JPWO2005027934A1 - Prolyl oligopeptidase inhibitor - Google Patents

Abstract

General formula (1) (In the above formula, Q represents — (CH 2) n — (n represents 0 to 3), R represents a hydrogen atom, an alkyl group, an aryl group, etc., X represents a carbonyl group, etc. Y and Z each represent a hydrogen atom, a sulfonic acid group, an acyl group, an alkyl group, an aryl group, or the like, and Q represents — (CH 2) n — (n represents 0 to 3). Compound [alpha] -acylamino-N- (diaminophosphinyl) lactam derivative or a pharmacologically acceptable salt thereof, a prolyl oligopeptidase inhibitor.

Description

  The present invention provides novel prolyl oligopeptidase inhibitors, memory and cognitive impairment improving or treating agents, and Chagas disease preventing or treating agents, and α-acylamino-N- (diaminophosphinyl) lactam derivatives, The salt, the hydrate or the solvate thereof, and the pharmaceutical composition containing the compound are provided.

Conventionally, it has been reported that choline acetyltransferase activity decreases in the brain of Alzheimer's disease, and that acetylcholinesterase activity fluctuates predominantly, and acetylcholinesterase inhibitors are drugs that increase the amount of acetylcholine in the brain accordingly. In particular, cholinergic neuron activators have been developed (Non-Patent Document 1: Brain, Vol. 99, p. 459 (1976)).
Currently, development of a drug that aims to improve memory from a new viewpoint focusing on amyloid β protein and its precursor accumulated in the brain of Alzheimer's disease together with acetylcholine drugs is awaited.

Prolyl oligopeptidase (EC 3.4.21.26) was discovered as an inactivating enzyme of oxytocin (Non-patent Document 2: Science, Vol. 173, p. 827 (1971)) and relates to its substrate specificity. Detailed examination revealed that the function was attributed to specific cleavage at the C-terminal side of proline (Non-patent Document 3: J. Biol. Chem., Vol. 251, p. 7593 (1976)). Non-Patent Document 4: Science, Vol. 221, p. 1310 (1983)).
Subsequent studies revealed that prolyl oligopeptidase inactivates neurotransmitters such as neurotensin, substance P, and THR (thyroid stimulating hormone) and vasopressin, which are thought to be related to memory. (Non-patent document 5: Nature, Vol. 308, p. 276 (1984), Non-patent document 6: Biochem. Biophys. Acta, Vol. 422, p. 138 (1976)). From these results, it was considered that prolyl oligopeptidase is involved in the control of the neurotransmission system. Therefore, as a result of examining prolyl oligopeptidase activity in patients with various diseases, an increase in enzyme activity in the brain of Alzheimer's disease patients was confirmed (Non-patent Document 7: Expertia, Vol. 46, p. 94). (1990)).

  Furthermore, prolyl oligopeptidase has been reported as a candidate for an enzyme that may cleave the C-terminal part when amyloid β protein is cleaved from amyloid precursor protein (Non-patent Document 8: Biochem. Biophys. Res). Commun., Vol.235, p.641 (1997)). Therefore, the increase in the enzyme activity is considered to be one of the causes of Alzheimer's disease, and research on therapeutic and therapeutic agents for memory and cognitive impairment such as Alzheimer's disease using a prolyl oligopeptidase inhibitor has been advanced (Non-patent Document 9). : Drugs of Today, Vol.36, p.415 (2000)).

  As an inhibitor of this enzyme, prolyl thiazolidide derivative S17092 (Non-patent Document 10: CNS Drug Reviews, Vol. 8, p.31 (2002)), 2-carbonylpyrrolidine derivative ONO1603 (Non-patent Document 11: J. Pharmacol.Exp.Ther., Vol.288, p.6 (1999)), etc. are known, but all of them have completely different basic skeletons from the compounds of the present invention. In addition, as compounds having a skeleton similar to the compound represented by the general formula (1) of the present invention, sulfostine and its analogs are known. Memory and recognition deficiencies of these compounds, and prolyl oligopeptidase Is not known (Patent Document 1: International Publication No. 99/25719, Patent Document 2: JP 2000-327689 A). In the general formula (1), R is a benzyloxy group, X is a carbonyl group (—CO—), both Y and Z are hydrogen atoms, one of Y and Z is a hydrogen atom, and the other is The compound which is a combination of sulfonic acid groups is a compound described in Patent Document 2 (Japanese Patent Laid-Open No. 2000-327689).

Moreover, Tc80 is known as an enzyme having a prolyl oligopeptidase-like action other than animals (Non-patent Document 12: Biochem. J., Vol. 325, p. 129 (1997)). This enzyme is an 80 kDa proteolytic enzyme discovered from Trypanozoma cruzi, the causative insect of Chagas disease, and is known to specifically cleave collagen I and IV in the extracellular matrix. In addition, prolyl oligopeptidase inhibitors are disclosed in T.W. It has been reported to inhibit the entry of cruzi into cells (Non-patent Document 13: J. Biol. Chem., Vol. 276, p. 47078 (2001)). Therefore, it is considered that this Tc80 plays an important role when Trypanozoma cruzi enters into human cells. These facts suggest that prolyl oligopeptidase inhibitors also inhibit Tc80, suggesting that they may be used as prophylactic or therapeutic agents for Chagas disease, and studies on the selectivity of these enzymes have been promoted (non- Patent Document 14: Bioorg.Med.Chem., Vol.10, p.1719 (2002)).
Brain, Vol. 99, p. 459 (1976) Science, Vol. 173, p. 827 (1971) J. et al. Biol. Chem. , Vol. 251, p. 7593 (1976) Science, Vol. 221, p. 1310 (1983) Nature, Vol. 308, p. 276 (1984) Biochem. Biophys. Acta, Vol. 422, p. 138 (1976) Experientia, Vol. 46, p. 94 (1990) Biochem. Biophys. Res. Commun. , Vol. 235, p. 641 (1997) Drugs of Today, Vol. 36, p. 415 (2000) CNS Drug Reviews, Vol. 8, p. 31 (2002) J. et al. Pharmacol. Exp. Ther. , Vol. 288, p. 6 (1999) Biochem. J. et al. , Vol. 325, p. 129 (1997) J. et al. Biol. Chem. , Vol. 276, p. 47078 (2001) Bioorg. Med. Chem. , Vol. 10, p. 1719 (2002) International Publication No. 99/25719 JP 2000-327689 A

  An object of the present invention is to provide a novel α-acylamino-N- (diaminophosphinyl) lactam derivative, a therapeutic or preventive agent and a prolyl oligopeptidase inhibitor for memory and cognitive impairments containing these as active ingredients. It is in.

  As a result of intensive research on the sulfostin derivative, the present inventors have found that the novel α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the general formula (1) and its pharmacologically acceptable condition. It was found that the salt has prolyl oligopeptidase inhibitory activity, and the present invention has been completed.

That is, the present invention relates to the following (1) to (28).
(1) General formula (1)

[Wherein, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, a carbamoyl group, is substituted with a lower alkylaminocarbonyl group, or an arylaminocarbonyl group. X represents a carbonyl group (—CO—), a thiocarbonyl group (—CS—), or a sulfonyl group (—SO ₂ —). Y and Z may be the same or different and are a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group. , A lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, a lower alkyl group, an aryl group, a heteroaryl group, a lower alkoxy group , Aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group Is done. Q is - _{(CH 2)} n - shows the (n denotes 0 to 3). A prolyl oligopeptidase inhibitor comprising as an active ingredient an α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the formula:
(2) In the general formula (1), R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, or a lower alkoxy. Group, aryloxy group, pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, lower alkyl group, cycloalkyl group, aryl Group, heteroaryl group, lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxy Carbonyl group, thiol group, lower alkylthio group, halogen Substituted with 1 to 3 substituents selected from the group consisting of a cyano group, a cyano group, a nitro group, a carbamoyl group, a lower alkylaminocarbonyl group, and an arylaminocarbonyl group, and X is a carbonyl group (—CO—) or a sulfonyl group (-SO 2 _-) wherein indicating the (1), wherein the prolyl oligopeptidase inhibitor,
(3) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted lower alkoxy group or a nitro group, X is a carbonyl group (-CO-) or a sulfonyl group (-SO 2 _-) wherein indicating the (1), wherein the prolyl oligopeptidase inhibitor,
(4) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group, the lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted The prolyl oligopeptidase inhibitor according to the above (1), which is substituted with a lower alkoxy group or a nitro group and represents an X carbonyl group (-CO-),
(5) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Inhibition of prolyl oligopeptidase according to (1) above, wherein X is substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, and X represents a carbonyl group (—CO—) Agent,

(6) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other is a sulfonic acid group, lower alkyl group, aryl group, heteroaryl group, cycloalkyl group, lower acyl group, arylcarbonyl group, heteroarylcarbonyl group, cycloalkanecarbonyl group, lower alkenylcarbonyl group, lower alkylamino group Each represents a carbonyl group or an arylaminocarbonyl group, Well, when substituted, lower alkyl group, aryl group, heteroaryl group, lower alkoxy group, aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkyl group The prolyl oligopeptidase inhibitor according to (1), which is substituted with an amino group, an N-protected amino group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group,
(7) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, or an arylaminocarbonyl group, each group may be substituted, When substituted, lower alkyl group, aryl group, lower alkoxy group, aryloxy group, benzine Oxy group, a nitro group, a halogen atom, or a hydroxyl group in the substituted (1), wherein the prolyl oligopeptidase inhibitor,
(8) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, or an arylaminocarbonyl group, and the lower acyl group and the arylaminocarbonyl group may be substituted, and if substituted, a lower alkoxy group, an aryloxy group, The prolyl oligopeptidase inhibitor according to (1), which is substituted with a benzyloxy group, a halogen atom, or a hydroxyl group;
(9) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. And the other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and when substituted, the above-mentioned substituted with a phenoxy group or a benzyloxy group ( 1) The prolyl oligopeptidase inhibitor according to the above,
(10) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and if substituted, is substituted with a phenoxy group or a benzyloxy group, and Q is The prolyl oligopeptidase inhibitor according to (1), which represents-(CH ₂ ) _2- ,

(11) In the general formula (1), R represents a benzyloxy group or selected from the group consisting of a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group, and a benzyloxycarbonylamino group. 1 represents a methyl group or an ethyl group substituted with 1 to 2 substituents, X represents a carbonyl group (—CO—), one of Y and Z represents a hydrogen atom, and the other represents a sulfonic acid group. , A phenoxyacetyl group, a benzyloxyacetyl group, or a phenylaminocarbonyl group, and Q represents — (CH ₂ ) ₂ —, the prolyl oligopeptidase inhibitor according to the above (1),
(12) The prolyl oligopeptidase inhibitor according to any one of (1) to (11) above for improving or treating memory and cognitive impairment,
(13) The prolyl oligopeptidase inhibitor according to (12), wherein the memory and cognitive impairment is amnesia,
(14) The prolyl oligopeptidase inhibitor according to (12), wherein the memory and cognitive impairment is dementia,
(15) The prolyl oligopeptidase inhibitor according to any one of (1) to (11) above for preventing or treating Chagas disease,

(16) The prolyl oligopeptidase inhibitor according to the above (15) for inhibiting infection of trypanosomes into cells,
(17) General formula (1)

Wherein R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, carbamoyl group, lower alkylaminocarbonyl group, or .X substituted with arylaminocarbonyl group carbonyl group (-CO-), a thiocarbonyl group (-CS-), or a sulfonyl group - a (-SO ₂₎ Y and Z may be the same or different, and may be a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkane. A carbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, the lower alkyl group, aryl group, heteroaryl group, lower group Alkoxy group, aryloxy group, benzyloxy group, nitro Group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group, Q is — (CH ₂ ). _n- (n represents 0 to 3), provided that R is a benzyloxy group, X is a carbonyl group (-CO-), and both Y and Z are a combination of hydrogen atoms, Y and Z An α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the following formula: or a pharmacologically acceptable salt thereof:
(18) In the general formula (1), R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, or a lower alkoxy. Group, aryloxy group, pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, lower alkyl group, cycloalkyl group, aryl Group, heteroaryl group, lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxy Carbonyl group, thiol group, lower alkylthio group, halogen Substituted with 1 to 3 substituents selected from the group consisting of an atom, a cyano group, a nitro group, a carbamoyl group, a lower alkylaminocarbonyl group, and an arylaminocarbonyl group, and X is a carbonyl group (—CO—) or An α-acylamino-N- (diaminophosphinyl) lactam derivative or a pharmaceutically acceptable salt thereof according to (17), which represents a sulfonyl group (—SO ₂ —);
(19) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted Α-acylamino-N- (diaminophosphini) described in the above (17), wherein X represents a carbonyl group (—CO—) or a sulfonyl group (—SO ₂ —). E) lactam derivatives or pharmacologically acceptable salts thereof,
(20) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted The α-acylamino-N- (diaminophosphinyl) lactam derivative according to the above (17), which is substituted with a lower alkoxy group or a nitro group and X represents a carbonyl group (—CO—), or a pharmacologically acceptable salt thereof salt,

(21) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Α-acylamino-N described in the above (17), which is substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, wherein X represents a carbonyl group (—CO—) -(Diaminophosphinyl) lactam derivative or a pharmacologically acceptable salt thereof,
(22) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other is a sulfonic acid group, lower alkyl group, aryl group, heteroaryl group, cycloalkyl group, lower acyl group, arylcarbonyl group, heteroarylcarbonyl group, cycloalkanecarbonyl group, lower alkenylcarbonyl group, lower alkylamino group Carbonyl group or arylaminocarbonyl group, each group is substituted If substituted, a lower alkyl group, aryl group, heteroaryl group, lower alkoxy group, aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower group The α-acylamino-N- (diaminophosphinyl) lactam derivative according to the above (17), which is substituted with an alkylamino group, an N-protected amino group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group, or a pharmacological thereof Acceptable salt,
(23) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, or an arylaminocarbonyl group, each group may be substituted, When substituted, the lower alkyl group, aryl group, lower alkoxy group, aryloxy group, Aryloxy group, a nitro group, a halogen atom, or wherein is substituted with a hydroxyl group (17), wherein the α- acylamino -N- (diamino phosphinyl) lactam derivative or a pharmacologically acceptable salt thereof,
(24) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, or an arylaminocarbonyl group, and the lower acyl group and the arylaminocarbonyl group may be substituted, and if substituted, a lower alkoxy group, an aryloxy group, Α-Acylamino-N- (diaminophos) described in the above (17) substituted with a benzyloxy group, a halogen atom or a hydroxyl group Iniru) lactam derivative or a pharmacologically acceptable salt thereof,
(25) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. And the other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and when substituted, the above-mentioned substituted with a phenoxy group or a benzyloxy group ( 17) α-acylamino-N- (diaminophosphinyl) lactam derivative or a pharmaceutically acceptable salt thereof according to 17),

(26) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group X represents a carbonyl group (—CO—), and Y and Z are either ones selected from the group consisting of a group consisting of a group, a cyclohexyl group, and a benzyloxycarbonylamino group. One represents a hydrogen atom, the other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group. The lower acyl group may be substituted, and if substituted, is substituted with a phenoxy group or a benzyloxy group. is the, Q is - _{(CH 2) 2} - wherein showing the (17) alpha-acylamino -N- (diamino phosphinyl) according lactam derivative or its Pharmacologically acceptable salts,
(27) In the general formula (1), R represents a benzyloxy group or selected from the group consisting of a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group, and a benzyloxycarbonylamino group. 1 represents a methyl group or an ethyl group substituted with 1 to 2 substituents, X represents a carbonyl group (—CO—), one of Y and Z represents a hydrogen atom, and the other represents a sulfonic acid group. An α-acylamino-N- (diaminophosphinyl) lactam derivative according to the above (17), which represents a phenoxyacetyl group, a benzyloxyacetyl group, or a phenylaminocarbonyl group, and Q represents — (CH ₂ ) ₂ — Its pharmacologically acceptable salts,
(28) A pharmaceutical or preventive or therapeutic agent for mammals comprising the compound according to any one of (17) to (27) or a pharmacologically acceptable salt thereof as an active ingredient.

  According to the present invention, a prolyl oligopeptidase inhibitory action is provided as a novel use of a sulfostine derivative, and an α-acylamino-N- (diaminophosphinyl) lactam derivative is provided as a novel compound. In addition, according to the present invention, a novel memory and cognitive impairment improving agent is provided, and further, a mammalian pharmaceutical comprising a novel α-acylamino-N- (diaminophosphinyl) lactam derivative as an active ingredient is provided. .

  In the present invention, the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group. Tert-butyl group, n-pentyl group, n-hexyl group and the like. Among these, preferred groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. More preferably, a methyl group and an ethyl group are mentioned.

  In the present invention, the aryl group represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Among these, a preferred group is a phenyl group.

  In the present invention, the heteroaryl group means a heteroaromatic group containing 1 to 3 of the same or different heteroatoms as nitrogen atoms, oxygen atoms or sulfur atoms as heteroatoms, such as a furyl group, a thienyl group, an imidazolyl group, An oxazolyl group, a thiazolyl group, a pyridyl group, an indolyl group, a pyrimidinyl group, a pyridazinyl group, and the like can be given. Among these, preferred groups include a pyridyl group and an indolyl group.

  In the present invention, the lower alkoxy group means a lower alkyloxy group, and the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms as described above, for example, methoxy group, ethoxy group, n- Examples thereof include a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, and a tert-butoxy group. Among these, preferred groups include a methoxy group, an ethoxy group, and a tert-butoxy group.

  In the present invention, as described above, the aryl group of the aryloxy group represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as a phenoxy group, a naphthoxy group, a biphenyloxy group, an anthryloxy group, a phenanthryloxy group. Groups and the like. Of these, preferred groups include a phenoxy group and a naphthoxy group.

  In the present invention, the lower alkenyl group means a straight or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group, an allyl group, an isopropenyl group, and a 3-butenyl group. Among these, a preferable group is a vinyl group.

  In the present invention, the cycloalkyl group represents a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Of these, preferred groups include a cyclopentyl group and a cyclohexyl group.

  In the present invention, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among these, preferred atoms include a fluorine atom, a chlorine atom, and a bromine atom.

  In the present invention, the lower alkylamino group refers to an amino group to which the above-mentioned lower alkyl group is bonded. For example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an n- A hexylamino group etc. can be mentioned. Of these, preferred groups include a methylamino group, an ethylamino group, and an n-propylamino group.

  In the present invention, the di-lower alkylamino group represents an amino group in which two of the aforementioned lower alkyl groups are bonded, and examples thereof include a dimethylamino group, a diethylamino group, and a di-n-propylamino group. Of these, preferred groups include a dimethylamino group and a diethylamino group.

  In the present invention, the lower alkoxycarbonyl group refers to a group in which a carbonyl is bonded to the above-mentioned lower alkoxy group, such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, An isobutoxycarbonyl group, a tert-butoxycarbonyl group, etc. can be mentioned. Of these, preferred groups include a methoxycarbonyl group and an ethoxycarbonyl group.

  In the present invention, the arylamino group means a group in which an amino group is bonded to the aforementioned aryl group, and examples thereof include a phenylamino group, a biphenylamino group, a naphthylamino group, an anthrylamino group, a phenanthrylamino group, and the like. Can do. Of these, a preferred group includes a phenylamino group.

  In the present invention, the heteroarylamino group refers to a group in which an amino group is bonded to the above-described heteroaryl group, such as a furylamino group, a thienylamino group, an imidazolylamino group, an oxazolylamino group, a thiazolylamino group, a pyridylamino group, An indolylamino group, a pyrimidinylamino group, a pyridazinylamino group, and the like can be given. Among these, preferred groups include a pyridylamino group and a furylamino group.

  In the present invention, the lower alkylaminocarbonyl group refers to a carbonyl group to which the above-mentioned lower alkylamino group is bonded. For example, a methylaminocarbonyl group, an ethylaminocarbonyl group, an n-propylaminocarbonyl group, an isopropylaminocarbonyl group, an n- A butylaminocarbonyl group etc. can be mentioned. Of these, preferred groups include an ethylamino group and an n-propylamino group.

  In the present invention, the arylaminocarbonyl group means a group in which a carbonyl group is bonded to the above-mentioned arylamino group, for example, phenylaminocarbonyl group, biphenylaminocarbonyl group, naphthylaminocarbonyl group, anthrylaminocarbonyl group, phenanthryl. An aminocarbonyl group etc. can be mentioned. Of these, a preferred group is a phenylaminocarbonyl group.

