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WO2018174283A1 - Dérivé de polyéthylène glycol - Google Patents

Dérivé de polyéthylène glycol Download PDF

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Publication number
WO2018174283A1
WO2018174283A1 PCT/JP2018/011904 JP2018011904W WO2018174283A1 WO 2018174283 A1 WO2018174283 A1 WO 2018174283A1 JP 2018011904 W JP2018011904 W JP 2018011904W WO 2018174283 A1 WO2018174283 A1 WO 2018174283A1
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WIPO (PCT)
Prior art keywords
optionally substituted
polyethylene glycol
following formula
mmol
glycol derivative
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PCT/JP2018/011904
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English (en)
Japanese (ja)
Inventor
知之 西川
祐輔 三浦
道寛 前本
篤史 細見
Original Assignee
協和発酵キリン株式会社
田辺三菱製薬株式会社
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Publication of WO2018174283A1 publication Critical patent/WO2018174283A1/fr

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  • the present invention relates to a polyethylene glycol derivative of 4- (3S- (1R- (1-naphthyl) ethylamino) pyrrolidin-1-yl) phenylacetic acid or a pharmaceutically acceptable salt thereof.
  • Parathyroid hormone is a hormone that has a physiological function of inducing bone resorption and increasing blood calcium (Ca), and plays a role in maintaining blood Ca homeostasis. If PTH secretion increases chronically, blood Ca concentration increases due to continuous Ca elution from bone, resulting in metabolic abnormalities. For this reason, secretion and synthesis of PTH are strictly controlled by signaling through a Ca-sensitive receptor (CaSR) that senses extracellular calcium ion (Ca 2+ ) concentration. Further, it has been reported that a compound having an activating effect on CaSR is expected to exhibit an anti-parathyroid function enhancing action through a decrease in blood PTH concentration (see Patent Document 1 and Non-Patent Documents 1 to 5). ).
  • CaSR Ca-sensitive receptor
  • Evocalcet having CaSR activating action.
  • Evocalcet 4- (3S- (1R- (1-naphthyl) ethylamino) pyrrolidin-1-yl) phenylacetic acid [Evocalcet] having CaSR activating action.
  • Evocalcet is known (see Patent Document 1).
  • Patent Document 2 a compound in which a compound having a CaSR activation action and a water-soluble oligomer such as polyethylene glycol are combined is known (see Patent Document 2).
  • An object of the present invention is to provide a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof that enables sustained release of evocalcet in plasma.
  • the present inventors have found that sustained release of evocalcet in plasma can be realized by using a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof.
  • the present invention is based on these findings.
  • One or more 4- (3S- (1R- (1-naphthyl) ethylamino) pyrrolidin-1-yl) phenylacetic acid moieties are bonded to one or more polyethylene glycol moieties directly or via a linker.
  • the multi-arm type polyethylene glycol residue has 2 to 20 arms, and each arm includes — (OCH 2 CH 2 ) n2 —, and n2 may be the same or different, and an integer of 10 to 1000
  • And A1 is The following formula (B): (Where * Represents the point of attachment, X a represents an X 1a X 2a, where X 1a is a bond, an oxygen atom, (wherein, R 0a represents a lower alkyl which may optionally be a hydrogen atom or a substituent) a sulfur atom or NR 0a represent , X 2a is a bond, optionally substituted lower alkylene, the following formula: [In the formula, Z represents CO or NR 1a (wherein R 1a represents a hydrogen atom or an optionally substituted lower alkyl), and Y 1A and Y 1B are the same or different and are bonded or substituted.
  • L is (I) The following formula (D): (Where * Represents the point of attachment to A1, ** represents the point of attachment with POLY, L 1A represents a bond, an oxygen atom, a sulfur atom, OCH 2 , or NR 11a (wherein R 11a represents a hydrogen atom or an optionally substituted lower alkyl, or R 11a is bonded to L 2A.
  • L 2A is a bond, an optionally substituted lower alkylene, an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted.
  • L 3A is a bond, an optionally substituted lower alkylene, an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted
  • L 3B represents a bond or optionally substituted lower alkylene
  • L 4B represents a bond, an oxygen atom, an optionally substituted lower alkylene, or a linker represented by the following formula: [Wherein Y 3A and Y 3B are the same or different and may be bonded, substituted lower alkylene, oxygen atom, sulfur atom or NR 15a (wherein R 15a may be hydrogen atom or substituted) Represents a good lower alkyl)], L 5B represents a bond, an oxygen atom, or an optionally substituted lower alkylene), or (iii) the following formula (F): (Where * Represents the point of attachment to A1, ** represents the point of attachment with POLY, L 1C represents a bond, an optionally substituted lower alkylene, or the following formula: (Wherein X 5a represents an oxygen atom, a sulfur atom, or NR 16a (wherein R 16a represents a linker represented by the following formula: [Wherein Y 3A and
  • each R 18a and R 19a may be the same or different), or represents:
  • Y 4 is an optionally substituted lower alkylene, an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted
  • Y 5 represents a bond or NR 20a (wherein R 20a represents a hydrogen atom or an optionally substituted lower alkyl), L 4C is a bond, optionally substituted lower alkyl, the following formula: (Wherein Y 6 represents an optionally substituted lower alkylene) Or the following formula: (Wherein n5 represents an integer of 0 to 5, n6 represents an integer of 1 to 10, and R 21a represents a hydrogen atom or an optionally substituted lower alkyl)) or (iv) G): (Where * Represents the point of attachment to A1, ** represents the point of attachment with POLY, L 1D is a bond, optionally substituted lower alkylene
  • each L 1D may be the same or different,
  • Each linker may be a linker linked via the following formula: [Wherein, X 7a represents an oxygen atom, a sulfur atom, or NR 24a (wherein R 24a represents a hydrogen atom or lower alkyl)], L 3D represents a bond, an oxygen atom, an optionally substituted lower alkylene, or the following formula: (Wherein Y 7 represents an optionally substituted lower alkylene)), m represents an integer of 1 to 20, and l represents an integer of 1 to 20.] (4) In the formula (A), A1 represents the formula (B), X 1a and X 2a are both a bond, and L represents the formula (D), or the polyethylene glycol derivative according to (3) or its A pharmaceutically acceptable salt.
  • L 1A is a lower alkylene which may be bonded or substituted
  • L 2A is bonded
  • the polyethylene glycol derivative or a pharmaceutically acceptable salt thereof according to any one of (4) to (8).
  • L 2A represents the following formula: (Wherein, R 3a represents a hydrogen atom or a lower alkyl, n a represents an integer of 1-5). (11) L 1A is a bond, L 2A represents the following formula: (Wherein, R 3a represents a hydrogen atom or a lower alkyl, n a represents an integer of 1-5), L 3A represents the following formula: [ Wherein Y 2A represents a nitrogen atom and Y 2B represents lower alkylene], L 4A represents an oxygen atom, The polyethylene glycol derivative or a pharmaceutically acceptable salt thereof according to (4).
  • X 2a in the formula (B) is represented by the following formula: (Where Y 6A represents a bond; Y 6B represents an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted aliphatic heterocyclic diyl), or Represents the following formula: (13) The polyethylene glycol derivative or a pharmaceutically acceptable salt thereof according to any one of (21) to (21). (23) The polyethylene glycol according to (3), wherein in formula (A), A1 represents formula (C), Y 1 , Y 2 and Y 3 are all bonds, and L represents formula (F) A derivative or a pharmaceutically acceptable salt thereof.
  • the multi-arm type polyethylene glycol residue has 2 to 20 arms, and each arm includes —CH 2 CH 2 (OCH 2 CH 2 ) n2 —, (38) to (45) Or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating hyperparathyroidism comprising the polyethylene glycol derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (46).
  • the pharmaceutical composition according to (47), wherein the hyperparathyroidism is primary hyperparathyroidism.
  • an intravenous formulation can be obtained by acquiring water solubility by adding polyethylene glycol.
  • the present invention is a polyethylene glycol derivative of 4- (3S- (1R- (1-naphthyl) ethylamino) pyrrolidin-1-yl) phenylacetic acid (evocalcet) or a pharmaceutically acceptable salt thereof.
  • one or more 4- (3S- (1R- (1-naphthyl) ethylamino) pyrrolidin-1-yl) phenylacetic acid moieties are linked directly or with one or more polyethylene glycol moieties.
  • a pharmaceutically acceptable salt thereof means a structure including, for example, — (OCH 2 CH 2 ) N — (where N represents an integer).
  • the 4- (3S- (1R- (1-naphthyl) ethylamino) pyrrolidin-1-yl) phenylacetic acid moiety is, for example, a structure of the above formula (B) or formula (C) or a structure of the following formula: means. (In the formula, * represents a bonding point, and R a represents a hydrogen atom or an optionally substituted lower alkyl).
  • a polyethylene glycol derivative represented by the following formula (A) or a pharmaceutically acceptable salt thereof:
  • POLY represents a non-multi-armed polyethylene glycol residue or a multi-armed polyethylene glycol residue, where The non-multi-arm type polyethylene glycol is represented by a residue — (CH 2 CH 2 O) n1 -M, where n1 is an integer of 10 to 1,000, and M is a hydrogen atom or an optionally substituted lower group.
  • A1 represents the following formula (B): (Where * Represents the point of attachment, X a represents an X 1a X 2a, where X 1a is a bond, an oxygen atom, (wherein, R 0a represents a lower alkyl which may optionally be a hydrogen atom or a substituent) a sulfur atom or NR 0a represent , X 2a is a bond, optionally substituted lower alkylene, the following formula: [In the formula, Z represents CO or NR 1a (wherein R 1a represents a hydrogen atom or an optionally substituted lower alkyl), and Y 1A and Y 1B are the same or different and are bonded or substituted.
  • L (eg as a linker)
  • L (eg as a linker)
  • L 1A represents a bond, an oxygen atom, a sulfur atom, OCH 2 , or NR 11a (wherein R 11a represents a hydrogen atom or an optionally substituted lower alkyl, or R 11a is bonded to L 2A.
  • L 2A is a bond, an optionally substituted lower alkylene, an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted.
  • L 3A is a bond, an optionally substituted lower alkylene, an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted
  • Y 2A and Y 2B are the same or different and may be bonded, substituted lower alkylene, nitrogen atom, oxygen atom, sulfur atom or NR 13a (wherein R 13a is a hydrogen atom or substituted Represents an optionally substituted
  • L 3B represents a bond or optionally substituted lower alkylene
  • L 4B represents a bond, an oxygen atom, an optionally substituted lower alkylene, or a linker represented by the following formula: [Wherein Y 3A and Y 3B are the same or different and may be bonded, substituted lower alkylene, oxygen atom, sulfur atom or NR 15a (wherein R 15a may be hydrogen atom or substituted) Represents a good lower alkyl)], L 5B represents a bond, an oxygen atom, or an optionally substituted lower alkylene), or (iii) the following formula (F): (Where * Represents the point of attachment to A1, ** represents the point of attachment with POLY, L 1C represents a bond, an optionally substituted lower alkylene, or the following formula: (Wherein X 5a represents an oxygen atom, a sulfur atom, or NR 16a (wherein R 16a represents a linker represented by the following formula: [Wherein Y 3A and
  • each R 18a and R 19a may be the same or different), or the following formula:
  • Y 4 is an optionally substituted lower alkylene, an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted And
  • Y 5 represents a bond or NR 20a (wherein R 20a represents a hydrogen atom or an optionally substituted lower alkyl))
  • L 4C represents a bond, an oxygen atom, an optionally substituted lower alkylene, the following formula: (Wherein Y 6 represents an optionally substituted lower alkylene) Or the following formula: (Wherein n5 represents an integer of 0 to 5, n6 represents an integer of 1 to 10, and R 21a represents a hydrogen atom or an optionally substituted lower alkyl)) or (iv) G): (Where * Represents the point of attachment to A1, ** represents the point of attachment with POLY, L 1D is
  • each L 1D may be the same or different,
  • Each linker may be a linker linked via the following formula: [Wherein, X 7a represents an oxygen atom, a sulfur atom, or NR 24a (wherein R 24a represents a hydrogen atom or lower alkyl)], L 3D represents a bond, an oxygen atom, an optionally substituted lower alkyl, or the following formula: (Wherein Y 7 represents an optionally substituted lower alkylene)), m represents an integer of 1 to 20, and l represents an integer of 1 to 20.]
  • the multi-arm type polyethylene glycol residue is a polyethylene glycol residue having a plurality of arms, such as 2-arm-polyethylene glycol (2-arm-PEG), 4-arm.
  • -Polyethylene glycol (4-arm-PEG) and 8-arm-polyethylene glycol (8-arm-PEG) have the following structures (wherein n is between 10 and 1000, May be the same or different).
  • a multi-arm type polyethylene glycol residue can introduce a plurality of evocalcet or a pharmaceutically acceptable salt thereof into one molecule, and a polyhydric alcohol corresponding to the desired number of functional groups is used as a raw material. It is common.
  • 3-arm type is ring-opening polymerization of ethylene oxide using glycerin or the like as raw material
  • 4-arm type is pentaerythritol or the like
  • 6-arm type or 8-arm type polyethylene glycol is tetraglycerin or hexaglycerin.
  • Such a polyglycerol is known as a low molecular weight raw material.
  • ⁇ represents the point of attachment with [(A1) m -L] l-in the above formula (A)).
  • the non-multi-arm type polyethylene glycol residue is a polyethylene glycol residue having no branched structure, and is preferably represented by — (CH 2 CH 2 O) n1 —M, where n1 is an integer of 10 to 1000 And M represents a hydrogen atom or an optionally substituted lower alkyl.
  • lower alkyl represents, for example, linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, Represents tert-butyl, cyclobutyl, pentyl, isopentyl, neopentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl and the like.
  • the lower alkyl moiety in lower alkoxy has the same meaning as the lower alkyl.
  • lower alkylene in lower alkylene and lower alkyleneoxy represents, for example, linear or branched alkylene having 1 to 10 carbon atoms, and more specifically, methylene, ethylene, trimethylene, propylene, tetramethylene, pentane. Methylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like are represented.
  • the cycloalkylene includes, for example, a group obtained by removing one hydrogen atom from a cycloalkyl having 3 to 8 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Represents a group obtained by removing one hydrogen atom from
  • aryl includes, for example, aryl having 6 to 14 carbon atoms, and more specifically represents phenyl, naphthyl, azulenyl, anthryl and the like.
  • Arylene is a group obtained by removing one hydrogen atom from the aryl.
  • the aromatic heterocyclic diyl represents a group obtained by removing one hydrogen atom from an aromatic heterocyclic group.
  • the aromatic heterocyclic group for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is condensed.
  • the aliphatic heterocyclic diyl represents a group obtained by removing one hydrogen atom from an aliphatic heterocyclic group.
  • the aliphatic heterocyclic group for example, a 5- or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is condensed.
  • the lower alkyl which may be substituted, the lower alkylene which may be substituted, the lower alkyleneoxy which may be substituted, and the lower alkoxy which may be substituted may be the same or different.
  • optionally substituted aryl, optionally substituted arylene, and optionally substituted aromatic heterocyclic diyl may have the same or different substituents.
  • substituents for example, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 1-10 alkyl, trifluoromethyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic hetero, having 1 to 3 substitutions Ring group, aromatic heterocyclic group, C 1-10 alkoxy, C 3-8 cycloalkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR Xa R Ya (wherein R Xa and R Ya are the same or different and represent a hydrogen atom; , C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, aromatic heterocyclic group
  • the cycloalkylene which may have a substituent and the substituent in the aliphatic heterocyclic diyl which may have a substituent may be the same or different, for example, having 1 to 3 substituents.
  • the two C 1-10 alkyl moieties in the diC 1-10 alkylcarbamoyl may be the same or different.
  • Examples of the aryl moiety of C 6-14 aryl, C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples. .
  • Examples of the aryl moiety of C 7-16 aralkyloxy, C 7-16 aralkyl, and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above aryl examples, and examples of the alkyl moiety include, for example, C 1-10 Examples thereof include alkylene, and more specifically, examples thereof include the groups exemplified in the lower alkylene.
  • aromatic heterocyclic group examples include the groups given as examples of the aromatic heterocyclic group.
  • Examples of the aliphatic heterocyclic group include the groups exemplified in the above-mentioned aliphatic heterocyclic group.
  • the linker which is a group having 2 to 5 bonds is, for example, a linker having the following 3 bonds:
  • These linkers may be connected to a plurality of linkers (preferably 2 to 10, more preferably 2 to 6, more preferably 3) directly or via the following structure:
  • X 10a represents an oxygen atom, a sulfur atom, or NR 4 (wherein R 4 represents a hydrogen atom or lower alkyl), and preferably represents an oxygen atom].
  • Examples of the linker in which a plurality of the above-mentioned linkers are connected directly or via the above-described structure include the following linkers.
  • the linker containing three nitrogen atoms may be expressed as follows.
  • A1 represents the above formula (B)
  • X 1a and X 2a are both a bond
  • L represents the above formula (D).
  • a derivative or a pharmaceutically acceptable salt thereof (hereinafter referred to as “polyethylene glycol derivative A”) is provided.
  • POLY may be either a non-multi-arm polyethylene glycol residue or a multi-arm polyethylene glycol residue. (CH 2 CH 2 O) n1 -M) is preferred.
