WO2022191338A1

WO2022191338A1 - Levodopa-prodrugs and carbidopa-prodrugs for use in the treatment of parkinson's disease

Info

Publication number: WO2022191338A1
Application number: PCT/JP2022/012484
Authority: WO
Inventors: Kenji Morokuma; Chihiro Sato; Kazuki Nakayama
Original assignee: Mitsubishi Tanabe Pharma Corporation
Priority date: 2021-03-10
Filing date: 2022-03-09
Publication date: 2022-09-15
Also published as: AR125072A1; TW202300140A; JP2024010252A

Abstract

An object of the present invention is to provide a combination medicament useful for treatment of Parkinson's disease. The present invention provides a prophylactic or therapeutic agent for Parkinson's disease, the agent containing a combination medicament containing a levodopa prodrug and a carbidopa prodrug.

Description

DESCRIPTION

Title of Invention: LEVODOPA-PRODRUGS AND CARBIDOPA-PRODRUGS

FOR USE IN THE TREATMENT OF PARKINSON'S DISEASE

Related Applications

[0001]

This application claims the benefit of and priority to Japanese Patent Application No. JP 2021-037959, filed on March 10, 2021, which is hereby incorporated by reference in its entirety for any and all purposes.

Technical Field

[0002]

The present invention relates to (a) a combination medicament containing a levodopa prodrug compound and a carbidopa prodrug compound, a pharmaceutical composition thereof and a pharmaceutical use thereof, (b) a novel carbidopa prodrug compound, and (c) a novel levodopa prodrug compound.

Background Art

[0003]

Parkinson's disease is a progressive neurodegenerative disease characterized by deficiency of the neurotransmitter dopamine in the brain. Levodopa, a drug of first choice for this disease, is a direct precursor of dopamine and, unlike dopamine, can cross the blood-brain barrier and transfer to the central nervous system. Levodopa is usually administered in combination with a peripheral aromatic L-amino acid decarboxylase inhibitor, such as carbidopa, in order to suppress peripheral metabolism and provide a high therapeutic effect.

[0004]

As prodrugs for the treatment of Parkinson's disease, a prodrug to which an amino acid is added (Patent Document 1) and a prodrug that has a phosphoric acid ester and has a different structure (Patent Document 2) are known.

Citation List Patent Literature [0005]

NPL 1 : US Patent Application Publication No. 3803120.

NPL 2: International Publication No. 2017/184871.

Summary of Invention Technical Problems [0006]

In an early stage of treatment for Parkinson's disease, oral levodopa medication alone can maintain efficacy for a relatively long period of time. However, along with long-term administration of levodopa and disease progression, an effective therapeutic range is gradually narrowed, and many patients have motor complications such as diurnal variation of motor symptoms (on-off phenomenon) and involuntary movements (dyskinesia). In an advanced stage of such a pathological condition, in order to avoid motor complications and maintain an effective blood concentration of levodopa in the brain, continuous administration into the body is required and it is necessary to develop a formulation suitable for the administration form.

[0007]

For continuous administration into the body, administration of a liquid composition is conceivable. Since levodopa and carbidopa are poorly soluble, means to increase the solubilities of the compounds are needed. An effective means is to add a solubilizing agent to preparation. However, it may not be possible to dissolve a desired amount of an active ingredient. On the other hand, creating a novel compound which is a prodrug of an active ingredient and exhibits a high solubility is a more effective means for obtaining a liquid composition having a desired concentration.

[0008]

The present invention is intended to provide a prodrug that improves the solubilities of levodopa and carbidopa, has a high stability in a solution, and is converted into an active substance in the body.

Solution to Problems [0009]

As a result of intensive studies to solve the above problem, the present inventors have found that a levodopa prodrug compound represented by a formula (I) or a formula (II) or a formula (XV) or a formula (XVI) and a carbidopa prodrug compound represented by any of formulas (III)- to (XIV) are each converted into an active substance in the body, and each have a high solubility and a high solution stability, and thus have accomplished the present invention. That is, the present invention is as follows.