  In the present invention, the lower acyl group means a group in which a carbonyl group is bonded to the above-mentioned lower alkyl group, and examples thereof include an acetyl group, a propionyl group, a butanoyl group, and a pentanoyl group. Of these, preferred examples include acetyl groups.

  In the present invention, the arylcarbonyl group refers to a group in which a carbonyl group is bonded to the aforementioned aryl group, and examples thereof include a benzoyl group and a naphthoyl group. Among these, a benzoyl group can be mentioned as a preferred group.

  In the present invention, the heteroarylcarbonyl group refers to a group in which a carbonyl group is bonded to the above-described heteroaryl group, and examples thereof include a nicotinoyl group, an isonicotinoyl group, a thiophenecarbonyl group, a pyrazinecarbonyl group, and a furoyl group. Among these, a preferred group is a thiophenecarbonyl group.

  In the present invention, the cycloalkanecarbonyl group refers to a group in which a carbonyl group is bonded to the above-described cycloalkyl group. For example, a cyclopropanecarbonyl group, a cyclobutanecarbonyl group, a cyclopentanecarbonyl group, a cyclohexanecarbonyl group, a cycloheptanecarbonyl group, a cyclohexane group, An octanecarbonyl group etc. can be mentioned. Among these, a preferred group is a cyclohexanecarbonyl group.

  In the present invention, the lower alkenylcarbonyl group refers to a group in which a carbonyl group is bonded to the aforementioned lower alkenyl group, and examples thereof include an acryloyl group, a crotonyl group, a vinylacetyl group, and a 4-pentenoyl group. Among these, acryloyl group can be mentioned as a preferable group.

  In the present invention, the lower alkylthio group means a thiol group to which the aforementioned lower alkyl group is bonded, and examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, and an n-hexylthio group. be able to. Among these, a preferred group is a methylthio group.

  In the present invention, the N-protected amino group refers to an amino group to which a commonly used amine protecting group is bonded. Examples of the amine protecting group include an acyl type, a carbamate type, and an imide type. Examples include acetyl group, propanoyl group, butanoyl group, pentanoyl group, acryloyl group, crotonyl group, cyclopropanecarbonyl group, cyclobutanecarbonyl group, cyclopentanecarbonyl group, cyclohexanecarbonyl group, cycloheptanecarbonyl group and the like. In the carbamate type, an optionally substituted benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group and the like are exemplified, and in the imide type, a phthaloyl group and the like are mentioned. Among these, preferred protecting groups include acetyl group, propanoyl group, butanoyl group, cyclohexanecarbonyl group, benzyloxycarbonyl group, and tert-butoxycarbonyl group.

  In the present invention, the N-protected pyrrolidinyl group refers to a pyrrolidinyl group in which a protecting group is bonded to an amine, and the amine protecting group is as described above, for example, an N-acetylpyrrolidinyl group, N-propanoylpyrrolidinyl. Group, N-butanoylpyrrolidinyl group, N- (cyclohexanecarbonyl) pyrrolidinyl group, optionally substituted N- (benzyloxycarbonyl) pyrrolidinyl group, N- (tert-butoxycarbonyl) pyrrolidinyl group, N-phthaloylpyrrolidinyl group etc. are mentioned. Among these, preferred protecting groups include N-acetylpyrrolidinyl group, N-propanoylpyrrolidinyl group, N-butanoylpyrrolidinyl group, N- (cyclohexanecarbonyl) pyrrolidinyl group, N- (benzyloxycarbonyl). ) Pyrrolidinyl group and N- (tert-butoxycarbonyl) pyrrolidinyl group.

In the present invention, Q in the lactam ring is an alkyl chain represented by — (CH ₂ ) _n —, n represents 0 to 3, and the size of the lactam ring is a 4 to 7 membered ring. Preferably, n is 1 or 2 (methylene group or ethylene group).

  The compound represented by the general formula (1) exists as a single optically active substance, a racemate or a mixture of optical isomers by having an asymmetric carbon and an asymmetric phosphorus atom depending on the compound. Such compounds are obtained as optically active, racemic or optical isomer mixtures. The compounds of the present invention should be understood as encompassing any of these optically active, racemic or optical isomer mixtures.

  The pharmacologically acceptable salts of the compounds of the present invention include salts with mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid And salts with organic acids such as benzenesulfonic acid, salts with inorganic bases such as inorganic metals such as sodium, potassium, lithium and calcium, and organic amine salts such as methylamine, ethylamine and diethanolamine. These salts can be produced according to a conventional method.

Examples of the compound represented by the general formula (1) include the following compounds.
(1) (3S, PR) -3-Benzoylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (2) (3S, PR) -3- (4-bromobenzoyl) amino-1-amino (sulfoamino) Phosphinyl-2-piperidone (3) (3S, PR) -3- (3-bromobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (4) (3S, PR) -3- (2-bromo Benzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (5) (3S, PR) -3- (4-chlorobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (6) (3S , PR) -3- (4-fluorobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (7) 3S, PR) -3- (4-Methylbenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (8) (3S, PR) -3- (3-methylbenzoyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (9) (3S, PR) -3- (2-methylbenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (10) (3S, PR) -3- (4- Methoxybenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone

(11) (3S, PR) -3- (4-Nitrobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (12) (3S, PR) -3- (4-cyanobenzoyl) amino-1 -Amino (sulfoamino) phosphinyl-2-piperidone (13) (3S, PR) -3- (4-hydroxybenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (14) (3S, PR) -3 -(4-Aminobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (15) (3S, PR) -3- (4-methylaminobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2- Piperidone (16) (3S, PR) -3- (4-dimethylaminobenzoyl) amino-1-amino (sulfo Mino) phosphinyl-2-piperidone (17) (3S, PR) -3-cyclohexanecarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (18) (3S, PR) -3-cyclopentanecarbonylamino-1 -Amino (sulfoamino) phosphinyl-2-piperidone (19) (3S, PR) -3- (2-naphthoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (20) (3S, PR) -3- (1-Naphthoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone

(21) (3S, PR) -3- (4-Phenylbenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (22) (3S, PR) -3-nicotinoylamino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (23) (3S, PR) -3-acryloylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (24) (3S, PR) -3-trans-crotonylamino-1- Amino (sulfoamino) phosphinyl-2-piperidone (25) (3S, PR) -3-isonicotinoylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (26) (3S, PR) -3-cinnamoylamino -1-amino (sulfoamino) phosphinyl-2-piperidone (27) (3S, PR) -3 Caproylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (28) (3S, PR) -3-valerylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (29) (3S, PR) -3- Butanoylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (30) (3S, PR) -3-propionylamino-1-amino (sulfoamino) phosphinyl-2-piperidone

(31) (3S, PR) -3-Acetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (32) (3S, PR) -3-formylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (33) (3S, PR) -3-tert-butylacetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (34) (3S, PR) -3-phenylacetylamino-1-amino (sulfoamino) phosphinyl 2-piperidone (35) (3S, PR) -3- (4-methoxyphenyl) acetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (36) (3S, PR) -3- (4-nitro Phenyl) acetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (37) 3S, PR) -3- (3-Phenylpropionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (38) (3S, PR) -3- (2-pyridylacetyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (39) (3S, PR) -3- (phenoxyacetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (40) (3S, PR) -3- (3-cyclohexanepropionyl) Amino-1-amino (sulfoamino) phosphinyl-2-piperidone

(41) (3S, PR) -3- (1-naphthoxyacetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (42) (3S, PR) -3- (N′-methylureido)- 1-amino (sulfoamino) phosphinyl-2-piperidone (43) (3S, PR) -3- (N′-ethylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (44) (3S, PR) — 3- (N′-n-propylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (45) (3S, PR) -3- (N′-n-butylureido) -1-amino (sulfoamino) Phosphinyl-2-piperidone (46) (3S, PR) -3- (N′-phenylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (4 ) (3S, PR) -3- (N ′-(3-cyanophenyl) ureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (48) (3S, PR) -3- (N ′-(1 "-Naphthyl) ureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (49) (3S, PR) -3- (N '-(2" -naphthyl) ureido) -1-amino (sulfoamino) phosphinyl- 2-piperidone (50) (3S, PR) -3- (N ′-(3 ″ -pyridyl) ureido) -1-amino (sulfoamino) phosphinyl-2-piperidone

(51) (3S, PR) -3- (N′-Benzylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (52) (3S, PR) -3- (tert-butoxycarbonyl) amino-1 -Amino (sulfoamino) phosphinyl-2-piperidone (53) (3S, PR) -3- (ethoxycarbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (54) (3S, PR) -3- ( Methoxycarbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (55) (3S, PR) -3- (phenoxycarbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (56) (3S, PR) -3- (6 ′-(benzyloxycarbonylamino) hexanoyl) amino-1-a No (sulfoamino) phosphinyl-2-piperidone (57) (3S, PR) -3- (4 ′-(benzyloxycarbonylamino) butanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (58) (3S , PR) -3-((benzyloxycarbonylamino) acetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (59) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) propionyl ) Amino-1-amino (sulfoamino) phosphinyl-2-piperidone (60) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) -3′-methylbutanoyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone

(61) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) -4′-methylpentanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (62) (3S, PR) -3- (2 '-(benzyloxycarbonylamino) -3'-methylpentanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (63) (3S, PR) -3- (2'-( Benzyloxycarbonylamino) -3′-phenylpropionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (64) (3S, PR) -3- (2 ′-(1 ′-(benzyloxycarbonyl) piperidine) ) Carbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (65) (3S, PR) -3- (2 ′-( Benzyloxycarbonylamino) -3′-carbamoylpropionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (66) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) -4 ′ -Carbamoylbutanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (67) (3S, PR) -3- (2 '-(benzyloxycarbonylamino) -4'-(methylthio) butanoyl) amino- 1-amino (sulfoamino) phosphinyl-2-piperidone (68) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) -3 ′-(3 ″ -indolyl) propionyl) amino-1-amino ( Sulfoamino) phosphinyl-2-piperidone (69) (3S, PR) -3-((tert-bu Xoxycarbonylamino) acetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (70) (3S, PR) -3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxy) propionyl Amino-1-amino (sulfoamino) phosphinyl-2-piperidone

(71) (3S, PR) -3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxy) butanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (72) (3S , PR) -3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxycarbonyl) propionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (73) (3S, PR) — 3- (2 ′-(tert-Butoxycarbonylamino) -3 ′-(benzyloxycarbonyl) butanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (74) (3S, PR) -3- (2 '-(Tert-butoxycarbonylamino) -3'-(4 "-benzyloxyphenyl) propionyl) amino -1-amino (sulfoamino) phosphinyl-2-piperidone (75) (3S, PR) -3- (2 ′-(tert-butoxycarbonylamino) -5′-nitroamidinopentanoyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (76) (3S, P (RS))-3-methanesulfonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (77) (3S, P (RS))-3-benzene Sulfonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (78) (3S, P (RS))-3- (4′-bromobenzenesulfonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone ( 79) (3S, P (RS))-3- (4′-toluenesulfonyl) amino-1-amino (sulfur Amino) phosphinyl-2-piperidone (80) (3S, P (RS)) - 3- (N'- phenyl thioureido) -1-amino (sulfoamino) phosphinyl-2-piperidone

(81) (3S, P (RS))-3- (N′-ethylthioureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (82) (3S) -3-benzyloxycarbonylamino-1- Bis (methylamino) phosphinyl-2-piperidone (83) (3S) -3-benzyloxycarbonylamino-1-bis (ethylamino) phosphinyl-2-piperidone (84) (3S) -3-benzyloxycarbonylamino- 1-bis (n-propylamino) phosphinyl-2-piperidone (85) (3S) -3-benzyloxycarbonylamino-1-bis (isopropylamino) phosphinyl-2-piperidone (86) (3S) -3-benzyl Oxycarbonylamino-1-bis (n-butylamino) phosphinyl-2-piperidone (8 7) (3S) -3-Benzyloxycarbonylamino-1-bis (phenylamino) phosphinyl-2-piperidone (88) (3S, P (RS))-3-benzyloxycarbonylamino-1-amino (n- Propylamino) phosphinyl-2-piperidone (89) (3S, PR) -3-benzyloxycarbonylamino-1-amino (cyclohexylamino) phosphinyl-2-piperidone (90) (3S, PR))-3-benzyloxy Carbonylamino-1-amino (phenylamino) phosphinyl-2-piperidone

(91) (3S, PR) -3-Benzyloxycarbonylamino-1- (acetylamino) aminophosphinyl-2-piperidone (92) (3S, PR) -3-benzyloxycarbonylamino-1-amino ( n-propionylamino) phosphinyl-2-piperidone (93) (3S, PR) -3-benzyloxycarbonylamino-1-amino (n-butanoylamino) phosphinyl-2-piperidone (94) (3S, PR)- 3-Benzyloxycarbonylamino-1-amino (tert-butylacetylamino) phosphinyl-2-piperidone (95) (3S, PR) -3-benzyloxycarbonylamino-1-amino (hydroxyacetylamino) phosphinyl-2- Piperidone (96) (3S, PR) -3-benzyloxycal Nylamino-1-amino (aminoacetylamino) phosphinyl-2-piperidone (97) (3S, PR) -3-benzyloxycarbonylamino-1-amino (methylaminoacetylamino) phosphinyl-2-piperidone (98) (3S , PR) -3-benzyloxycarbonylamino-1-amino (dimethylaminoacetylamino) phosphinyl-2-piperidone (99) (3S, PR) -3-benzyloxycarbonylamino-1-amino ((N-benzoylamino Acetyl) amino) phosphinyl-2-piperidone (100) (3S, PR) -3-benzyloxycarbonylamino-1-amino ((N-benzyloxycarbonylaminoacetyl) amino) phosphinyl-2-piperidone

(101) (3S, PR) -3-Benzyloxycarbonylamino-1-amino (carboxyacetylamino) phosphinyl-2-piperidone (102) (3S, PR) -3-benzyloxycarbonylamino-1-amino (methoxy) Acetylamino) phosphinyl-2-piperidone (103) (3S, PR) -3-benzyloxycarbonylamino-1-amino (phenylacetylamino) phosphinyl-2-piperidone (104) (3S, PR) -3-benzyloxy Carbonylamino-1-amino (phenylpropionylamino) phosphinyl-2-piperidone (105) (3S, PR) -3-benzyloxycarbonylamino-1-amino (phenoxyacetylamino) phosphinyl-2-piperidone (106) (3S , PR) -3 Benzyloxycarbonylamino-1-amino (benzyloxyacetylamino) phosphinyl-2-piperidone (107) (3S, PR) -3-benzyloxycarbonylamino-1-amino (cinnamoylamino) phosphinyl-2-piperidone (108 ) (3S, PR) -3-benzyloxycarbonylamino-1-amino (cyclohexanecarbonylamino) phosphinyl-2-piperidone (109) (3S, PR) -3-benzyloxycarbonylamino-1-amino (2-thiophene) Carbonylamino) phosphinyl-2-piperidone (110) (3S, PR) -3-benzyloxycarbonylamino-1-amino (nicotinoylamino) phosphinyl-2-piperidone

(111) (3S, PR) -3-Benzyloxycarbonylamino-1-amino (benzoylamino) phosphinyl-2-piperidone (112) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4- Methoxybenzoylamino) phosphinyl-2-piperidone (113) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-nitrobenzoylamino) phosphinyl-2-piperidone (114) (3S, PR) -3 -Benzyloxycarbonylamino-1-amino (4-cyanobenzoylamino) phosphinyl-2-piperidone (115) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-fluorobenzoylamino) phosphinyl-2 Piperidone (116) (3S) -3 Benzyloxycarbonylamino-1-bis (4-fluorobenzoylamino) phosphinyl-2-piperidone (117) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-chlorobenzoylamino) phosphinyl-2- Piperidone (118) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-bromobenzoylamino) phosphinyl-2-piperidone (119) (3S, PR) -3-benzyloxycarbonylamino-1- Amino (phenylureido) phosphinyl-2-piperidone (120) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-bromophenylureido) phosphinyl-2-piperidone

(121) (3S, PR) -3-Benzyloxycarbonylamino-1-amino (ethylureido) phosphinyl-2-piperidone (122) (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 Piperidone (123) (3R) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (124) (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-per Hydroazepinone (125) (3R) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-perhydroazepinone (126) (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl -2-pyrrolidinone (127) (3R) -3-benzyloxycarboni Amino-1-diaminophosphinyl-2-pyrrolidinone (128) (3S, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (129) (3R, PR) -3- Benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (130) (3S, PS) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone

(131) (3R, PS) -3-Benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (132) (3S, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl 2-perhydroazepinone (133) (3R, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-perhydroazepinone (134) (3S, PS) -3-benzyloxy Carbonylamino-1-amino (sulfoamino) phosphinyl-2-perhydroazepinone (135) (3R, PS) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-perhydroazepinone (136) (3S, PR) -3-Benzyloxyca Bonylamino-1-amino (sulfomino) phosphinyl-2-pyrrolidinone (137) (3R, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-pyrrolidinone (138) (3S, PS) -3 -Benzyloxycarbonylamino-1-amino (sulfomino) phosphinyl-2-pyrrolidinone (139) (3R, PS) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-pyrrolidinone (140) (3S, PR) -3-Cyclohexylpropionylamino-1-amino (phenylureido) phosphinyl-2-piperidone (141) (3S, PR) -3-benzyloxycarbonylamino-1-amino ((benzyloxycarbonylamino) acetylamino Phosphinyl-2-piperidone

The compound of the present invention can be produced as follows in accordance with a method for synthesizing sulfostin (Japanese Patent Laid-Open No. 2000-327689).
First, it can be easily produced by cyclization (lactamization) by reacting an ester such as methyl ester of an amino acid having an amino group in the side chain with a base or the like, or a reagent (for example, sold by Sigma) Q is - _{(CH 2) 3} - Bruno α- amino -ε- caprolactam, etc.) which can be purchased as the general formula (2)

（式中、Ｑは前記に記載の通りである。）の化合物に、アシル化の場合には塩基性条件下で対応する酸クロリド、酸無水物、活性エステル体などを作用させ、スルホニル化の場合には対応するスルホン酸クロリドなどを作用させ、カルバメート化の場合には対応するオキシカルボニルクロリド、ジカーボナート、活性カーボナートエステルなどを作用させ、ウレイド化の場合には対応するイソシアナート化合物を作用させ、チオウレイド化の場合には対応するイソチオイソシアナートなどを作用させて反応を行い、一般式（３）

In the case of acylation, a corresponding acid chloride, acid anhydride, active ester or the like is allowed to act on the compound of the formula (wherein Q is as described above) under basic conditions. In some cases, the corresponding sulfonic acid chloride is allowed to act, in the case of carbamate formation, the corresponding oxycarbonyl chloride, dicarbonate, active carbonate ester, etc. In the case of thioureidation, the reaction is carried out by reacting the corresponding isothioisocyanate, etc.

（式中のＱ、及びＲ及びＸは前記に記載の通りである。）で表される化合物とすることができる。次いで、Ｙ及びＺに低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基を含まない化合物群は、ラクタム環内のアミドをｎ−ブチルリチウム、水素化ナトリウムなどの塩基によって活性化した後に、オキシ塩化リンなどのオキシハロゲン化リン、アンモニアを順に作用させるジアミノホスフィニル基導入反応を行うことにより、一般式（４）

(Wherein Q, R and X are as described above). Next, a compound group not containing a lower alkyl group, aryl group, heteroaryl group or cycloalkyl group in Y and Z is obtained by activating the amide in the lactam ring with a base such as n-butyllithium or sodium hydride. By carrying out a diaminophosphinyl group introduction reaction in which phosphorus oxyhalide such as phosphorus oxychloride and ammonia act in this order, the general formula (4)

（式中のＱ及び、Ｒ及びＸは前記に記載の通りである。）で表される本発明の化合物とすることができる。また、Ｙ又はＺが、スルホン酸基である化合物群は、三酸化イオウーアミン錯体などを作用させ、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、アルケニルカルボニル基の場合には対応する酸クロリド、酸無水物などを作用させ、アルキルアミノカルボニル基及びアリールアミノカルボニル基の場合には対応するイソシアナート試薬を作用させることによって、また必要に応じてこれらの反応を組み合わせることによって、下記一般式（１）

(Wherein Q, R and X are as described above). In the case where Y or Z is a sulfonic acid group, a sulfur trioxide amine complex is allowed to act, and in the case of a lower acyl group, arylcarbonyl group, heteroarylcarbonyl group, cycloalkanecarbonyl group, alkenylcarbonyl group, By reacting the corresponding acid chloride, acid anhydride, etc., in the case of alkylaminocarbonyl and arylaminocarbonyl groups, by reacting the corresponding isocyanate reagent, and combining these reactions as required, The following general formula (1)

（式中のＱ及びＲは前記に記載の通りである。）で表される本発明の化合物に導くことができる。一方、Ｙ及びＺに低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基を含む化合物群は、ジアミノホスフィニル基導入反応の際、アンモニアの代わりに、対応する低級アルキルアミン、アリールアミン、ヘテロアリールアミン、シクロアルキルアミンを作用させ、また必要に応じてこれらの対応するアミンとアンモニアとを組み合わせて作用させることによって、一般式（１）で表される本発明の化合物に導くことができる。

(Q and R in the formula are as described above) can be led to the compound of the present invention. On the other hand, a compound group containing a lower alkyl group, an aryl group, a heteroaryl group, and a cycloalkyl group in Y and Z is substituted with a corresponding lower alkylamine, arylamine, instead of ammonia during the diaminophosphinyl group introduction reaction. It can be led to the compound of the present invention represented by the general formula (1) by acting a heteroarylamine or cycloalkylamine and, if necessary, a combination of these corresponding amine and ammonia. .