  • M is preferably lower alkyl, and more preferably methyl.
  • n1 or n2 is preferably an integer of 10 to 1000, more preferably an integer of 200 to 1000.
  • n1 is preferably an integer of 10 to 1000, more preferably an integer of 200 to 1000.
  • l is preferably 1 to 20, more preferably 1 to 10, and further preferably 1.
  • m is preferably 1.
  • l is preferably 1 and n1 is preferably an integer of 10 to 800, more preferably 1 is 1 and n1 is an integer of 200 to 800.
  • L 1A is preferably a bond or an oxygen atom.
  • L 1A is a bond, an oxygen atom, or OCH 2 ;
  • L 2A is substituted, optionally substituted, lower alkylene, substituted by a 5- or 6-membered monocyclic aliphatic heterocyclic group containing a nitrogen atom, a 5- or 6-membered cycloalkylene, or a lower alkyl group Arylene, optionally substituted aromatic heterocyclic diyl, or the following formula:
  • R 3a represents a hydrogen atom
  • L 3A represents a bond, an optionally substituted lower alkylene, or the following formula:
  • Y 2A represents a bond or NR 13a (wherein R 13a represents a hydrogen atom or an optionally substituted lower alkyl)
  • Y 2B represents an unsubstituted lower alkylene (preferably methylene).
  • L 4A represents a bond or an oxygen atom.
  • L 1A is a bond or OCH 2 and L 2A is a bond, Or the following formula: (Wherein Y 4A and Y 4B are the same or different and may be bonded, substituted lower alkylene, oxygen atom, sulfur atom or NR 25a (wherein R 25a may be hydrogen atom or substituted) Represents a good lower alkyl)), And L 4A is an oxygen atom.
  • POLY is a non-multi-armed polyethylene glycol residue
  • L 1A represents unsubstituted lower alkylene (preferably methylene)
  • L 2A is an aromatic heterocyclic diyl (preferably represents the following formula:
  • L 3A is unsubstituted lower alkylene (preferably ethylene)
  • L 4A is an oxygen atom.
  • POLY is a non-multi-arm type polyethylene glycol residue
  • L 1A is an oxygen atom
  • any of L 2A , L 3A , and L 4A is a bond.
  • POLY is a non-multi-armed polyethylene glycol residue
  • L 1A is an oxygen atom
  • L 2A is an optionally substituted lower alkylene (preferably ethylene), wherein the lower alkylene is methyl, isopropyl (iPr), isobutyl (i-Bu), tert-butyl (tBu), or aryl Preferably substituted with one or two of (more preferably phenyl or benzyl)
  • L 3A represents the following formula: [Wherein Y 2A represents NR 13a (wherein R 13a represents a hydrogen atom or an optionally substituted lower alkyl), and Y 2B represents an unsubstituted lower alkylene (preferably methylene)]
  • L 4A is an oxygen atom.
  • POLY is a non-multi-armed polyethylene glycol residue
  • L 1A is an oxygen atom
  • L 2A contains a nitrogen atom (preferably contains one)
  • a 5-membered or 6-membered unsubstituted monocyclic aliphatic heterocyclic diyl preferably a pyrrolidinediyl group or piperidinediyl group
  • L 3A represents the following formula: [ Wherein Y 2A represents a bond and Y 2B represents an unsubstituted lower alkylene (preferably methylene)], L 4A is an oxygen atom.
  • POLY is a non-multi-armed polyethylene glycol residue
  • L 1A is an oxygen atom
  • L 2A is a 5- or 6-membered cycloalkylene
  • L 3A represents the following formula: [Wherein Y 2A represents NR 13a (wherein R 13a represents a hydrogen atom or an optionally substituted lower alkyl), and Y 2B represents an unsubstituted lower alkylene (preferably methylene)]
  • L 4A is an oxygen atom.
  • POLY is a non-multi-armed polyethylene glycol residue
  • L 1A is an oxygen atom
  • L 2A is arylene (preferably phenylene) substituted by lower alkyl (preferably methyl)
  • L 3A represents the following formula: [Wherein Y 2A represents NR 13a (wherein R 13a represents a hydrogen atom or an optionally substituted lower alkyl), and Y 2B represents an unsubstituted lower alkylene (preferably methylene)]
  • L 4A is an oxygen atom.
  • POLY is a non-multi-armed polyethylene glycol residue
  • L 1A is a bond
  • L 2A represents the following formula: (Wherein R 3a represents a hydrogen atom)
  • L 3A represents the following formula: [Wherein Y 2A represents NR 13a (wherein R 13a represents a hydrogen atom or an optionally substituted lower alkyl), and Y 2B represents an unsubstituted lower alkylene (preferably methylene)]
  • L 4A is an oxygen atom.
  • POLY is a non-multi-arm polyethylene glycol residue or a multi-arm polyethylene glycol residue (preferably 4-arm-polyethylene glycol or 8-arm-polyethylene glycol),
  • l represents an integer of 2 to 8 (preferably 4 or 8)
  • L 1A is a bond
  • L 2A represents the following formula: (Wherein R 3a represents a hydrogen atom)
  • L 3A represents the following formula: [ Wherein Y 2A represents a bond, Y 2B represents unsubstituted lower alkylene (preferably methylene)], and L 4A represents an oxygen atom.
  • L 2A having the following structure is a preferred embodiment:
  • POLY is a non-multi-armed polyethylene glycol residue
  • L 1A is a bond
  • L 2A represents the following formula:
  • L 3A represents the following formula: [ Wherein Y 2A represents a bond and Y 2B represents an unsubstituted lower alkylene (preferably methylene)],
  • L 4A is an oxygen atom.
  • Polyethylene glycol derivative B According to another preferred embodiment of the present invention, in the above formula (A), A1 represents the above formula (B), X 1a and X 2a are not simultaneously bonded, and L represents the above formula (E).
  • a polyethylene glycol derivative (hereinafter referred to as “polyethylene glycol derivative B”) is provided.
  • POLY may be either a non-multi-arm polyethylene glycol residue or a multi-arm polyethylene glycol residue, but is a multi-arm polyethylene glycol residue. Is preferred.
  • POLY is a multi-arm polyethylene glycol, it preferably has 2 to 15 arms, more preferably 3 to 8 arms, and even more preferably 4 or 8 arms.
  • each arm includes — (OCH 2 CH 2 ) n2 —, and n2 may be the same or different and is an integer of 10 to 1000, preferably It is an integer from 100 to 400.
  • l is preferably 1 to 20, more preferably 1 to 10, and further preferably an integer of 2 to 8. l may correspond to the number of arms when POLY is a multi-arm polyethylene glycol residue.
  • m is preferably 1 or 2.
  • L 1B preferably represents a nitrogen atom or the following formula: [ Wherein X 8a represents an oxygen atom].
  • L 2B preferably represents a linker that is a group having 2 to 5 bonds, more preferably a linker that is a heterocyclic group having 3 bonds, and more preferably Represents any linker of the formula:
  • each m1 is an integer of 2 to 4
  • each L 1B may be the same or different, but more preferably a linker in which L 2B is a group having three bonds , M1 is 2, and each L 1B is the same.
  • L 2B represents the following formula:
  • L 3B represents a bond
  • L 4B represents the following formula: [ Wherein Y 5A and Y 5B are the same or different and each represents an optionally bonded or substituted lower alkylene], and L 5B represents an oxygen atom.
  • X 1a in the formula (B) is a bond or an oxygen atom.
  • X 2a in the formula (B) is represented by the following formula: (Where Y 6A represents a bond; Y 6B represents an optionally substituted cycloalkylene, an optionally substituted arylene, an optionally substituted aromatic heterocyclic diyl, or an optionally substituted aliphatic heterocyclic diyl. Y 6A is preferably bonded to L), or represents the following formula:
  • POLY is a multi-armed polyethylene glycol residue (preferably 4-arm-polyethylene glycol or 8-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 4 or 8), X 1a in formula (B) is a bond; X 2a in formula (B) represents the following formula: (Wherein R 3a represents a hydrogen atom), L 1B represents the following formula: [ Wherein X 4a represents an oxygen atom], m1 is an integer of 2 to 4 (preferably 2), L 2B represents a linker of the formula: L 3B is a bond, L 4B represents the following formula: [ Wherein Y 3A represents a bond and Y 3B represents an unsubstituted lower alkylene (preferably methylene)], L 5B is an oxygen atom.
  • A1 represents the above formula (C)
  • Y 1 , Y 2 and Y 3 are simultaneously a bond
  • L is the above formula (F).
  • a polyethylene glycol derivative (hereinafter referred to as “polyethylene glycol derivative C”) is provided.
  • POLY may be either a non-multi-arm polyethylene glycol residue or a multi-arm polyethylene glycol residue. (CH 2 CH 2 O) n1 -M) is preferred. Further, when POLY is a non-multi-arm type polyethylene glycol residue, M is preferably lower alkyl.
  • n1 or n2 is preferably an integer of 50 to 1000, more preferably an integer of 200 to 800.
  • n1 is preferably an integer of 50 to 1000, more preferably an integer of 200 to 800.
  • l is preferably 1 to 20, more preferably 1 to 10, and further preferably an integer of 1 to 8.
  • m is preferably 1.
  • m is 1 and l is an integer of 1 to 8.
  • L 1C is represented by the following formula:
  • L 2C is represented by the following formula: (Wherein R 27 represents a hydrogen atom or an optionally substituted lower alkyl).
  • L 3C is represented by the following formula: (In the formula, n9 represents an integer of 1 to 5, R 28 represents a hydrogen atom or an optionally substituted lower alkyl, and R 29 represents a hydrogen atom, an optionally substituted lower alkyl, or a substituted alkyl. And when n9 is an integer of 2 to 5, each R 28 and R 29 may be the same or different.
  • L 3C is represented by the following formula: (In the formula, n9 represents an integer of 2, R 28a represents a hydrogen atom, and R 29a represents an optionally substituted lower alkyl).
  • R 29a is isopropyl or propyl substituted by the following formula:
  • L 3C is represented by the following formula: (In the formula, n9 represents 1, R 28a represents a hydrogen atom, R 29a represents an optionally substituted lower alkyl or an optionally substituted aryl. The terminal on the nitrogen atom side is bonded to L 4C . Preferably).
  • R 29a represents an optionally substituted lower alkyl.
  • R 29a represents lower alkyl
  • L 4C is represented by the following formula: (In the formula, Y 8 represents an optionally substituted lower alkylene).
  • Y 8 is methylene
  • L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents a hydrogen atom or unsubstituted lower alkyl (preferably methyl or isopropyl)), L 3C is a bond, the following formula: (Wherein n4 represents 1 or 2, R 18a represents a hydrogen atom, R 19a represents a hydrogen atom, optionally substituted lower alkyl (preferably methyl, isopropyl (iPr), isobutyl (i-Bu ), Tert-butyl (tBu)), or aryl (preferably benzyl)), or the following formula: (Wherein Y 4 represents a 5- or 6-membered monocyclic aliphatic heterocyclic diyl containing a nitrogen atom, or a 4-membered monocyclic aliphatic heterocyclic diyl containing an oxygen atom, having 1 to 5 carbon atoms) Lower
  • L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents a hydrogen atom or unsubstituted lower alkyl (preferably methyl or isopropyl)), L 3C represents the following formula: (Wherein n4 represents 1, R 18a represents a hydrogen atom, R 19a represents a hydrogen atom, an unsubstituted lower alkyl (preferably methyl, isopropyl (iPr), isobutyl (i-Bu), tert-butyl). (TBu)), or unsubstituted aryl (preferably benzyl)) and L 4C represents the following formula: (Wherein Y 6 represents unsubstituted lower alkylene (preferably methylene)).
  • L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents unsubstituted lower alkyl (preferably methyl)), L 3C represents the following formula: (Wherein Y 4 includes a nitrogen atom (preferably includes one), a 5-membered or 6-membered unsubstituted monocyclic aliphatic heterocyclic diyl, or an oxygen atom (preferably includes one).
  • L 4C represents the following formula: (Wherein Y 6 represents unsubstituted lower alkylene (preferably methylene)).
  • L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents unsubstituted lower alkyl (preferably methyl)), L 3C represents the following formula: (Wherein Y 4 represents lower alkylene having 1 to 5 carbon atoms, 4- to 6-membered (preferably 5-membered) cycloalkylene, and Y 5 represents NH), L 4C represents the following formula: (Wherein Y 6 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a multi-arm type polyethylene glycol residue (preferably 4-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 4), L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents unsubstituted lower alkyl (preferably methyl or isopropyl)), L 3C represents the following formula: (Wherein n4 represents 1, R 18a represents a hydrogen atom, R 19a represents unsubstituted lower alkyl (preferably isopropyl (iPr) or isobutyl (i-Bu)), and L 4C is Represents the following formula: (Wherein Y 6 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a multi-arm type polyethylene glycol residue (preferably 4-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 4), L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents a hydrogen atom or an unsubstituted lower alkyl (preferably isopropyl)), L 3C represents the following formula: (Wherein n4 represents 1, R 18a represents a hydrogen atom, R 19a represents a hydrogen atom or unsubstituted lower alkyl (preferably isopropyl (iPr)), and L 4C represents the following formula: : (In the formula, n5 represents 1, n6 represents 2, and R 21a represents a hydrogen atom).
  • POLY is a multi-armed polyethylene glycol residue (preferably 4-arm-polyethylene glycol or 8-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 4 or 8), L 1C represents the following formula: ( Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents unsubstituted lower alkyl (preferably isopropyl)), L 3C is a bond, and L 4C represents the following formula: (In the formula, n5 represents 1, n6 represents 2, and R 21a represents a hydrogen atom).
  • POLY is a multi-armed polyethylene glycol residue (preferably 4-arm-polyethylene glycol or 8-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 4 or 8), L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents unsubstituted lower alkyl (preferably isopropyl)), L 3C represents the following formula: (Wherein n4 represents 2, R 18a represents a hydrogen atom, and R 19a represents an optionally substituted lower alkyl (preferably isopropyl or propyl substituted by the following formula: ) And L 4C represents the following formula: (Wherein Y 6 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a multi-arm type polyethylene glycol residue (preferably 8-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 8), L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents unsubstituted lower alkyl (preferably isopropyl)), L 3C represents the following formula: (Wherein n4 represents 1, R 28a represents a hydrogen atom, R 29a represents an optionally substituted lower alkyl (preferably represents isopropyl), and L 4C represents the following formula: (Wherein Y 6 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a multi-arm type polyethylene glycol residue (preferably 8-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 8), L 1C represents the following formula: (Wherein X 5a represents an oxygen atom), L 2C represents the following formula: (Wherein R 17a represents a hydrogen atom or an unsubstituted lower alkyl (preferably isopropyl)), L 3C represents the following formula: (Wherein n4 represents 1, R 18a represents a hydrogen atom, R 19a represents a hydrogen atom or an unsubstituted lower alkyl (preferably represents isopropyl), and L 4C represents the following formula: (In the formula, n5 represents 1, n6 represents 2, and R 21a represents a hydrogen atom).
  • Polyethylene glycol derivative D According to another preferred embodiment of the present invention, in the above formula (A), A1 represents the above formula (C), Y 1 , Y 2 and Y 3 are not simultaneously a bond, and L is the above formula (G).
  • a polyethylene glycol derivative (hereinafter referred to as “polyethylene glycol derivative D”) is provided.
  • n1 or n2 is preferably an integer of 100 to 1000, more preferably an integer of 200 to 800.
  • m is preferably an integer of 2 to 8, more preferably an integer of 2 to 4.
  • l is preferably 1 to 8, more preferably 2, 4 or 8 and POLY is a multi-arm type polyethylene glycol residue.
  • Y 1 is the following formula:
  • Y 2 is the following formula: (Wherein R 5 represents lower alkyl).
  • Y 3 is represented by the following formula: (Wherein n3 represents an integer of 1, R 9 represents a hydrogen atom or optionally substituted lower alkyl, and R 10 represents a hydrogen atom).
  • L 1D is the following formula: [ Wherein X 9a represents an oxygen atom].
  • L 1D is the following formula: (In the formula, n11 represents 0, n12 represents 2, and R 32a represents a hydrogen atom).
  • L 2D represents a linker which is preferably a group having 2 to 5 bonds, and more preferably a heterocyclic ring having 3 bonds Represents a linker which is a group, more preferably any linker of the following formula:
  • each L 2D is a linker that is a group having two bonds
  • m2 is 1, and L 2D is a group having 3 to 5 bonds.
  • each m2 is an integer of 2 to 4
  • each L 2D may be the same or different, but more preferably a linker in which L 2D is a group having three bonds , M2 is 2, and each L 1D is the same.
  • L 3D is represented by the following formula: (Wherein Y 9 represents methylene).
  • Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom], Y 2 represents the following formula: (Wherein R 5a represents a hydrogen atom or an unsubstituted lower alkyl (preferably methyl or isopropyl)), Y 3 represents a bond or the following formula: (Wherein n3 represents 1, R 9a represents an unsubstituted lower alkyl (preferably isopropyl, isobutyl, or cyclopropyl), R 10a represents a hydrogen atom, or R 9a and R 10a together To form a 6-membered aliphatic heterocyclic diyl containing a nitrogen atom)) L 1D is a bond, the following formula: [ Wherein X 6a represents an oxygen atom] or the following formula: (Wherein n7 represents 0, n8 represents an integer of 1 to 10, and R 23a represents a hydrogen atom), m2 is an integer from 2 to 4, L 2D
  • POLY is a non-multi-arm polyethylene glycol residue or a multi-arm polyethylene glycol residue (preferably 8-arm-polyethylene glycol), and
  • l represents an integer of 2 to 8 (preferably 8)
  • Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom]
  • Y 2 represents the following formula: (Wherein R 5a represents a hydrogen atom or an unsubstituted lower alkyl (preferably methyl or isopropyl)), Y 3 is a bond
  • L 1D represents the following formula: [ Wherein X 6a represents an oxygen atom], m2 is 2,
  • L 2D represents the following formula:
  • L 3D represents the following formula: (Wherein Y 7 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a non-multi-arm polyethylene glycol residue or a multi-arm polyethylene glycol residue (preferably 4-arm-polyethylene glycol or 8-arm-polyethylene glycol),
  • l represents an integer of 2 to 8 (preferably 4 or 8)
  • Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom]
  • Y 2 represents the following formula: (Wherein R 5a represents a hydrogen atom or an unsubstituted lower alkyl (preferably methyl or isopropyl)),
  • Y 3 represents the following formula: (Wherein n3 represents 1, R 9a represents an unsubstituted lower alkyl (preferably isopropyl, isobutyl, or cyclopropyl),
  • R 10a represents a hydrogen atom, or R 9a and R 10a together
  • a 6-membered aliphatic heterocyclic diyl containing nitrogen atom preferably isopropyl, or R 9a and R 10a together
  • POLY is a non-multi-armed polyethylene glycol residue
  • Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom]
  • Y 2 represents the following formula: (Wherein R 5a represents a hydrogen atom or an unsubstituted lower alkyl (preferably methyl or isopropyl)), Y 3 is a bond
  • L 1D represents the following formula: [ Wherein X 6a represents an oxygen atom], m2 is 4, L 2D represents the following formula:
  • L 3D represents the following formula: (Wherein Y 7 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a non-multi-arm polyethylene glycol residue or a multi-arm polyethylene glycol residue (preferably 4-arm-polyethylene glycol);
  • l represents an integer of 2 to 8 (preferably 4)
  • Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom]
  • Y 2 represents the following formula: (Wherein R 5a represents unsubstituted lower alkyl (preferably methyl)), Y 3 is a bond, L 1D is a bond, m2 is 2, L 2D represents the following formula:
  • L 3D represents the following formula: (Wherein Y 7 represents unsubstituted lower alkylene (preferably methylene)).
  • Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom], Y 2 represents the following formula: (Wherein R 5a represents unsubstituted lower alkyl (preferably isopropyl)), Y 3 represents the following formula: (Wherein n3 represents 1, R 9a represents unsubstituted lower alkyl (preferably isopropyl), and R 10a represents a hydrogen atom), L 1D represents the following formula: [ Wherein X 6a represents an oxygen atom], m2 is 2, L 2D represents the following formula: L 3D represents the following formula: (Wherein Y 7 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a multi-arm type polyethylene glycol residue (preferably 2-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 2), Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom], Y 2 represents the following formula: (Wherein R 5a represents unsubstituted lower alkyl (preferably methyl or isopropyl)), Y 3 represents a bond or the following formula: (Wherein n3 represents 1, R 9a represents an optionally substituted lower alkyl (preferably isopropyl), and R 10a represents a hydrogen atom), L 1D represents the following formula: [ Wherein X 6a represents an oxygen atom], m2 is an integer from 2 to 4, L 2D represents the following formula: L 3D represents the following formula: (Wherein Y 7 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a multi-arm type polyethylene glycol residue (preferably 4-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 4), Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom], Y 2 represents the following formula: (Wherein R 5a represents unsubstituted lower alkyl (preferably isopropyl)), Y 3 represents the following formula: (Wherein n3 represents 1, R 9a represents unsubstituted lower alkyl (preferably isopropyl), and R 10a represents a hydrogen atom), L 1D represents the following formula: [ Wherein X 6a represents an oxygen atom], m2 is 2, L 2D represents the following formula: L 3D represents the following formula: (Wherein Y 7 represents unsubstituted lower alkylene (preferably methylene)).
  • POLY is a multi-arm type polyethylene glycol residue (preferably 4-arm-polyethylene glycol), l represents an integer of 2 to 8 (preferably 4), Y 1 represents the following formula: [ Wherein X 3a represents an oxygen atom], Y 2 represents the following formula: (Wherein R 5a represents unsubstituted lower alkyl (preferably isopropyl)), Y 3 represents the following formula: (Wherein n3 represents 1, R 9a represents an unsubstituted lower alkyl (preferably an isopropyl group), and R 10a represents a hydrogen atom), L 1D represents the following formula: (Wherein n7 represents 0, n8 represents an integer of 1 to 10, and R 23a represents a hydrogen atom), m2 is 2, L 2D represents the following formula: L 3D represents the following formula: (Wherein Y 7 represents unsubstituted lower alkylene (preferably methylene)).
  • Polyethylene glycol derivative E According to another preferred embodiment of the present invention, there is provided a polyethylene glycol derivative (hereinafter referred to as “polyethylene glycol derivative E”) in which A1 represents the above formula (B) and L represents the above formula (E). .
  • POLY is a multi-arm type polyethylene glycol residue, m is 1, and l is 8.
  • X 1a is a bond and X 2a represents the following formula: (Wherein R 3a represents a hydrogen atom).
  • L 2B preferably represents a linker which is a group having 2 to 5 bonds, and more preferably represents any linker of the following formula :
  • a linker in which the azabicyclo [2.2.1] heptane ring is connected via a carbonyl or the like is also suitable, and examples thereof are shown below.
  • “pharmaceutically acceptable salt” includes, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, and fumarate.
  • Organic acid salts such as citrate, benzoate, methanesulfonate, and the like
  • pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, magnesium salt, calcium Examples thereof include alkaline earth metal salts such as salts, aluminum salts, and zinc salts.
  • pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium, and pharmaceutically acceptable organic salts.
  • the amine addition salt include addition salts such as morpholine and piperidine.
  • the pharmaceutically acceptable amino acid addition salt include lysine and glycine. Phenylalanine, aspartic acid, addition salts, such as glutamic acid, and the like.
  • polyethylene glycol derivatives of evocalcet or pharmaceutically acceptable salts thereof may have stereoisomers such as geometric isomers and optical isomers, tautomers, and the like. Including these, all possible isomers and mixtures thereof are included.
  • each atom in the polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof may be replaced with the corresponding isotope atom, and the present invention relates to polyethylene substituted with these isotope atoms. Also included are glycol derivatives.
  • the polyethylene glycol derivative of evocalcet of the present invention or a pharmaceutically acceptable salt thereof is a polyethylene glycol derivative of an active metabolite of evocalcet (for example, various conjugates are included as active metabolites) or a pharmaceutically acceptable salt thereof. Also included are acceptable salts.
  • the production method of the compound of the present invention will be described below.
  • introduction of a protective group commonly used in organic synthetic chemistry, And removal methods e.g., Protective Groups in Organic Synthesis, third edition, written by TW Greene, John Wiley & Sons Inc. (1999), etc.
  • the target compound can be produced by using the above method. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
  • R 4 is a linker
  • R 6 is selected from the group consisting of ethyl, benzyl or tert-butyl
  • R 7 is selected from the group consisting of chain or cycloalkyl
  • R 8 and R 9 are hydrogen
  • P is selected from the group consisting of tert-butoxycarbonyl or benzyloxycarbonyl
  • X represents a halogen atom
  • Compound (b-3) is compound (b-1) and 0.5 to 5 equivalents of compound (b-2) added in the presence of 1 to 5 equivalents of a condensing agent in a solvent, if necessary in an amount of 1 to 5 equivalents. It can be produced by reacting in the presence of an agent at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • Examples of the condensing agent include 1,3-dicyclohexanecarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (EDC), carbonyldiimidazole (CDI), 2-chloroiodide -1-methylpyridinium, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), O- (7-azabenzotriazole-1 -Yl) -N, N, N ', N'-tetramethyluronium ⁇ hexafluorophosphate (HATU), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexa Examples thereof include fluorophosphate (COMU).
  • DCC 1,3-dicyclohex
  • additives examples include 1-hydroxybenzotriazole monohydrate (HOBt), triethylamine (TEA), N, N-diisopropylethylamine (DIPEA) and the like.
  • HOBt 1-hydroxybenzotriazole monohydrate
  • TEA triethylamine
  • DIPEA N-diisopropylethylamine
  • solvent examples include methanol, ethanol, dichloromethane (DCM), chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), dioxane, N , N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), pyridine, water and the like, and these may be used alone or in combination.
  • DCM dichloromethane
  • chloroform 1,2-dichloroethane
  • toluene ethyl acetate
  • acetonitrile diethyl ether
  • THF tetrahydrofuran
  • DME 1,2-dimethoxyethane
  • dioxane N , N-dimethylformamide (DMF), N, N-
  • Compound (b-1) can be obtained by a known method [WO2015 / 034031, paragraphs 20-24] or a method analogous thereto.
  • Compound (b-2) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • compound (b-3) is compound (b-1) in the presence of a large excess of compound (b-2), without solvent, or in a solvent, preferably 1 equivalent to a large excess of acid. It can also be produced by treating at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid (TFA), p-toluenesulfonic acid (TsOH), methanesulfonic acid, titanium tetrachloride, boron trifluoride and the like. Or mixed.
  • solvent examples include DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP and the like. These may be used alone or in combination. It is done.
  • Compound (b-5) is compound (b-3) and 0.5 to 5 equivalents of compound (b-4) in the presence of 1 to 5 equivalents of an additive at -20 ° C and the boiling point of the solvent used. By reacting at a temperature between 5 minutes and 96 hours.
  • additives examples include TEA and DIPEA.
  • solvent examples include DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine and the like. These may be used alone or in combination. Used.
  • Compound (b-4) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • Compound (b-7) is compound (b-6) and 0.5 to 5 equivalents of compound (b-4) in the presence of 1 to 5 equivalents of an additive at ⁇ 20 ° C. and the boiling point of the solvent used. By reacting at a temperature between 5 minutes and 96 hours.
  • additives examples include TEA and DIPEA.
  • solvent examples include DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine and the like. These may be used alone or in combination. Used.
  • Compound (b-6) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • Compound (b-8) is a solvent in which when P is tert-butylcarbonyl, the compound (b-8) is used at 0 ° C. without solvent or in a solvent, preferably in the presence of 1 equivalent to a large excess of acid. It can be produced by treating at a temperature between the boiling point of 5 minutes to 96 hours.
  • Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, TFA, p-toluenesulfonic acid, methanesulfonic acid, titanium tetrachloride, boron trifluoride, and the like. These may be used alone or in combination.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, and the like. Used as a mixture.
  • the compound (b-8) when P is a benzyloxycarbonyl group, the compound (b-8) is used in a solvent, in a hydrogen atmosphere or in the presence of a hydrogen source, in the presence of a catalyst, between -20 ° C and the boiling point of the solvent used. It can be produced by treating at normal temperature or under pressure for 5 minutes to 72 hours.
  • the catalyst examples include palladium carbon, palladium, palladium hydroxide, palladium acetate, palladium black and the like, and these are preferably used in an amount of 0.01 to 200% by weight based on the compound (b-8).
  • hydrogen source examples include formic acid, ammonium formate, sodium formate, cyclohexadiene, hydrazine and the like, and these are preferably used in an amount of 2 equivalents to a large excess with respect to compound (b-8).
  • solvent examples include methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, water and the like, and these can be used alone or in combination.
  • Compound (b-9) is compound (b-8) and 0.001 to 5 equivalents of compound (a-5) added in the presence of 1 to 1000 equivalents of a condensing agent in a solvent and 1 to 5 equivalents as necessary. In the presence of the agent, the reaction can be carried out at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-5) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • R 6 is a tert-butyl group
  • the compound (b-10) is used at 0 ° C. without solvent or in a solvent, preferably in the presence of 1 equivalent to a large excess of acid. It can be produced by treating at a temperature between the boiling point of the solvent and 5 minutes to 96 hours.
  • Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, TFA, TsOH, methanesulfonic acid, titanium tetrachloride, boron trifluoride, and the like. These may be used alone or in combination.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, and the like. Used as a mixture.
  • the temperature between -20 ° C. and the boiling point of the solvent used in the presence of a catalyst in the presence of a hydrogen source or in the presence of a catalyst in the presence of a compound (b-9) in a solvent can be produced by treating at normal pressure or under pressure for 5 minutes to 72 hours.
  • the catalyst examples include palladium carbon, palladium, palladium hydroxide, palladium acetate, palladium black and the like, and these are preferably used in an amount of 0.01 to 200% by weight based on the compound (b-8).
  • hydrogen source examples include formic acid, ammonium formate, sodium formate, cyclohexadiene, hydrazine and the like, and these are preferably used in an amount of 2 equivalents to a large excess with respect to compound (b-8).
  • solvent examples include methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, water and the like, and these can be used alone or in combination.
  • Compound (b-11) is compound (b-5) and 0.5 to 5 equivalents of compound (a-7) in the presence of 1 to 5 equivalents of an additive in a solvent at -20 ° C and the boiling point of the solvent used. By reacting at a temperature between 5 minutes and 96 hours.
  • additives examples include TEA and DIPEA.
  • solvent examples include DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine and the like. These may be used alone or in combination. Used.
  • Compound (a-7) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • Process 2 Compound (b-12) is obtained by reacting compound (b-11) without solvent or in a solvent, preferably in the presence of 1 equivalent to a large excess of acid, at a temperature between 0 ° C. and the boiling point of the solvent used. It can be produced by treating for 5 minutes to 96 hours.
  • Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, TFA, TsOH, methanesulfonic acid, titanium tetrachloride, boron trifluoride, and the like. These may be used alone or in combination.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, and the like. Used as a mixture.
  • Compound (b-13) is compound (b-12) and 0.001 to 5 equivalents of compound (a-5) added in the presence of 1 to 1000 equivalents of a condensing agent in a solvent, if necessary, in an amount of 1 to 5 equivalents.
  • the reaction can be carried out at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-5) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • R 6 is a tert-butyl group
  • the compound (b-14) is used in the absence of a solvent or in a solvent, preferably in the presence of 1 equivalent to a large excess of acid at 0 ° C. It can be produced by treating at a temperature between the boiling point of the solvent and 5 minutes to 96 hours.
  • Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, TFA, TsOH, methanesulfonic acid, titanium tetrachloride, boron trifluoride, and the like. These may be used alone or in combination.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, and the like. Used as a mixture.
  • the temperature between ⁇ 20 ° C. and the boiling point of the solvent used in the presence of a catalyst in the presence of a hydrogen source or in the presence of a catalyst in the presence of a compound (b-13) in a solvent.
  • it can be produced by treating at normal pressure or under pressure for 5 minutes to 72 hours.
  • the catalyst examples include palladium carbon, palladium, palladium hydroxide, palladium acetate, palladium black and the like, and these are preferably used in an amount of 0.01 to 200% by weight based on the compound (b-8).
  • hydrogen source examples include formic acid, ammonium formate, sodium formate, cyclohexadiene, hydrazine and the like, and these are preferably used in an amount of 2 equivalents to a large excess with respect to compound (b-8).
  • solvent examples include methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, water and the like, and these can be used alone or in combination.
  • the compound (a-6) shown below can be produced, for example, according to the following steps.
  • R 1 and R 2 are composed of a chain or cycloalkyl which may contain a hetero atom
  • R 3 is composed of a group containing a PEG unit
  • X is an oxygen atom or a nitrogen atom.
  • Compound (a-3) is compound (a-1) and 0.5 to 5 equivalents of compound (a-2) added in the presence of 1 to 5 equivalents of a condensing agent in a solvent, if necessary in an amount of 1 to 5 equivalents.
  • the reaction can be carried out at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-1) can be obtained by a known method [WO2015 / 034031, paragraphs 20-24] or a method analogous thereto.
  • Compound (a-2) can be obtained as a commercial product, or can be obtained by a known method [eg, US2015 / 0166518, section 11-12] or a method analogous thereto.
  • Process 2 Compound (a-4) is obtained by reacting compound (a-3) without solvent or in a solvent, preferably in the presence of 1 equivalent to a large excess of acid, at a temperature between 0 ° C. and the boiling point of the solvent used. It can be produced by treating for 5 minutes to 96 hours.
  • Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, TFA, TsOH, methanesulfonic acid, titanium tetrachloride, boron trifluoride, and the like. These may be used alone or in combination.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, and the like. Used as a mixture.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-5) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • the compound (a-10) shown below can be produced, for example, according to the following steps. (Wherein R 1 , R 2 , R 3 and R 3 are the same as defined above, R 4 is a linker, and X represents an oxygen atom or a nitrogen atom)
  • Compound (a-8) is compound (a-4) and 0.1 to 5 equivalents of compound (a-7) added in a solvent in the presence of 1 to 5 equivalents of a condensing agent, if necessary, in an amount of 1 to 20 equivalents. It can be produced by reacting in the presence of an agent at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-7) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • Process 2 Compound (a-9) is obtained by subjecting compound (a-8) to a temperature between 0 ° C. and the boiling point of the solvent used in the absence of solvent or in the presence of a solvent, preferably in the presence of 1 equivalent to a large excess of acid. It can be produced by treating for 5 minutes to 96 hours.
  • Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, TFA, TsOH, methanesulfonic acid, titanium tetrachloride, boron trifluoride, and the like. These may be used alone or in combination.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, and the like. Used as a mixture.
  • Compound (a-10) is compound (a-9) and 0.001 to 5 equivalents of compound (a-5) added in the presence of 1 to 1000 equivalents of a condensing agent in a solvent, if necessary, in an amount of 1 to 5 equivalents. It can be produced by reacting in the presence of an agent at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-5) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • the compound (a-12) shown below can be produced, for example, according to the following steps. (Wherein R 3 is composed of a group containing PEG units)
  • Compound (a-12) is compound (a-1) and 0.5 to 5 equivalents of compound (a-11) added in the presence of 1 to 5 equivalents of a condensing agent in a solvent, if necessary, in an amount of 1 to 5 equivalents. It can be produced by reacting in the presence of an agent at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-1) can be obtained by a known method [WO2015 / 034031, paragraphs 20-24] or a method analogous thereto.
  • Compound (a-2) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • the following compound (a-15) can be produced, for example, according to the following steps. (Wherein R ′ is a chain or cycloalkyl which may contain a hetero atom, R ′′ is composed of a group containing PEG units)
  • Compound (a-14) is compound (a-1) and compound (a-13) added in an amount of 1 to 5 equivalents in the presence of 1 to 5 equivalents of a condensing agent in a solvent. It can be produced by reacting in the presence of an agent at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours.
  • condensing agent examples include DCC, EDC, CDI, 2-chloro-1-methylpyridinium iodide, HBTU, HATU, COMU and the like.
  • additives examples include HOBt, TEA, DIPEA and the like.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-1) can be obtained by a known method [WO2015 / 034031, paragraphs 20-24] or a method analogous thereto.
  • Compound (a-13) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • Process 2 Compound (a-15) is reacted with Compound (a-14) in the presence of 0.1 to 5 equivalents of an additive at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 96 hours. Can be manufactured.
  • additives examples include copper sulfate pentahydrate and sodium ascorbate.
  • solvent examples include methanol, ethanol, DCM, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, water, and the like. Are used alone or in combination.
  • Compound (a-14) can be obtained as a commercial product, or can be obtained by a known method or a method analogous thereto.
  • a pharmaceutical composition comprising a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof.
  • This pharmaceutical composition can be used, for example, as a prophylactic or therapeutic agent for hypercalcemia in hyperparathyroidism, parathyroid cancer or primary hyperparathyroidism that cannot be removed or recurred after surgery.
  • it can be used as a preventive or therapeutic agent for hyperparathyroidism (more preferably, secondary hyperparathyroidism).
  • the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine, but includes excipients, binders, disintegrants, lubricants, coloring agents, and brightening agents. It may be included.
  • the pharmaceutical composition of the present invention may be either an oral preparation or a parenteral preparation, and is preferably a parenteral preparation.
  • the parenteral preparation (for example, an injection) contains a salt solution, a glucose solution or saline.
  • a diluent or solvent such as a mixed solution of glucose and glucose solution can be further added.
  • the shape of the pharmaceutical composition of the present invention is not particularly limited, but may be a solid preparation, and preferably has a tablet, powder, fine granule, granule, capsule or dry syrup shape.
  • the method for producing the pharmaceutical composition of the present invention is not particularly limited.
  • the pharmaceutical composition can be produced by a method generally used in the technical field of pharmaceutics such as compression molding. (By screw extrusion granulator, roll extrusion granulator, etc.), rolling granulation method (by rotary drum granulator, centrifugal rolling granulator, etc.), fluidized bed granulation method (fluidized bed It can be produced by wet granulation using a granulator, a rolling fluidized bed granulator, etc.), a stirring granulation method (by a stirring granulator, etc.), etc.
  • administering to a subject (preferably a subject in need thereof) a composition comprising an effective amount of a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof.
  • a composition comprising an effective amount of a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof.
  • composition comprising a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof for use as a medicament.
  • composition comprising a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of hyperparathyroidism.
  • composition comprising a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of hyperparathyroidism.
  • composition comprising a polyethylene glycol derivative of evocalcet or a pharmaceutically acceptable salt thereof for the treatment or prevention of hyperparathyroidism.
  • Et represents ethyl
  • Me represents methyl
  • iPr represents isopropyl
  • iBu represents isobutyl
  • tBu represents tert-butyl
  • PEG MW represents the molecular weight of polyethylene glycol in each polyethylene glycol derivative, and in the case of multi-arm type polyethylene glycol, represents the total molecular weight of polyethylene glycol in all arms.
  • 10K represents a molecular weight of 10,000.
  • mPEG represents Me (OCH 2 CH 2 ) n1 (wherein n1 is as defined above).
  • Reference example 1 Evocalcet was obtained by a known method [WO2015 / 034031, paragraphs 20-24].
  • Reference Example 3 Evocalcet (900 mg, 2.403 mmol) obtained in Reference Example 1 was dissolved in ethanol (10 mL), sulfuric acid (0.320 mL, 6.01 mmol) was added, and the mixture was heated to reflux for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and ethyl 2- (4-((S) -3-(((R) -1- (naphthalene-1) as an oily substance. 1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (1.03 g, 106%) was obtained.
  • Process 2 The product of Step 1 (1.94 g, 3.40 mmol) was dissolved in acetonitrile (5 mL), TEA (1.42 mL, 10.2 mmol) and N-Boc-L-leucine (3.22 g, 13.9 mmol) were added, and 70 ° C. And stirred overnight.
  • Process 3 The product of Step 2 (530 mg, 0.692 mmol) was dissolved in DCM (1 mL), cooled to 0 ° C., trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 1 hr. The crude product obtained by evaporating the solvent was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate.
  • Process 4 The product of Step 3 (461 mg, 0.692 mmol) was dissolved in DCM (30 mL), and mPEG-AA, MW 10k (Creative PEGWorks, Catalog No. PSB-226) (2.93 g, 0.277 mmol), EDC ( 663 mg, 3.46 mmol) and DMAP ⁇ TsOH (81.0 mg, 0.277 mmol) were added, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, the resulting crude product was dissolved in a small amount of chloroform, and diethyl ether / 2-propanol (1: 1) was added dropwise to collect the precipitated solid by filtration.
  • the obtained solid (42.4 mg) was dissolved in 200 ⁇ L of methanol and 150 ⁇ L of 4 mol / L NaOH aqueous solution, and completely decomposed into evocalcet by stirring overnight. Subsequently, the reaction solution was made up to 1 mL with methanol.
  • a solution A was prepared by mixing 200 ⁇ L of the diluted solution and 200 ⁇ L of a methanol solution of o-terphenyl (1 mg / mL) as an internal standard substance. Subsequently, 200 ⁇ L of evocalcet standard solution (1 mg / mL) and 200 ⁇ L of o-terphenyl methanol solution (1 mg / mL) were mixed to prepare Solution B.
  • the evocalcet content was calculated from the absorption peak area by HPLC analysis according to the following formula.
  • Evocalcet content (Evocalcet area of solution A / o-terphenyl area of solution A) ⁇ (o-terphenyl area of solution B / Evocalcet area of solution B) ⁇ (100 / sample weight used)
  • Process 5 The product of Step 4 (3.00 g, 0.267 mmol) was dissolved in acetonitrile (120 mL), and 10% Pd / C (3.00 g) washed with acetonitrile just before use was added. After replacing with a hydrogen atmosphere, the mixture was stirred at room temperature for 2 hours. After dilution by adding acetonitrile (780 mL), the mixture was filtered using a 0.2 ⁇ m membrane filter. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether / 2-propanol (1: 1) and then vacuum dried to obtain compound N-1 (2.52 g, yield 85%). . As a result of HPLC analysis of the product, the purity was 70% (condition A; RT: 4.9-6.0 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.64 wt%.
  • Example 2 Synthesis process 1 of compound N-2 Using ethyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate obtained in Reference Example 3, In the same manner as in Step 1 of Example 1, ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) A crude product of amino) pyrrolidin-1-yl) phenyl) acetate was obtained and used as such in the next reaction.
  • Process 4 Compound N-2 (71.0 mg, 85%) was obtained as a white solid in the same manner as in Step 4 of Example 1, using the product of Step 3 (23.0 mg, 0.038 mmol). As a result of HPLC analysis of the product, the purity was 94.1% (condition A; RT: 5.53 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.63 wt%.
  • Example 3 Synthesis of Compound N-3 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R ) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl L-leucineate (18.0 mg, 0.0290 mmol) and mPEG-AA, MW 20k (Creative PEGWorks, Catalog No. PSB-225) (250 mg) , 0.0120 mmol), and in the same manner as in Step 4 of Example 1, compound N-3 (211 mg, 82%) was obtained as a white solid. HPLC analysis of the product showed a purity of 91%. A quantitative experiment by hydrolysis showed that the evocalcet content was 0.740 wt%.
  • Example 5 Synthesis process 1 of compound N-5 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (250 mg, 0.621 mmol) and N-Boc-glycine (143 mg, 0.813 mmol) in the same manner as step 2 of Example 1 (2R, 3R) -1- (2-((tert-butoxycarbonyl) amino) acetoxy) ethyl 2- (3- (4- (2-ethoxy-2-oxoethyl) phenylimidazolidin-1-yl) -3- (naphthalene-1 -Ill) butanoate (105 mg, 82%) was obtained.
  • Step 2-3 Using the product of Step 1, compound N-5 (170 mg, 2 steps 92%) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 98.6% (Condition A; RT: 5.41 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.98 wt%.
  • Example 6 Synthesis process 1 of compound N-6 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (98.0 mg, 0.193 mmol) and N-Boc-L-valine (171 mg, 0.789 mmol) in the same manner as in step 2 of Example 1 (2R, 3R) -1-(((S) -2-((tert-butoxycarbonyl) amino) -3-methylbutanoyl) oxy) ethyl 2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl ) Imidazolidin-1-yl) 3- (naphthalen-1-yl) butanoate (85.0 mg, 64%) was obtained as an oil. ESI / MS
  • Step 2-3 Using the product of Step 1, Compound N-6 (145 mg, 2 steps 100%) was obtained as a white solid in the same manner as Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 87.8% (Condition A; RT: 5.55 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.87 wt%.
  • Example 7 Synthesis process 1 of compound N-7 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (103 mg, 0.202 mmol) and N-Boc-L-alanine (157 mg, 0.830 mmol) in the same manner as in step 2 of Example 1 (2R, 3R) -1-(((S) -2-((tert-butoxycarbonyl) amino) propanoyl) oxy) ethyl 2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) imidazolidine-1 -Il) -3- (Naphthalen-1-yl) butanoate (110 mg, 82%) was obtained as an oil (110 mg, 82%).
  • Step 2-3 Using the product of Step 1, compound N-7 (144 mg, 2 steps 85%) was obtained as a white solid in the same manner as Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 90.6% (condition A; RT: 5.45 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.75 wt%.
  • Example 8 Synthesis process 1 of compound N-8 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (92.0 mg, 0.181 mmol) and N-Boc-L-phenylalanine (197 mg, 0.741 mmol) in the same manner as in step 2 of Example 1 (2R, 3R) -1-(((S) -2-((tert-butoxycarbonyl) amino-3-phenylpropanoyl) oxy) ethyl 2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) Imidazolidin-1-yl) -3- (naphthalen-1-yl) butanoate (104 mg, 78%) was obtained as an oil.
  • Step 2-3 Using the product of Step 1, compound N-8 (160 mg, 2 steps 89%) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 94%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.57 wt%.
  • Example 9 Synthesis process 1 of compound N-9 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (87.0 mg, 0.171 mmol) and N-Boc-isoleucine (162 mg, 0.701 mmol) as in step 2 of Example 1, -((((2R, 3R) -2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) imidazolidin-1-yl) -3- (naphthalen-1-yl) butanoyl) oxy) ethyl 2-((tert-butoxycarbonyl) amino) -3-methylpentanoate (98 mg, 81%) was obtained as an oil.
  • Step 2-3 Using the product of Step 1, compound N-9 (153 mg, two steps: 87%) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 98%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.39 wt%.
  • Example 10 Synthesis process 1 of compound N-10 Ethyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (41.3 mg) obtained in Reference Example 3 , 0.103 mmol) and chloromethyl chloroformate (14.0 ⁇ L, 0.154 mmol) in the same manner as in Step 1 of Example 1, 2- (4-((S) -3-(((chloromethoxy) carbonyl ) ((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (63.3 mg) was obtained and used as such in the next reaction.
  • Process 4 Compound N-10 (172 mg, 93%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 3 (24.0 mg, 0.0410 mmol). As a result of HPLC analysis of the product, the purity was 96%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.33 wt%.
  • Example 11 Synthesis process 1 of compound N-11 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (60.0 mg, 0.118 mmol) and (S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoic acid (112 mg, 0.483 mmol) In the same manner as in Step 2 of Example 1, (2S) -1-(((2R, 3R) -2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) imidazolidine) was used.
  • Step 2-3 Using the product of Step 1, compound N-11 (151 mg, 83% for 2 steps) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. HPLC analysis of the product showed a purity of 97%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.34 wt%.
  • Example 12 Synthesis process 1 of compound N-12 Ethyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (250 mg) obtained in Reference Example 3 , 0.621 mmol) and 1-chloro-2-methylpropyl chloroformate (136 ⁇ L, 0.932 mmol) in the same manner as in Step 1 of Example 1, 2- (4-((3S) -3- ( A crude product (382 mg) of ((1-chloro-2-methylpropoxy) carbonyl) ((R) -1 (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate was obtained. This was used in the next reaction as it was.
  • Process 4 Compound N-12 (162 mg, 95%) was obtained as a white solid in the same manner as in Step 4 of Example 1, using the product of Step 3 (23.0 mg, 0.038 mmol). HPLC analysis of the product showed a purity of 97%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.54 wt%.
  • Example 13 Synthesis of Compound N-13 (2S) -1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl obtained in Step 3 of Example 12 ) ((R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2-amino-3-methylbutanoate (109 mg, 0.176 mmol) and mPEG-AA, MW 20k
  • Compound N-13 (1.30 g, 84%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using (1.50 g, 0.0700 mmol).
  • the purity was 94% (condition A; RT: 5.41 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 0.751 wt%.
  • Example 14 Synthesis of Compound N-14 (2S) -1-((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl obtained in Step 3 of Example 12 ) ((R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2-amino-3-methylbutanoate (101 mg, 0.163 mmol) and mPEG-AA, MW 30k (2.00 g, 0.0650 mmol) was used in the same manner as in Step 4 of Example 1, to obtain compound N-14 (1.73 g, 85%) as a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition A; RT: 5.34 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.17 wt%.
  • Example 15 Synthesis process 1 of compound N-15
  • the evocalcet (0.40 g, 1.07 mmol) obtained in Reference Example 1 was heated and stirred overnight at 80 ° C. in the presence of N, N-dimethylformamide di-tert-butylacetal (1.09 g, 5.34 mmol).
  • Process 2 Dissolve the product of step 1 (0.993 g, 2.31 mmol) in DCM (10 mL) and add DIPEA (0.806 mL, 4.61 mmol) and 1-chloro-2-methylpropyl chloroformate (0.473 g, 2.77 mmol). And stirred at room temperature for 3 hours.
  • Process 3 Dissolve the product of step 2 (1.11 g, 1.96 mol) in acetonitrile (10 mL), add TEA (0.955 mL, 6.86 mmol), N-Cbz-valine (1.97 g, 7.83 mmol) and overnight at 80 ° C. Stir.
  • Step 4 The product of Step 3 (0.34 g, 0.436 mmol) was added with 0.2 g of 10% Pd / C washed with acetonitrile immediately before use. After replacing with a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 1-((((S) -1- (4- (2- (tert-butoxy) -2-oxoethyl) phenyl) pyrrolidin-3-yl). ((R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl L-valinate (0.282 mg, 100% yield) was obtained. ESI / MS m / z: 646 [M + H] +
  • Process 5 The product of Step 4 (32 mg, 0.049 mmol) was dissolved in DCM (3 mL), mPEG-AA, MW 30k (0.6 g, 0.02 mmol), EDC (47 mg, 0.244 mmol), DMAP (2.4 mg, 0.02 mmol) was added and stirred at room temperature overnight. After the solvent was distilled off, the resulting crude product was dissolved in a small amount of chloroform, and diethyl ether / 2-propanol (1: 1) was added dropwise to collect the precipitated solid by filtration. The solid was washed with diethyl ether / 2-propanol (1: 1) and then vacuum dried to obtain a crude product (546 mg, yield 89%) as a white solid.
  • Process 6 The crude product (0.06 g) obtained in Step 5 was dissolved in DCM (0.8 mL), cooled to 0 ° C., trifluoroacetic acid (0.8 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with toluene and evaporated under reduced pressure. The obtained residue was reslurried with ether / 2-propanol (1: 1) and then vacuum dried to obtain Compound N-15 (20.8 mg, yield 35%) as a white solid. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 0.64 wt%.