[0010]

(1) A combination medicament comprising a compound or a pharmacologically acceptable salt thereof selected from the following group A and a compound or a pharmacologically acceptable salt thereof selected from the following group B:

<group A> a compound selected from a group consisting of a compound represented by a formula (I) and a compound represented by a formula (II), a compound represented by a formula (XV) and a compound represented by a formula (XVI) or a pharmacologically acceptable salt thereof: a compound represented by the formula (I):

wherein R^10a is an amino acid side chain or an O-phosphorylated amino acid side chain thereof;

R^11a and R^12a are the same or different, and are each a hydrogen, an alkyl, a cycloalkyl, a phenyl, P(=O)(OR’)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^13a and R^14a are the same or different, and are each a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a phenyl, -O-C(=O)-R', -C(=O)-OR', -C(=O)-R', -C(=S)-R', -O- C(=O)-NR’R”, -O-C(=S)-NR’R”, or O-C(O)-R’”;

R^15a is a hydrogen, an alkyl, a cycloalkyl or a phenyl; R’ and R’ ’ are the same or different, and are each a hydrogen, an alkyl, an alkenyl, a cycloalkyl or a phenyl, or R’ and R”, taken together with an adjacent nitrogen atom thereto, form a heteroaryl; and R”’ is a hydrogen, an alkyl, an alkenyl or an alkynyl, and a compound represented by the formula (II):

wherein R^20a is an amino acid side chain that may be substituted;

R^21a and R^22a are the same or different and are each a hydrogen, an alkyl, an alkanoyl, a P(=O)(OH)₂, S(=O)(OH) or a glycosyl that may be substituted; and R^23a, R^24a, and R^25a are the same or different, and are each a hydrogen or an alkyl, a compound represented by the formula (XV):

wherein R^31a and R^32a are the same or different and are each a hydrogen, an alkyl, an alkanoyl, a P(=O)(OH)₂, S(=O)(OH) or a glycosyl that may be substituted; and R^33a is a hydrogen, or an alkyl that may be substituted; a compound represented by the formula (XVI):

wherein R^41a and R^42a are the same or different and are each a hydrogen, an alkyl, an alkanoyl, a P(=O)(OH)₂, S(=O)(OH) or a glycosyl that may be substituted;

R^43a is an alkyl that may be substituted, -R^45a-O-R^46a or a 5-membered heterocyclyl containing at least one nitrogen atom, wherein R^45a is an alkylene, and R^46a is a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R⁴⁴⁸ is a hydrogen or an alkyl,

<group B> a compound selected from a group consisting of compounds represented by formulas (III) to (XIV) respectively or a pharmacologically acceptable salt thereof: a compound represented by the formula (III):

wherein R^10b is an amino acid side chain, or R^10b, taken together with the adjacent nitrogen atom, forms a 5-membered heterocyclyl containing at least one nitrogen atom; R^11b and R^12b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^13b is a hydrogen or an alkyl, a compound represented by the formula (IV):

wherein R^20b is an amino acid side chain;

R^21b and R^22b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^23b is a hydrogen or an alkyl, a compound represented by the formula (V):

wherein R^30b is an amino acid side chain; R^31b and R^32b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^33b is a hydrogen or an alkyl, a compound represented by the formula (VI):

wherein R^41b and R^42b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^43b and R^44b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^43b and R^44b taken together form an alkylene that may be substituted; and R^45b is a hydrogen or an alkyl, a compound represented by the formula (VII):

wherein R^51b and R^52b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^53b and R^54b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^53b and R^54b taken together form an alkylene that may be substituted; and R^55b is a hydrogen or an alkyl, a compound represented by the formula (VIII):

wherein R^61b and R^62b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; R^63b and R^64b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^63b and R^64b taken together form an alkylene that may be substituted; and R^65b is a hydrogen or an alkyl, a compound represented by the formula (IX):

wherein R^71b and R^72b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^73b and R^74b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^73b and R^74b taken together form an alkylene that may be substituted; and R^75b is a hydrogen or an alkyl, a compound represented by the formula (X):