  Furthermore, the compound of the present invention having an amino (sulfoamino) phosphinyl group at the 1-position of the lactam ring can be synthesized by the method of JP-A No. 2000-327689 and has the following general formula (5)

（式中のＱは前記に記載の通りである。）で表されるスルフォスチン類縁体に、塩基性条件下、酸クロリド、酸無水物、活性エステル体などによってアシル化反応を、塩基性条件下、イソシアナート化合物によってウレイド化を、チオイソシアナート化合物によってチオウレイド化を、スルホン酸クロリドなどによってスルホン化を行うことによっても合成可能である。

(In the formula, Q is as described above.) The sulfostin analog represented by the formula is subjected to an acylation reaction under basic conditions under acid conditions, acid anhydrides, active ester compounds, etc. under basic conditions. It can also be synthesized by ureidoization with an isocyanate compound, thioureido formation with a thioisocyanate compound, and sulfonation with sulfonic acid chloride or the like.

  In order to isolate and purify the target product from the reaction mixture obtained by each of the above-mentioned production methods, solvent extraction, concentration, crystallization, distillation, suspension purification, various chromatographies, etc. can be used as necessary. it can.

  When the compound of the present invention is used as a preventive or therapeutic agent for memory and cognitive impairment or as a prolyl oligopeptidase inhibitor, it is used alone or mixed with an excipient or carrier to form a suspension, emulsion, injection, inhalant Tablets, pills, granules, fine granules, powders, capsules, oral solutions, suppositories, eye drops, eye ointments, transdermal solutions, transdermal patches, ointments, transmucosal solutions, transmucosal It is prepared as a preparation such as a mucosal patch or spray, and is administered orally or parenterally. As additives such as excipients or carriers, pharmaceutically acceptable ones are selected, and their types and compositions are determined by the administration route and administration method. For example, in the case of injections, saccharides such as sodium chloride, glucose and mannitol can be generally used. In the case of an oral preparation, starch, lactose, crystalline cellulose, magnesium stearate and the like can be used. If desired, auxiliary, stabilizer, wetting agent, emulsifier, buffer solution or other commonly used additives may be contained in the above preparation.

The content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98% by weight. For example, in the case of an injection, the active ingredient is usually 0.1 to 30% by weight, preferably 1 to 10% by weight. In the case of an oral preparation, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with additives. Capsules, tablets, granules, powders generally contain 5-100% by weight, preferably 25-98% by weight, of the active ingredient.
The dose is determined depending on the age, sex, weight, symptoms, therapeutic purpose, etc. of the patient. The therapeutic amount is usually 0.001 to 200 mg / kg / day for parenteral administration, and 0. 01 to 500 mg / kg / day, preferably 0.1 to 100 mg / kg / day, which is administered once or divided into 2 to 5 times.

Next, the present invention will be specifically described with reference to synthesis examples of compounds as reference examples and synthesis examples and pharmacological experimental examples of the compounds of the present invention as examples. However, the present invention is not limited thereto. Moreover, below, room temperature shows 10-30 degreeC.
When there was no internal standard substance in NMR, the solvent peak (4.65 ppm for D ₂ O, 2.49 ppm for DMSO-D ₆ and 3.30 ppm for CD ₃ OD) was used as a reference.

Reference example 1
(3S) -3-Benzyloxycarbonylamino-2-piperidone Under ice-cooling, thionyl chloride (69.2 mL, 0.9487 mol) was added to methanol (1.2 L), and the mixture was stirred for 20 minutes. Next, L-ornithine hydrochloride (80.00 g, 0.4744 mol) was added in four portions, and the mixture was stirred at the same temperature for 3 hours and at room temperature for 19 hours.
The reaction solution was concentrated under reduced pressure, crystallized with ether-hexane, and then washed with ether to obtain colorless crystals.
The obtained colorless crystals were dissolved in water (1 L), sodium hydrogen carbonate (119.56 g, 1.4232 mol) was added in several portions under ice cooling, and the mixture was stirred at room temperature for 15 hr.
Next, THF (0.5 L) and sodium hydrogen carbonate (59.78 g, 0.7116 mol) were added to the reaction solution, and then benzyloxycarbonyl chloride (81.3 mL, 0.5695 mol) was added under ice-cooling. For 18 hours.
The reaction solution in two layers was separated, and the aqueous layer was neutralized with hydrochloric acid and extracted with chloroform. The organic layer separated above was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. After ether was added to the residue for crystallization, the residue was washed with ether to obtain crude crystals (105.60 g). The crystallized mother liquor and the ether wash were combined and purified by silica gel chromatography (chloroform: ethyl acetate = 10: 1 to 2: 1) to obtain crude crystals (2.20 g). The crude crystals were combined and recrystallized (chloroform-ether) to obtain the target compound (106.34 g).

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.28-7.38 (5H, m), 6.36 (1H, br s), 5.79 (1 H, br s), 5.11 (2H, s), 4.06-4.12 ( 1H, m), 3.27-3.33 (2H, m), 2.46-2.53 (1H, m), 1.82-1.95 (2H, m), 1.61 (1H, tdd, J = 11.7, 12.7, 5.4 Hz).
MS (FAB, POS)
m / z: 249 (M + H) ⁺ , 271 (M + Na) ⁺ .

Reference example 2
(3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone In a nitrogen stream, the compound of Reference Example 1 (40.00 g, 0.1611 mol) was dissolved in anhydrous THF (450 mL). After cooling at a temperature of −78 ° C., n-butyllithium hexane solution (1.54M, 99 mL, 0.1525 mol) was slowly added and stirred for 45 minutes. Next, a solution of phosphoryl chloride (15.0 mL, 0.1609 mol) in anhydrous THF (20 mL) was added at the same temperature, and the mixture was stirred for 1.5 hours and at room temperature for 1 hour. After cooling again at an external temperature of −78 ° C., liquid ammonia (15 mL, 0.6791 mol) was added and stirred for 5 minutes.
Saturated brine (about 500 mL) was added to the reaction solution, the reaction solution in two layers was separated, and the aqueous layer was extracted with chloroform. The separated organic layer was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was crystallized from chloroform-ether to obtain the target compound (19.63 g).

¹ H-NMR (DMSO-D ₆ )
7.28-7.41 (5H, m), 5.00 (2H, s), 4.19 (2H, br s), 4.14 (2H, br s), 4.06-4.12 ( 1H, m), 3.55-3.61 (1H, m), 3.43-3.48 (1H, m), 1.98-2.03 (1H, m), 1.73-1. 78 (2H, m), 1.58-1.66 (1H, m).
MS (FAB, POS)
m / z: 327 (M + H) ⁺ .

Reference example 3
(3S) -3-benzyloxycarbonylamino-2-caprolactam To a solution of 3 (S) -amino-2-caprolactam (5.00 g, 39.01 mmol) in THF (20 mL) and water (40 mL) was added ice. Under cooling, sodium hydrogen carbonate (4.92 g, 58.56 mol) and benzyloxycarbonyl chloride (5.57 mL, 39.01 mmol) were added, and the mixture was stirred at room temperature for 18 hours.
The reaction mixture was concentrated under reduced pressure, water was added, and the precipitated crystals were collected by filtration. The crystals were washed with ether, dissolved in chloroform, and dried over anhydrous sodium sulfate. After the solvent was distilled off, recrystallization (chloroform-ether) was performed to obtain the target compound (5.23 g).

¹ H-NMR (CDCl ₃ )
7.26-7.36 (5H, m), 6.14-6.24 (2H, m), 5.10 (2H, d, J = 2.8 Hz), 4.34 (1H, ddd, J = 1.6, 6.8, 13.6 Hz), 3.19-3.31 (2H, m), 2.09-2.15 (1H, m), 1.98-2.05 (1H, m), 1.73-1.87 (2H, m), 1.48-1.58 (1H, m), 1.33-1.44 (1H, m).

Reference example 4
(3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-caprolactam In a solution of the compound of Reference Example 3 (4.00 g, 15.25 mmol) dissolved in anhydrous THF (120 mL) under a nitrogen stream. Then, an n-butyllithium hexane solution (1.55 M, 8.9 mL, 13.80 mmol) was slowly added at an external temperature of −78 ° C., and the mixture was stirred for 30 minutes. Next, a solution of phosphoryl chloride (2.57 g, 16.76 mmol) in anhydrous THF (10 mL) was added, and the mixture was stirred at the same temperature for 2 hours and at room temperature for 30 minutes. The reaction solution was cooled again at an external temperature of −78 ° C., liquid ammonia (2 mL, 90.55 mmol) was added, and the mixture was stirred for 5 minutes.
Saturated saline was added to the reaction solution, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with chloroform. Combined with the separated organic layer, washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform: methanol = 29: 1-14: 1), and the obtained crystals were washed with chloroform-ether to obtain the desired compound (1.55 g).

¹ H-NMR (DMSO-D ₆ )
7.25-7.38 (5H, m), 5.01 (2H, d, J = 4.8 Hz), 4.39-4.45 (1H, m) 4.162H, br s), 4. 11 (2H, br s), 3.20-3.30 (2H, m), 1.48-1.80 (5H, m), 1.33-1.43 (1H, m).
MS (FAB, POS)
m / z: 341 (M + H) ⁺ .

Reference Example 5
L- (N-benzyloxycarbonyl) glutamine methyl ester L- (N-benzyloxycarbonyl) glutamine (8.00 g, 28.54 mmol) was dissolved in DMF (80 mL) in sodium bicarbonate (4.80 g, 57 .14 mol) and methyl iodide (4.44 mL, 71.32 mmol) were added, and the mixture was stirred at room temperature for 22 hours.
Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ethyl acetate-ether to obtain the target compound (6.60 g).

¹ H-NMR (CD ₃ OD)
7.26-7.37 (5H, m), 5.09 (2H, s), 4.21 (1H, dd, J = 5.2, 9.2 Hz), 3.72 (3H, s), 2.31 (2H, t, J = 7.8 Hz), 2.10-2.19 (1H, m), 1.88-1.97 (1H, m).

Reference Example 6
(3S) -3-Benzyloxycarbonylamino-2-pyrrolidone bis (trifluoroacetoxy) iodobenzene (10.45 g, 24.30 mmol) in acetonitrile (50 mL), water (50 mL) and pyridine (3.02 mL, 37. 34 mmol), the compound of Reference Example 5 (5.50 g, 18.69 mmol) was added, and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated.
A sodium hydrogen carbonate aqueous solution (5 g / 100 mL) was added to a solution obtained by dissolving the residue in chloroform (100 mL), and the mixture was stirred at room temperature for 17 hours.
The reaction solution was separated into an aqueous layer and a chloroform layer, and the aqueous layer was extracted with chloroform. The chloroform layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was washed with ether to obtain the target compound (2.41 g).

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.28-7.38 (5 H, m), 6.49 (1 H, br s), 5.49 (1 H, br d, J = 4.9 Hz), 5.11 (2 H, s), 4. 21-4.27 (1H, m), 3.29-3.38 (2H, m), 2.65-2.73 (1H, m), 1.98 (1H, qd, J = 9.8) , 12.2 Hz).

Reference Example 7
(3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-pyrrolidone To a solution of the compound of Reference Example 6 (3.00 g, 12.81 mmol) dissolved in anhydrous THF (210 mL) under a nitrogen stream. Then, an n-butyllithium hexane solution (1.54M, 7.9 mL, 12.17 mmol) was slowly added at an external temperature of −78 ° C., and the mixture was stirred for 45 minutes. Next, a solution of phosphoryl chloride (1.96 g, 12.78 mmol) in anhydrous THF (4 mL) was added, and the mixture was stirred at the same temperature for 50 minutes and at room temperature for 1 hour. The reaction solution was cooled again at an external temperature of −78 ° C., liquid ammonia (2.5 mL, 113 mmol) was added, and the mixture was stirred for 5 minutes.
The solvent was distilled off under reduced pressure, brine was added to the residue, the aqueous layer was washed with hexane and chloroform, and then purified with HP-20SS. The obtained crystals were washed with chloroform-ether to obtain the target compound (1.83 g).

¹ H-NMR (CD ₃ OD)
7.26-7.37 (5H, m), 5.01 (2H, s), 4.35 (1H, dd, J = 8.4, 11.2 Hz), 3.72 (1H, dd, J = 8.8, 10.0 Hz), 3.53 (1 H, td, J = 10.0, 6.4 Hz), 2.37-2.44 (1 H, m), 1.95-2.06 ( 1H, m).
MS (FAB, POS)
m / z: 313 (M + H) ⁺ , 335 (M + Na) ⁺ .

Reference Example 8
(3S, PR) -3-Benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt Sulfostin monohydrate (600.6 mg, 2.0694 mmol) was dissolved in water (15 mL). Sodium hydrogen carbonate (434.6 mg, 5.1732 mmol), tetrahydrofuran (10 mL), and benzyloxycarbonyl chloride (0.38 mL, 2.6618 mmol) were added, and the mixture was stirred overnight at room temperature.
Tetrahydrofuran in the reaction solution was distilled off under reduced pressure, and then purified with Diaion HP-20 (150 mL, water-methanol gradient elution). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.39-7.48 (5H, m), 5.12-5.21 (2H, m), 4.32 (1H, dd, J = 11.7, 6.8), 3.70-3 .79 (1H, m), 3.55-3.67 (1H, m), 2.15-2.25 (1H, m), 1.98-2.07 (1H, m), 1.85 -1.95 (1H, m), 1.76 (1H, tdd, J = 11.7, 9.3, 6.8 Hz).
MS (FAB, POS)
m / z: 451 (M + Na) ⁺ .

Reference Example 9
(3R) -3-Benzyloxycarbonylamino-2-piperidone Under ice-cooling, thionyl chloride (13.0 mL, 178.22 mmol) was added to methanol (300 mL), and the mixture was stirred for 30 minutes. Next, D-ornithine hydrochloride (20.00 g, 118.61 mmol) was added over 20 minutes, and the mixture was stirred at the same temperature for 30 minutes and at room temperature overnight.
After concentrating the reaction solution under reduced pressure, the obtained oil was dissolved in water (200 mL), and sodium hydrogen carbonate (29.89 g, 355.79 mmol) was added in several portions under ice cooling, followed by stirring at room temperature for 20 hours. did.
Next, THF (100 mL) and sodium hydrogen carbonate (14.95 g, 177.90 mmol) were added to the reaction solution, and then benzyloxycarbonyl chloride (22.0 mL, 154.10 mmol) was added under ice-cooling. Stir for hours.
The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. After ether-n-hexane was added to the residue for crystallization, the residue was washed with ether-n-hexane to obtain the target compound (21.46 g, 73%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.30-7.37 (5H, m), 6.43 (1H, br s), 5.81 (1H, br s), 5.03 (2H, s), 4.09 (1H, td, J = 5.8, 11.6 Hz), 3.27-3.32 (2H, m), 2.45-2.52 (1H, m), 1.83-1.95 (2H, m), 1.61 (1H, tdd, J = 11.6, 12.8, 5.2 Hz).

Reference Example 10
(3R) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone The compound of Reference Example 9 (16.00 g, 64.44 mmol) was dissolved in anhydrous THF (200 mL) under a nitrogen stream, After cooling at -78 ° C, n-butyllithium hexane solution (2.46M, 25mL, 61.50mmol) was slowly added and stirred for 1.5 hours. Next, a solution of phosphoryl chloride (11.86 g, 77.35 mmol) in anhydrous THF (40 mL) was added at the same temperature and stirred for 35 minutes. Further, liquid ammonia (8.8 mL, 398.40 mmol) was added and stirred for 5 minutes.
The reaction mixture was concentrated and purified with Diaion HP-20 (500 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the desired compound (4.91 g, 23%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
7.42 (1H, d, J = 8.9 Hz), 7.30-7.39 (5H, m), 5.03 (2H, s), 4.21 (2H, br s), 4.16 (2H, br s), 4.10 (1H, td, J = 7.9, 11.9 Hz), 3.56-3.62 (1H, m), 3.44-3.50 (1H, m ), 1.98-2.06 (1H, m), 1.74-1.80 (2H, m), 1.59-1.67 (1H, m).
MS (FAB, POS)
m / z: 327 (M + H) ⁺

Example 1
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3-benzoylamino-2-piperidone sodium salt Sulfostin monohydrate (100.3 mg, 0.3456 mmol) dissolved in water (2 mL) was dissolved in carbonic acid. Sodium hydride (145.2 mg, 1.7284 mmol), acetonitrile (2 mL), and benzoyl chloride (0.080 mL, 0.6892 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (86.0 mg, 63%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.83 (2H, d, J = 7.8 Hz), 7.64 (1H, t, J = 7.8 Hz), 7.55 (2H, t, J = 7.8 Hz), 4.79 (1H , Dd, J = 11.2, 6.8 Hz), 3.68-3.83 (2H, m), 2.25-2.31 (1H, m), 2.06-2.17 (1H, m), 1.86-2.03 (2H, m).
HR-MS (ESI, POS)
m / z: found, 421.0342 (M + Na) ⁺
calcd. _{for C 12 H 16 N 4 Na} 2 O 6, 421.0324

Example 2
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-bromobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.5 mg, 0.5186 mmol) dissolved in water (3 mL) To the solution was added sodium bicarbonate (217.8 mg, 2.5925 mmol), acetonitrile (3 mL), and 4-bromobenzoyl chloride (227.6 mg, 1.0370 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (218.8 mg, 88%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.68-7.74 (4H, m), 4.69 (1H, dd, J = 10.7, 6.8 Hz), 3.81 (1H, tdd, J = 9.3, 7.8, 4.9 Hz), 3.63-3.71 (1H, m), 2.21-2.28 (1H, m), 2.01-2.10 (1H, m), 1.82-1. 92 (2H, m).
HR-MS (ESI, POS)
m / z: found, 498.9433 (M + Na) ⁺
calcd. _{for C 12 H 15 BrN 4 Na} 2 O 6 PS, 498.9429

Example 3
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (3-bromobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and 3-bromobenzoyl chloride (0.137 mL, 1.0439 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (151.2 mg, 61%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.98-8.00 (1H, m), 7.75-7.89 (2H, m), 7.44 (1H, t, J = 7.8 Hz), 4.72 (1H, dd, J = 11.2, 6.8 Hz), 3.78-3.85 (1H, m), 3.65-3.72 (1H, m), 2.22-2.30 (1H, m), 2 .03-2.12 (1H, m), 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 498.9409 (M + Na) ⁺
calcd. _{for C 12 H 15 BrN 4 Na} 2 O 6 PS, 498.9429

Example 4
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (2-bromobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and 2-bromobenzoyl chloride (0.136 mL, 1.0404 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (173.5 mg, 70%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.72 (1H, d, J = 7.8 Hz), 7.54 (1H, dd, J = 7.8, 2.0 Hz), 7.49 (1H, t, J = 7.8 Hz), 7 .42 (1H, td, J = 7.8, 2.0 Hz), 4.68 (1H, dd, J = 10.7, 6.8 Hz), 3.79-3.86 (1H, m), 3.62-3.69 (1H, m), 2.28-2.37 (1H, m), 2.02-2.09 (1H, m), 1.84-2.00 (2H, m) ).
HR-MS (ESI, POS)
m / z: found, 498.9412 (M + Na) ⁺
calcd. _{for C 12 H 15 BrN 4 Na} 2 O 6 PS, 498.9429

