substrate, N-Boc aminohydroxy ketone 5A-01 was obtained as a colorless liquid (yield 69%).

[0281] 1 H NMR (300MHz, CDCl3): δ0.83 (t, 3H, J = 7.5Hz), 1.16-1.76 (m, 10H), 1.40 (s, 9H) ,2.32-2.60(m,6H),3.16-3.44(m,2H),4.00-4.26(m,1H),4.96-5.04(br,1H).

[0282] (Process 4 and 5)

[0283] In the same manner as in steps 4 and 5 of Example 1, using N-Boc aminohydroxyketone 5A-01 as a substrate, a mixture of aminohydroxyketone 4A-01 and cyclic semiamine aldehyde 3A-01 was obtained as a yellow liquid (yield 90%).

[0284] 1 H NMR (300MHz, CDCl3): δ0.83 (t, 3H, J = 7.5Hz), 1.16-1.76 (m, 10H), 2.32-2.60 (m, 6H), 2.64-3.02 (m, 2H), 3.98-4.16 (m, 1H).

[0285] (Steps 6 and 7)

[0286] In the same manner as step 6 of Example 1, a mixture of aminohydroxyketone 4A-01 and cyclic seminaldehyde 3A-01 was used as a substrate to obtain cyclic imine 2A-01, and then, in the same manner as step 7 of Example 1, bicyclic oxaziridine 1A-01 was obtained as a yellow liquid (yield 23%).

[0287] 1H NMR (300MHz, CDCl3): δ0.83 (t, 3H, J = 7.5Hz), 1.20-1.74 (m, 10H), 1.92-2.20 (m, 2H), 2.32-2.60 (m, 4H), 3.78-4.12 (m, 2H), 4.12-4.22 (m, 1H).

[0288] MS: m / z 214 ([M+1], C 12 H 23 NO2)

[0289] Example 3

[0290] [Chemical formula 24]

[0291]

[0292] (Process 2)

[0293] In the same manner as in step 2 of Example 1, 3-phenylpropionaldehyde oxime 8A-02 and N-Boc-aminobutene 7A-01 were used as substrates to obtain dihydroisobutene in the form of a colorless liquid. Ole 6A-02 (yield 77%).

[0294] 1 H NMR (300MHz, CDCl3): δ1.43(s,9H),1.62-1.80(m,2H),2.40-2.66(m,2H),2.82-3.02 (m,4H),3.16-3.24(m,2H),4.50-4.62(m,1H),4.85-4.98(br,1H),7.14-7.48(m,5H).

[0295] (Process 3)

[0296] In the same manner as in step 3 of Example 1, dihydroisoquinoline Using oxadiazole 6A-02 as substrate, N-Boc aminohydroxy ketone 5A-02 was obtained as a colorless liquid (yield 69%).

[0297] 1 H NMR (300MHz, CDCl3): δ1.41(s,9H),1.60-1.80(m,2H),2.46-2.62(m,2H),2.64-2.94 (m,4H),3.04-3.42(m,2H),4.02-4.18(m,1H),4.98-5.04(br,1H),7.14-7.32(m,5H).

[0298] (Process 4 and 5)

[0299] In the same manner as in steps 4 and 5 of Example 1, using N-Boc aminohydroxyketone 5A-02 as a substrate, a mixture of aminohydroxyketone 4A-02 and cyclic semiamine aldehyde 3A-02 was obtained as a yellow liquid (yield 92%).

[0300] 1 H NMR (300MHz, CDCl3): δ1.42(s,9H),1.60-1.80(m,2H),2.46-2.62(m,2H),2.62-3.20(m,6H),4.00-4.18(m,1H),7.12-7.34(m,5H).

[0301] (Steps 6 and 7)

[0302] In the same manner as step 6 of Example 1, a mixture of aminohydroxyketone 4A-02 and cyclic semiamine aldehyde 3A-02 was used as a substrate to obtain cyclic imine 2A-02, and then, in the same manner as step 7 of Example 1, bicyclic oxaziridine 1A-02 was obtained as a yellow liquid (yield 23%).

[0303] 1 H NMR (300MHz, CDCl3): δ1.58-1.98(m,6H), 2.46-2.54(m,2H), 3.86-4.20(m,2H), 4.14-4.24(m,1H), 7.22-7.40(m,5H).