  • Example 16 Synthesis process 1 of compound N-16 2- (4-((3S) -3-(((1-chloro-2-methylpropoxy) carbonyl) ((R) -1 (naphthalen-1-yl) ethyl) obtained in Step 1 of Example 12.
  • Step 2-3 Using the product of Step 1, Compound N-16 (154 mg, 2 steps 90%) was obtained as a white solid in the same manner as Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 96%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.69 wt%.
  • Example 17 Synthesis process 1 of compound N-17 2- (4-((3S) -3-(((1-chloro-2-methylpropoxy) carbonyl) ((R) -1 (naphthalen-1-yl) ethyl) obtained in Step 1 of Example 12.
  • Step 2-3 Using the product of Step 1, Compound N-17 (128 mg, 2 steps 75%) was obtained as a white solid in the same manner as Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 95%. A quantitative experiment by hydrolysis showed that the evocalcet content was 1.96 wt%.
  • Example 18 Synthesis process 1 of compound N-18 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (89.0 mg, 0.175 mmol) and N-Boc-L-proline (154 mg, 0.717 mmol) as in step 2 of Example 1 (2S) -1-tert-butyl 2- (1-(((2R, 3R) -2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) imidazolidin-1-yl) -3- (naphthalene -1-yl) butanoyl) oxy) ethyl) pyrrolidine-1,2-dicarboxylate (99 mg, 82%) was obtained as an oil.
  • Step 2-3 Using the product of Step 1, Compound N-18 (142 mg, 2 steps 79%) was obtained as a white solid in the same manner as Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 98%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.84 wt%.
  • Example 19 Synthesis process 1 of compound N-19 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 Example) using) pyrrolidin-1-yl) phenyl) acetate (87.0 mg, 0.171 mmol) and 2-((tert-butoxycarbonyl) amino) -2-methylpropanoic acid (142 mg, 0.701 mmol) (2R, 3R) -1-((2-((tert-butoxycarbonyl) amino) -2-methylpropanoyl) oxy) ethyl 2- (3- (4- (2 -Ethoxy-2-oxoethyl) phenyl) imidazolidin-1-yl) -3- (naphthalen-1-yl) butanoate (90.4 mg, 78%) was obtained as an oil.
  • Step 2-3 Using the product of Step 1, compound N-19 (143 mg, 2 steps 80%) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 1.98 wt%.
  • Example 20 Synthesis process 1 of compound N-20 (2S) -1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R)-obtained in Step 1 of Example 2 1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl 2-((tert-butoxycarbonyl) amino) -4-methylpentanoate (80.7 mg, 0.159 mmol) and N-Boc-D-leucine ( (2R) -1-(((2R, 3R) -2- (3- (4- (2-Ethoxy-2-ethoxy-2)) in the same manner as in Step 2 of Example 1, using 150 mg, 0.65 mmol).
  • Step 2-3 Using the product of Step 1, Compound N-20 (161 mg, 2 steps 94%) was obtained as a white solid in the same manner as Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.27 wt%.
  • Example 21 Synthesis process 1 of compound N-21 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (83.0 mg, 0.163 mmol) and 1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (153 mg, 0.669 mmol) and Similarly, 1-tert-butyl 3- (1-(((2R, 3R) -2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) imidazolidin-1-yl) -3 -(Naphthalen-1-yl) butanoyl) oxy) ethyl) piperidine-1,3-dicarboxylate (56.0 mg, 49%) was obtained as an oil. ES
  • Step 2-3 Using the product of Step 1, Compound N-21 (160 mg, 2 steps 93%) was obtained as a white solid in the same manner as Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 98%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.47 wt%.
  • Example 22 Synthesis process 1 of compound N-22 Benzyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino obtained in Step 1 of Example 1 ) Pyrrolidin-1-yl) phenyl) acetate (87.8 mg, 0.172 mmol) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (162 mg, 0.707 mmol) Similarly, 1-tert-butyl 4- (1-(((2R, 3R) -2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) imidazolidin-1-yl) -3 -(Naphthalen-1-yl) butanoyl) oxy) ethyl) piperidine-1,4-dicarboxylate (92.0 mg, 76%) was obtained as an oil.
  • Step 2-3 Using the product of Step 1, compound N-22 (155 mg, 2 steps 89%) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 98%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.10 wt%.
  • Example 23 Synthesis process 1 of compound N-23 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 Step 2 of Example 1 using) pyrrolidin-1-yl) phenyl) acetate (86.0 mg, 0.169 mmol) and 6-((tert-butoxycarbonyl) amino) hexanoic acid (160 mg, 0.693 mmol).
  • Step 2-3 Using the product of Step 1, compound N-23 (171 mg, 2 steps 89%) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 98%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.54 wt%.
  • Example 24 Synthesis process 1 of compound N-24 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (126 mg, 0.248 mmol) and N- (tert-butoxycarbonyl) - ⁇ -alanine (187 mg, 0.990 mmol) as in step 2 of Example 1.
  • Step 2-3 Using the product of Step 1, Compound N-24 (415 mg, 93% for 2 steps) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 98%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.70 wt%.
  • Example 25 Synthesis process 1 of compound N-25 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (87.0 mg, 0.171 mmol) and 1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (161 mg, 0.701 mmol) Similarly, 1-tert-butyl 2- (1-(((2R, 3R) -2- (3- (4- (2-ethoxy-2-oxoethyl) phenyl) imidazolidin-1-yl) -3 -(Naphthalen-1-yl) butanoyl) oxy) ethyl) piperidine-1,2-dicarboxylate (94.0 mg, 78%) was obtained as an oil. ESI /
  • Example 26 Synthesis process 1 of compound N-26 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 Step 2 of Example 1 using) pyrrolidin-1-yl) phenyl) acetate (60.0 mg, 0.118 mmol) and 1-((tert-butoxycarbonyl) amino) cyclopentanecarboxylic acid (111 mg, 0.483 mmol).
  • Example 27 Synthesis process 1 of compound N-27 2- (4-((3S) -3-(((1-chloro-2-methylpropoxy) carbonyl) ((R) -1 (naphthalen-1-yl) ethyl) obtained in Step 1 of Example 12.
  • Step 2-3 Using the product of Step 1, compound N-27 (159 mg, 2 steps 93%) was obtained as a white solid in the same manner as in Steps 3 to 4 of Example 1. As a result of HPLC analysis of the product, the purity was 96%. A quantitative experiment by hydrolysis showed that the evocalcet content was 1.91 wt%.
  • Example 28 Synthesis process 1 of compound N-28 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2) Pyrrolidin-1-yl) phenyl) acetate (103 mg, 0.202 mmol) and 7- (tert-butoxycarbonyl) -7-azabicyclo [2.2.1] heptane-2,3-dicarboxylic acid (23.0) obtained in Reference Example 4 mg, 0.0810 mmol) and 7-tert-butyl 2,3-bis (1-(((S) -1- (4- (2-ethoxy- 2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl)
  • Process 2 Using the product of Step 1 (76.0 mg, 0.0620 mmol) in the same manner as Step 3 of Example 1, bis (1-((((S) -1- (4- (2-ethoxy-2- Oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1 (naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl) 7-azabicyclo [2.2.1] heptane-2,3-dicarboxylate crude The product (61.6 mg, 88%) was obtained and used as such for the next reaction.
  • Process 3 Compound N-28 (69.0 mg, 83%) was obtained in the same manner as in Step 4 of Example 1 using the product of Step 2 (32.0 mg, 0.0280 mmol). HPLC analysis of the product showed a purity of 97%. A quantitative experiment by hydrolysis showed that the evocalcet content was 3.76 wt%.
  • Example 29 Synthesis process 1 of compound N-29 Bis (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (Naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl) 7-azabicyclo [2.2.1] heptane-2,3-dicarboxylate (19.0 mg, 0.0160 mmol) and mPEG-AA, MW 20k (140 mg, In the same manner as in Step 4 of Example 1, Compound N-29 (115 mg, 81%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 1.35 wt%.
  • Example 30 Synthesis of Compound N-30 Bis (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 2 of Example 28) (R) -1 (Naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl) 7-azabicyclo [2.2.1] heptane-2,3-dicarboxylate (13.0 mg, 0.0110 mmol) and mPEG-AA, MW Compound 30 (122 mg, 84%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using 30k (140 mg, 0.00500 mmol). As a result of HPLC analysis of the product, the purity was 93%. A quantitative experiment by hydrolysis showed that the evocalcet content was 1.68 wt%.
  • Example 31 Synthesis process 1 of compound N-31 2- (4-((S) -3-(((Chloromethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidine-1 obtained in Step 1 of Example 10 -Yl) phenyl) acetate (0.0450 g, 0.0910 mmol), and (1R, 3S, 4S) -7- (tert-butoxycarbonyl) -7-azabicyclo [2.2.1] heptane-2 obtained in Reference Example 4, Using 3-dicarboxylic acid (10.4 mg, 0.0360 mmol) in the same manner as in Step 2 of Example 1, 7- (tert-butyl) 2,3-bis ((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamo
  • Process 3 Compound N-31 (0.174 g, 88.0%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 2 (0.0370 g, 0.0340 mmol). As a result of HPLC analysis of the product, the purity was 91% (condition B; RT: 6.43 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 5.37 wt%.
  • Example 32 Synthesis process 1 of compound N-32 2- (4-((3S) -3-(((1-chloro-2-methylpropoxy) carbonyl) ((R) -1 (naphthalen-1-yl) ethyl) obtained in Step 1 of Example 12) Amino) pyrrolidin-1-yl) phenyl) acetate (0.0500 g, 0.0930 mmol) is dissolved in acetonitrile (1.00 mL) and obtained in Reference Example 4 (1R, 3S, 4S) -7- (tert-butoxycarbonyl) ) -7-azabicyclo [2.2.1] heptane-2,3-dicarboxylic acid (10.6 mg, 0.0370 mmol), DIPEA (0.0200 mL, 0.112 mmol), sodium iodide (0.0170 g, 0.112 mmol), Stir at 80 ° C.
  • Process 3 Compound N-32 (0.0733 g, 66.0%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 2 (0.0170 g, 0.0140 mmol). As a result of HPLC analysis of the product, the purity was 97% (condition B; RT: 6.86 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 5.43 wt%.
  • Example 33 Synthesis process 1 of compound N-33
  • the (1R, 3S, 4S) -7- (tert-butoxycarbonyl) -7-azabicyclo [2.2.1] heptane-2,3-dicarboxyl acid (50.0 mg, 0.175 mmol) obtained in Example 4 was converted to DCM. (1.00 mL), thionyl chloride (0.0640 mL, 0.876 mmol) and DMF (0.00136 mL, 0.0180 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
  • Process 3 The product of Step 2 (0.0300 g, 0.0200 mmol) was dissolved in DCM (1.00 mL), TFA (0.233 mL, 3.03 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hr. The crude product obtained by evaporating the solvent was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate.
  • Example 34 Synthesis process 1 of compound N-34 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- () obtained in steps 1 to 3 of Example 2 Tert-Butyl (1S, 2S, 4R) -2 using naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl L-leucineate (0.0490 g, 0.0810 mmol) as in Step 2 of Example 33 -(((2R) -1- (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalene -1-yl) ethyl) carbamoyl) oxy) ethoxy) -4-methyl-1-oxopentan-2-y
  • Process 2 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl)) was obtained in the same manner as in Step 3 of Example 32 using the product of Step 1 (0.0230 g, 0.0160 mmol) (Phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl ((1R, 3S, 4S) -3-(((2R) -1- (1 -(((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) Ethoxy) -4-methyl-1-oxopentan-2-yl) carbamoyl) -7-azabicyclo [2.2.1]
  • Process 3 Compound N-34 (0.0260 g, 64.1%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 2 (0.00690 g, 0.00515 mmol). As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 6.90 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 4.99 wt%.
  • Example 35 Synthesis process 1 of compound N-35 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- () obtained in steps 1 to 3 of Example 6.
  • Process 2 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl)) was obtained in the same manner as in Step 3 of Example 32 using the product of Step 1 (0.0342 g, 0.0240 mmol).
  • Process 3 Compound N-35 (0.0342 g, 69.1%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 2 (0.00724 g, 0.00545 mmol). As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 6.80 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 3.75 wt%.
  • Example 36 Synthesis process 1 of compound N-36 Ethyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (0.300 g) obtained in Reference Example 3 , 0.683 mmol) and using ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalene) in the same manner as in Step 1 of Example 1.
  • Step 2 Using the product of Step 1 (0.0560 g, 0.110 mmol) and 1-((tert-butoxycarbonyl) amino) cyclopropane-1-carboxylic acid (0.0890 g, 0.440 mmol), Step 2 of Example 1 1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) Ethyl) carbamoyl) oxy) ethyl 1-((tert-butoxycarbonyl) amino) cyclopropane-1-carboxylate (0.0740 g, quant.) was obtained as a white amorphous.
  • Process 4 The product of Step 3 (0.0610 g, 0.107 mmol), and tert-butyl (1R, 3S, 4S) -2,3-bis (chlorocarbonyl) -7-azabicyclo [2.2. 1] Bis (1-((((S) -1- (4- (2-ethoxy) in the same manner as in Step 2 of Example 33, using heptane-7-carboxylate (0.0160 g, 0.050 mmol).
  • Example 37 Synthesis process 1 of compound N-37 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 36)
  • Example 1 using pyrrolidin-1-yl) phenyl) acetate (0.0560 g, 0.110 mmol) and (S) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.101 g, 0.440 mmol) 1- (tert-butyl) 2- (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ( (R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) (2S) -piperidine-1,2-dicarbox
  • Process 5 Compound N-37 (0.133 g, 79.0%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 4 (0.0390 g, 0.0290 mmol). As a result of HPLC analysis of the product, the purity was 95% (condition B; RT: 6.78 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 4.95 wt%.
  • Example 38 Synthesis process 1 of compound N-38 (1R, 3S, 4S) -bis (1-(((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 2 of Example 28 ((R) -1 (Naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl) 7-azabicyclo [2.2.1] heptane-2,3-dicarboxylate (0.0650 g, 0.0570 mmol) and examples Tert-Butyl (1R, 3S, 4S) -2,3-bis (chlorocarbonyl) -7-azabicyclo [2.2.1] heptane-7-carboxylate (0.00900 g, 0.0280 mmol) obtained in 33 step 1 , Dissolved in pyridine (1.00 mL), added TEA (0.0190 mL, 0.140 mmmol), and stirred
  • Process 3 Compound N-38 (0.0964 g, 89.0%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 2 (0.0140 g, 0.00586 mmol). As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 6.77 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.74 wt%.
  • Example 39 Synthesis of Compound N-39 Compound N-39 (0.0921 g, 87.0%) was converted to white using the product of Step 2 of Example 38 (0.0106 g, 0.00440 mmol) in the same manner as Step 4 of Example 1. Obtained as a solid. As a result of HPLC analysis of the product, the purity was 97% (condition B; RT: 6.54 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.50 wt%.
  • Example 40 Synthesis process 1 of compound N-40 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 Example) using) pyrrolidin-1-yl) phenyl) acetate (104 mg, 0.204 mmol) and 5-((tert-butoxycarbonyl) amino) isophthalic acid (23.0 mg, 0.0820 mmol) obtained in Reference Example 5.
  • Process 3 Compound N-40 (132 mg, 85%) was obtained as a white solid in the same manner as in Step 4 of Example 1, using the product of Step 2 (37.0 mg, 0.0330 mmol). As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 3.74 wt%.
  • Example 41 Synthesis of Compound N-41Bis (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 2 of Example 40) (R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) using 5-aminoisophthalate (14.0 mg, 0.0120 mmol) and mPEG-AA, MW 20k (105 mg, 0.00500 mmol) In the same manner as in Step 4 of Example 1, compound N-41 (98.4 mg, 85%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 95%. A quantitative experiment by hydrolysis showed that the evocalcet content was 0.790 wt%.
  • Example 42 Synthesis of Compound N-42Bis (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 2 of Example 40 ( (R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) 5-aminoisophthalate (12.0 mg, 0.0110 mmol) and mPEG-AA, MW 30k (130 mg, 0.00400 mmol) In the same manner as in Step 4 of Example 1, compound N-42 (111 mg, 82%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 0.730 wt%.
  • Example 43 Synthesis process 1 of compound N-43 Ethyl 2- (4-((3S) -3-(((1-chloroethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) obtained in Step 1 of Example 2 ) Pyrrolidin-1-yl) phenyl) acetate (104 mg, 0.204 mmol) and commercially available N- (tert-butoxycarbonyl) iminodiacetic acid (19.0 mg, 0.0810 mmol) using bis (1-(((S ) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) 2,2 ' -((tert-Butoxycarbonyl) azanezyl) diacetate (71.7 mg, 75%) was
  • Process 2 Using the product of Step 1 (37.9 mg, 0.0320 mmol) in the same manner as Step 3 of Example 1, bis (1-((((S) -1- (4- (2-ethoxy-2- Oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) 2,2'-azanezyl diacetate crude product (34.9 mg, 101 %) Was obtained and used as such in the next reaction.
  • Process 3 Compound N-43 (143 mg, 93%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using the product of Step 2 (35.0 mg, 0.0330 mmol). As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 3.75 wt%.