Example 5
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-chlorobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.3 mg, 0.5179 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.5 mg, 2.5890 mmol), acetonitrile (3 mL), and 4-chlorobenzoyl chloride (0.13 mL, 1.0229 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (133.4 mg, 60%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.79 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz), 4.71 (1H, dd, J = 11.2, 6.8 Hz), 3 .78-3.85 (1H, m), 3.65-3.71 (1H, m), 2.22-2.28 (1H, m), 2.02-2.11 (1H, m) , 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 454.9929 (M + Na) ⁺
calcd. for C ₁₂ H ₁₅ ClN ₄ Na ₂ O ₆ PS, 454.9934

Example 6
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-fluorobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.3 mg, 0.5179 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.5 mg, 2.5890 mmol), acetonitrile (3 mL), and 4-fluorobenzoyl chloride (0.12 mL, 1.0232 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (98.7 mg, 46%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.87 (1H, d, J = 8.3 Hz), 7.86 (1H, d, J = 8.3 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.25 (1H , D, J = 8.3 Hz), 4.71 (1H, dd, J = 10.7, 6.8 Hz), 3.78-3.86 (1H, m), 3.65-3.72 ( 1H, m), 2.21-2.31 (1H, m), 2.02-2.12 (1H, m), 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 439.0229 (M + Na) ⁺
calcd. _{for C 12 H 15 FN 4 Na} 2 O 6 PS, 439.0229

Example 7
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-methylbenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.5 mg, 0.5186 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.8 mg, 2.5925 mmol), acetonitrile (3 mL), and 4-methylbenzoyl chloride (0.137 mL, 1.0359 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (179.5 mg, 84%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.73 (2H, d, J = 8.3 Hz), 7.37 (2H, d, J = 8.3 Hz), 4.76 (1H, dd, J = 11.2, 6.8 Hz), 3 .76-3.83 (1H, m), 3.68-3.74 (1H, m), 2.41 (3H, s), 2.23-2.30 (1H, m), 2.05 -2.14 (1H, m), 1.85-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 435.0493 (M + Na) ⁺
calcd. _{for C 13 H 18 N 4 Na} 2 O 6 PS, 435.0480

Example 8
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (3-methylbenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.0 mg, 0.5168 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.1 mg, 2.5842 mmol), acetonitrile (3 mL), and 3-methylbenzoyl chloride (0.14 mL, 1.0622 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (61.2 mg, 29%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.65 (1H, s), 7.62 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7) .8 Hz), 4.72 (1H, dd, J = 11.2, 6.8 Hz), 3.78-3.85 (1H, m), 3.65-3.72 (1H, m), 2 .41 (3H, s), 2.23-2.29 (1H, m), 2.03-2.12 (1H, m), 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 435.0499 (M + Na) ⁺
calcd. _{for C 13 H 18 N 4 Na} 2 O 6 PS, 435.0480

Example 9
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (2-methylbenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.0 mg, 0.5168 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.1 mg, 2.5842 mmol), acetonitrile (3 mL), and 2-methylbenzoyl chloride (0.14 mL, 1.0773 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (83.3 mg, 39%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.42-7.47 (2H, m), 7.30-7.37 (2H, m), 4.68 (1H, dd, J = 11.2, 6.8 Hz), 3.83 (1H , Tdd, J = 4.9, 12.2, 7.3 Hz), 3.63-3.70 (1H, m), 2.40 (3H, s), 2.24-2.35 (1H, m), 2.01-2.10 (1H, m), 1.82-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 435.0499 (M + Na) ⁺
calcd. _{for C 13 H 18 N 4 Na} 2 O 6 PS, 435.0480

Example 10
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-methoxybenzoyl) amino-2-piperidone sodium salt 4-methoxybenzoic acid (118.3 mg, 0.7775 mmol), dicyclohexylcarbodiimide (160.5 mg) , 0.7779 mmol) and N-hydroxysuccinimide (89.5 mg, 0.7777 mmol) were added acetonitrile (5 mL), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 4-methoxybenzoic acid active ester solution was added to a solution of sulfostine monohydrate (150.5 mg, 0.5186 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (93.0 mg, 42%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.82 (2H, td, J = 2.0, 8.8 Hz), 7.08 (2H, td, J = 2.0, 8.8 Hz), 4.76 (1H, dd, J = 1.11. 2,6.8 Hz) 3.89 (3H, s), 3.79 (1 H, tdd, J = 4.9, 12.7, 7.3 Hz), 3.67-3.74 (1 H, m) 2.23-2.30 (1H, m), 2.08-2.15 (1H, m), 1.85-2.03 (2H, m).
HR-MS (ESI, POS)
m / z: found, 451.0443 (M + Na) ⁺
calcd. for C ₁₃ H ₁₈ N ₄ Na ₂ O ₇ PS, 451.0429

Example 11
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (4-nitrobenzoyl) amino-2-piperidone sodium salt 4-nitrobenzoic acid (129.8 mg, 0.7767 mmol), dicyclohexylcarbodiimide (160.3 mg) , 0.7769 mmol) and N-hydroxysuccinimide (89.4 mg, 0.7769 mmol) were added acetonitrile (5 mL), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 4-nitrobenzoic acid active ester solution was added to a solution of sulfostine monohydrate (150.3 mg, 0.5179 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (177.0 mg, 77%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
8.35 (2H, d, J = 8.8 Hz), 8.00 (2H, d, J = 8.8 Hz), 4.82 (1H, dd, J = 11.7, 6.8 Hz), 3 68-3.84 (2H, m), 2.28-2.35 (1H, m), 2.08-2.17 (1H, m), 1.88-2.05 (2H, m) .
HR-MS (ESI, POS)
m / z: found, 466.00211 (M + Na) ⁺
calcd. _{for C 12 H 15 N 5 Na} 2 O 8 PS, 466.0174

Example 12
(3S, PR) -3-cyclohexanecarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt Sulfostin monohydrate (150.0 mg, 0.5168 mmol) was dissolved in water (3 mL) in a solution of carbonic acid. Sodium hydride (217.1 mg, 2.5842 mmol), acetonitrile (3 mL), and cyclohexanecarbonyl chloride (0.14 mL, 1.0773 mmol) were added, and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (142.7 mg, 68%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
4.48 (1H, dd, J = 11.2, 6.8 Hz), 3.77 (1H, tdd, J = 4.9, 12.2, 7.9 Hz), 3.58-3.65 ( 1H, m), 2.29 (1H, td, J = 11.7, 3.4 Hz), 2.13 (1H, td, J = 12.2, 5.9 Hz), 1.95-2.03 (1H, m), 1.66-1.92 (7H, m), 1.15-1.44 (5H, m).
HR-MS (ESI, POS)
m / z: found, 427.0808 (M + Na) ⁺
calcd. _{for C 12 H 22 N 4 Na} 2 O 6 PS, 427.0793

Example 13
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (2-naphthalenecarbonyl) amino-2-piperidone sodium salt 2-naphthalenecarboxylic acid (134.1 mg, 0.7788 mmol), dicyclohexylcarbodiimide (160.7 mg) , 0.7788 mmol) and N-hydroxysuccinimide (89.6 mg, 0.7785 mmol) were added acetonitrile (5 mL) and dimethylformamide (1 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 2-naphthalenecarboxylic acid active ester solution was added to a solution of sulfostine monohydrate (150.7 mg, 0.5192 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (90.2 mg, 39%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
8.26 (1H, s), 7.96 (1H, d, J = 8.3 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.75 (1H, dd, J = 8) .3, 2.0 Hz), 7.58-7.66 (2H, m), 4.74 (1H, dd, J = 11.2, 6.8 Hz), 3.78-3.85 (1H, m), 3.64-3.73 (1H, m), 2.22-2.28 (1H, m), 2.07-2.15 (1H, m), 1.86-2.02 ( 2H, m).
HR-MS (ESI, POS)
m / z: found, 471.0500 (M + Na) ⁺
calcd. for C ₁₆ H ₁₈ N ₄ Na ₂ O ₆ PS, 471.0480

Example 14
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3-nicotinoylamino-2-piperidone sodium salt Nicotinic acid (96.0 mg, 0.7798 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N Acetonitrile (5 mL) was added to -hydroxysuccinimide (89.7 mg, 0.7794 mmol), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, nicotinic acid active ester solution was added to a solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium bicarbonate (48.0 mg, 0.5714 mmol) in water (3 mL), and at room temperature. Stir overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (110.0 mg, 53%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
8.93 (1H, dd, J = 2.5, 1.5 Hz), 8.71 (1H, dd, J = 4.9, 1.5 Hz), 8.25 (1H, ddd, J = 7. 8, 2.5, 1.5 Hz), 7.59 (1H, ddd, J = 7.8, 4.9, 1.5 Hz), 4.82 (1H, dd, J = 11.2, 6.). 8Hz), 3.77-3.84 (1H, m), 3.69-3.76 (1H, m), 2.27-2.34 (1H, m), 2.07-2.16 ( 1H, m), 1.88-2.05 (2H, m).
HR-MS (ESI, POS)
m / z: found, 422.0272 (M + Na) ⁺
calcd. for C ₁₁ H ₁₅ N ₅ Na ₂ O ₆ PS, 422.0276

Example 15
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-isonicotinoylamino-2-piperidone sodium salt isonicotinic acid (96.0 mg, 0.7798 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) Acetonitrile (5 mL) was added to N-hydroxysuccinimide (89.7 mg, 0.7794 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, to the solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) dissolved in water (3 mL), the solution obtained by filtering the crystals is added. Stir at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (138.0 mg, 67%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
8.71 (2H, d, J = 4.9 Hz), 7.77 (2H, d, J = 4.9 Hz), 4.78-4.84 (1H, m), 3.62-3.84 (2H, m), 2.27-2.33 (1H, m), 2.07-2.16 (1H, m), 1.87-2.04 (2H, m).
HR-MS (ESI, POS)
m / z: found, 422.0267 (M + Na) ⁺
calcd. for C ₁₁ H ₁₅ N ₅ Na ₂ O ₆ PS, 422.0276

Example 16
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-cinnamoylamino-2-piperidone sodium salt Sulfostin monohydrate (200.2 mg, 0.6898 mmol) was dissolved in water (4 mL) in a solution of carbonic acid. Sodium hydride (289.8 mg, 3.496 mmol), acetonitrile (4 mL), and cinnamoyl chloride (229.9 mg, 1.3799 mmol) were added, and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (121.8 mg, 42%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.63-7.68 (2H, m), 7.57 (1H, d, J = 16.1 Hz), 7.45-7.53 (3H, m), 6.68 (1H, d, J = 16.1 Hz), 4.60 (1 H, dd, J = 11.2, 6.8 Hz), 3.83 (1 H, tdd, J = 4.9, 12.2, 7.3 Hz), 3. 63 (1H, tdd, J = 4.9, 11.2, 7.3 Hz), 2.18-2.26 (1H, m), 1.99-2.08 (1H, m), 1.75 -1.96 (2H, m).
HR-MS (ESI, POS)
m / z: found, 447.0498 (M + Na) ⁺
calcd. for C ₁₄ H ₁₈ N ₄ Na ₂ O ₆ PS, 447.0480

Example 17
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3-n-caproylamino-2-piperidone sodium salt Sulfostin monohydrate (120.8 mg, 0.4162 mmol) dissolved in water (3 mL) Were added sodium hydrogen carbonate (139.9 mg, 1.6653 mmol), acetonitrile (3 mL), and n-caproic anhydride (0.15 mL, 0.6481 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, purification was performed with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (146.2 mg, 90%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
4.47 (1H, dd, J = 11.2, 6.8 Hz), 3.75-3.82 (1H, m), 3.56-3.63 (1H, m), 2.31 (2H , T, J = 7.3 Hz), 2.09-2.19 (1H, m), 1.94-2.03 (1H, m), 1.81-1.92 (1H, m), 1 .68-1.78 (1H, m), 1.58-1.66 (2H, m), 1.26-1.37 (4H, m), 0.88 (3H, t, J = 7. 3 Hz).
HR-MS (ESI, POS)
m / z: found, 415.0786 (M + Na) ⁺
calcd. _{for C 11 H 22 N 4 Na} 2 O 6 PS, 415.0793

Example 18
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (phenylacetyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.1 mg, 0.5172 mmol) dissolved in water (3 mL) Were added sodium hydrogen carbonate (217.2 mg, 2.5854 mmol), acetonitrile (3 mL), and phenylacetyl chloride (0.14 mL, 1.0586 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (110.9 mg, 52%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.36-7.45 (5H, m), 4.50 (1H, dd, J = 11.2, 6.8Hz), 3.76 (1H, tdd, J = 4.9, 12.2, 7.3 Hz), 3.68 (2H, s), 3.57-3.65 (1H, m), 2.09-2.17 (1H, m), 1.94-2.04 (1H, m), 1.81-1.92 (1H, m), 1.68-1.77 (1H, m).
HR-MS (ESI, POS)
m / z: found, 435.0499 (M + Na) ⁺
calcd. _{for C 13 H 18 N 4 Na} 2 O 6 PS, 435.0480

Example 19
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((4-methoxyphenyl) acetyl) amino-2-piperidone sodium salt 4-methoxyphenylacetic acid (129.3 mg, 0.7781 mmol), dicyclohexylcarbodiimide ( Acetonitrile (5 mL) was added to 160.5 mg, 0.77779 mmol) and N-hydroxysuccinimide (89.5 mg, 0.7777 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 4-methoxyphenylacetic acid active ester solution was added to a solution of sulfostine monohydrate (150.5 mg, 0.5186 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (160.0 mg, 70%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.30 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 4.55 (1H, dd, J = 11.7, 6.8 Hz), 3 .84 (3H, s), 3.70-3.77 (1H, m), 3.57-3.68 (1H, m), 3.62 (2H, s), 2.11-2.19 (1H, m), 1.98-2.08 (1H, m), 1.85-1.95 (1H, m), 1.69-1.80 (1H, m).
HR-MS (ESI, POS)
m / z: found, 465.0598 (M + Na) ⁺
calcd. for C ₁₄ H ₂₀ N ₄ Na ₂ O ₇ PS, 465.0586

Example 20
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((4-nitrophenyl) acetyl) amino-2-piperidone sodium salt 4-nitrophenylacetic acid (140.7 mg, 0.7767 mmol), dicyclohexylcarbodiimide ( Acetonitrile (5 mL) was added to 160.3 mg, 0.7769 mmol) and N-hydroxysuccinimide (89.4 mg, 0.7768 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 4-nitrophenylacetic acid activated ester solution was added to a solution of sulfostine monohydrate (150.3 mg, 0.5179 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (162.0 mg, 68%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
8.22 (2H, td, J = 2.4, 8.8 Hz), 7.54 (2H, td, J = 2.4, 8.8 Hz), 4.58 (1H, dd, J = 1.11. 2,6.8 Hz), 3.83 (2H, s), 3.74 (1 H, tdd, J = 4.9, 12.2, 5.9 Hz), 3.60-3.68 (1 H, m ), 2.18 (1H, td, J = 12.2, 5.9 Hz), 1.99-2.09 (1H, m), 1.86-1.97 (1H, m), 1.78. (1H, tdd, J = 12.2, 9.3, 6.4 Hz).
HR-MS (ESI, POS)
m / z: found, 480.0338 (M + Na) ⁺
calcd. for C ₁₃ H ₁₇ N ₅ Na ₂ O ₈ PS, 480.0331

Example 21
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (3-phenylpropionyl) amino-2-piperidone sodium salt 3-phenylpropionic acid (117.1 mg, 0.7797 mmol), dicyclohexylcarbodiimide (160.8 mg) , 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) were added acetonitrile (5 mL), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, 3-phenylpropionic acid active ester solution was added to a solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) dissolved in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (187.0 mg, 84%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.35-7.40 (2H, m), 7.27-7.31 (3H, m), 4.37 (1H, dd, J = 12.2, 6.4 Hz), 3.72 (1H , Tdd, J = 4.9, 12.2, 7.9 Hz), 3.52-3.59 (1H, m), 2.89-3.02 (2H, m), 2.56-2. 68 (2H, m), 1.84-1.93 (2H, m), 1.73-1.84 (1H, m), 1.44-1.54 (1H, m).
HR-MS (ESI, POS)
m / z: found, 449.0645 (M + Na) ⁺
calcd. for C ₁₄ H ₂₀ N ₄ Na ₂ O ₆ PS, 449.00637

Example 22
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (phenoxyacetyl) amino-2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) Were added sodium hydrogen carbonate (2219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and phenoxyacetyl chloride (0.144 mL, 1.0424 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (207.7 mg, 93%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.41 (2H, t, J = 7.8 Hz), 7.10 (1H, t, J = 7.8 Hz), 7.05 (2H, d, J = 7.8 Hz), 4.70 (2H , D, J = 6.4 Hz), 4.64 (1H, dd, J = 11.7, 6.8 Hz), 3.75 (1H, tdd, J = 4.9, 12.2, 7.8 Hz) ), 3.62-3.69 (1H, m), 2.12-2.20 (1H, m), 1.98-2.07 (1H, m), 1.85-1.95 (1H) , M), 1.73-1.83 (1H, m).
HR-MS (ESI, POS)
m / z: found, 451.0442 (M + Na) ⁺
calcd. for C ₁₃ H ₁₈ N ₄ Na ₂ O ₇ PS, 451.0429

Example 23
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (3-cyclohexylpropionyl) amino-2-piperidone sodium salt 3-cyclohexylpropionic acid (122.7 mg, 0.7854 mmol), dicyclohexylcarbodiimide (162.1 mg) , 0.7856 mmol) and N-hydroxysuccinimide (90.4 mg, 0.7855 mmol) were added acetonitrile (5 mL), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, a solution of 3-cyclohexylpropionic acid active ester was added to a solution of sulfostine monohydrate (152.0 mg, 0.5237 mmol) and sodium hydrogen carbonate (48.4 mg, 0.5761 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (130.0 mg, 57%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
4.46 (1H, dd, J = 10.7, 6.8 Hz), 3.75-3.64 (1H, m), 3.56-3.64 (1H, m), 2.31-2 .35 (2H, m), 2.09-2.17 (1H, m), 1.93-2.03 (1H, m), 1.81-1.91 (1H, m), 1.58 -1.78 (6H, m), 1.48-1.55 (2H, m), 1.09-1.29 (4H, m), 0.85-0.97 (2H, m).
HR-MS (ESI, POS)
m / z: found, 455.1130 (M + Na) ⁺
calcd. _{for C 14 H 26 N 4 Na} 2 O 6 PS, 455.1106

Example 24
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (1-naphthoxyacetyl) amino-2-piperidone sodium salt 1-naphthoxyacetic acid (157.5 mg, 0.7789 mmol), dicyclohexylcarbodiimide (160.8 mg) , 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) were added acetonitrile (5 mL) and dimethylformamide (1 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, 1-naphthoxyacetic acid active ester solution was added to a solution of sulfostine monohydrate (150.7 mg, 0.5192 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (3 mL), Stir at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (175.9 mg, 71%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
8.23-8.28 (1H, m), 7.88-7.91 (1H, m), 7.54-7.61 (3H, m), 7.40 (1H, t, J = 7) .8 Hz), 6.82 (1 H, d, J = 17.8 Hz), 4.73 (1 H, t, J = 15.1 Hz), 4.65 (1 H, t, J = 15.1 Hz), 4 .59 (1H, dd, J = 12.2, 7.3 Hz), 3.74 (1H, tdd, J = 4.9, 12.2, 7.3 Hz), 3.60-3.69 (1H , M), 2.12-2.19 (1H, m), 1.97-2.07 (1H, m), 1.84-1.94 (1H, m), 1.76 (1H, tdd , J = 5.9, 18.1, 9.8 Hz).
HR-MS (ESI, POS)
m / z: found, 501.0600 (M + Na) ⁺
calcd. for C ₁₇ H ₂₀ N ₄ Na ₂ O ₇ PS, 501.0586

Example 25
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (N′-benzylureido) -2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and benzyl isocyanate (0.144 mL, 1.0404 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (197.7 mg, 89%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.31-7.44 (5H, m), 4.27-4.40 (3H, m), 3.75-3.83 (1H, m), 3.53-3.60 (1H, m) ), 2.11-2.19 (1H, m), 1.92-2.02 (1H, m), 1.80-1.91 (1H, m), 1.64-1.75 (1H) , M).
HR-MS (ESI, POS)
m / z: found, 450.0581 (M + Na) ⁺
calcd. for C ₁₃ H ₁₉ N ₅ Na ₂ O ₆ PS, 450.0589