wherein R^81b and R^82b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^83b is an alkyl that may be substituted, an aryl that may be substituted, a heteroaryl, -R^85b- NHCO-R^86b, -O-R^85b-OC(=O)-R^86b, -CO-R^86b, -R^85b-NR^86b-C(=NH)-NR^87bR^88b, -R^85b-aryl that may be substituted, a glycosyl that may be substituted, wherein R^85b is an alkylene that may be substituted, R^86b is an alkyl that may be substituted, and R^87b and R^88b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^84b is a hydrogen or an alkyl, a compound represented by the formula (XI):

wherein R^91b and R^92b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; R^93b is an alkyl that may be substituted, -R^95b-OC(=O)-R^96b, -R^95b-OC(=O)-NH-^R96b, -R^95b- 0C(=O)-R^96b, or a benzyl or phenetyl that may be substituted, wherein R^95b is an alkylene, that may be substituted, and R^96b is an alkyl that may be substituted; and R^94b is a hydrogen or an alkyl, a compound represented by the formula (XII):

wherein R^101b and R^102b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^103b is an alkyl that may be substituted; and R^104b is a hydrogen or an alkyl, and a compound represented by the formula (XIII):

( X I I I ) wherein R^111b and R^112b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; R^113b is an amino, -NH-R^115b-SO₃H, -NH-SO₂-R^n4b, -O-R^114b, -O-R^115b-NHCO-R^116b, or -O- R^115b-NHCO-O-R^114b, wherein R^114b is an alkyl that may be substituted, R^115b is an alkylene that may be substituted, and R^116b is an aryl that may be substituted, or

R^113b is a single bond and, taken together with a nitrogen atom of a primary amino group in the compound, forms a diazetidine ring, and a compound represented by the formula (XIV):

wherein R^121b is a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^122b is a hydrogen or an alkyl.

[0011]

(2) A combination medicament comprising a compound or a pharmacologically acceptable salt thereof selected from the following group A and a compound or a pharmacologically acceptable salt thereof selected from the following group B:

<group A> a compound selected from a group consisting of a compound represented by a formula (I) and a compound represented by a formula (II) or a pharmacologically acceptable salt thereof: a compound represented by the formula (I):

R^11a and R^12a are the same or different, and are each a hydrogen, an alkyl, a cycloalkyl, a phenyl, P(=O)(OR’)2, S(=O)(OH), or a glycosyl that may be substituted;

R^13a and R^14a are the same or different, and are each a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a phenyl, -O-C(=O)-R’, -C(=O)-OR’, -C(=O)-R’, -C(=S)-R’, -O- C(=O)-NR’R”, -O-C(=S)-NR’R”, or O-C(=O)-R” ;

R^15a is a hydrogen, an alkyl, a cycloalkyl or a phenyl;

R’ and R” are the same or different, and are each a hydrogen, an alkyl, an alkenyl, a cycloalkyl or a phenyl, or R’ and R”, taken together with an adjacent nitrogen atom thereto, form a heteroaryl; and R’” is a hydrogen, an alkyl, an alkenyl or an alkynyl, and

[0012] a compound represented by the formula (II):

wherein R^20a is an amino acid side chain that may be substituted;

R^21a and R^22a are the same or different and are each a hydrogen, an alkyl, an alkanoyl, P(=O)(OH)2, S(=O)(OH) or a glycosyl that may be substituted; and R^23a, R^24a, and R^25a are the same or different, and are each a hydrogen or an alkyl,

[0013] <group B> a compound selected from a group consisting of compounds represented by formulas (III) to (IX) respectively or a pharmacologically acceptable salt thereof: a compound represented by the formula (III):

wherein R^10b is an amino acid side chain;

R^11b and R^12b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^13b is a hydrogen or an alkyl,

[0014] a compound represented by the formula (IV):

wherein R^20b is an amino acid side chain;

wherein R^30b is an amino acid side chain;

R^31b and R^32b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^33b is a hydrogen or an alkyl,

[0016] a compound represented by the formula (VI):

wherein R^4,b and R^42b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^43b and R^44b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^43b and R^44b taken together form an alkylene that may be substituted; and R^45b is a hydrogen or an alkyl,

[0017] a compound represented by the formula (VII):

R^53b and R^54b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^53b and R^54b taken together form an alkylene that may be substituted; and R^55b is a hydrogen or an alkyl,

[0018] a compound represented by the formula (VIII):

wherein R^61b and R^62b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^63b and R^64b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^63b and R^64b taken together form an alkylene that may be substituted; and R^65b is a hydrogen or an alkyl, and

[0019] a compound represented by the formula (IX):

R^73b and R^74b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^73b and R^74b taken together form an alkylene that may be substituted; and R^75b is a hydrogen or an alkyl.