  • Example 44 Synthesis of Compound N-44 Bis (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 2 of Example 43) (R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) 2,2'-azanezyl diacetate (7.00 mg, 0.0070 mmol) and mPEG-AA, MW 30k (80 mg, 0.000300 mmol) ) was used in the same manner as in Step 4 of Example 1 to obtain compound N-44 (69.0 mg, 83%) as a white solid. As a result of HPLC analysis of the product, the purity was 93%. Quantitative experiments by hydrolysis showed that the evocalcet content was 1.00 wt%.
  • Example 45 Synthesis process 1 of compound N-45 N- (tert-butoxycarbonyl) iminodiacetic acid (0.0405 g, 0.174 mmol) is dissolved in DMF (2.00 mL), COMU (0.223 g, 0.521 mmol) and DIPEA (0.0910 mL, 0.521 mmol) are added, and at room temperature. Stir for 30 minutes.
  • Step 3 Using the product of Step 2 (0.0180 g, 0.0140 mmol), Compound N-45 (0.0729 g, 81.0%) was obtained as a white solid in the same manner as Step 4 of Example 1. As a result of HPLC analysis of the product, the purity was 91% (condition B; RT: 6.90 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.94 wt%.
  • Example 46 Synthesis of Compound N-46 (1R, 3S, 4S) -Bis (1-(((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl)) obtained in Step 2 of Example 28 Pyrrolidin-3-yl) ((R) -1 (naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl) 7-azabicyclo [2.2.1] heptane-2,3-dicarboxylate (0.0220 g, 0.0200 mmol ) And AA-PEG-AA 40k (Creative PEGWorks, custom synthesized product) (0.200 g, 0.00488 mmol) in the same manner as in Step 4 of Example 1, compound N-46 (0.162 g, 77.0% ) Was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 93% (condition B; RT: 6.51 min). A quantitative
  • Example 47 Synthesis of Compound N-47 As in Step 4 of Example 1, using the product of Step 2 of Example 38 (0.0120 g, 0.00497 mmol) and AA-PEG-AA 40k (0.0650 g, 0.00159 mmol). Compound N-47 (0.0619 g, 85.0%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 6.20-9.00 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 6.37 wt%.
  • Example 48 Synthesis process 1 of compound N-48 (1R, 3S, 4S) -7-tert-butyl 2,3-bis (1-(((S) -1- (4- (2-ethoxy-2-oxoethyl) obtained in Step 1 of Example 28 ) Phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl) 7-azabicyclo [2.2.1] heptane-2,3,7-tricarboxylate (0.143 g, 0.127 mmol) and tert-butyl (1R, 3S, 4S) -2,3-bis (chlorocarbonyl) -7-azabicyclo [2.2.1] heptane-7 obtained in Step 1 of Example 32 -Carboxylate (0.0190 g, 0.296 mmol) was dissolved in DCM (1.00 mL), TEA (0.0410 m
  • Process 2 The product of Step 1 (0.0234 g, 0.0170 mmol) was dissolved in DCM (1.00 mL), COMU (0.0140 g, 0.0330 mmol) and DIPEA (0.00585 mL, 0.0330 mmol) were added, and the mixture was stirred at room temperature for 10 minutes.
  • Step 3 The product of Step 2 (0.0117 g, 0.00586 mmol) was treated in the same manner as in Step 3 of Example 1 with bis (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) (Phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) (1R, 3S, 4S) -7-((1S, 2S, 4R) -3 -(((2R) -1- (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalene -1-yl) ethyl) carbamoyl) oxy) -2-methylpropoxy) -3-methyl-1-oxobutan-2-yl)
  • Process 4 Using the product of Step 3 (0.0110 g, 0.00586 mmol) and AA-PEG-AA 40k (0.0800 g, 0.00195 mmol) in the same manner as in Step 4 of Example 1, Compound N-48 (0.0811 g, 92.0 %) As a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.90-8.60 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 4.17 wt%.
  • Example 49 Synthesis of Compound N-49 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R ) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl L-leucineate (82.0 mg, 0.135 mmol) and 4-Arm PEG-acid, MW 10k (Creative PEGWorks, Catalog No. PSB-481) (150 mg, 0.0140 mmol) was used in the same manner as in Step 4 of Example 1 to obtain compound N-49 (142 mg, 78%) as a white solid. As a result of HPLC analysis of the product, the purity was 94.2% (Condition A; RT: 5.20-7.50 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 10.1 wt%.
  • Example 50 Synthesis process 1 of compound N-50 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalene) obtained in Step 3 of Example 2 -1-yl) ethyl) carbamoyl) oxy) ethyl L-leucineate (48.0 mg, 0.0800 mmol) and 4-Arm PEG-acid, MW 20k (Creative PEGWorks, Catalog No. PSB-482) (160 mg, 0.0080 mmol) )
  • Compound N-50 (159 mg, 89%) as a white solid in the same manner as in Step 4 of Example 1.
  • the purity was 97.6% (condition A; RT: 5.00-7.10 min). Quantitative experiments by hydrolysis showed that the evocalcet content was 2.79 wt%.
  • Example 51 Synthesis of Compound N-51 (2S) -1-((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 3 of Example 12 ((R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2-amino-3-methylbutanoate (0.0240 g, 0.0390 mmol) and 4-Arm PEG-acid, Compound N-51 (0.0655 g, 58.6%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using MW 20k (0.100 g, 0.00487 mmol). As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.79-7.88 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 5.36 wt%.
  • Example 52 Synthesis of Compound N-52 (2S) -1-((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 3 of Example 12 ((R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2-amino-3-methylbutanoate (0.0110 g, 0.019 mmol) and 4arm PEG Carboxyl, MW 40000 Compound N-52 (0.0840 g, 80.0%) was obtained as a white solid in the same manner as in Step 4 of Example 1 using (JenKem Technology USA, A7066) (0.100 g, 0.00233 mmol). As a result of HPLC analysis of the product, the purity was 97% (condition B; RT: 6.00-6.49 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 3.31 wt%.
  • Example 53 Synthesis process 1 of compound N-53 Using the compound obtained in Step 5 of Example 15 (0.014 g, 0.022 mmol) and 4arm PEG Carboxyl, MW 40000 (0.12 g) in the same manner as in Step 4 of Example 1, the product (100 mg, 79%) was obtained as a white solid.
  • Step 2 Using the product of Step 1 (60 mg), Compound N-53 (20.8 mg) was obtained as a white solid in the same manner as Step 6 of Example 15. As a result of HPLC analysis of the product, the purity was 98.7% (Condition A; RT: 5.30-7.00 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.52 wt%.
  • Example 54 Synthesis process 1 of compound N-54 (2S) -1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1 obtained in Step 3 of Example 12 -(Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2-amino-3-methylbutanoate (0.103 g, 0.167 mmol) was dissolved in DMF (1.00 mL) to give 1- (9H -Fluoren-9-yl) -3-oxo-2,7,10-trioxa-4-azadodecane-12-euic acid (0.0970 g, 0.251 mmol), HATU (0.0950 g, 0.251 mmol), DIPEA (0.0880 mL) , 0.501 mmol) and stirred at room temperature for 2.5 hours.
  • Process 2 The product of Step 1 (0.0150 g, 0.015 mmol) was dissolved in DMF (1.00 mL), piperidine (0.00754 mL, 0.0760 mmol) was added, and the mixture was stirred at room temperature for 30 min. The mixture was diluted with ethyl acetate, 2 mol / L hydrochloric acid was added, washed with saturated brine, and dried over magnesium sulfate.
  • Process 3 Using the product of Step 2 (0.0110 g, 0.0150 mmol) and 4-Arm PEG-Acid, MW 20k (0.0500 g, 0.00244 mmol) in the same manner as Step 4 of Example 1, Compound N-54 (0.0466 g , 81.0%) as a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.20-8.20 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.11 wt%.
  • Example 55 Synthesis process 1 of compound N-55 2- (4-((3S) -3-(((1-chloro-2-methylpropoxy) carbonyl) ((R) -1 (naphthalen-1-yl) ethyl) obtained in Step 1 of Example 12) Amino) pyrrolidin-1-yl) phenyl) acetate (0.350 g, 0.652 mmol) and (tert-butoxycarbonyl) glycine (0.457 g, 2.61 mmol) were used in the same manner as in Step 2 of Example 1, -(((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-Methylpropyl (tert-butoxycarbonyl) glycinate (0.205 g, 46.6
  • Process 2 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl)) in the same manner as in Step 1 of Example 1 using the product of Step 1 (0.205 g, 0.303 mmol).
  • Phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl glycinate (0.175 g, quant.) was obtained as a colorless oil.
  • Process 3 The product of Step 2 (0.174 g, 0.303 mmol) was dissolved in DMF (2.00 mL) and dicyclohexylamine 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-13 eate (0.202 g, 0.455 mmol), HATU (0.173 g, 0.455 mmol), and DIPEA (0.159 mL, 0.909 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate.
  • Process 4 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl)) was obtained in the same manner as in Step 3 of Example 1 using the product of Step 3 (0.0900 g, 0.110 mmol).
  • Process 5 Using the product of Step 4 (0.00805 g, 0.0110 mmol) and 4arm PEG Carboxyl, MW 40000 (0.0800 g, 0.00186 mmol) in the same manner as Step 4 of Example 1, Compound N-55 (0.0680 g, 80.0 %) As a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.30-6.90 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.98 wt%.
  • Example 56 Synthesis process 1 of compound N-56 2- (4-((S) -3-(((Chloromethoxy) carbonyl) ((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidine-1 obtained in Step 1 of Example 10 -(Yl) phenyl) acetate (0.400 g, 0.808 mmol) and (tert-butoxycarbonyl) -L-valine (0.702 g, 3.23 mmol) in the same manner as in step 2 of Example 1 ((((( S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) methyl (tert-butoxy Carbonyl) -L-valinate (0.194 g, 35.5%) was obtained as a colorless oil.
  • Process 4 Using the product of step 3 (0.110 g, 0.134 mmol) as in step 3 of example 1, ((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) Pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) methyl (2- (2- (2-aminoethoxy) ethoxy) acetyl) -L-valinate (0.0970 g , quant.) as a colorless oil.
  • Process 5 Using the product of Step 4 (0.00805 g, 0.0110 mmol) and 4arm PEG Carboxyl, MW 40000 (0.0800 g, 0.00186 mmol) in the same manner as in Step 4 of Example 1, Compound N-56 (0.0604 g, 70.9 mmol) %) As a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.70-6.40 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.80 wt%.
  • Example 57 Synthesis process 1 of compound N-57 2- (4-((3S) -3-(((1-chloro-2-methylpropoxy) carbonyl) ((R) -1 (naphthalen-1-yl) ethyl) obtained in Step 1 of Example 12) Amino) pyrrolidin-1-yl) phenyl) acetate (0.223 g, 0.415 mmol) and dicyclohexylamine 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13 ate (0.185 g, 0.415 mmol) and 1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ( (R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2,2-dimethyl-4-oxo-3,8,11-
  • Process 2 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl)) in the same manner as in Step 1 of Example 1 using the product of Step 1 (0.141 g, 0.184 mmol). Phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2- (2- (2-aminoethoxy) ethoxy) acetate (0.122 g , quant.) as a colorless oil.
  • Process 3 Compound N-57 (0.0900 g, 77.0) using the product of Step 3 (0.0102 g, 0.0150 mmol) and 4arm PEG Carboxyl, MW 40000 (0.110 g, 0.00256 mmol) in the same manner as Step 4 of Example 1. %) As a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.30-6.90 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 0.95 wt%.
  • Example 58 Synthesis process 1 of compound No. N-58 (2S) -1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1 obtained in Step 3 of Example 12 -(Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2-amino-3-methylbutanoate (0.327 g, 0.529 mmol), and N ⁇ -[(9H-fluoren-9-ylmethoxy ) carbonyl] -N ⁇ - (2,2,4,6,7- pentamethyl-dihydrobenzofuran-5-sulfonyl) -L- arginine (1.03 g, with 1.59 mmol), similar to the step 1 of example 54 1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) pheny
  • Process 2 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl)) in the same manner as in Step 2 of Example 54, using the product of Step 1 (0.0512 g, 0.0410 mmol).
  • (Phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl N ⁇ -((2,2,4,6,7-pentamethyl- 2,3-Dihydrobenzofuran-5-yl) sulfonyl) -L-arginyl-L-valinate (0.0420 g, quant.) was obtained as a colorless oil.
  • Process 3 Using the product of Step 2 (0.0400 g, 0.0390 mmol) and 4-Arm PEG-Acid, MW 20k (0.100 g, 0.00487 mmol) in the same manner as Step 4 of Example 1, the product (0.0910 g, 76.0%) was obtained as a white solid.
  • Process 4 The product of Step 3 (0.0300 g, 0.00122 mmol) was dissolved in TFA (0.489 mL) and stirred at room temperature overnight. After the solvent was distilled off, the resulting crude product was dissolved in a small amount of chloroform, and diethyl ether / 2-propanol (1: 1) was added dropwise to collect the precipitated solid by filtration. The solid was washed with diethyl ether / 2-propanol (1: 1) and then vacuum dried to obtain Compound N-58 (0.0227 g, 79.0%) as a white solid. As a result of HPLC analysis of the product, the purity was 97% (condition B; RT: 5.10-6.80 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.59 wt%.
  • Example 59 Synthesis process 1 of compound N-59 (2S) -1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1 obtained in Step 3 of Example 12 -(Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2-amino-3-methylbutanoate (0.128 g, 0.207 mmol), and N ⁇ - (tert-butoxycarbonyl) -N ⁇ 1-((((((((1-methoxy-2,3,6-trimethylphenyl) sulfonyl) -L-arginine) (0.151 g, 0.311 mmol) was used in the same manner as in Step 1 of Example 54.
  • Process 2 The product of Step 1 (0.212 g, 0.195 mmol) was dissolved in DCM (2.00 mL), TFA (0.752 mL, 0.00976 mmol) was added, and the mixture was stirred at room temperature for 3 hr.
  • Process 3 Using the product of Step 2 (0.0190 g, 0.0200 mmol) and 4arm PEG Carboxyl, MW 40000 (0.140 g, 0.00326 mmol) in the same manner as Step 4 of Example 1 (0.139 g, 91.0%) was obtained as a white solid.
  • Process 4 The product of Step 3 (0.139 g, 0.00296 mmol) was dissolved in a TFA / triisopropylsilane (1.00 mL / 0.0500 mL) solution and stirred overnight at room temperature. After the solvent was distilled off, the resulting crude product was dissolved in a small amount of chloroform, and diethyl ether / 2-propanol (1: 1) was added dropwise to collect the precipitated solid by filtration. The solid was washed with diethyl ether / 2-propanol (1: 1) and then vacuum dried to obtain Compound N-59 (0.105 g, 77.0%) as a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.40-6.40 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 0.80 wt%.
  • Example 60 Synthesis of Compound N-60 1-((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) obtained in Step 3 of Example 33 -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl ((1R, 3S, 4S) -3-(((2R) -1- (1-((((S)- 1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropoxy) -3 -Methyl-1-oxobutan-2-yl) carbamoyl) -7-azabicyclo [2.2.1] heptane-2-carbonyl) -L-val
  • Example 61 Synthesis of Compound N-61 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) obtained in Step 3 of Example 33 -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl ((1R, 3S, 4S) -3-(((2R) -1- (1-((((S)- 1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropoxy) -3 -Methyl-1-oxobutan-2-yl) carbamoyl) -7-azabicyclo [2.2.1] heptane-2-carbonyl) -
  • Example 62 Synthesis process 1 of compound N-62 (1R, 3S, 4S) -7- (tert-butoxycarbonyl) -7-azabicyclo [2.2.1] heptane-2,3-dicarboxylic acid (6.61 mg, 0.0230 mmol) obtained in Reference Example 4 is DMF (1.00 mL), COMU (0.0300 g, 0.0700 mmol) and DIPEA (0.0200 mL, 0.116 mmol) were added, and the mixture was stirred at room temperature for 10 minutes.
  • Process 2 The product of Step 1 (0.0560 g, 0.0320 mmol) was dissolved in DCM (1.00 mL), TFA (0.243 mL, 0.00315 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hr. The mixture was diluted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified using preparative HPLC to give the product (0.0110 g, 20.8%) as a yellow oil.
  • Process 3 Using the product of Step 2 (0.0110 g, 0.00658 mmol) and 4-Arm PEG-Acid, MW 20k (0.0300 g, 0.00146 mmol) in the same manner as in Step 4 of Example 1, compound N-62 ( 0.0320 g, 81.0%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.80-9.50 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 5.56 wt%.
  • Example 63 Synthesis of Compound N-63 Bis (1-((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) obtained in Step 2 of Example 40 ( (R) -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) ethyl) 5-aminoisophthalate (33.0 mg, 0.0290 mmol) and 4-Arm PEG-Acid, MW 20k (75.0 mg, 0.00400 mmol) In the same manner as in Step 4 of Example 1, compound N-63 (56.0 mg, 61%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 100% (condition A; RT: 5.10-7.50 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 4.96 wt%.