[0304] MS: m / z 220([M+1],C 13 H 17 NO2)

[0305] Example 4

[0306] [Chemical formula 25]

[0307]

[0308] (Process 2)

[0309] In the same manner as in step 2 of Example 1, using benzaldehyde oxime 8A-03 and N-Boc-aminobutene 7A-01 as substrates, dihydroisobutene was obtained in the form of a colorless liquid. Ole 6A-03 (yield 72%).

[0310] 1H NMR (300MHz, CDCl3): δ1.18-1.64(m,2H),1.43(s,9H),2.78-2.83(m,2H),3 .08-3.42(m,2H),4.14-4.28(m,1H),4.75-5.10(br,1H),7.20-7.52(m,5H).

[0311] (Process 3)

[0312] In the same manner as in step 3 of Example 1, dihydroisoquinoline Using oxazole 6A-03 as substrate, N-Boc aminohydroxy ketone 5A-03 was obtained as a colorless liquid (yield 67%).

[0313] 1 H NMR (300MHz, CDCl3): δ1.18-1.64(m,2H),1.44(s,9H),2.76-2.84(m,2H),3 .08-3.42(m,2H),4.15-4.29(m,1H),4.72-5.12(br,1H),7.20-7.52(m,5H).

[0314] (Process 4 and 5)

[0315] In the same manner as in steps 4 and 5 of Example 1, using N-Boc aminohydroxy ketone 5A-03 as a substrate, a mixture of aminohydroxy ketone 4A-03 and cyclic semiamine aldehyde 3A-03 was obtained as a yellow liquid (yield 90%).

[0316] 1 H NMR (300MHz, CDCl3): δ1.16-1.66(m,2H), 2.74-2.84(m,2H), 2.62-2.98(m,2H), 4.14-4.28(m,1H), 7.20-7.52(m,5H).

[0317] (Steps 6 and 7)

[0318] In the same manner as step 6 of Example 1, a mixture of aminohydroxyketone 4A-03 and cyclic semiamine aldehyde 3A-03 was used as a substrate to obtain cyclic imine 2A-03, and then, in the same manner as step 7 of Example 1, bicyclic oxaziridine 1A-03 was obtained as a yellow liquid (yield 25%).

[0319] 1H NMR (300MHz, CDCl3): δ1.40-1.52(m,1H),1.82-1.98(m,1H),2.30-2.48(m,1H) ),2.78-2.86(m,1H),3.48-3.84(m,2H),4.14-4.22(m,1H),7.25-7.50(m,5H).

[0320] Example 5

[0321] [Chemical formula 26]

[0322]

[0323] (Process 2)

[0324] In the same manner as in step 2 of Example 1, 2-naphthylaldoxime 8A-04 and N-Boc-aminobutene 7A-01 were used as substrates to obtain dihydroisobutene in the form of a colorless liquid. Ole 6A-04 (yield 73%).

[0325] 1 H NMR (300MHz, CDCl3): δ1.45(s,9H),1.84-2.00(m,2H),3.02-3.20(m,1H),3.28-3.40 (m,2H),3.50-3.62(m,1H),4.78-4.88(m,1H),4.90-5.18(br,1H),7.42-8.00(m,7H).

[0326] (Process 3)

[0327] In the same manner as in step 3 of Example 1, dihydroisoquinoline Using oxazole 6A-04 as substrate, N-Boc aminohydroxy ketone 5A-04 was obtained as a colorless liquid (yield 62%).

[0328] 1 H NMR (300MHz, CDCl3): δ1.43(s,9H),1.62-1.84(m,2H),3.18-3.52(m,4H),4.30-4.42(m,1H),5.02-5.18(br,1H),7.42-8.02(m,6H),8.40(s,1H).

[0329] (Process 4 and 5)

[0330] In the same manner as in steps 4 and 5 of Example 1, using N-Boc aminohydroxy ketone 5A-04 as a substrate, a mixture of aminohydroxy ketone 4A-04 and cyclic semiamine aldehyde 3A-04 was obtained as a yellow liquid (yield 91%).

[0331] 1 H NMR (300MHz, CDCl3): δ1.60-1.86(m,2H),2.76-3.50(m,4H),4.28-4.40(m,1H),7.40-8.02(m,6H),8.42(s,1H).

[0332] (Steps 6 and 7)

[0333] In the same manner as in step 6 of Example 1, a mixture of aminohydroxyketone 4A-04 and cyclic seminaldehyde 3A-04 was used as a substrate to obtain cyclic imine 2A-04, and then, in the same manner as in step 7 of Example 1, bicyclic oxaziridine 1A-04 was obtained as a yellow liquid (yield 24%).