Example 26
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4 ′-(benzyloxycarbonylamino) butanoyl) amino-2-piperidone sodium salt 4- (benzyloxycarbonylamino) butyric acid (184.3 mg, 0 7768 mmol), dicyclohexylcarbodiimide (160.3 mg, 0.7769 mmol) and N-hydroxysuccinimide (89.4 mg, 0.7768 mmol) were added with acetonitrile (5 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. did. Then, 4- (benzyloxycarbonylamino) butyric acid activity was added to a solution of sulfostine monohydrate (150.3 mg, 0.5179 mmol) and sodium hydrogen carbonate (47.9 mg, 0.5702 mmol) in water (3 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (177.0 mg, 77%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.38-7.48 (5H, m), 5.01 (2H, s), 4.51 (1H, dd, J = 11.7, 6.8 Hz), 3.69-3.77 (1H M), 3.56-3.65 (1H, m), 3.18 (2H, t, J = 6.4 Hz), 3.18 (2H, t, J = 6.8 Hz), 2.33 (2H, t, J = 6.8 Hz), 2.07-2.16 (1H, m), 1.96-2.05 (1H, m), 1.67-1.92 (4H, m) .
HR-MS (ESI, POS)
m / z: found, 536.0944 (M + Na) ⁺
calcd. for C ₁₇ H ₂₅ N ₅ Na ₂ O ₈ PS, 536.0957

Example 27
(3S, PR) -3- (6 ′-(benzyloxycarbonylamino) caproyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt 6- (benzyloxycarbonylamino) caproic acid (137.8 mg, 0.5194 mmol), dicyclohexylcarbodiimide (107.2 mg, 0.5196 mmol) and N-hydroxysuccinimide (59.8 mg, 0.5196 mmol) were added with acetonitrile (4 mL), and the mixture was stirred at room temperature for 2 hours. Left. Subsequently, 6- (benzyloxycarbonylamino) caproic acid was added to a solution of sulfostine monohydrate (100.5 mg, 0.3463 mmol) and sodium bicarbonate (32.0 mg, 0.3809 mmol) in water (3 mL). The active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (110.3 mg, 59%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.38-7.48 (5H, m), 5.11 (2H, s), 4.52 (1H, dd, J = 11.7, 6.8 Hz), 3.69-3.77 (1H M), 3.58-3.65 (1H, m), 3.12 (2H, t, J = 6.4 Hz), 2.30 (2H, t, J = 6.8 Hz), 2.09 -2.17 (1H, m), 1.96-2.05 (1H, m), 1.81-1.92 (1H, m), 1.68-1.78 (1H, m), 1 .58-1.68 (2H, m), 1.46-1.54 (2H, m), 1.28-1.36 (2H, m).
HR-MS (ESI, POS)
m / z: found, 564.1262 (M + Na) ⁺
calcd. for C ₁₉ H ₂₉ N ₅ Na ₂ O ₈ PS, 5644.1270

Example 28
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (tert-butoxycarbonyl) amino-2-piperidone sodium salt Sulfostin monohydrate (306.8 mg, 1.0571 mmol) dissolved in water (5 mL) To this solution were added sodium hydrogen carbonate (97.7 mg, 1.1630 mmol), tetrahydrofuran (5 mL), and anhydrous tert-butoxycarboxylic acid (253.8 mg, 1.1629 mmol), and the mixture was stirred at room temperature overnight.
Tetrahydrofuran in the reaction solution was distilled off under reduced pressure, then purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (312.0 mg, 75%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
4.26 (1H, dd, J = 11.7, 6.8 Hz), 3.69-3.77 (1H, m), 3.60-3.67 (1H, m), 2.15-2 .23 (1H, m), 1.98-2.08 (1H, m), 1.86-1.97 (1H, m), 1.68-1.79 (1H, m), 1.46 (9H, s).
HR-MS (ESI, POS)
m / z: found, 417.0606 (M + Na) ⁺
calcd. for C10H ₂₀ N ₄ Na ₂ O ₇ PS, 417.0586

Example 29
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((benzyloxycarbonylamino) acetyl) amino-2-piperidone sodium salt N-benzyloxycarbonylglycine (325.4 mg, 1.5554 mmol), dicyclohexylcarbodiimide Acetonitrile (15 mL) was added to (321.0 mg, 1.5558 mmol) and N-hydroxysuccinimide (179.0 mg, 1.5553 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. Then, N-benzyloxycarbonyl was added to a solution of sulfostine monohydrate (301.0 mg, 1.0371 mmol) and sodium hydrogen carbonate (87.1 mg, 1.0367 mmol) in water (5 mL) and acetonitrile (3 mL). Glycine active ester solution was added and stirred overnight at room temperature.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (466.1 mg, 93%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.39-7.48 (5H, m), 5.16 (2H, s), 4.59 (1H, dd, J = 11.7, 6.8 Hz), 3.90 (2H, s), 3.70-3.77 (1H, m), 3.61-3.68 (1H, m), 1.53-2.19 (4H, m).
HR-MS (ESI, POS)
m / z: found, 508.0623 (M + Na) ⁺
calcd. for C ₁₅ H ₂₁ N ₅ Na ₂ O ₈ PS, 508.0644

Example 30
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) propionyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl-L-alanine (173 0.06 mg, 0.7750 mmol), dicyclohexylcarbodiimide (160.0 mg, 0.7755 mmol) and N-hydroxysuccinimide (89.2 mg, 0.7750 mmol) were added acetonitrile (6 mL) and dimethylformamide (1 mL), and 2 at room temperature. The mixture was stirred for a period of time, and the precipitated crystals were removed by filtration. Next, N-benzyloxycarbonyl-L-alanine activity was dissolved in a solution of sulfostin monohydrate (150.0 mg, 0.5168 mmol) and sodium hydrogen carbonate (47.8 mg, 0.5690 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (188.6 mg, 73%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.37-7.48 (5H, m), 5.01-5.23 (2H, m), 4.48-4.56 and 4.25-4.37 (1H, m), 4.17 (1H , Q, J = 7.3 Hz), 3.52-3.79 (2H, m), 1.34-2.20 (4H, m), 1.40 (3H, d, J = 7.3 Hz) .
HR-MS (ESI, POS)
m / z: found, 522.0792 (M + Na) ⁺
calcd. for C ₁₆ H ₂₃ N ₅ Na ₂ O ₈ PS, 522.0800

Example 31
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3′-methylbutanoyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl -L-valine (196.6 mg, 0.7824 mmol), dicyclohexylcarbodiimide (161.4 mg, 0.7822 mmol) and N-hydroxysuccinimide (90.0 mg, 0.7820 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) And stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-benzyloxycarbonyl-L-valine activity was added to a solution of sulfostine monohydrate (151.4 mg, 0.5217 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5734 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (201.1 mg, 73%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.38-7.48 (5H, m), 5.04-5.24 (2H, m), 4.55 and 4.31-4.38 (1H, dd, J = 11.2, 6.8 Hz, and m), 3.97 and 3.87-3.92 (1H, d, J = 6.8 Hz, and m), 3.53-3.79 (2H, m), 1.44-2.22 (5H). , M), 0.98 and 0.94 (6H, d, J = 6.8 Hz).
HR-MS (ESI, POS)
m / z: found, 550.10.82 (M + Na) ⁺
calcd. for C ₁₈ H ₂₇ N ₅ Na ₂ O ₈ PS, 550.1113

Example 32
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -4′-methylpentanoyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl -L-leucine (206.8 mg, 0.7795 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-benzyloxycarbonyl-L-leucine activity was dissolved in a solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium bicarbonate (48.0 mg, 0.5714 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (140.0 mg, 50%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.37-7.48 (5H, m), 5.04-5.25 (2H, m), 4.53 and 4.28-4.36 (1H, dd, J = 11.2, 6.8 Hz, and m), 4.16 (1H, d, J = 7.3 Hz), 3.54-3.78 (2H, m), 2.10-2.19 (2H, m), 1.97-2. .08 (1H, m), 1.87-1.97 (1H, m), 1.64-1.83 (1H, m), 1.62 (2H, t, J = 6.8 Hz), 0 .94 (3H, d, J = 6.8 Hz), 0.89 (3H, d, J = 6.8 Hz).
HR-MS (ESI, POS)
m / z: found, 5644.1248 (M + Na) ⁺
calcd. for C ₁₉ H ₂₉ N ₅ Na ₂ O ₈ PS, 5644.1270

Example 33
(3S, PR, 2 ′S, 3 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3′-methylpentanoyl) amino-2-piperidone sodium salt N -Benzyloxycarbonyl-L-isoleucine (206.8 mg, 0.7795 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) in acetonitrile (6 mL) and dimethyl Formamide (1 mL) was added, the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-isoleucine activity was added to a solution of sulfostin monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (190.0 mg, 68%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.38-7.48 (5H, m), 5.04-5.24 (2H, m), 4.55 (1H, dd, J = 11.2, 6.8 Hz), 4.00 (1H , D, J = 6.8HZ), 3.61-3.78 (2H, m), 2.12-2.20 (1H, m), 1.98-2.07 (1H, m), 1 .71-1.96 (3H, m), 1.42-1.52 (1H, m), 1.16-1.26 (1H, m), 0.98 (3H, d, J = 6. 8 Hz), 0.88 (3H, t, J = 7.3 Hz).
HR-MS (ESI, POS)
m / z: found, 5644.1250 (M + Na) ⁺
calcd. for C ₁₉ H ₂₉ N ₅ Na ₂ O ₈ PS, 5644.1270

Example 34
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3′-phenylpropionyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl- L-phenylalanine (234.4 mg, 0.7831 mmol), dicyclohexylcarbodiimide (161.6 mg, 0.7832 mmol) and N-hydroxysuccinimide (90.1 mg, 0.7829 mmol) were mixed with acetonitrile (6 mL) and dimethylformamide (1 mL). The mixture was further stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-phenylalanine activity was dissolved in a solution of sulfostine monohydrate (151.5 mg, 0.5220 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5737 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (204.2 mg, 68%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.23-7.43 (10H, m), 5.06 and 5.00 (2H, d, J = 12.7 Hz), 4.32-4.57 (2H, m), 3.55-3.78 (2H, m), 3.25 and 3.18 (1H, dd, J = 14.2, 4.4 Hz), 2.91 (1H, dd, J = 14.2, 9.8 Hz), 1.50− 2.20 (4H, m).
HR-MS (ESI, POS)
m / z: found, 598.186 (M + Na) ⁺
calcd. for C ₂₂ H ₂₇ N ₅ Na ₂ O ₈ PS, 598.1113

Example 35
Synthesis of (3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3-((2 ′-(1′-benzyloxycarbonyl) piperidine) carbonyl) amino-2-piperidone sodium salt N-benzyloxy Carbonyl-L-proline (195.2 mg, 0.7831 mmol), dicyclohexylcarbodiimide (161.6 mg, 0.7832 mmol) and N-hydroxysuccinimide (90.1 mg, 0.7829 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-proline activity was added to a solution of sulfostine monohydrate (151.5 mg, 0.5220 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5737 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (176.6 mg, 64%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.37-7.49 (5H, m), 5.17 (1H, d, J = 12.2 Hz), 5.04 (1H, d, J = 12.2 Hz), 4.33 (1H, dd) , J = 7.8, 4.9 Hz), 4.29 (1H, dd, J = 11.7, 6.8 Hz), 3.51-3.80 (4H, m), 2.27-2. 39 (1H, m), 1.85-2.07 (4H, m), 1.73-1.83 (1H, m), 1.63-1.71 (1H, m), 1.37- 1.47 (1H, m).
HR-MS (ESI, POS)
m / z: found, 548.0949 (M + Na) ⁺
calcd. for C ₁₈ H ₂₅ N ₅ Na ₂ O ₈ PS, 548.0957

Example 36
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3′-carbamoylpropionyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl- L-asparagine (210.1 mg, 0.7891 mmol), dicyclohexylcarbodiimide (162.8 mg, 0.7890 mmol) and N-hydroxysuccinimide (90.8 mg, 0.7891 mmol) were mixed with acetonitrile (6 mL) and dimethylformamide (1 mL). The mixture was further stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-asparagine activity was added to a solution of sulfostine monohydrate (152.7 mg, 0.5261 mmol) and sodium hydrogen carbonate (48.6 mg, 0.5785 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (220.8 mg, 77%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.38-7.49 (5H, m), 5.10-5.20 (2H, m), 4.51-4.59 (2H, m), 3.55-3.77 (2H, m) ), 2.86 (1H, dd, J = 15.6, 4.9 Hz), 2.72 (1H, dd, J = 15.6, 8.8 Hz), 1.48-2.16 (4H, m).
HR-MS (ESI, POS)
m / z: found, 565.0830 (M + Na) ⁺
calcd. for C ₁₇ H ₂₄ N ₆ Na ₂ O ₉ PS, 565.0859

Example 37
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -4′-carbamoylbutanoyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl -L-glutamine (220.6 mg, 0.7870 mmol), dicyclohexylcarbodiimide (162.4 mg, 0.7871 mmol) and N-hydroxysuccinimide (90.6 mg, 0.7872 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, N-benzyloxycarbonyl-L-glutamine activity was dissolved in a solution of sulfostin monohydrate (152.3 mg, 0.5248 mmol) and sodium hydrogen carbonate (48.5 mg, 0.5773 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (247.7 mg, 85%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.37-7.48 (5H, m), 5.04-5.25 (2H, m), 4.52-4.59 and 4.31-4.38 (1H, m), 4.07-4 .17 (1H, m), 3.54-3.77 (2H, m), 2.41 (2H, t, J = 7.3 Hz), 1.43-2.19 (6H, m).
HR-MS (ESI, POS)
m / z: found, 579.1001 (M + Na) ⁺
calcd. for C ₁₈ H ₂₆ N ₆ Na ₂ O ₉ PS, 579.

Example 38
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -4 ′-(methylthio) butanoyl) amino-2-piperidone sodium salt N-benzyloxy Carbonyl-L-methionine (220.8 mg, 0.7792 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7793 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-methionine activity was added to a solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium bicarbonate (48.0 mg, 0.5714 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (198.5 mg, 68%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.38-7.48 (5H, m), 5.15 (2H, q, J = 12.7 Hz), 4.55 and 4.26-4.38 (1H, dd, J = 11.2, 6. 8 Hz and m), 4.29 (1H, dd, J = 9.3, 4.4 Hz), 3.54-3.78 (2H, m), 2.53-2.71 (2H, m), 1.40-2.20 (6H, m), 2.10 (3H, s).
HR-MS (ESI, POS)
m / z: found, 582.0809 (M + Na) ⁺
calcd. for C ₁₈ H ₂₇ N ₅ Na ₂ O ₈ PS ₂ , 582.0834

Example 39
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3 ′-(3 ″ -indolyl) propionyl) amino-2-piperidone sodium salt N -Benzyloxycarbonyl-L-tryptophan (264.6 mg, 0.7820 mmol), dicyclohexylcarbodiimide (161.3 mg, 0.7818 mmol) and N-hydroxysuccinimide (90.0 mg, 0.7820 mmol) in acetonitrile (6 mL) and dimethyl Formamide (1 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off, then sulfostin monohydrate (151.3 mg, 0.5213 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5737 mmol). ) Water (5m The solution in), the N- benzyloxycarbonyl -L- tryptophan active ester solution, and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (238.9 mg, 75%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.65 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.8 Hz), 7.33-7.43 (3H, m), 7.17-7.27 (4H, m), 7.13 (1H, t, J = 7.8Hz), 5.05 (1H, d, J = 12.7Hz), 4.94 (1H, d, J = 12.7Hz) , 4.52 (1H, dd, J = 8.8, 5.4 Hz), 4.46 (1H, dd, J = 12.2, 6.8 Hz), 3.66-3.76 (1H, m ), 3.52-3.66 (1H, m), 3.36 (1H, dd, J = 14.7, 5.4 Hz), 3.17 (1H, dd, J = 14.7, 8.. 8Hz), 1.43-2.04 (4H, m).
HR-MS (ESI, POS)
m / z: found, 637.1174 (M + Na) ⁺
calcd. for C ₂₄ H ₂₈ N ₆ Na ₂ O ₈ PS, 637.1222

Example 40
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((tert-butoxycarbonylamino) acetyl) amino-2-piperidone sodium salt N-tert-butoxycarbonylglycine (137.3 mg, 0.7838 mmol), Acetonitrile (6 mL) was added to dicyclohexylcarbodiimide (161.8 mg, 0.7842 mmol) and N-hydroxysuccinimide (90.2 mg, 0.7837 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-tert-butoxycarbonylglycine active ester solution was added to a solution of sulfostine monohydrate (151.7 mg, 0.5227 mmol) and sodium hydrogen carbonate (48.3 mg, 0.5749 mmol) in water (5 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (125.0 mg, 53%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
4.61 (1H, dd, J = 11.7, 6.8 Hz), 3.83 (2H, brs), 3.74 (1H, tdd, J = 4.8, 12.2, 7.8 Hz) 3.62-3.69 (1H, m), 2.14-2.22 (1H, m), 2.02-2.09 (1H, m), 1.87-1.98 (1H, m), 1.73-1.84 (1H, m), 1.45 (9H, s).
HR-MS (ESI, POS)
m / z: found, 474.0794 (M + Na) ⁺
calcd. _{for C 12 H 23 N 5 Na} 2 O 8 PS, 474.0800

Example 41
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxy) propionyl) amino-2-piperidone sodium salt N— tert-Butoxycarbonyl-O-benzyl-L-serine (383.0 mg, 1.2969 mmol), dicyclohexylcarbodiimide (267.6 mg, 1.2970 mmol) and N-hydroxysuccinimide (149.2 mg, 1.2964 mmol) in acetonitrile ( 10 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-tert-butoxycarbonyl-O-benzyl was dissolved in a solution of sulfostin monohydrate (250.9 mg, 0.8645 mmol) and sodium hydrogen carbonate (79.9 mg, 0.9511 mmol) in water (5 mL). -L-Serine active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (448.3 mg, 91%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.38-7.48 (5H, m), 4.57-4.65 (2H, m), 4.54 (1H, dd, J = 11.7, 6.8 Hz), 4.30-4 .40 (1H, m), 3.80-3.90 (2H, m), 3.74 (1H, tdd, J = 4.9, 12.7, 7.3 Hz), 3.60-3. 68 (1H, m), 2.13-2.22 (1H, m), 1.98-2.08 (1H, m), 1.86-1.97 (1H, m), 1.71- 1.83 (1H, m), 1.44 (9H, s).
HR-MS (ESI, POS)
m / z: found, 594.1353 (M + Na) ⁺
calcd. for C ₂₀ H ₃₁ N ₅ Na ₂ O ₉ PS, 5944.1376

Example 42
(3S, PR, 2'S, 3'R) -1-Amino (sulfoamino) phosphinyl-3- (2 '-(tert-butoxycarbonylamino) -3'-(benzyloxy) butanoyl) amino-2-piperidone Sodium salt N-tert-butoxycarbonyl-O-benzyl-L-threonine (401.8 mg, 1.29888 mmol), dicyclohexylcarbodiimide (268.0 mg, 1.2989 mmol) and N-hydroxysuccinimide (149.5 mg, 1.2990 mmol) ) Was added acetonitrile (10 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, N-tert-butoxycarbonyl-O-benzyl was dissolved in a solution of sulfostin monohydrate (251.3 mg, 0.8659 mmol) and sodium hydrogen carbonate (80.0 mg, 0.9523 mmol) in water (5 mL). -L-threonine active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (212.2 mg, 42%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.36-7.46 (5H, m), 4.66 (1H, d, J = 11.2 Hz), 4.46-4.55 (2H, m), 4.18 (2H, s), 3.71-3.79 (1H, m), 3.59-3.67 (1H, m), 2.10-2.21 (1H, m), 1.97-2.08 (1H, m ), 1.85-1.97 (1H, m), 1.67-1.79 (1H, m), 1.46 (9H, s), 1.29 (3H, d, J = 5.4 Hz) ).
HR-MS (ESI, POS)
m / z: found, 608.1489 (M + Na) ⁺
calcd. for C ₂₁ H ₃₃ N ₅ Na ₂ O ₉ PS, 608.1532