  • Example 64 Synthesis of Compound N-64 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) obtained in Step 2 of Example 45 -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl (2-(((2S) -1- (1-(((1- (4- (2-ethoxy-2- Oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropoxy) -3-methyl-1-oxobutan-2-yl) amino ) -2-Oxoethyl) glycyl-L-valinate (0.0250 g, 0.0190 mmol) and 4arm PEG Carboxyl, MW 40
  • Example 65 Synthesis of Compound N-65 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) obtained in Step 3 of Example 33 -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl ((1R, 3S, 4S) -3-(((2R) -1- (1-((((S)- 1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropoxy) -3 -Methyl-1-oxobutan-2-yl) carbamoyl) -7-azabicyclo [2.2.1] heptane-2-carbonyl) -L
  • Example 66 Synthesis process 1 of compound N-66 Using the compound obtained in Step 5 of Example 15 (0.024 g, 0.037 mmol) and 8-Arm PEG-Acid, MW 40k (0.1 g) in the same manner as in Step 4 of Example 1, the product ( 87.7 mg, 79%) was obtained as a white solid.
  • Step 2 The product of Step 1 (87.7 mg), Compound N-66 (61.3 mg, yield 71%) was obtained as a white solid in the same manner as Step 6 of Example 15. As a result of HPLC analysis of the product, the purity was 98.6% (Condition A; RT: 5.20-6.90 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 3.76 wt%.
  • Example 67 Synthesis of Compound N-67 1-((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) obtained in Step 4 of Example 55 -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl (2- (2- (2-aminoethoxy) ethoxy) acetyl) glycinate (0.0560 g, 0.0780 mmol), and 8-Arm Compound N-67 (0.280 g, 88.0%) was obtained as a pale yellow solid in the same manner as in Step 4 of Example 1 using PEG-Acid, MW 40k (0.280 g, 0.00650 mmol). As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.30-7.20 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.51 wt
  • Example 68 Synthesis of Compound N-68 ((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1 -(Naphthalen-1-yl) ethyl) carbamoyl) oxy) methyl (2- (2- (2-aminoethoxy) ethoxy) acetyl) -L-valinate (0.0680 g, 0.0950 mmol), and 8-Arm PEG-Acid , MW 40k (0.340 g, 0.00789 mmol) was used in the same manner as in Step 4 of Example 1 to obtain compound N-68 (0.285 g, 74.1%) as a pale yellow solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.30-7.40 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 3.14 wt%.
  • Example 69 Synthesis of Compound N-69 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) obtained in Step 2 of Example 57 -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl 2- (2- (2-aminoethoxy) ethoxy) acetate (0.0810 g, 0.123 mmol), and 8-Arm PEG-Acid , MW 40k (0.440 g, 0.0102 mmol) was used in the same manner as in Step 4 of Example 1 to obtain compound N-69 (0.423 g, 86.0%) as a pale yellow solid. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.30-7.80 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.99 wt%.
  • Example 70 Synthesis process 1 of compound N-70 1-(((((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalene--) obtained in Step 2 of Example 59 1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl N ⁇ - ((4- methoxy-2,3,6-trimethylphenyl) sulfonyl) -L- arginyl -L- valinate (0.104 g, 0.106 mmol) And 8-Arm PEG-Acid, MW 40k (0.380 g, 0.00882 mmol) in the same manner as in Step 4 of Example 1 to obtain the product (0.374 g, 83.0%) as a white solid.
  • Process 2 N-70 (0.300 g, 83.0%) was obtained as a white solid in the same manner as in Step 4 of Example 59, using the product of Step 1 (0.374 g, 0.00735 mmol). As a result of HPLC analysis of the product, the purity was 98% (condition B; RT: 5.40-6.70 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 0.46 wt%.
  • Example 71 Synthesis of Compound N-71 (1R, 3S, 4S) -bis (1-(((S) -1- (4- (2-ethoxy-2-oxoethyl) phenyl) obtained in Step 2 of Example 28) (Pyrrolidin-3-yl) ((R) -1 (naphthalen-1-yl) ethyl) carbomoyl) oxy) ethyl) 7-azabicyclo [2.2.1] heptane-2,3-dicarboxylate (0.0630 g, 0.0560 mmol ), And 8-Arm PEG-Acid, MW 40k (0.200 g, 0.00464 mmol) in the same manner as in Step 4 of Example 1, compound N-71 (0.197 g, 82.0%) as a pale yellow solid Obtained. As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 6.50-9.80 min). A quantitative experiment by hydrolysis showed that the e
  • Example 72 Synthesis of Compound N-72 1-(((((S) -1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) obtained in Step 3 of Example 33 -1- (Naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropyl ((1R, 3S, 4S) -3-(((2R) -1- (1-((((S)- 1- (4- (2-Ethoxy-2-oxoethyl) phenyl) pyrrolidin-3-yl) ((R) -1- (naphthalen-1-yl) ethyl) carbamoyl) oxy) -2-methylpropoxy) -3 -Methyl-1-oxobutan-2-yl) carbamoyl) -7-azabicyclo [2.2.1] heptane-2-carbonyl) -L
  • Example 73 Synthesis of Compound C-1 Evocalcet (140 mg, 0.375 mmol) obtained in Reference Example 1 was suspended in DCM (2 mL), and mPEG-OH, MW 1k (Creative PEGWorks, Catalog No. PJK-206) (150 mg, 0.150 mmol), EDC (144 mg, 0.750 mmol), and DMAP (18.0 mg, 0.150 mmol) were added and stirred overnight.
  • the purity was 99%.
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 26.6 wt%.
  • Example 74 Synthesis of Compound C-2 Carried out using evocalcet (70.0 mg, 0.188 mmol) mPEG-OH, MW 2k (Creative PEGWorks, Catalog No. PJK-205) (150 mg, 0.0750 mmol) obtained in Reference Example 1.
  • compound C-2 (109 mg, 62%) was obtained as a waxy compound.
  • the purity was 99%.
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 16.3 wt%.
  • Example 75 Synthesis of Compound C-3 Evocalcet (9.00 mg, 0.131 mmol) obtained in Reference Example 1 was suspended in DCM (1 mL), oxalyl chloride (0.023 mL, 0.262 mmol) and 1 drop of DMF were added at 0 ° C. Stir for 5 minutes. After the solvent was distilled off under reduced pressure, the solvent and excess oxalyl chloride were distilled off under reduced pressure, and the crude product was dissolved in DCM (1 mL). mPEG-OH, MW 5k (Creative PEGWorks, Catalog No. PJK-204) (262 mg, 0.052 mmol) was added and stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure.
  • Example 76 Synthesis process 1 of compound C-4 Evocalcet (100 mg, 0.267 mmol) obtained in Reference Example 1 was dissolved in DCM (2 mL), EDC (77.0 mg, 0.401 mmol), N-Boc-L-valinol (65.0 mg, 0.320 mmol), DMAP ( 9.80 mg, 0.080 mmol) and TEA (0.0570 mL, 0.0800 mmol) were added and stirred for 10 hours.
  • Example 77 Synthesis process 1 of compound C-5 Using the evocalcet (89.3 mg, 0.186 mmol) and N-Boc-L-leucinol (0.053 mg, 0.241 mmol) obtained in Reference Example 1, in the same manner as in Step 1 of Example 76, ((S) -4 -Methyl-1- (2- (4-((S-3-((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetamido) pentan-2-yl ) Carbamate (104 mg, 98%) was obtained as an oil.
  • Example 78 Synthesis process 1 of compound C-6 Using evocalcet (100 mg, 0.267 mmol) and (S)-(-)-N-Boc-tert-leucinol (70.0 mg, 0.320 mmol) obtained in Reference Example 1, in the same manner as in Step 1 of Example 76.
  • (S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutyl 2- (4-((S) -3-(((R) -1 (naphthalen-1-yl) Ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (173 mg, quant.) was obtained.
  • Step 2 Using the product of Step 1, compound C-6 (137 mg, 66%) was obtained as a white solid in the same manner as in Step 2 of Example 4. As a result of HPLC analysis of the product, the purity was 90% (condition A; RT: 4.85 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 1.84 wt%.
  • Example 79 Synthesis process 1 of compound C-7 Similar to Step 1 of Example 76 using evocalcet (100 mg, 0.267 mmol) and N- (tert-butoxycarbonyl) -L-2-phenylglycinol (76.0 mg, 0.320 mmol) obtained in Reference Example 1.
  • Example 80 Synthesis process 1 of compound C-8 In the same manner as in Step 1 of Example 76, using evocalcet (100 mg, 0.267 mmol) and N- (tert-butoxycarbonyl) -L-phenylalaninol (81.0 mg, 0.320 mmol) obtained in Reference Example 1. , (S) -2-((tert-butoxycarbonyl) amino) -3-phenylpropyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) Amino) pyrrolidin-1-yl) phenyl) acetate (154 mg, 95%) was obtained.
  • Example 81 Synthesis process 1 of compound C-9 Using evocalcet (100 mg, 0.267 mmol) obtained in Reference Example 1 and tert-butyl (2-hydroxy-4-methylphenyl) carbamate (70.0 mg, 0.320 mmol) obtained in Reference Example 7, In the same manner as in Step 1, 1-((tert-butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene-1- Ir) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (137 mg, 89%) was obtained.
  • Step 2 Using the product of Step 1, compound C-9 (167 mg, 80%) was obtained as a white solid in the same manner as Step 2 of Example 4. As a result of HPLC analysis of the product, the purity was 99% (condition A; RT: 4.78 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.45 wt%.
  • Example 82 Synthesis process 1 of compound C-10 Example using evocalcet (100 mg, 0.267 mmol) obtained in Reference Example 1 and tert-butyl (2-hydroxy-3,3-dimethylbutyl) carbamate (70.0 mg, 0.320 mmol) obtained in Reference Example 8 1-((tert-butoxycarbonyl) amino-3,3-dimethylbutan-2-yl 2- (4-((S) -3-(((R) -1- (Naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (125 mg, 82%) was obtained.
  • Example 83 Synthesis process 1 of compound C-11 Using evocalcet (100 mg, 0.267 mmol) obtained in Reference Example 1 and tert-butyl (2-hydroxy-3-phenylpropyl) carbamate (81.0 mg, 0.320 mmol) obtained in Reference Example 9, In the same manner as in Step 1, 1-((tert-butoxycarbonyl) amino) -3-phenylpropan-2-yl 2- (4-((S) -3-(((R) -1- (naphthalene- 1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (147 mg, 91%) was obtained.
  • Example 84 Synthesis process 1 of compound C-12 In the same manner as in Step 1 of Example 76, using evocalcet (100 mg, 0.267 mmol) and N-Boc-2-amino-2-methyl-1-propanol (61.0 mg, 0.320 mmol) obtained in Reference Example 1. 2-((tert-butoxycarbonyl) amino) -2-methylpropyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidine 1-yl) phenyl) acetate (145 mg, quant.) Was obtained.
  • Example 85 Synthesis step 1 of compound number C-13 Similar to Step 1 of Example 76 using evocalcet (200 mg, 0.534 mmol) and tert-butyl- (R) -3-hydroxypyrrolidine 1-carboxylate (150 mg, 0.801 mmol) obtained in Reference Example 1.
  • tert-butyl (R) -3- (2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetoxy ) Pyrrolidine-1-carboxylate (311 mg, quant.) Was obtained.
  • Example 86 Synthesis step 1 of compound number C-14 Using evocalcet (200 mg, 0.534 mmol) and tert-butyl- (R) -3-hydroxypiperidine-1-carboxylate (101 mg, 0.502 mmol) obtained in Reference Example 1, step 1 of Example 76 and Similarly, tert-butyl- (R) -3- (2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidine-1-carboxylate (230 mg , 78%).
  • Process 3 In the same manner as in Step 4 of Example 1, using the product of Step 2 (16 mg, 0.36 mmol) and mPEG-AA, MW 10k (150 mg, 0.014 mmol), Compound C-14 (143 mg, 91 %) As a white solid. As a result of HPLC analysis of the product, the purity was 93% (condition A; rt 4.88 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 3 wt%.
  • Example 87 Synthesis process 1 of compound C-15 Using evocalcet (100 mg, 0.267 mmol) and (1S, 2S) -trans-N-Boc-aminocyclohexanol (69.0 mg, 0.320 mmol) obtained in Reference Example 1, as in Step 1 of Example 76.
  • Process 2 The product of step 1 (30.0 mg, 0.0520 mmol) was dissolved in DCM (1 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 hr. The solvent was distilled off, and the resulting crude product (1S, 2S) -2-aminocyclohexyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl The amino) pyrrolidin-1-yl) phenyl) acetate was used as such in the next reaction.
  • Process 3 The product of Step 2 (27.0 mg, 0.0460 mmol) was dissolved in DCM (2 mL), mPEG-AA, MW 10k (200 mg, 0.0180 mmol), EDC (44.0 mg, 0.231 mmol), DMAP (2.30 mg, 0.0180 mmol) and TEA (0.0520 mL, 0.370 mmol) were added, and the mixture was stirred overnight at room temperature. After the solvent was distilled off, the resulting crude product was dissolved in a small amount of chloroform, and diethyl ether / 2-propanol (1: 1) was added dropwise to collect the precipitated solid by filtration. The obtained solid was suspended in 2-propanol and stirred at room temperature for 1 hour.
  • Example 88 Synthesis process 1 of compound C-16 Using evocalcet (100 mg, 0.267 mmol) and (1R, 2S) -cis-N-Boc-2-aminocyclohexanol (69.0 mg, 0.320 mmol) obtained in Reference Example 1, step 1 of Example 76 and Similarly, (1R, 2S) -2-((tert-butoxycarbonyl) amino) cyclohexyl 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl ) Amino) pyrrolidin-1-yl) phenyl) acetate (102 mg, 67% yield) was obtained.
  • Example 89 Synthesis process 1 of compound C-17 Step 1 of Example 76 using evocalcet (150 mg, 0.401 mmol) and (1S, 2S) -trans-N-Boc-2-aminocyclopentanol (105 mg, 0.521 mmol) obtained in Reference Example 1.
  • Example 90 Synthesis process 1-2 of compound C-18 (1S, 2S) -2-((tert-butoxycarbonyl) amino) cyclopentyl 2- (4-((S) -3-(((R) -1- (naphthalene) obtained in Step 1 of Example 89
  • Compound C-18 (2.09 g, 2.0-1 g) using 1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and mPEG-AA, MW 30k, in analogy to steps 2-3 of Example 15. 86%) was obtained as a white solid.
  • the purity was 99% (condition A; RT: 4.83 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 0.743 wt%.
  • Example 91 Synthesis process 1 of compound C-19 Step 1 of Example 76 using evocalcet (100 mg, 0.267 mmol) and (1R, 2S) -cis-N-Boc-2-aminocyclopentanol (64.0 mg, 0.320 mmol) obtained in Reference Example 1.
  • Example 92 Synthesis process 1 of compound C-20 Using evocalcet (100 mg, 0.267 mmol) and N-Boc-4-hydroxyaniline (67.0 mg, 0.320 mmol) obtained in Reference Example 1, in the same manner as in Step 1 of Example 76, 4-((tert -Butoxycarbonyl) amino) phenyl 2- (4-((S) -3-((R) -1- (naphthalen-1-yl) ethylamino) pyrrolidin-1-yl) phenyl) acetate (131 mg, yield Rate 87%).
  • Example 93 Synthesis process 1 of compound C-21 Using evocalcet (100 mg, 0.267 mmol) obtained in Reference Example 1 and tert-butyl (4-hydroxy-3-methylphenyl) carbamate (72.0 mg, 0.320 mmol) obtained in Reference Example 10, 4-((tert-butoxycarbonyl) amino) -2-methylphenyl 2- (4-((S) -3-((R) -1- (naphthalen-1-yl) ethyl) as in step 1 Amino) pyrrolidin-1-yl) phenyl) acetate (135 mg, 87% yield) was obtained.
  • Example 94 Synthesis process 1 of compound C-22 Example using evocalcet (140 mg, 0.374 mmol) obtained in Reference Example 1 and tert-butyl (4-hydroxy-3,5-dimethylphenyl) carbamate (106 mg, 0.449 mmol) obtained in Reference Example 11 As in Step 1 of 76, 4-((tert-butoxycarbonyl) amino) -2,6-dimethylphenyl 2- (4-((S) -3-((R) -1- (naphthalene-1 -Ill) ethylamino) pyrrolidin-1-yl) phenyl) acetate (189 mg, 85% yield) was obtained.
  • Process 2-3 4-((tert-Butoxycarbonyl) amino) -2,6-dimethylphenyl obtained in step 1 2- (4-((S) -3-((R) -1- (naphthalen-1-yl) Compound C-22 (157 mg, 75%) was obtained as a white solid in the same manner as in Steps 2 to 3 of Example 87 using ethylamino) pyrrolidin-1-yl) phenyl) acetate. As a result of HPLC analysis of the product, the purity was 99% (condition A; RT: 4.84 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 0.202 wt%.
  • Example 95 Synthesis process 1 of compound C-23 Evocalcet (527 mg, 1.41 mmol) obtained in Reference Example 1 was suspended in DCM (4 mL), and tert-butyl 1-imino-1 ⁇ 6-thiomorpholine-4-carboxylate 1-oxide obtained in Reference Example 6 ( 0.22 g, 0.938 mmol), EDC (360 mg, 1.87 mmol), and DMAP (23 mg, 0.188 mmol) were added and stirred overnight.