[0334] 1 H NMR (300MHz, CDCl3): δ1.42-1.82(m,2H), 1.96-2.26(m,2H), 3.46-3.86(m,2H), 4.13-4.21(m,1H), 7.10-8.20(m,7H).

[0335] MS: m / z 242([M+1],C 15 H 15 NO2)

[0336] Example 6

[0337] [Chemical formula 27]

[0338]

[0339] (Process 1)

[0340] In the same manner as in step 1 of Example 1, aldehyde 9a-02 and hydroxylamine hydrochloride were used as substrates to obtain oxime 8a-02 as a colorless solid (yield 90%).

[0341] (Process 2)

[0342] In the same manner as in step 2 of Example 1, oxime 8a-02 and N-Boc-aminobutene 7A-01 were used as substrates to obtain dihydroisobutene in the form of a colorless liquid. Ole 6Aa-02 (yield 71%).

[0343] 1H NMR (300MHz, CDCl3): δ1.47(s,9H),2.40-2.84(m,7H),3.12-3.40(m,3H),3.80(s,2H) ),4.60-4.74(m,1H),4.76-5.00(br,1H),5.92(t,1H,J=6.6Hz),7.16-7.40(m,10H).

[0344] (Process 3)

[0345] In the same manner as in step 3 of Example 1, dihydroisoquinoline Using oxadiazole 6Aa-02 as substrate, N-Boc aminohydroxy ketone 5Aa-002 was obtained in the form of a colorless liquid (yield 62%).

[0346] 1 H NMR (300MHz, CDCl3): δ1.43(s,9H),2.56-2.82(m,7H),3.02-3.44(m,3H),3.82(s,2H) ),4.02-4.16(m,1H),4.92-5.02(br,1H),6.81(t,1H,J=6.6Hz),7.10-7.38(m,10H).

[0347] (Process 4 and 5)

[0348] In the same manner as in steps 4 and 5 of Example 1, using N-Boc aminohydroxyketone 5Aa-002 as a substrate, a mixture of aminohydroxyketone 4Aa-002 and cyclic semiamine aldehyde 3Aa-002 was obtained as a yellow liquid (yield 92%).

[0349] 1 H NMR (300MHz, CDCl3): δ2.56-2.82(m,7H),2.94-3.40(m,3H),3.81(s,2H),43.98-4.10(m,1H),6.78(t,1H,J=6.6Hz),7.10-7.40(m,10H).

[0350] (Steps 6 and 7)

[0351] In the same manner as step 6 of Example 1, a mixture of aminohydroxyketone 4Aa-002 and cyclic semiamine aldehyde 3Aa-002 was used as a substrate to obtain cyclic imine 2Aa-002, and then, in the same manner as step 7 of Example 1, bicyclic oxaziridine 1Aa-002 was obtained as a yellow liquid (yield 22%).

[0352] MS: m / z 336([M+1],C 22 H25 NO2)

[0353] Example 7

[0354] [Chemical formula 28]

[0355]

[0356] (Process 1)

[0357] In the same manner as in step 1 of Example 1, aldehyde 9a-03 and hydroxylamine hydrochloride were used as substrates to obtain oxime 8a-03 as a colorless solid (yield 85%).

[0358] (Process 2)

[0359] In the same manner as in step 2 of Example 1, oxime 8a-03 and N-Boc-aminobutene 7A-01 were used as substrates to obtain dihydroisobutene in the form of a colorless liquid. Ole 6Aa-03 (yield 72%).

[0360] 1 H NMR (300MHz, CDCl3): δ1.42 (s, 9H), 1.70-1.84 (m, 2H), 1.76 (d, 3H, J = 6.6Hz), 1.92 (s, 3H), 2. 64-2.80(m,1H),3.22-3.35(m,3H),4.58-4.64(m,1H),4.80-4.98(br,1H),5.72-5.82(m,1H).

[0361] (Process 3)

[0362] In the same manner as in step 2 of Example 1, dihydroisoquinoline Using oxadiazole 6Aa-03 as substrate, N-Boc aminohydroxy ketone 5Aa-003 was obtained in the form of a colorless liquid (yield 66%).

[0363] 1 H NMR (300MHz, CDCl3): δ1.42 (s, 9H), 1.50-1.70 (m, 2H), 1.76 (s, 3H), 1.84 (d, 3H, J = 6.6Hz), 2. 72-2.82(m,2H),3.10-3.42(m,2H),4.12-4.20(m,1H),4.96-5.10(br,1H),6.70-6.82(m,1H).