Example 43
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3- (2′-tert- (butoxycarbonylamino) -3 ′-(benzyloxycarbonyl) propionyl) amino-2-piperidone sodium salt N -Tert-Butoxycarbonyl-L-aspartic acid 4-benzyl ester (418.3 mg, 1.2936 mmol), dicyclohexylcarbodiimide (266.9 mg, 1.2936 mmol) and N-hydroxysuccinimide (148.9 mg, 1.2938 mmol) Acetonitrile (10 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-tert-butoxycarbonyl-L-asparagine was added to a solution of sulfostine monohydrate (250.3 mg, 0.8624 mmol) and sodium bicarbonate (79.7 mg, 0.9487 mmol) in water (5 mL). Acid 4-benzyl ester-1-active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (425.6 mg, 82%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.40-7.49 (5H, m), 5.21 (2H, brs), 4.46-4.57 (2H, m), 3.68-3.78 (1H, m), 3. 58-3.67 (1H, m), 3.01 (1 H, dd, J = 16.6, 4.9 Hz), 2.82-2.93 (1 H, m), 1.97-2.20. (2H, m), 1.82-1.95 (1H, m), 1.67-1.79 (1H, m), 1.42 (9H, m).
HR-MS (ESI, POS)
m / z: found, 622.1363 (M + Na) ⁺
calcd. for C ₂₁ H ₃₁ N ₅ Na ₂ O ₁₀ PS, 622.1325

Example 44
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxycarbonyl) butanoyl) amino-2-piperidone sodium salt N -Tert-Butoxycarbonyl-L-glutamic acid 5-benzyl ester (436.4 mg, 1.2935 mmol), dicyclohexylcarbodiimide (266.9 mg, 1.2936 mmol) and N-hydroxysuccinimide (148.9 mg, 1.2938 mmol) in acetonitrile (10 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-tert-butoxycarbonyl-L-glutamic acid was added to a solution of sulfostine monohydrate (250.3 mg, 0.8624 mmol) and sodium hydrogen carbonate (79.7 mg, 0.9487 mmol) in water (5 mL). 5-Benzyl ester-1-active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (338.1 mg, 64%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.40-7.48 (5H, m), 5.19 (2H, s), 4.53 (1H, dd, J = 12.2, 6.8 Hz), 4.03-4.14 (1H M), 3.74 (1H, tdd, J = 4.9, 12.7, 7.3 Hz), 3.60-3.68 (1H, m), 2.55-2.63 (2H, m), 2.12-2.23 (2H, m), 1.86-2.07 (3H, m), 1.71-1.83 (1H, m), 1.42 (9H, s) .
HR-MS (ESI, POS)
m / z: found, 636.1438 (M + Na) ⁺
calcd. _{for C 22 H 33 N 5 Na} 2 O 10 PS, 636.1481

Example 45
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(4 ″ -benzyloxyphenyl) propionyl) amino-2-piperidone Sodium salt N-tert-butoxycarbonyl-O-benzyl-L-tyrosine (481.4 mg, 1.2961 mmol), dicyclohexylcarbodiimide (267.4 mg, 1.2960 mmol) and N-hydroxysuccinimide (149.2 mg, 1.2964 mmol) Acetonitrile (10 mL) was added to the mixture, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration, then sulfostin monohydrate (250.8 mg, 0.8641 mmol) and sodium hydrogen carbonate (79.9 mg, 0 .9511 mmol) in water (5 mL To a solution of the added N-tert-butoxycarbonyl -O- benzyl -L- tyrosine active ester solution was stirred overnight at room temperature.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (503.8 mg, 78%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.03-7.22 (7H, m), 6.68-6.78 (2H, m), 4.74 and 4.67 (2H, brs), 4.48-4.57 (1H, m), 4.24-4.38 (1H, m), 3.72-3.82 (1H, m), 3.60-3.72 (1H, m), 3.08-3.18 (1H, m ), 2.66-2.76 (1H, m), 2.09-2.20 (1H, m), 1.97-2.08 (1H, m), 1.86-1.96 (1H) , M), 1.71-1.85 (1H, m), 1.19 (9H, s).
HR-MS (ESI, POS)
m / z: found, 670.1651 (M + Na) ⁺
calcd. for C ₂₆ H ₃₅ N ₅ Na ₂ O ₉ PS, 670.1689

Example 46
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3-((2′-tert-butoxycarbonylamino) -5′-nitroamidinopentanoyl) amino-2-piperidone sodium salt Nα-tert Acetonitrile (10 mL) was added to -butoxycarbonyl-Nω-nitroarginine (413.9 mg, 1.2962 mmol), dicyclohexylcarbodiimide (267.4 mg, 1.2960 mmol) and N-hydroxysuccinimide (149.2 mg, 1.2964 mmol). The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, a solution of sulfostine monohydrate (250.8 mg, 0.8641 mmol) and sodium bicarbonate (79.9 mg, 0.9511 mmol) in water (5 mL) was added to Nα-tert-butoxycarbonyl-Nω-nitro. Arginine active ester solution was added and stirred overnight at room temperature.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (256.7 mg, 50%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
4.56 (1H, dd, J = 11.2, 6.4 Hz), 4.02-4.12 (1H, m), 3.74 (1H, tdd, J = 4.9, 12.2, 7.8 Hz), 3.62-3.70 (1H, m), 3.28-3.36 (2H, m), 2.15-2.26 (1H, m), 2.00-2. 10 (1H, m), 1.68-1.98 (6H, m), 1.43 (9H, s).
HR-MS (ESI, POS)
m / z: found, 618.1423 (M + Na) ⁺
calcd. for C ₁₆ H ₃₁ N ₉ Na ₂ O ₁₀ PS, 618.1448

Example 47
(3S, P (RorS))-1- (acetylamino) aminophosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S, P (SorR))-1- (acetylamino) aminophosphinyl -3-Benzyloxycarbonylamino-2-piperidone (3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (2.00 g, 6.13 mmol) was dissolved in pyridine (80 mL) by heating. To this solution, acetyl chloride (0.52 mL, 7.31 mmol) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 6 hours.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the resulting residue, and the precipitated crystals were collected by filtration. Acetone was added to the obtained crystals, insolubles were filtered off, the filtrate was concentrated, and the crystals were washed with a mixed solvent of ethyl acetate-ether to obtain the desired (3S, P (SorR))-3-benzyloxy. Carbonylamino-1- (acetylamino) aminophosphinyl-2-piperidone (0.41 g, 18%) was obtained.
In addition, the crystal mother liquor and the washing solution were combined and purified by Diaion HP-20 (100 mL, water-acetone gradient elution) column chromatography. The eluate was concentrated under reduced pressure, and the resulting crystal was dissolved in ethyl acetate and insoluble. The product was filtered. The filtrate was concentrated under reduced pressure, and the resulting crystals were washed with ether to give the desired (3S, P (RorS))-3-benzyloxycarbonylamino-1- (acetylamino) aminophosphinyl-2- Piperidone (0.72 g, 32%) was obtained.

(3S, P (SorR))-1- (acetylamino) aminophosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 47A)
¹ H-NMR (DMSO-D ₆ , internal standard TMS)
9.41 (1H, brs), 7.48 (1H, d, J = 8.8 Hz), 7.29-7.39 (5H, m), 5.03 (2H, s), 4.63 ( 2H, brs), 4.00-4.07 (1H, m), 3.52-3.63 (2H, m), 1.96-2.04 (1H, m), 1.90 (3H, s), 1.74-1.81 (2H, m), 1.61-1.72 (1H, m).
¹³ C-NMR (DMSO-D ₆ , internal standard TMS)
173.1, 171.9, 155.9, 136.9, 128.3 (X2), 127.7 (X3), 65.3, 51.2, 43.4, 25.9, 23.7, 20.8.
HR-MS (ESI, POS)
m / z: 391 (M + Na) ⁺ .

(3S, P (RorS))-1- (acetylamino) aminophosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 47B)
¹ H-NMR (DMSO-D ₆ , internal standard TMS)
9.40 (1H, brs), 7.46 (1H, d, J = 8.3 Hz), 7.29-7.39 (5H, m), 5.03 (2H, s), 4.59 ( 2H, brs), 4.14 (1H, td, J = 7.8, 11.7 Hz), 3.71-3.79 (1H, m), 3.46-3.54 (1H, m), 1.97-2.05 (1H, m), 1.83-1.94 (1H, m), 1.89 (3H, s), 1.70-1.80 (1H, m), 1. 52-1.62 (1H, m).
¹³ C-NMR (DMSO-D ₆ , internal standard TMS)
173.2, 171.7, 156.0, 136.9, 128.2 (X2), 127.7 (X2), 127.6, 65.3, 51.2, 43.0, 25.6 23.7, 20.4.
HR-MS (ESI, POS)
m / z: 391 (M + Na) ⁺ .

Example 48
(3S, P (SR))-1-amino (n-butanoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -Butyric anhydride (0.31 mL, 1.8950 mmol) was added dropwise to a solution of piperidone (520.5 mg, 1.5952 mmol) dissolved in pyridine (20 mL) at room temperature, and the mixture was stirred at an external temperature of 60 ° C. for 2 days. did.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the resulting residue, and purification was performed with Diaion HP-20 (20 mL, water-acetone gradient elution). The obtained oil was purified with Sephadex LH-20 (200 mL, methanol) to obtain the target compound (300.3 mg, 47%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
Stereoisomer A
7.85-7.93 (1H, m), 7.29-7.37 (5H, m), 5.65-5.72 (1H, m), 5.11 (2H, m), 4. 21-4.31 (1H, m), 3.82-4.02 (3H, m), 3.67-3.75 (1H, m), 2.32-2.46 (1H, m), 2.26 (2H, t, J = 7.3 Hz), 1.80-1.96 (2H, m), 1.52-1.66 (3H, m), 0.91 (3H, t, J = 7.3 Hz).
Stereoisomer B
7.74-7.84 (1H, m), 7.29-7.37 (5H, m), 5.57-5.65 (1H, m), 5.11 (2H, m), 4. 21-4.31 (1H, m), 3.82-4.02 (3H, m), 3.56-3.66 (1H, m), 2.32-2.46 (1H, m), 2.26 (2H, t, J = 7.3 Hz), 2.00-2.10 (1H, m), 1.80-1.96 (1H, m), 1.52-1.66 (3H , M), 0.91 (3H, t, J = 7.3 Hz).
HR-MS (ESI, POS)
m / z: 419 (M + Na) ⁺ .

Example 49
(3S, P (SR))-1-amino (t-butylacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by heating and dissolving piperidone (503.0 mg, 1.5416 mmol) in pyridine (20 mL), t-butylacetyl chloride (0.26 mL, 1.8716 mmol) was added dropwise at room temperature, followed by stirring at the same temperature for 3 days. did.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the obtained residue, and purification was performed by Diaion HP-20 (20 mL, water-acetone gradient elution) column chromatography. Acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained oil was crystallized from n-hexane to obtain the target compound (624.7 mg, 95%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.28 (1H, brd, J = 9.8 Hz), 7.41 (1H, brd, J = 8.3 Hz), 7.29-7.38 (5H, m), 5.03 (2H, s ), 4.57 (1H, brs), 4.56 (1H, brs), 4.14 (1H, td, J = 7.8, 12.2 Hz), 3.77-3.84 (1H, m ), 3.44-3.57 (1H, m), 1.97-2.07 (3H, m), 1.84-1.93 (1H, m), 1.72-1.81 (1H) , M), 1.56 (1H, tt, J = 12.2, 7.8 Hz), 0.94 (9H, s).
Stereoisomer B
9.28 (1H, brd, J = 9.8Hz), 7.47 (1H, brd, J = 8.8Hz), 7.29-7.38 (5H, m), 5.03 (2H, s ), 4.59 (1H, brs), 4.58 (1H, brs), 3.95-4.04 (1H, m), 3.61-3.68 (1H, m), 3.44- 3.57 (1H, m), 1.97-2.07 (3H, m), 1.62-1.81 (3H, m), 0.94 (9H, s).
HR-MS (ESI, POS)
m / z: 447 (M + Na) ⁺ .

Example 50
(3S, P (SR))-1-amino (cyclohexanecarbonylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (545.4 mg, 1.6715 mmol) was dissolved in pyridine (20 mL) by heating, and cyclohexanecarbonyl chloride (0.27 mL, 2.0183 mmol) was added dropwise at room temperature, and the mixture was cooled with ice for 3 hours and at room temperature for 4 hours. Stir.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the resulting residue, and purification was performed with Diaion HP-20 (20 mL, water-acetone gradient elution). Acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (555.2 mg, 69%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.23 (1H, brs), 7.42 (1H, d, J = 8.3 Hz), 7.28-7.38 (5H, m), 5.02 (2H, s), 4.53- 4.57 (2H, m), 4.11 (1H, td, J = 7.8, 12.2 Hz), 3.73-3.82 (1H, m), 3.53-3.63 (1H M), 2.14-2.23 (1H, m), 1.95-2.04 (1H, m), 1.47-1.92 (7H, m), 1.06-1.30. (6H, m).
Stereoisomer B
9.23 (1H, brs), 7.46 (1H, d, J = 8.3 Hz), 7.28-7.38 (5H, m), 5.02 (2H, s), 4.53- 4.57 (2H, m), 3.94-4.02 (1H, m), 3.43-3.52 (2H, m), 2.14-2.23 (1H, m), 1. 95-2.04 (1H, m), 1.47-1.92 (7H, m), 1.06-1.30 (6H, m).
HR-MS (ESI, POS)
m / z: 459 (M + Na) ⁺ .

Example 51
(3S, P (SR))-1-amino (phenoxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone To a solution obtained by heating and dissolving (504.0 mg, 1.5446 mmol) in pyridine (20 mL), phenoxyacetyl chloride (0.32 mL, 2.3165 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 16 hours.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the obtained residue, and purification was performed by Diaion HP-20 (20 mL, water-acetone gradient elution) column chromatography. Acetone in the eluate was distilled off under reduced pressure, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (421.2 mg, 67%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.57 (1H, brs), 7.52 (1H, d, J = 8.3 Hz), 7.27-7.39 (7H, m), 6.95 (1H, t, J = 7.3 Hz) ), 6.87 (2H, d, J = 7.3 Hz), 5.03 (2H, s), 4.82 (1H, brs), 4.81 (1H, brs), 4.55 (2H, q, J = 16.1 Hz), 4.14 (1H, td, J = 7.8, 12.2 Hz), 3.72-3.80 (1H, m), 3.48-3.58 (1H M), 1.96-2.06 (1H, m), 1.64-1.88 (2H, m), 1.56 (1H, tt, J = 12.2, 7.8 Hz).
Stereoisomer B
9.57 (1H, brs), 7.53 (1H, d, J = 8.3 Hz), 7.27-7.39 (7H, m), 6.95 (1H, t, J = 7.3 Hz) ), 6.84 (2H, d, J = 7.3 Hz), 5.04 (2H, s), 4.82 (1H, brs), 4.81 (1H, brs), 4.50-4. 64 (2H, m), 3.98-4.07 (1H, m), 3.48-3.66 (2H, m), 1.96-2.06 (1H, m), 1.64 1.88 (3H, m).
HR-MS (ESI, POS)
m / z: 483 (M + Na) ⁺ .

Example 52
(3S, P (SR))-1-amino (cinnamoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone Cinnamoyl chloride (511.9 mg, 3.0726 mmol) was added at room temperature to a solution obtained by heating (835.5 mg, 2.5606 mmol) in pyridine (33 mL), and the mixture was stirred at room temperature for 18 hours.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the obtained residue, and purification was performed by Diaion HP-20 (20 mL, water-acetone gradient elution) column chromatography. Acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (833.3 mg, 73%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.61 (1H, s), 7.57-7.60 (2H, m), 7.52 (1H, d, J = 16.1 Hz), 7.41-7.48 (4H, m), 7.27-7.37 (5H, m), 6.72 (1H, d, J = 16.1 Hz), 5.00 (2H, s), 4.72 (1H, brs), 4.72 ( 1H, brs), 4.18 (1H, td, J = 7.8, 11.7 Hz), 3.82-3.90 (1H, m), 3.51-3.59 (1H, m), 1.54-2.07 (4H, m).
Stereoisomer B
9.61 (1H, s), 7.57-7.60 (2H, m), 7.52 (1H, d, J = 16.1 Hz), 7.41-7.48 (4H, m), 7.27-7.37 (5H, m), 6.72 (1H, d, J = 16.1 Hz), 5.00 (2H, s), 4.75 (1H, brs), 4.75 ( 1H, brs), 4.03 (1H, q, J = 6.8 Hz), 3.58-3.72 (2H, m), 1.54-2.07 (4H, m).
HR-MS (ESI, POS)
m / z: 479 (M + Na) ⁺ .

Example 53
(3S, P (RS))-1-amino (4-methoxybenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by dissolving piperidone (602.0 mg, 1.8450 mmol) in pyridine (24 mL) by heating, 4-methoxybenzoyl chloride (377.7 mg, 2.4121 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. .
The reaction mixture was concentrated under reduced pressure, 30% aqueous acetone was added to the resulting residue, and the crystals were collected by filtration. Acetone was added to the obtained crystals, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with a mixed solvent of ethyl acetate-ether to obtain the target compound (220.1 mg, 26%). Obtained.

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.49 (1H, brs), 7.89 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m ), 7.01 (2H, dd, J = 8.8, 2.0 Hz), 4.99 (2H, s), 4.69-4.73 (2H, m), 4.12-4.20. (1H, m), 3.84-3.93 (1H, m), 3.82 (3H, s), 3.53-3.62 (1H, m), 1.50-2.07 (4H , M).
Stereoisomer B
9.49 (1H, brs), 7.89 (2H, d, J = 8.8 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m ), 7.01 (2H, dd, J = 8.8, 2.0 Hz), 4.99 (2H, s), 4.69-4.73 (2H, m), 3.99-4.07 (1H, m), 3.81 (3H, s), 3.62-3.72 (2H, m), 1.50-2.07 (4H, m).
HR-MS (ESI, POS)
m / z: 483 (M + Na) ⁺ .

Example 54
(3S, P (RorS))-1-amino (benzyloxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S, P (SorR))-1-amino (benzyloxyacetylamino) phosphinyl -3-Benzyloxycarbonylamino-2-piperidone (3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (666.0 mg, 2.04 mmol) was dissolved in pyridine (26 mL) by heating. To this solution was added benzyloxyacetyl chloride (0.48 mL, 3.04 mmol) at room temperature, and the mixture was stirred at the same temperature for 5 hours.
After concentrating the reaction solution under reduced pressure, the resulting residue was purified by Diaion HP-20SS (25 mL, water-acetone gradient elution) column chromatography, and the crystals precipitated from the eluate were collected by filtration (3S, P (RorS))-3-Benzyloxycarbonylamino-1-amino (benzyloxyacetylamino) phosphinyl-2-piperidone (470.9 mg, 49%) was obtained.
The crystal filtrate was concentrated under reduced pressure, and purified again with Diaion HP-20SS (25 mL, water-acetone gradient elution) to give (3S, P (SorR))-3-benzyloxycarbonylamino-1-amino (benzyl Oxyacetylamino) phosphinyl-2-piperidone (100.5 mg, 10%) was obtained.

(3S, P (RorS))-1-amino (benzyloxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 54A)
¹ H-NMR (CDCl ₃ , internal standard TMS)
7.90 (1H, brd, J = 12.2 Hz), 7.30-7.40 (10H, m), 5.44 (1H, brd, J = 6.8 Hz), 5.12 (1H, s ), 5.11 (1H, s), 4.57 (1H, s), 4.57 (1H, s), 4.25-4.33 (1H, m), 4.05 (1H, qd, J = 6.3, 12.7 Hz), 3.93 (1H, s), 3.92 (1H, s), 3.73 (1H, brs), 3.72 (1H, brs), 3.58. -3.68 (1H, m), 2.36-2.46 (1H, m), 2.04-2.14 (1H, m), 1.82-1.92 (1H, m), 1 .51-1.63 (1H, m).
MS (APCI, POS)
m / z: 475 (M + H) ⁺ .

(3S, P (SorR))-1-amino (benzyloxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 54B)
¹ H-NMR (DMSO-D ₆ , internal standard TMS)
7.85-7.93 (1H, m), 7.30-7.40 (10H, m), 5.53 (1H, brd, J = 5.9 Hz), 5.11 (2H, s), 4.56 (1H, s), 4.19-4.33 (1H, m), 3.86-3.96 (3H, m), 3.70-3.82 (3H, m), 2. 43-2.53 (1H, m), 1.91-1.99 (2H, m), 1.55-1.66 (1H, m).
MS (APCI, POS)
m / z: 475 (M + H) ⁺ .