  • Step 2 The product of Step 1 (0.13 g, 0.22 mmol) was dissolved in DCM (0.8 mL), trifluoroacetic acid (0.8 mL) was added, and the mixture was stirred for 30 min. The reaction mixture was diluted with toluene, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure and 2- (4-((S) -3-((( R) -1- (Naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) -N- (1-oxide-1 ⁇ 6-thiomorpholin-1-ylidene) acetamide (85.9 mg, 80% yield) ) Was obtained as a white amorphous.
  • Process 3 Using the product of step 2 (29 mg, 0.06 mmol) and mPEG-AA, MW 10k (0.25 g), compound C-23 (0.208 g, 80% yield) was obtained as a white solid in the same manner as in Example 1. Got as. As a result of HPLC analysis of the product, the purity was 81%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.72 wt%.
  • Example 96 Synthesis of Compound C-24
  • Compound C was prepared in the same manner as in Step 3 of Example 23, using the compound obtained in Step 2 of Example 23 (64 mg, 0.13 mmol) and mPEG-AA, MW 30k (1.6 g). -24 (1.45 g, 89% yield) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 1.23 wt%.
  • Example 97 Synthesis process 1 of compound C-25 Evocalcet (200 mg, 0.534 mmol) obtained in Reference Example 1 was suspended in DCM (15 mL), EDC (133 mg, 0.694 mmol), propargyl alcohol (0.0640 mL, 1.07 mmol), HOBT (106 mg, 0.694) mmol) was added and stirred for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and the solvent was evaporated and concentrated.
  • Step 1 product (54.0 mg, 0.131 mmol), mPEG-Azide, MW 10k (Creative PEGWorks, Catalog No. PSB-2023) (450 mg, 0.0440 mmol), 1,4-dioxane (1 mL), water (0.2 mL) and sodium (R) -2-((S) -1,2-dihydroxyethyl) -4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate) (17.0 mg , 0.0870 mmol) and copper sulfate pentahydrate (16.0 mg, 0.0650 mmol) were added, and the mixture was stirred for 48 hours.
  • Example 98 Synthesis of Compound C-26 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R ) -1- (Naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and 4arm PEG Carboxyl, MW 40000 in analogy to step 2 of Example 76, compound C-26 (876 mg, 84%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition A; RT: 4.95 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.89 wt%.
  • Example 99 Synthesis of Compound C-27 1-((tert-Butoxycarbonyl) amino) -3-phenylpropan-2-yl 2- (4-((S) -3-(( Compound C using (R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and 4arm PEG Carboxyl, MW 40000 as in Step 2 of Example 76 -27 (671 mg, 64%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 99% (condition A; RT: 4.95 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 2.50 wt%.
  • Example 100 Synthesis of Compound C-28 Compound C was prepared in the same manner as in Step 3 of Example 23 using Compound (160 mg, 0.326 mmo) obtained in Step 2 of Example 23 and 4arm PEG Carboxyl, MW 40000 (1.4 g). -28 (1.21 g, 83% yield) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 96%. A quantitative experiment by hydrolysis showed that the evocalcet content was 2.75 wt%.
  • Example 101 Synthesis process 1 of compound C-29 1-((tert-Butoxycarbonyl) amino) -3-phenylpropan-2-yl 2- (4-((S) -3 (((R) -1- ( Naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (50.0 mg, 0.0820 mmol) was dissolved in DCM (1 mL), TFA (1 mL) was added, and the mixture was stirred for 1 hr. The crude product obtained by distilling off the solvent was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate.
  • Step 2 Using the product of Step 1 (25.0 mg, 0.0200 mmol) and 4arm PEG Carboxyl, MW 40000 (100 mg, 2.33 ⁇ mol) in the same manner as in Step 2 of Example 76, Compound C-29 (55.0 mg, yield) 50%). As a result of HPLC analysis of the product, the purity was 97% (condition A; RT: 5.01 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 3.68 wt%.
  • Example 102 Synthesis process 1 of compound C-30
  • the compound (150 mg, 0.307 mmol) obtained in Step 2 of Example 23 and the compound (35 mg, 0.123 mmol) obtained in Reference Example 4 were dissolved in DCM (2 mL) and EDC (118 mg, 0.613 mmol) , DMAP (15 mg, 0.123 mmol) and TEA (51 ⁇ L, 0.368 mmol) were added and stirred overnight.
  • ESI / MS m / z 616 [M / 2 + H] +
  • Process 2 The product of Step 1 (0.19 g, 0.154 mmol) was dissolved in DCM (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred for 3 hr. The reaction mixture was diluted with toluene and concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate and concentrated.
  • Process 3 The product of Step 2 (231 mg, 0.205 mol) and 4arm PEG Carboxyl, MW 40000 (0.88 g) were dissolved in DMF (6 mL), then COMU (0.11 g, 0.256 mmol), TEA (43 ⁇ L, 0.307) mmol) was added and stirred overnight. The reaction mixture was diluted with water and purified by ultrafiltration to give compound C-30 (814 mg, yield 84%) as a yellow solid. As a result of HPLC analysis of the product, the purity was 96%. A quantitative experiment by hydrolysis indicated that the evocalcet content was 6.06 wt%.
  • Example 103 Synthesis of Compound C-31 1-((tert-Butoxycarbonyl) amino) -3-phenylpropan-2-yl 2- (4-((S) -3-(( (R) -1- (Naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and 8-Arm PEG-Acid, MW 40k, as in Step 2 of Example 4.
  • Compound C-31 (102 mg, 47%) was obtained as a white solid.
  • the purity was 99% (condition A; RT: 4.92 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 3.01 wt%.
  • Example 104 Synthesis of Compound C-32 Using compound (18 mg, 0.037 mmol) obtained in Step 2 of Example 23 and 8-Arm PEG-Acid, MW 40k (0.1 g), the same method as in Step 3 of Example 23 Gave compound C-32 (72 mg, 66% yield) as a white solid. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 4.44 wt%.
  • Example 105 Synthesis of Compound C-33 Using the compound obtained in Step 2 of Example 30 (273 mg, 0.241 mmol) and 4arm PEG Carboxyl, MW 40000 (520 mg) in the same manner as in Step 3 of Example 30, compound C-33 (487 mg, yield 78%) was obtained as a yellow solid. As a result of HPLC analysis of the product, the purity was 99%. A quantitative experiment by hydrolysis showed that the evocalcet content was 9.26 wt%.
  • Example 106 Synthesis of Compound C-34 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl)-obtained in Step 2 of Example 95 N- (1-oxide-1 ⁇ 6-thiomorpholine-1-ylidene) acetamide (53 mg, 0.107 mmol), mPEG-AA 2k (150 mg), WSCD (27 mg, 0.143 mmol), a piece of DMAP in methylene chloride (2 mL) and stirred overnight.
  • Example 107 Synthesis of Compound C-35 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl)-obtained in Step 2 of Example 95
  • Compound C-35 was prepared in the same manner as in Example 106, using N- (1-oxide-1 ⁇ 6-thiomorpholine-1-ylidene) acetamide (21 mg, 0.043 mmol) and mPEG-AA 5k (150 mg). (60 mg, 37% yield) was obtained as a white solid.
  • the purity was 91% (condition B; RT: 5.13 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 6.4 wt%.
  • Example 108 Synthesis of Compound C-36 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene) obtained in Step 1 of Example 81.
  • Compound C— was prepared in the same manner as in Step 2 of Example 76 using -1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and mPEG-AA, MW 5k (200 mg, 0.038 mmol). 36 (157 mg, 72%) was obtained as a white solid.
  • the purity was 74% (condition B; RT: 5.47 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 3.08 wt%.
  • Example 109 Synthesis of Compound C-37 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl)-obtained in Step 2 of Example 95
  • N- (1-oxide-1 ⁇ 6-thiomorpholine-1-ylidene) acetamide 34 mg, 0.069 mmol
  • AA-PEG-AA 10k 150 mg.
  • Compound C-37 (135 mg, 83% yield) was obtained as a white solid.
  • the purity was 97% (condition B; RT: 5.0-5.5 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 6.22 wt%.
  • Example 110 Synthesis of Compound C-38 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene) obtained in Step 1 of Example 81.
  • Compound C— was prepared in the same manner as in Step 2 of Example 76 using -1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and AA-PEG-AA 10k (200 mg, 0.018 mmol). 38 (136 mg, 63%) was obtained as a white solid.
  • the purity was 99% (condition B; RT: 5.3-6.0 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 4.04 wt%.
  • Example 111 Synthesis of Compound C-39 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl)-obtained in Step 2 of Example 95
  • N- (1-oxide-1 ⁇ 6-thiomorpholine-1-ylidene) acetamide (66 mg, 0.135 mmol) and 4-Arm PEG acid 10k (150 mg) were used in the same manner as in Step 3 of Example 95.
  • Compound C-39 (149 mg, yield 85%) was obtained as a white solid.
  • the purity was 98% (condition B; RT: 5.0-5.8 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 9.02 wt%.
  • Example 112 Synthesis of Compound C-40 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl)-obtained in Step 2 of Example 95
  • N- (1-oxide-1 ⁇ 6-thiomorpholine-1-ylidene) acetamide 35 mg, 0.07 mmol
  • 4-Arm PEG acid 20k 150 mg
  • Compound C-40 (121 mg, yield 74%) was obtained as a white solid.
  • the purity was 98% (condition B; RT: 5.1-5.7 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 4.63 wt%.
  • Example 114 Synthesis of Compound C-42 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene) obtained in Step 1 of Example 81.
  • Compound C— was prepared in the same manner as in Step 2 of Example 76 using -1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and 4-Arm PEG acid 10k (200 mg, 0.02 mmol). 42 (138 mg, 59%) was obtained as a white solid.
  • the purity was 98% (condition B; RT: 5.2-6.7 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 4.67 wt%.
  • Example 115 Synthesis of Compound C-43 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene) obtained in Step 1 of Example 81.
  • Step 2 of Example 76 using 1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and 4-Arm PEG acid 20k (200 mg, 0.00977 mmol)
  • compound C- 43 (117 mg, 54%) was obtained as a white solid.
  • the purity was 97% (condition B; RT: 5.0-6.7 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 2.05 wt%.
  • Example 116 Synthesis of Compound C-44 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene) obtained in Step 1 of Example 81.
  • Step 2 of Example 76 using 1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and 4arm PEG Carboxyl, MW 30000 (200 mg, 0.00657 mmol), compound C- 44 (133 mg, 63%) was obtained as a white solid.
  • the purity was 98% (condition B; RT: 5.3-6.3 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 2.95 wt%.
  • Example 117 Synthesis of Compound C-45 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene) obtained in Step 1 of Example 81. 1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate and 4arm PEG Carboxyl, MW 40000 (200 mg, 0.00465 mmol), in analogy to steps 1-2 of Example 101 C-45 (157 mg, 71%) was obtained as a white solid. As a result of HPLC analysis of the product, the purity was 98% (condition A; RT: 5.17 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 4.49 wt%.
  • Example 118 Compound C-46 synthesis 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl)-obtained in Step 2 of Example 95 N- (1-oxide-1 ⁇ 6-thiomorpholin-1-ylidene) acetamide (69 mg, 0.14 mmol), 8-Arm PEG acid 20k (150 mg), WSCD (34 mg, 0.177 mmol), a piece of DMAP in methylene chloride (2 mL) and stirred overnight.
  • the crude product is diluted with a water-methanol mixed solvent and subjected to ultrafiltration using a Microsep Advance centrifugal filtration device Omega membrane (molecular weight cutoff 10k, product number: MAP010C38, manufactured by Pall) (5000 ⁇ g, 15 ° C.) to change the solvent to water-methanol.
  • Methanol of the obtained high molecular weight fraction was distilled off, and then lyophilized to obtain Compound C-46 (133 mg, yield 75%) as a white solid.
  • the purity was 98% (condition B; RT: 5.45 min).
  • a quantitative experiment by hydrolysis showed that the evocalcet content was 10.5 wt%.
  • Example 119 Synthesis of Compound C-47 1-((tert-Butoxycarbonyl) amino-4-methylpentan-2-yl 2- (4-((S) -3-((R) -1- (naphthalene) obtained in Step 1 of Example 81. -1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl) acetate (110 mg, 0.192 mmol) was dissolved in DCM (2 mL), TFA (2 mL) was added, and the mixture was stirred for 1 hour. The crude product obtained by distilling off the solvent was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate.
  • Example 120 Synthesis of Compound C-48 Process 1 2- (4-((S) -3-(((R) -1- (naphthalen-1-yl) ethyl) amino) pyrrolidin-1-yl) phenyl)-obtained in Step 2 of Example 95 N- (1-oxide-1 ⁇ 6-thiomorpholin-1-ylidene) acetamide (300 mg, 0.611 mmol), dicyclohexylamine 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13 -Oate (326 mg, 0.734 mmol), WSCD (234 mg, 122 mmol), DMAP (15 mg, 0.122 mmol), triethylamine (0.17 mL, 1.223 mmol) were dissolved in DMF (2 mL) and stirred for 2 hours .
  • N- (1-oxide-1 ⁇ 6-thiomorpholin-1-ylidene) acetamide 300 mg, 0.6
  • Step 4 The product obtained in Step 3 (91.7 mg, 0.06 mmol), TFA (1 mL), and methylene chloride (1 mL) were mixed at 0 ° C. and stirred for 30 minutes. After evaporating the solvent under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate to obtain the product (75.9 mg, 89%).
  • Process 5 Dissolve the product obtained in step 4 (75 mg, 0.053 mmol), 8-arm PEG acid 40k, COMU (30 mg, 0.071 mmol), triethylamine (12 uL, 0.088 mmol) in acetonitrile (2 mL) overnight. Stir. Furthermore, after adding COMU (9 mg, 0.237 mmol) and triethylamine (10 uL, 0.088 mmol), the mixture was cooled to 0 ° C. and 6 mL of ethanol was added. After evaporating the solvent under reduced pressure, the residue was purified by ultrafiltration to obtain Compound C-48 (199 mg, 83%). As a result of HPLC analysis of the product, the purity was 99% (condition B; RT: 5.42 min). A quantitative experiment by hydrolysis showed that the evocalcet content was 7.24 wt%.
  • PBS phosphate buffer
  • test compound dissolved in ultrapure water to the plasma to a concentration of 1-10 ⁇ mol / L as the evocalcet concentration, what it was thoroughly stirred and allowed to stand for 24 hours in a CO 2 incubator.
  • Evocalcet labeled was synthesized by a known method using the corresponding raw material) and acetonitrile containing 0.1% formic acid, and centrifuge. Separation (5000 ⁇ g, 4 ° C., 5 minutes). 50 ⁇ L of the supernatant was collected, and 100 ⁇ L of 0.1% formic acid was added to prepare a measurement sample.
  • the concentration of evocalcet in the measurement sample was measured using a liquid chromatogram-tandem mass spectrometer (LC / MS / MS).
  • the evocalcet release rate (%) was calculated by dividing the quantified evocalcet concentration by the added theoretical concentration.
  • the results are shown in Tables 44 to 46. According to the results in Tables 44 to 46, the evocalcet release rate (%) at 24 hours after the addition of plasma is between 0.5 and 25% for all compounds, which is good from the pharmacokinetic point of view. I understood that.
  • Mass analysis conditions / ionization method Electrospray ionization (ESI), positive ⁇ Detection method: Multiple reaction monitoring (MRM) ⁇
  • Source temperature 500 °C ⁇
  • Ion spray potential 5500 V ⁇
  • Nebulizer gas 20 ⁇
  • Curtain gas 15 ⁇ Collision gas: 12
  • a plasma sample was added with acetonitrile containing the internal standard substance (same as above) and 0.1% formic acid, stirred, and then centrifuged (5000 ⁇ g, 4 ° C., 5 minutes). 50 ⁇ L of the supernatant was collected, and 100 ⁇ L of 0.1% formic acid was added to prepare a measurement sample.
  • the concentration of evocalcet in the measurement sample was measured using LC / MS / MS (conditions are the same as in Test Example 1).
  • plasma pharmacokinetic parameters maximum plasma concentration C max , elimination half-life t 1/2 , area under the plasma concentration time curve AUC 0-t , AUC 0- ⁇ ) of evocalcet were calculated by non-compartment model analysis .
  • the polyethylene glycol derivatives of the present invention showed sustained plasma release of evocalcet.
  • the maximum plasma concentration C max is particularly important for the onset of drug efficacy,
  • the elimination half-life t 1/2 is particularly important, the maximum plasma concentration C max is 10 (ng / mL) or more, and the elimination half-life t 1/2 is 70 (h) or more. It is preferable from a dynamic viewpoint.
  • the compounds represented by the formula (B) (C-26, C-27, C-28, and C-32) are more preferred than the compounds represented by the formula (C) ( N-12 to 15 and N-28) were found to be preferable.

Landscapes

  • Medicinal Preparation (AREA)
  • Polyethers (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne une formulation à libération prolongée d'évocalcet ou d'un sel pharmacologiquement acceptable de celui-ci. L'invention concerne également l'utilisation d'un dérivé de polyéthylène glycol d'évocalcet ou d'un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2018/011904 2017-03-24 2018-03-23 Dérivé de polyéthylène glycol WO2018174283A1 (fr)

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