[0020]

(3) The combination medicament according to the above (1) or (2), wherein the compound of group A is a compound represented by formula (I) or a pharmacologically acceptable salt thereof.

[0021]

(4) The combination medicament according to the above (1) or (2), wherein the compound of group A is a compound represented by formula (II) or a pharmacologically acceptable salt thereof.

[0022] (5) The combination medicament according to the above (1), wherein the compound of group A is a compound represented by formula (XV) or a pharmacologically acceptable salt thereof.

[0023]

(6) The combination medicament according to the above (1), wherein the compound of group A is a compound represented by formula (XVI) or a pharmacologically acceptable salt thereof.

[0024]

(7) The combination medicament according to any one of the above (1) to (6), wherein the compound of group B is a compound represented by formula (III) or a pharmacologically acceptable salt thereof.

[0025]

(8) The combination medicament according to any one of the above (1) to (6), wherein the compound of group B is a compound represented by formula (IV) or a pharmacologically acceptable salt thereof.

[0026]

(9) The combination medicament according to any one of the above (1) to (6), wherein the compound of group B is a compound represented by formula (V) or a pharmacologically acceptable salt thereof.

[0027]

(10) The combination medicament according to any one of the above (1) to (6), wherein the compound of group B is a compound represented by formula (VI) or a pharmacologically acceptable salt thereof.

[0028]

(11) The combination medicament according to any one of the above (1) to (6), wherein the compound of group B is a compound represented by formula (VII) or a pharmacologically acceptable salt thereof.

[0029] (12) The combination medicament according to any one of the above (1) to (6), wherein the compound of group B is a compound represented by formula (VIII) or a pharmacologically acceptable salt thereof.

[0030]

(13) The combination medicament according to any one of the above (1) to (6), wherein the compound of group B is a compound represented by formula (IX) or a pharmacologically acceptable salt thereof.

[0031]

(14) The combination medicament according to any one of the above (1) and (3) to (6), wherein the compound of group B is a compound represented by formula (X) or a pharmacologically acceptable salt thereof.

[0032]

(15) The combination medicament according to any one of the above (1) and (3) to (6), wherein the compound of group B is a compound represented by formula (XI) or a pharmacologically acceptable salt thereof.

[0033]

(16) The combination medicament according to any one of the above (1) and (3) to (6) wherein the compound of group B is a compound represented by formula (XII) or a pharmacologically acceptable salt thereof.

[0034]

(17) The combination medicament according to any one of the above (1) and (3) to (6), wherein the compound of group B is a compound represented by formula (XIII) or a pharmacologically acceptable salt thereof.

[0035]

(18) The combination medicament according to any one of the above (1) and (3) to (6), wherein the compound of group B is a compound represented by formula (XIV) or a pharmacologically acceptable salt thereof.

[0036] (19) The combination medicament according to the above (1), (2) or (3), wherein in the formula (I), R^10a is an amino acid side chain or an O-phosphorylated amino acid side chain selected from a group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, O-phosphorylated tyrosine, tryptophan, ornithine, lanthionine, 3,4-dihydroxyphenylalanine, and 3,4- dihydroxyphenylalanine in which one or two hydroxy groups are O-phosphorylated.

[0037]

(20) The combination medicament according to the above (1), (2) or (3), wherein in the formula (I), R^10a is an amino acid side chain or an O-phosphorylated amino acid side chain selected from a group consisting of lysine, valine, tyrosine, O-phosphorylated tyrosine, and 3,4-dihydroxyphenylalanine.

[0038]

(21) The combination medicament according to the above (1), (2), (3), (19) or (20), wherein in the formula (I), R^11a and R^12a are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^13a, R^14a, R^15a are each a hydrogen.