Example 55
(3S, P (RS))-1-amino (benzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone ( To a solution obtained by heating and dissolving 333.0 mg, 1.02 mmol) in pyridine (8 mL), benzoyl chloride (0.18 mL, 1.55 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 3 days.
The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (chloroform: methanol = 14: 1 to 9: 1) to give the target compound (248.6 mg, 57%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.71 (1H, brs), 7.84-7.92 (2H, m), 7.56-7.62 (1H, m), 7.40-7.52 (3H, m), 7. 27-7.37 (5H, m), 4.99 (2H, s), 4.70-4.78 (2H, m), 4.16 (1H, td, J = 7.8, 11.7 Hz) ), 3.84-3.94 (1H, m), 3.54-3.64 (1H, m), 1.89-2.09 (2H, m), 1.75-1.87 (1H) , M), 1.56 (1H, tt, J = 12.7, 7.8 Hz).
Stereoisomer B
9.71 (1H, brs), 7.84-7.92 (2H, m), 7.56-7.62 (1H, m), 7.40-7.52 (3H, m), 7. 27-7.37 (5H, m), 4.99 (2H, s), 4.70-4.78 (2H, m), 4.03 (1H, td, J = 7.8, 11.7 Hz) ), 3.64-3.74 (2H, m), 1.97-2.07 (1H, m), 1.75-1.87 (2H, m), 1.68 (1H, tt, J = 12.7, 7.8 Hz).
MS (APCI, POS)
m / z: 431 (M + H) ⁺ .

Example 56
(3S, P (RS))-1-amino (2-thiophenecarbonylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by dissolving piperidone (502.0 mg, 1.54 mmol) in pyridine (24 mL) by heating, 2-thiophenecarbonyl chloride (0.20 mL, 1.87 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. .
After concentrating the reaction solution under reduced pressure, a 30% acetone aqueous solution was added to the resulting residue, and the residue was purified by Diaion HP-20 (30 mL, water-acetone gradient elution) column chromatography. Acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (345.0 mg, 51%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.79 (1H, brs), 8.01 (1H, td, J = 3.9, 1.0 Hz), 7.88 (1H, t, J = 3.9 Hz), 7.47 (1H, t , J = 3.3 Hz), 7.28-7.38 (5H, m), 7.18 (1H, ddd, J = 4.9, 3.9, 2.4 Hz), 5.00 (2H, s), 4.81 (1H, brs), 4.80 (1H, brs), 4.18 (1H, td, J = 8.3, 12.2 Hz), 3.85 (1H, td, J = 12.2, 6.4 Hz), 3.62-3.71 (1H, m), 1.51-2.06 (4H, m).
Stereoisomer B
9.79 (1H, brs), 8.01 (1H, td, J = 3.9, 1.0 Hz), 7.88 (1H, t, J = 3.9 Hz), 7.47 (1H, t , J = 8.3 Hz), 7.28-7.38 (5H, m), 7.18 (1H, ddd, J = 4.9, 3.9, 2.4 Hz), 5.00 (2H, s), 4.78 (1H, brs), 4.77 (1H, brs), 4.04 (1H, td, J = 8.3, 11.7 Hz), 3.56 (1H, qd, J = 8.8, 3.9 Hz), 3.62-3.71 (1H, m), 1.51-2.06 (4H, m).
MS (APCI, POS)
m / z: 437 (M + H) ⁺ .

Example 57
(3S, P (RS))-1-amino (4-nitrobenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by dissolving piperidone (606.0 mg, 1.845572 mmol) in pyridine (24 mL) by heating, 4-nitrobenzoyl chloride (413.6 mg, 2.2289 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. .
The reaction mixture was concentrated under reduced pressure, 30% aqueous acetone was added to the resulting residue, and the crystals were collected by filtration. Acetone was added to the obtained crystals, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the obtained crystals were washed with a mixed solvent of ethyl acetate-ether to obtain the target compound (448.0 mg, 51%). Obtained.

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
10.16 (1H, brs), 8.32 (2H, dd, J = 8.8, 2.9 Hz), 8.09 (2H, dd, J = 8.8, 2.9 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m), 4.99 (2H, s), 4.80 or 4.84 (1H, brs), 4.81 or 4.85 (1H, brs), 4.14 (1H, ddd, J = 11.7, 8.3, 7.3 Hz), 3.83-3.91 (1H, m), 3.56-3.66 ( 1H, m), 1.53-2.06 (4H, m).
Stereoisomer B
10.16 (1H, brs), 8.32 (2H, dd, J = 8.8, 2.9 Hz), 8.09 (2H, dd, J = 8.8, 2.9 Hz), 7.46 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m), 4.98 (1H, s), 4.97 (1H, s), 4.84 or 4.80 (1H , Brs), 4.85 or 4.81 (1H, brs) 4.04 (1H, td, J = 7.8, 11.7 Hz), 3.64-3.72 (2H, m), 1.53- 2.06 (4H, m).
MS (APCI, POS)
m / z: 476 (M + H) ⁺ .

Example 58
(3S, P (RS))-1-amino (4-fluorobenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S) -3-benzyloxycarbonylamino-1-bis (4-fluoro Synthesis of benzoylamino) phosphinyl-2-piperidone (3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (335.5 mg, 1.0282 mmol) was dissolved in pyridine (24 mL) by heating. 4-Fluorobenzoyl chloride (377.7 mg, 2.4121 mmol) was added to the solution at room temperature, and the mixture was stirred at the same temperature for 6 hours.
After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel (chloroform: methanol = 14: 1 to 9: 1) column chromatography to obtain (3S, P (RS))-3-benzyloxy. Carbonylamino-1-amino (4-fluorobenzoylamino) phosphinyl-2-piperidone (210.9 mg, 46%) and (3S) -3-benzyloxycarbonylamino-1-bis (4-fluorobenzoylamino) phosphinyl- 2-Piperidone (88.8 mg, 15%) was obtained.

(3S, P (RS))-1-amino (4-fluorobenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 58A)
¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
9.71 (1H, brs), 7.95-7.99 (2H, m), 7.44 (1H, brd, J = 8.8 Hz), 7.28-7.37 (7H, m), 4.99 (2H, s), 4.74 (1H, brs), 4.73 (1H, brs), 4.15 (1H, td, J = 7.8, 12.2 Hz), 3.83- 3.91 (1H, m), 3.57 (1H, qd, J = 8.3, 4.4 Hz), 1.89-2.05 (2H, m), 1.75-1.85 (1H , M), 1.56 (1H, tt, J = 12.2, 7.8 Hz).
Stereoisomer B
9.71 (1H, brs), 7.95-7.99 (2H, m), 7.48 (1H, brd, J = 8.8 Hz), 7.28-7.37 (7H, m), 4.99 (2H, s), 4.77 (1H, brs), 4.76 (1H, brs), 3.99-4.07 (1H, m), 3.63-3.71 (2H, m), 1.96-2.05 (1H, m), 1.75-1.85 (2H, m), 1.62-1.73 (1H, m).
MS (APCI, POS)
m / z: 449 (M + H) ⁺ .

(3S) -3-Benzyloxycarbonylamino-1-bis (4-fluorobenzoylamino) phosphinyl-2-piperidone (Example 58B)
¹ H-NMR (DMSO-D ₆ , internal standard TMS)
9.88-10.02 (2H, m), 7.92-8.00 (4H, m), 7.38-7.50 (5H, m), 7.23-7.33 (5H, m ), 4.95 (1H, s), 4.94 (1H, s), 4.17 (1H, td, J = 7.8, 11.7 Hz), 3.86-3.94 (1H, m ), 3.64-3.74 (1H, m), 2.00-2.10 (1H, m), 1.92-2.00 (1H, m), 1.82-1.92 (1H) M), 1.63 (1H, tt, J = 12.2, 7.8 Hz).
MS (APCI, POS)
m / z: 571 (M + H) ⁺ .

Example 59
(3S, P (RS))-1-amino (phenylureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone ( To a solution obtained by heating and dissolving 460.6 mg, 1.4116 mmol) in pyridine (12 mL), phenyl isocyanate (0.31 mL, 2.8418 mmol) was added at room temperature, and the mixture was stirred at the same temperature overnight. Further, phenyl isocyanate (0.31 mL, 2.8418 mmol) was added, and the mixture was stirred at the same temperature for 5 hours.
The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (chloroform: methanol = 14: 1 to 9: 1) to give the target compound (250.2 mg, 40%).

¹ H-NMR (DMSO-D ₆ , internal standard TMS)
Stereoisomer A
8.79 (1H, d, J = 7.8 Hz), 7.89 or 7.84 (1H, d, J = 9.8 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.24 -7.40 (9H, m), 6.95-7.01 (1H, m), 5.01 (2H, s), 4.78 (1H, brs), 4.79 (1H, brs), 4.19 (1H, td, J = 7.8, 11.7 Hz), 3.79-3.89 (1H, m), 3.50-3.64 (1H, m), 1.89-2 .08 (2H, m), 1.76-1.84 (1H, m), 1.55-1.65 (1H, m).
Stereoisomer B
8.79 (1H, d, J = 7.8 Hz), 7.84 or 7.89 (1H, d, J = 9.8 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.24 -7.40 (9H, m), 6.95-7.01 (1H, m), 5.01 (2H, s), 4.78 (1H, brs), 4.79 (1H, brs), 4.06 (1H, td, J = 7.8, 11.7 Hz), 3.64-3.72 (1H, m), 3.50-3.64 (1H, m), 1.98-2 .10 (2H, m), 1.75-1.85 (1H, m), 1.54-1.76 (1H, m).
MS (APCI, POS)
m / z: 446 (M + H) ⁺ .

Example 60
(3S, P (RorS))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S, P (SorR))-1-amino (N ′-(4 ″ -Bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (500.3 mg , 1.5333 mmol) was dissolved in pyridine (20 mL) with heating, 4-bromophenyl isocyanate (364.4 mg, 1.8401 mmol) was added at room temperature, and the mixture was stirred overnight at the same temperature.
The reaction mixture was concentrated under reduced pressure, 50% aqueous acetone was added to the resulting residue, and the crystals were collected by filtration. The obtained crystals were washed with 50% acetone to obtain (3S, P (SorR))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone In addition, the crystal filtrate and the washing solution were combined and purified by Diaion HP-20 (30 mL, water-acetone gradient elution) column chromatography, and then acetone in the elution part was removed. Distilled under reduced pressure and extracted with ethyl acetate, the ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting oil was crystallized from ether-n-hexane. 3S, P (RorS))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino- - was obtained piperidone (225.1mg, 28%).

(3S, P (SorR))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 60A)
¹ H-NMR (DMSO-D ₆ , internal standard TMS)
8.95 (1H, brs), 7.98 (1H, brs), 7.49 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.31- 7.38 (7H, m), 5.01 (2H, s), 4.80 (1H, brs), 4.79 (1H, brs), 4.04-4.08 (1H, m), 3 .64-3.72 (1H, m), 3.55-3.63 (1H, m), 1.97-2.05 (1H, m), 1.76-1.84 (2H, m) , 1.64-1.74 (1H, m).
MS (APCI, POS)
m / z: 526 (M + H) ⁺ .

(3S, P (RorS))-1-Amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 60B)
¹ H-NMR (DMSO-D ₆ , internal standard TMS)
8.92 (1H, brs), 7.89 (1H, brd, J = 8.3 Hz), 7.49 (1H, brd, J = 8.8 Hz), 7.44 (2H, d, J = 8) .8 Hz), 7.28-7.38 (7H, m), 5.01 (2H, s), 4.81 (1H, brs), 4.80 (1H, brs), 4.18 (1H, td, J = 8.3, 16.1 Hz), 3.78-3.87 (1H, m), 3.50-3.58 (1H, m), 1.88-2.06 (2H, m) ), 1.72-1.84 (1H, m), 1.54-1.65 (1H, m).
MS (APCI, POS)
m / z: 526 (M + H) ⁺ .

Example 61
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (N′-phenyl) thioureido-2-piperidone sodium salt Sulfostin monohydrate (136.0 mg, 0.4686 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (59.0 mg, 0.7023 mmol), acetonitrile (3 mL), and phenyl isothiocyanate (0.112 mL, 0.9362 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by dianion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (170.6 mg, 85%). It was.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.49 (2H, t, J = 7.3 Hz), 7.38 (1H, tt, J = 7.3, 1.5 Hz), 7.34 (2H, td, J = 1.5, 7. 3 Hz), 3.69-3.79 (1H, m), 3.60-3.68 (1H, m), 2.25-2.35 (1H, m), 1.86-1.96 ( 1H, m), 1.68-1.82 (1H, m).
HR-MS (ESI, POS)
m / z: found, 452.0217 (M + Na) ⁺ .
calcd. _{for C 12 H 17 N 5 Na} 2 O 5 PS 2, 452.0204

Example 62
(3S, PR) -3- (4′-Bromobenzenesulfonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt Sulfostin monohydrate (100.5 mg, 0.3463 mmol) in water (3 mL) Sodium hydrogen carbonate (87.3 mg, 1.0392 mmol), acetonitrile (3 mL), and 4-bromobenzenesulfolyl chloride (0.1327 mg, 0.5193 mmol) were added to the solution dissolved in 1, and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (122.2 mg, 69%). Obtained.

¹ H-NMR (D ₂ O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D ₄ sodium salt)
7.81 (4H, brs), 4.05 (1H, dd, J = 11.2, 6.8 Hz), 3.68-3.76 (1H, m), 3.50 (1H, ddd, J = 12.7, 7.8, 4.4 Hz), 1.86-2.02 (2H, m), 1.61-1.83 (2H, m).
HR-MS (ESI, POS)
m / z: found, 536.9040 (M + Na) ⁺ .
calcd. for C ₁₁ H ₁₅ BrN ₄ Na ₂ O ₇ PS ₂ , 536.9078

Example 63
(3S) -3-Benzyloxycarbonylamino-1-bis (methylamino) phosphinyl-2-piperidone (3S) -3-Benzyloxycarbonylamino-2-piperidone (3.73 g, 15.02 mmol) in tetrahydrofuran (60 mL) ) After cooling the solution at an external temperature of −78 ° C., an n-butyllithium hexane solution (1.54M, 9.3 mL, 14.32 mmol) was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 20 minutes. Next, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (10 mL) was added and stirred for 20 minutes, and then a solution of methylamine (40% aqueous solution, 5.8 mL, 74.69 mmol) in tetrahydrofuran (50 mL) was added. It was added after drying with potassium carbonate and stirred for 10 minutes.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure to obtain a pale yellow oil. This oil was purified by Diaion HP-20 (200 mL, water-methanol gradient elution) column chromatography to obtain the target compound (1.98 g, 37%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.30-7.37 (5H, m), 5.61 (1H, brd, J = 5.4 Hz), 5.12 (2H, s), 4.26-4.31 (1H, m), 3.93 (1H, qd, J = 5.3 Hz, 13.2 Hz), 3.48-3.56 (1H, m), 3.06-3.15 (1H, m), 2.98-3 .06 (1H, m), 2.61 (3H, t, J = 5.9 Hz), 2.58 (3H, t, J = 5.9 Hz), 2.47-2.55 (1H, m) , 1.86-1.95 (2H, m), 1.55 (1H, tt, J = 13.2 Hz, 8.3 Hz).
MS (FAB, POS)
m / z: 355 (M + H) ⁺ .

Example 64
(3S) -3-Benzyloxycarbonylamino-1-bis (ethylamino) phosphinyl-2-piperidone (3S) -3-Benzyloxycarbonylamino-2-piperidone (3.73 g, 15.02 mmol) in tetrahydrofuran (60 mL) ) After cooling the solution at an external temperature of −78 ° C., an n-butyllithium hexane solution (1.54M, 9.3 mL, 14.32 mmol) was added dropwise over 15 minutes, followed by stirring at the same temperature for 20 minutes. Next, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (6 mL) was added and stirred for 30 minutes, and then a solution of ethylamine (70% aqueous solution, 5.47 mL, 84.92 mmol) in tetrahydrofuran (50 mL) was carbonated. It was added after drying with potassium and stirred for 5 minutes.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give a pale yellow oil. This oil was purified by silica gel chromatography (150 g, chloroform: methanol = 19: 1) to obtain an oil. This oil was divided into 6 portions and purified by Sephadex LH-20 (180 mL, methanol) column chromatography, and then silica gel (100 g, chloroform: methanol = 29: 1 to 19: 1 to 14: 1) column chromatography again. To obtain an oil (1.95 g). The obtained oil was crystallized from ethanol-ether to obtain the target compound (1.78 g, 31%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.29-7.33 (5H, m), 5.60 (1H, brd, J = 4.9 Hz), 5.13 (2H, s), 4.22-4.28 (1H, m), 3.95 (1H, qd, J = 5.9 Hz, 13.2 Hz), 3.47-3.56 (1H, m), 3.12-3.18 (1H, m), 2.89-3 .08 (5H, m), 2.48-2.54 (1H, m), 1.84-1.96 (2H, m), 1.53 (1H, tt, J = 13.2 Hz, 8. 3 Hz), 1.12 (3H, t, J = 6.8 Hz), 1.11 (3H, t, J = 6.8 Hz).
MS (FAB, POS)
m / z: 383 (M + H) ⁺ .

Example 65
Tetrahydrofuran of (3S) -3-benzyloxycarbonylamino-1-bis (n-propylamino) phosphinyl-2-piperidone (3S) -3-benzyloxycarbonylamino-2-piperidone (3.73 g, 15.02 mmol) (45 mL) After cooling the solution at an external temperature of −78 ° C., n-butyllithium hexane solution (1.54 M, 9.3 mL, 14.32 mmol) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 20 minutes. Then, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (5 mL) was added and stirred for 30 minutes, then n-propylamine (d = 0.719, 5.2 mL, 63.25 mmol) was added, Stir for 1 hour.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give a pale yellow oil. This oil was purified twice by silica gel chromatography (100 g, chloroform: methanol = 29: 1 to 19: 1) to obtain the target compound (0.98 g, 16%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.30-7.37 (5H, m), 5.58-5.63 (1H, m), 5.12 (2H, s), 4.22-4.29 (1H, m), 3. 96 (1H, qd, J = 5.9 Hz, 13.7 Hz), 3.46 to 3.55 (1H, m), 3.17-3.24 (1H, m), 3.03 to 3.11. (1H, m), 2.83-2.95 (4H, m), 2.49-2.57 (1H, m), 1.84-1.96 (2H, m), 1.43-1 .57 (5H, m), 0.89 (3H, t, J = 7.3 Hz), 0.88 (3H, t, J = 7.3 Hz).
MS (FAB, POS)
m / z: 411 (M + H) ⁺ .

Example 66
(3S, P (RS))-1-amino (n-propylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-2-piperidone (3.73 g, 15 0.02 mmol) in tetrahydrofuran (60 mL) was cooled at an external temperature of −78 ° C., and then n-butyllithium hexane solution (1.54 M, 9.3 mL, 14.32 mmol) was added dropwise over 15 minutes. Stir for 30 minutes. Next, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (10 mL) was added and stirred for 30 minutes, and then n-propylamine (d = 0.719, 0.93 mL, 11.31 mmol) and triethylamine ( d = 0.7225, 1.58 mL, 11.28 mmol) in tetrahydrofuran (5 mL) was slowly added and stirred for 10 minutes. Then, a chloroform solution of ammonia (1M, 40 mL, 40.00 mmol) was added and stirred for 10 minutes.
After adding brine to the reaction solution, n-hexane was added to separate the two layers. The aqueous layer was extracted with chloroform, the organic layers were combined and concentrated under reduced pressure, and purified by Diaion HP-20 (200 mL, water-methanol gradient elution) column chromatography to obtain the target compound (0.34 g, 6%). Got.

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.30-7.39 (5H, m), 5.63 (1H, brd, J = 4.9 Hz), 5.12 (2H, s), 4.20-4.28 (1H, m), 3.90 (1H, qd, J = 5.9 Hz, 13.7 Hz), 3.52 to 3.60 (1H, m), 3.30 and 3.25 (2H, brs), 3.14 and 3.08 (1H , Brq, J = 7.8 Hz), 2.78 to 2.96 (2H, m), 2.46 to 2.54 (1H, m), 1.87 to 1.95 (2H, m), 1 .53 to 1.63 (1H, m), 1.43 to 1.52 (2H, m) 0.89 and 0.88 (3H, t, J = 7.3 Hz).
MS (FAB, POS)
m / z: 369 (M + H) ⁺ .