[0364] (Process 4 and 5)

[0365] In the same manner as in steps 4 and 5 of Example 1, using N-Boc aminohydroxyketone 5Aa-003 as a substrate, a mixture of aminohydroxyketone 4Aa-003 and cyclic semiamine aldehyde 3Aa-003 was obtained as a yellow liquid (yield 82%).

[0366] 1 H NMR (300MHz, CDCl3): δ1.48-1.72(m,2H),1.76(s,3H),1.84(d,3H,J=6.6Hz) ,2.72-2.82(m,2H),2.96-3.22(m,2H),4.02-4.12(m,1H),6.68-6.82(m,1H).

[0367] (Steps 6 and 7)

[0368] In the same manner as step 6 of Example 1, a mixture of aminohydroxyketone 4Aa-003 and cyclic semiamine aldehyde 3Aa-003 was used as a substrate to obtain cyclic imine 2Aa-003, and then, in the same manner as step 7 of Example 1, bicyclic oxaziridine 1Aa-003 was obtained as a yellow liquid (yield 18%).

[0369] MS: m / z 170([M+1],C9H 15 NO2)

[0370] Example 8

[0371] [Chemical formula 29]

[0372]

[0373] (Process 1)

[0374] In the same manner as in step 1 of Example 1, aldehyde 9a-04 and hydroxylamine hydrochloride were used as substrates to obtain oxime 8a-04 as a colorless solid (yield 87%).

[0375] (Process 2)

[0376] In the same manner as in step 2 of Example 1, oxime 8a-04 and N-Boc-aminobutene 7A-01 were used as substrates to obtain dihydroisobutene in the form of a colorless liquid. Ole 6Aa-04 (yield 62%).

[0377] 1H NMR (300MHz, CDCl3): δ1.43(s,9H),2.44-2.80(m,2H),3.12-3.40(m,4H),3.94 (s,2H),4.62-4.76(m,1H),5.10-5.18(br,1H),6.80(s,1H),7.12-7.56(m,9H).

[0378] (Process 3)

[0379] In the same manner as in step 3 of Example 1, dihydroisoquinoline Using oxadiazole 6Aa-04 as substrate, N-Boc aminohydroxy ketone 5Aa-004 was obtained as a colorless liquid (yield 65%).

[0380] 1 H NMR (300MHz, CDCl3): δ1.43(s,9H),2.46-2.84(m,2H),3.14-3.42(m,4H),3.95(s,2H),4.14-4.22(m,1H),5.12-5.20(br,1H),7.10-7.60(m,10H).

[0381] (Process 4 and 5)

[0382] In the same manner as in steps 4 and 5 of Example 1, using N-Boc aminohydroxyketone 5Aa-004 as a substrate, a mixture of aminohydroxyketone 4Aa-004 and cyclic semiamine aldehyde 3Aa-004 was obtained as a yellow liquid (yield 80%).

[0383] 1 H NMR (300MHz, CDCl3): δ2.46-2.84(m,2H),3.12-3.42(m,4H),3.94(s,2H),4.08-4.20(m,1H),6.20(s,1H),7.12-7.60(m,9H).

[0384] (Steps 6 and 7)

[0385] In the same manner as step 6 of Example 1, a mixture of aminohydroxyketone 4Aa-004 and cyclic semiamine aldehyde 3Aa-004 was used as a substrate to obtain cyclic imine 2Aa-004, and then, in the same manner as step 7 of Example 1, bicyclic oxaziridine 1Aa-004 was obtained as a yellow liquid (yield 15%).

[0386] MS: m / z 342([M+1],C 20 H 20 ClNO2)

[0387] Industrial Applicability

[0388] According to the present invention, kakeromycin and its derivatives which show antifungal activity and cytotoxicity and are expected to be novel antifungal agents and anticancer agents can be produced by chemical synthesis.

[0389] This application is based on Japanese Patent Application No. 2015-039363 filed in Japan, the entire contents of which are intended to be incorporated herein by reference.

Claims

1. A compound represented by formula (6) or a salt thereof, In formula (6), R is a group represented by formula (A): in, R 1 and R 2 Same or different and each is C 1-20 Alkyl or C 7-20 Aralkyl, R 4 Represents C 1-20 Alkyl-oxy, n represents 1.

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