[0039]

(22) The combination medicament according to the above (1), (2), (3), (19) or (20), wherein in the formula (I), one of R^11a and R^12a is a hydrogen and the other is P(=O)(OH)₂; and R^13a, R^14a, R^15a are each a hydrogen.

[0040]

(23) The combination medicament according to the above (1), (2) or (4), wherein in the formula (II), R^20a is an amino acid side chain selected from a group consisting of a glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine and tyrosine.

[0041]

(24) The combination medicament according to the above (1), (2), (4) or (23), wherein in the formula (II), R^21a and R^22a are the same or different and are each a hydrogen, an acetyl, or P(=O)(OH)₂; and R^23a and R^24a are each a hydrogen.

[0042] (25) The combination medicament according to the above (1), (2), (4) or (23), wherein in the formula (II), one of R^21a and R^22a is a hydrogen and the other is P(=O)(OH)₂; and R^23a, R^24a, R^25a are each a hydrogen.

[0043]

(26) The combination medicament according to the above (1) or (5), wherein in the formula (XV), R^31a and R^32a are the same or different and are each a hydrogen, an acetyl, or P(=O)(OH)₂.

[0044]

(27) The combination medicament according to the above (1) or (5), wherein in the formula (XV), one of R^31a and R^32a is a hydrogen and the other is P(=O)(OH)₂.

[0045]

(28) The combination medicament according to the above (1) or (6), wherein in the formula (XVI), R^41a and R^42a are the same or different and are each a hydrogen, an acetyl, or P(=O)(OH)₂, and R^44a is a hydrogen.

[0046]

(29) The combination medicament according to the above (1) or (6), wherein in the formula (XVI), one of R^41a and R^42a is a hydrogen and the other is P(=O)(OH)₂, and R^44a is a hydrogen.

[0047]

(30) The combination medicament according to the above (1), (2) or (7), wherein in the formula (III), R^11b and R^12b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^13b is a hydrogen.

[0048]

(31) The combination medicament according to the above (1), (2) or (8), wherein in the formula (IV), R^21b and R^22b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^23b is a hydrogen.

[0049] (32) The combination medicament according to the above (1), (2) or (9), wherein in the formula (V), R^31b and R^32b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^33b is a hydrogen.

[0050]

(33) The combination medicament according to the above (1), (2) or (10), wherein in the formula (VI), R^41b and R^42b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^45b is a hydrogen.

[0051]

(34) The combination medicament according to the above (1), (2) or (11), wherein in the formula (VII), R^51b and R^52b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^55b is a hydrogen.

[0052]

(35) The combination medicament according to the above (1), (2) or (12), wherein in the formula (VIII), R^61b and R^62b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^65b is a hydrogen.

[0053]

(36) The combination medicament according to the above (1), (2) or (13), wherein in the formula (IX), R^71b and R^72b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^75b is a hydrogen.

[0054]

(37) The combination medicament according to the above (1) or (14), wherein in the formula (X), R^81b and R^82b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^84b is a hydrogen.

[0055]

(38) The combination medicament according to the above (1) or (15), wherein in the formula (XI), R^91b and R^92b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^94b is a hydrogen.

[0056] (39) The combination medicament according to the above (1) or (16), wherein in the formula (XII), R^101b and R^102b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^104b is a hydrogen.

[0057]

(40) The combination medicament according to the above (1) or (17), wherein in the formula (XIII), R^111b and R^112b are the same or different and are each a hydrogen or P(=O)(OH)₂.

[0058]

(41) The combination medicament according to the above ( 1 ) or ( 18), wherein in the formula (XIV), R^121b is a hydrogen or P(=O)(OH)₂; and R^122b is a hydrogen.

[0059]

(42) A compound represented by a formula (III) or a pharmacologically acceptable salt thereof:

wherein R^10b is an amino acid side chain, or R^10b, taken together with the adjacent nitrogen atom, forms a 5-membered heterocyclyl containing at least one nitrogen atom;

R^11b and R^12b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^13b is a hydrogen or an alkyl.