Example 67
(3S, P (RorS))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and ((3S, P (SorR))-1-amino (phenylamino) phosphinyl-3- After cooling a solution of benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-2-piperidone (2.48 g, 9.99 mmol) in tetrahydrofuran (30 mL) at an external temperature of −78 ° C., n- A butyllithium hexane solution (1.59 M, 6.2 mL, 9.86 mmol) was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 30 minutes, followed by phosphorus oxychloride (1.53 g, 9.98 mmol) in tetrahydrofuran (3 mL). ) Solution was added and stirred for 30 minutes, then aniline (d = 1.022, 1.8). mL, 19.75 mmol) was added, and the mixture was stirred for 1 hour, and then a solution of ammonia in chloroform (1.15 M, 17.4 mL, 20.01 mmol) was added and stirred for 30 minutes.
The reaction mixture was concentrated under reduced pressure, brine was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give a pale yellow oil. This oil was purified twice by silica gel chromatography (100 g, chloroform: ethyl acetate = 4: 1-3: 1 to 2: 1) to obtain the desired (3S, P (RorS))-1-amino (phenylamino). ) Phosphinyl-3-benzyloxycarbonylamino-2-piperidone (0.10 g, 2%), and (3S, P (SorR))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2- Piperidone (0.06 g, 1%) was obtained.

(3S, P (RorS))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 67A)
¹ H-NMR (CDCl ₃ , internal standard TMS)
7.30-7.38 (5H, m), 7.23 (2H, t, J = 7.8 Hz), 7.05 (2H, d, J = 7.8 Hz), 7.01 (1H, t , J = 7.8 Hz), 5.52 (1H, brd, J = 6.8 Hz), 5.43 (1H, brd, J = 2.0 Hz), 5.08-5.14 (2H, m) 4.16-4.22 (1H, m), 3.92 (1H, tdd, J = 6.8 Hz, 13.7 Hz, 4.8 Hz), 3.54 (2H, brs), 3.46- 3.53 (1H, m), 2.20-2.28 (1H, m), 1.70-1.78 (1H, m), 1.42-1.52 (1H, m), 1. 22-1.31 (1H, m)
MS (FAB, POS)
m / z: 403 (M + H) ⁺ .
MS (FAB, NEG)
m / z: 401 (M−H) ⁻ .

(3S, P (SorR))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 67B)
¹ H-NMR (CDCl ₃ , internal standard TMS)
7.30-7.38 (5H, m), 7.23 (2H, t, J = 7.8 Hz), 7.01 (2H, d, J = 7.8 Hz), 7.00 (1H, t , J = 7.8 Hz), 5.48-5.52 (1H, m), 5.44 (1H, brd, J = 7.3 Hz), 5.10 (2H, s), 3.94-4 .03 (1H, m), 3.88-3.94 (1H, m), 3.55 (2H, brs), 3.50-3.54 (1H, m), 2.40-2.47 (1H, m), 1.85-1.94 (1H, m), 1.73-1.83 (1H, m), 1.52-1.63 (1H, m).
MS (FAB, POS)
m / z: 403 (M + H) ⁺ .
MS (FAB, NEG)
m / z: 401 (M−H) ⁻ .

Example 68
(3S, P (RS))-1-amino ((benzyloxycarbonylamino) acetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone benzyloxycarbonylglycine (836.8 mg, 4.0000 mmol) was dissolved in toluene ( To a solution dissolved in 15 mL) and tetrahydrofuran (15 mL) was added thionyl chloride (0.29 mL, 3.9757 mmol), and the mixture was stirred at room temperature for 2 hours. This solution was added to a solution obtained by heating and dissolving (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (652.9 mg, 2.0010 mmol) in pyridine (20 mL). Stir for hours.
The reaction mixture was concentrated under reduced pressure, saturated brine was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel (chloroform: methanol = 14: 1 to 9: 1) column chromatography to obtain the target compound (278.2 mg, 27%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
8.61 (1H, brs), 7.24-7.37 (10H, m), 5.99 and 5.58 (1H, m), 5.74 and 5.45 (1H, s), 5.00-5. 15 (4H, m), 3.52-4.27 (7H, m), 1.46-2.32 (4H, m).
MS (APCI, POS)
m / z: 518 (M + H) ⁺ .

Example 69
(3S, P (RorS))-3-Amino-1-amino (phenylureido) phosphinyl-2-piperidone hydrobromide Compound of Example 60B (200.2 mg, 0.3818 mmol) in methanol (10 mL) Palladium black (20.0 mg) was added to the dissolved solution, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (160.0 mg, 97%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
7.43 (2H, t, J = 7.3 Hz), 7.35 (2H, d, J = 7.3 Hz), 7.25 (1H, t, J = 7.3 Hz), 4.16 (1H , Dd, J = 12.2, 6.8 Hz), 3.81-3.89 (1H, m), 3.68-3.76 (1H, m), 2.35-2.45 (1H, m), 2.06-2.14 (1H, m), 1.94-2.05 (1H, m), 1.79-1.90 (1H, m).

Example 70
(3S, P (RorS))-1-amino (phenylureido) phosphinyl-3-cyclohexylpropionylamino-2-piperidone 3-cyclohexylpropionic acid (31.2 mg, 0.1997 mmol), dicyclohexylcarbodiimide (41.2 mg, 0 (1997 mmol) and N-hydroxysuccinimide (27.1 mg, 0.2005 mmol) were added dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hours, and the compound of Example 69 (19.0 mg, 0.0440 mmol) and Triethylamine (0.05 mL, 0.3570 mmol) was added and stirred at room temperature for 2 hours.
Water was added to the reaction solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel (chloroform: methanol = 14: 1 to 9: 1) column chromatography to obtain the target compound (14.5 mg, 73%).

¹ H-NMR (CDCl ₃ , internal standard TMS)
8.83 (1H, m), 7.43-7.47 (1 H, m), 7.39 (2H, d, J = 7.3 Hz), 7.26 (2H, t, J = 7.3 Hz) ), 7.05 (1H, t, J = 7.3 Hz), 6.58 (1H, brd, J = 7.3 Hz), 4.58 (1H, td, J = 6.8, 12.2 Hz) 3.98 (2H, brd, J = 3.9 Hz), 3.89-3.97 (1H, m), 3.63-3.72 (1H, m), 2.19-2.27 ( 2H, m), 1.87-2.01 (2H, m), 1.47-1.71 (8H, m), 1.08-1.24 (4H, m), 0.80-0. 92 (2H, m).
MS (APCI, POS)
m / z: 450 (M + H) ⁺ .

Pharmacological test example 1
Measurement of prolyl oligopeptidase inhibitory activity Prolyl oligopeptidase inhibitory activity was performed according to the method of Yoshimoto et al. (Biochim. Biophys. Acta, 569, 184-192 (1979)). Drug and water are added to 0.04 mL of 20% aqueous dioxane solution of 0.5 mM benzyloxycarbonyl, glycyl, prolyl, β-naphthylamide and 0.1 mL of 50 mM Tris-HCl buffer (pH 7.8) to bring the final volume to 0. Adjusted to 2 mL. The mixed solution was heated at 37 ° C. for 10 minutes, and 1 mM of a prolyl oligopeptidase solution partially purified using a porcine kidney according to the method of Koida et al. (J. Biol. Chem., 251, 7593-7599 (1976)). 0.01 mL of 25 mM sodium phosphate buffer (pH 6.8) containing dithiothreitol and 1 mM ethylenediaminetetraacetic acid / disodium salt was added and reacted at 37 ° C. for 1 hour. After completion of the reaction, 0.1 mL of 0.5 M sodium citrate buffer solution (pH 3.78) containing 10% polyoxyethylene (20) sorbitan monourate of 0.2% first garnet GBC salt was added to release β -The diazo compound of naphthylamine was measured by absorbance at 525 nm. The inhibition rate of the drug is calculated by the following formula: Absorbance including the sample (a), Absorbance of the blind not including the sample (b), and Absorbance (a ′, b ′) when each prolyl oligopeptidase is not added did.
Inhibition rate = {(bb ′) − (aa ′) / (bb ′)} × 100
The 50% inhibitory activity value of prolyl oligopeptidase of the compound of the present invention was determined from the inhibition rate calculated by this method, and is shown in Table 1.

Table 1
50% inhibitory activity value of prolyl oligopeptidase of the compound (unit: microgram / milliliter)
Compound No. 50% Inhibitory Activity Value Compound of Reference Example 2 0.0023
Compound of Reference Example 4 0.10
Compound of Reference Example 7 0.0022
Compound of Reference Example 8 0.0020
Compound of Reference Example 10 0.035

Compound of Example 1 0.069
Compound of Example 2 0.13
Compound of Example 3 0.031
Compound of Example 4 0.15
Compound of Example 5 0.10
Compound of Example 6 0.050
Compound of Example 7 0.48
Compound of Example 8 0.10
Compound of Example 9 0.10
Compound of Example 10 0.12

Compound of Example 11 0.094
Compound of Example 12 0.012
Compound of Example 13 0.036
Compound of Example 14 0.036
Compound of Example 15 0.064
Compound of Example 16 0.480
Compound of Example 17 0.0053
Compound of Example 18 0.0039
Compound of Example 19 0.0022
Compound of Example 20 0.0010

Compound of Example 21 0.0035
Compound of Example 22 0.013
Compound of Example 23 0.00080
Compound of Example 24 0.0025
Compound of Example 25 0.013
Compound of Example 26 0.0099
Compound of Example 27 0.0016
Compound of Example 28 0.049
Compound of Example 29 0.090
Compound of Example 30 0.041

Compound of Example 31 0.011
Compound of Example 32 0.014
Compound of Example 33 0.0041
Compound of Example 34
Compound of Example 35 0.021
Compound of Example 36 0.087
Compound of Example 37 0.25
Compound of Example 38 0.0055
Compound of Example 39 0.00067
Compound of Example 40 0.056

Compound of Example 41 0.041
Compound of Example 42 0.19
Compound of Example 43 0.020
Compound of Example 44 0.033
Compound of Example 45 0.031
Compound of Example 46 0.45
Compound of Example 47A 0.080
Compound of Example 47B 0.0029
Compound of Example 48 0.0029
Example 49 Compound 0.0039

Compound of Example 50 0.0043
Compound of Example 51 0.0025
Compound of Example 52 0.0023
Compound of Example 53 0.0045
Compound of Example 54A 0.00089
Compound of Example 54B 0.014
Compound of Example 55 0.0073
Compound of Example 56 0.0046
Compound of Example 57 0.0026
Compound of Example 58A 0.0033

Compound of Example 58B 0.30
Compound of Example 59 0.0025
Compound of Example 60A 0.25
Compound of Example 60B 0.0013
Compound of Example 61 0.18
Compound of Example 62 0.0067
Compound of Example 63 0.40
Compound of Example 64 0.11
Compound of Example 65 0.18
Compound of Example 66 0.013

Compound of Example 67A 0.0024
Compound of Example 67B 0.13
Compound of Example 68 0.013
Compound of Example 70 0.0016
SUAM14746 0.016

  As described above, the α-acylamino-N- (diaminophosphinyl) lactam derivative of the present invention has a strong prolyl oligopeptidase action. In addition, the compound of the present invention is more active than SUAM14746 (generic name: 3-[[4- (2- (E) -Styrylphenoxy) Butanoyl] -L-4-Hydroxypropyl] -Thiazolidene, Peptide Institute, Inc.). Became clear. Based on the above, the compound of the present invention can be used as a prophylactic or therapeutic agent for diseases considered to involve prolyl oligopeptidases such as memory and cognitive impairment, and as a prophylactic or therapeutic agent for Chagas disease. It was revealed.

Claims (28)

General formula (1)

Wherein R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, carbamoyl group, lower alkylaminocarbonyl group, or .X substituted with arylaminocarbonyl group carbonyl group (-CO-), a thiocarbonyl group (-CS-), or a sulfonyl group - a (-SO ₂₎ Y and Z may be the same or different, and may be a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkane. A carbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, the lower alkyl group, aryl group, heteroaryl group, lower group Alkoxy group, aryloxy group, benzyloxy group, nitro Group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group, Q is — (CH ₂ ). _n- (n represents 0 to 3).) Prolyl containing an α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the formula: or a pharmacologically acceptable salt thereof as an active ingredient Oligopeptidase inhibitor. In the general formula (1), R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryl An oxy group, a pyrrolidinyl group, an N-protected pyrrolidinyl group, a benzyl group, or a benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a hetero group Aryl group, lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, Thiol group, lower alkylthio group, halogen atom, Substituted with 1 to 3 substituents selected from the group consisting of an ano group, a nitro group, a carbamoyl group, a lower alkylaminocarbonyl group, and an arylaminocarbonyl group, and X is a carbonyl group (—CO—) or a sulfonyl group (-SO 2 _-) prolyl oligopeptidase inhibitor according to claim 1 showing a. In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, an aryl group, hetero When substituted with 1 to 3 substituents selected from the group consisting of an aryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and a benzyl group is substituted, a lower alkoxy group or a nitro group, X is a carbonyl group (-CO-) or a sulfonyl group (-SO 2 _-) prolyl oligopeptidase inhibitor according to claim 1 showing a. In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, an aryl group, hetero When substituted with 1 to 3 substituents selected from the group consisting of an aryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and a benzyl group is substituted, a lower alkoxy group Or the prolyl oligopeptidase inhibitor of Claim 1 substituted by a nitro group and X shows a carbonyl group (-CO-). In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. The prolyl oligopeptidase inhibitor according to claim 1, which is substituted with 1 to 2 substituents selected from the group consisting of a group and a benzyloxycarbonylamino group, and X represents a carbonyl group (-CO-). In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other is a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, Or an arylaminocarbonyl group, each group may be substituted When substituted, lower alkyl group, aryl group, heteroaryl group, lower alkoxy group, aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group The prolyl oligopeptidase inhibitor according to claim 1, which is substituted with an N-protected amino group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other represents a sulfonic acid group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, or an arylaminocarbonyl group, and each group may be substituted or substituted. In this case, a lower alkyl group, aryl group, lower alkoxy group, aryloxy group, benzyloxy Group, a nitro group, a halogen atom, or a prolyl oligopeptidase inhibitor according to claim 1, which is substituted with a hydroxyl group. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other represents a sulfonic acid group, a lower acyl group, or an arylaminocarbonyl group, and the lower acyl group and the arylaminocarbonyl group may be substituted, and when substituted, the lower alkoxy group, aryloxy group, benzyloxy group The prolyl oligopeptidase inhibitor according to claim 1, which is substituted with a halogen atom or a hydroxyl group. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other is a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and if substituted, is substituted with a phenoxy group or a benzyloxy group. Prolyl oligopeptidase inhibitor. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group. The lower acyl group may be substituted, and if substituted, is substituted with a phenoxy group or a benzyloxy group, and Q is — (CH ₂ ) The prolyl oligopeptidase inhibitor according to claim 1, which shows _2- . In the general formula (1), R represents a benzyloxy group or is selected from the group consisting of a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group, and a benzyloxycarbonylamino group. A methyl group or an ethyl group substituted with one substituent, X represents a carbonyl group (—CO—), one of Y and Z represents a hydrogen atom, the other represents a sulfonic acid group, phenoxyacetyl. group, benzyloxy acetyl group, or a phenylamino group, Q is - (CH ₂₎ 2 _- prolyl oligopeptidase inhibitor according to claim 1 showing a. The prolyl oligopeptidase inhibitor according to any one of claims 1 to 11, for improving or treating memory and cognitive impairment. The prolyl oligopeptidase inhibitor according to claim 12, wherein the memory and cognitive impairment is amnesia. The prolyl oligopeptidase inhibitor according to claim 12, wherein the memory and cognitive impairment is dementia. The prolyl oligopeptidase inhibitor according to any one of claims 1 to 11, for preventing or treating Chagas disease. 16. The prolyl oligopeptidase inhibitor according to claim 15, which inhibits trypanosome infection into cells. General formula (1)

Wherein R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, carbamoyl group, lower alkylaminocarbonyl group, or .X substituted with arylaminocarbonyl group carbonyl group (-CO-), a thiocarbonyl group (-CS-), or a sulfonyl group - a (-SO ₂₎ Y and Z may be the same or different, and may be a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkane. A carbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, the lower alkyl group, aryl group, heteroaryl group, lower group Alkoxy group, aryloxy group, benzyloxy group, nitro Group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group, Q is — (CH ₂ ). _n- (n represents 0 to 3), provided that R is a benzyloxy group, X is a carbonyl group (-CO-), and both Y and Z are a combination of hydrogen atoms, Y and Z An α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the following formula: or a pharmacologically acceptable salt thereof. In the general formula (1), R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryl An oxy group, a pyrrolidinyl group, an N-protected pyrrolidinyl group, a benzyl group, or a benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a hetero group Aryl group, lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, Thiol group, lower alkylthio group, halogen atom, Substituted with 1 to 3 substituents selected from the group consisting of an ano group, a nitro group, a carbamoyl group, a lower alkylaminocarbonyl group, and an arylaminocarbonyl group, and X is a carbonyl group (—CO—) or a sulfonyl group The α-acylamino-N- (diaminophosphinyl) lactam derivative or a pharmacologically acceptable salt thereof according to claim 17, which represents (—SO ₂ —). In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, an aryl group, hetero When substituted with 1 to 3 substituents selected from the group consisting of an aryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and a benzyl group is substituted, a lower alkoxy group Or an α-acylamino-N- (diaminophosphinyl) lactam derivative according to claim 17, wherein X represents a carbonyl group (—CO—) or a sulfonyl group (—SO ₂ —). Or a pharmacologically acceptable salt thereof. In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, an aryl group, hetero When substituted with 1 to 3 substituents selected from the group consisting of an aryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and a benzyl group is substituted, a lower alkoxy group The α-acylamino-N- (diaminophosphinyl) lactam derivative or a pharmacologically acceptable salt thereof according to claim 17, which is substituted with a nitro group and X represents a carbonyl group (—CO—). In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. The α-acylamino-N- (diaminophos) according to claim 17, which is substituted with 1 to 2 substituents selected from the group consisting of the group benzyloxycarbonylamino group, and X represents a carbonyl group (—CO—). Finyl) lactam derivatives or pharmacologically acceptable salts thereof. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other is a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, Or an arylaminocarbonyl group, each group may be substituted When substituted, lower alkyl group, aryl group, heteroaryl group, lower alkoxy group, aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group The α-acylamino-N- (diaminophosphinyl) lactam derivative or a pharmacologically acceptable derivative thereof according to claim 17, which is substituted with an N-protected amino group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group. salt. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other represents a sulfonic acid group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, or an arylaminocarbonyl group, and each group may be substituted or substituted. In this case, a lower alkyl group, aryl group, lower alkoxy group, aryloxy group, benzyloxy Group, a nitro group, a halogen atom, or a hydroxyl group are as claimed in claim 17, wherein the substituted α- acylamino -N- (diamino phosphinyl) lactam derivative or a pharmacologically acceptable salt thereof. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other represents a sulfonic acid group, a lower acyl group, or an arylaminocarbonyl group, and the lower acyl group and the arylaminocarbonyl group may be substituted, and when substituted, the lower alkoxy group, aryloxy group, benzyloxy group The α-acylamino-N- (diaminophosphinyl) according to claim 17, which is substituted with a halogen atom or a hydroxyl group. Kutamu derivative or a pharmacologically acceptable salt thereof. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. Substituted with 1 to 2 substituents selected from the group consisting of a group, benzyloxycarbonylamino group, X represents a carbonyl group (-CO-), Y and Z either represents a hydrogen atom, The other is a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and if substituted, it is substituted with a phenoxy group or a benzyloxy group. 17. The α-acylamino-N- (diaminophosphinyl) lactam derivative according to 17, or a pharmacologically acceptable salt thereof. In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group. A benzyloxycarbonylamino group is substituted with 1 to 2 substituents selected from the group consisting of benzyloxycarbonylamino group, X is a carbonyl group (—CO—), Y and Z are either hydrogen An atom, the other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and if substituted, is substituted with a phenoxy group or a benzyloxy group; Q is - _{(CH 2)} 2 - α- acylamino -N- according to claim 17, wherein indicating the (diamino phosphinyl) lactam derivative or a pharmacologically Salt content. In the general formula (1), R represents a benzyloxy group or is selected from the group consisting of a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group, and a benzyloxycarbonylamino group. A methyl group or an ethyl group substituted with one substituent, X represents a carbonyl group (—CO—), one of Y and Z represents a hydrogen atom, the other represents a sulfonic acid group, phenoxyacetyl. The α-acylamino-N- (diaminophosphinyl) lactam derivative according to claim 17 or a pharmacological thereof, which represents a group, benzyloxyacetyl group, or phenylaminocarbonyl group, and Q represents — (CH ₂ ) ₂ —. Acceptable salt. A pharmaceutical or preventive or therapeutic agent for mammals, comprising the compound according to any one of claims 17 to 27 or a pharmacologically acceptable salt thereof as an active ingredient.