[0060]

(43) The compound according to the above (42) or a pharmacologically acceptable salt thereof, wherein R^11b and R^12b are the same or different and are each a hydrogen or P(=O(OH)₂, and R^13b is a hydrogen. [0061]

(44) A compound represented by a formula (IV) or a pharmacologically acceptable salt thereof:

wherein R^20b is an amino acid side chain;

R^21b and R^22b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^23b is a hydrogen or an alkyl.

[0062]

(45) The compound according to the above (44) or a pharmacologically acceptable salt thereof, wherein R^21b and R^22b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^23b is a hydrogen.

[0063]

(46) A compound represented by a formula (V) or a pharmacologically acceptable salt thereof:

wherein R^30b is an amino acid side chain;

R^31b and R^32b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^33b is a hydrogen or an alkyl.

[0064]

(47) The compound according to the above (46) or a pharmacologically acceptable salt thereof, wherein R^31b and R^32b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^33b is a hydrogen.

[0065]

(48) A compound represented by a formula (VI) or a pharmacologically acceptable salt thereof:

R^43b and R^44b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^43b and R^44b taken together form an alkylene that may be substituted; and R^45b is a hydrogen or an alkyl.

[0066]

(49) The compound according to the above (48) or a pharmacologically acceptable salt thereof, wherein R^41b and R^42b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^45b is a hydrogen.

[0067]

(50) A compound represented by a formula (VII) or a pharmacologically acceptable salt thereof:

R^53b and R^54b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^53b and R^54b taken together form an alkylene that may be substituted; and R^55b is a hydrogen or an alkyl. [0068]

(51) The compound according to the above (50) or a pharmacologically acceptable salt thereof, wherein R^51b and R^52b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^55b is a hydrogen.

[0069]

(52) A compound represented by a formula (VIII) or a pharmacologically acceptable salt thereof:

R^63b and R^64b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^63b and R^64b taken together form an alkylene that may be substituted; and R^65b is a hydrogen or an alkyl.

[0070]

(53) The compound according to the above (52) or a pharmacologically acceptable salt thereof, wherein R^61b and R^62b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^65b is a hydrogen.

[0071] (54) A compound represented by a formula (IX) or a pharmacologically acceptable salt thereof:

[0072]

(55) The compound according to the above (54) or a pharmacologically acceptable salt thereof, wherein R^71b and R^72b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^75b is a hydrogen.

[0073]

(56) A compound represented by the formula (X) or a pharmacologically acceptable salt thereof:

R^83b is an alkyl that may be substituted, an aryl that may be substituted, a heteroaryl, -R^85b- NHCO-R^86b, -O-R^85b-OC(=O)-R^86b, -CO-R^86b, -R^85b-NR^86b-C(=NH)-NR^87bR^88b, -R^85b-aryl that may be substituted, a glycosyl that may be substituted, wherein R^85b is an alkylene that may be substituted, R^86b is an alkyl that may be substituted, and R^87b and R^88b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^84b is a hydrogen or an alkyl.

[0074]

(57) The compound according to the above (56) or a pharmacologically acceptable salt thereof, wherein

R^81b and R^82b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^84b is a hydrogen.

[0075]

(58) A compound represented by the formula (XI) or a pharmacologically acceptable salt thereof:

wherein R^91b and R^92b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^93b is an alkyl that may be substituted, -R^95b-OC(=O)-R^96b, -R^95b-OC(=O)-NH-^R96b, -R^95b- 0C(=O)-R^96b, a benzyl or phenethyl that may be substituted, wherein R^95b is an alkylene, that may be substituted, and R^96b is an alkyl that may be substituted; and R^94b is a hydrogen or an alkyl.

[0076]

(59) The compound according to the above (58) or a pharmacologically acceptable salt thereof, wherein

R^91b and R^92b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^94b is a hydrogen.

[0077]

(60) A compound represented by the formula (XII) or a pharmacologically acceptable salt thereof:

R^103b is an alkyl that may be substituted; and R^104b is a hydrogen or an alkyl.

[0078]

(61) The compound according to the above (60) or a pharmacologically acceptable salt thereof, wherein

R^101b and R^102b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^104b is a hydrogen.

[0079]

(62) A compound represented by the formula (XIII) or a pharmacologically acceptable salt thereof:

wherein R^mb and R^112b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; R^113b is an amino, -NH-R^115b-SO₃H, -NH-SO₂-R^114b, -O-R^114b, -O-R^115b-NHCO-R^116b, or -O- R^115b-NHCO-O-R^114b, wherein R^114b is an alkyl that may be substituted, R^115b is an alkylene that may be substituted, and R^116b is an aryl that may be substituted, or

R^113b is a single bond and, taken together with a nitrogen atom of a primary amino group in the compound, forms a diazetidine ring.

[0080]

(63) The compound according to the above (62) or a pharmacologically acceptable salt thereof, wherein R^111b and R^112b are the same or different and are each a hydrogen or P(=O)(OH)₂.

[0081]

(64) A compound represented by the formula (XIV) or a pharmacologically acceptable salt thereof:

[0082]

(65) The compound according to the above (58) or a pharmacologically acceptable salt thereof, wherein R^121b is a hydrogen or P(=O)(OH)₂; and R^122b is a hydrogen.

[0083]

(66) A compound represented by a formula (1-1) or a pharmacologically acceptable salt thereof:

wherein R^10a is an amino acid side chain; and R^11a and R^12a are the same or different and are each a hydrogen, S(=O)(OH) or a glycosyl that may be substituted,

R^15a is a hydrogen or an alkyl, provided that R^11a and R^12a are not both each simultaneously a hydrogen.

[0084]

(67) A liquid pharmaceutical composition comprising a combination medicament containing a compound selected from the group A and a compound selected from the group B.

[0085]

(68) A therapeutic agent for a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain, the therapeutic agent comprising a combination medicament containing a compound selected from the group A and a compound selected from the group B.

[0086]

(69) The therapeutic agent according to the above (68), wherein the neurodegenerative disease and/or the disease or symptom caused by a decrease in dopamine concentration in the brain is Parkinson's disease.

Advantageous Effect of Invention [0087]

The combination medicament containing a levodopa prodrug and a carbidopa prodrug of the present invention is useful as a prophylactic or therapeutic agent for a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain, for example, Parkinson's disease. Further, the compounds (I) to (XIV) of the present invention described in the above groups A and B and the combination medicament thereof exhibit a high solubility and a high solution stability, and thus, can be used in a form of a liquid composition, and, for example, are useful as a minimally invasive continuous subcutaneous administration preparation suitable as a prophylactic or therapeutic agent for the above-described neurodegenerative disease or the like.

Description of Embodiments [0088]

Features of the present disclosure are described in detail below. Unless otherwise specified, definitions of groups in the present specification can be freely combined.

[0089]

The term “treatment” as used herein generally refers to obtaining a desired pharmacological and/or physiological effect. The term “treatment” as used herein includes treatment of a disease in a mammal, particularly a human, and includes: (a) inhibiting a disease, that is, preventing a disease from increasing in severity or scope ; (b) relieving a disease, that is, causing partial or complete amelioration of a disease; or (c) preventing relapse of a disease, that is, preventing a disease from returning to an active state after a previous successful treatment of the disease or symptoms of the disease.

[0090]

The term “preventing” as used herein includes delaying the onset of clinical symptoms, complications, or biochemical indicia of a state, disorder, disease, or condition that a subject is afflicted with or is predisposed to, but does not include yet experience or display of clinical or subclinical symptoms of the state, disorder, disease, or condition. “Preventing” includes prophylactically treating a state, disorder, disease, or condition of a subject, and includes prophylactically treating clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition of a subject.

[0091]

The term “patient” or “subject” as used herein includes any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or non-human primates, and humans. In some embodiments, a mammal treated using a method of the present invention is a human suffering from a neurodegenerative disease such as Parkinson’s disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain.

[0092]

The term “about” as used herein, unless specifically mentioned otherwise, is used to cover a range of ±10% of a stated value. Even without the use of the term “about,” a presented value may be considered to cover a range of ±10% of that value.

[0093]

The term “stable” as used herein, unless specifically mentioned otherwise, refers to a state of a substance that does not or is difficult to decompose in a solution. Therefore, the term “stable” as used herein means that, for example, when a solution of the substance is prepared and a peak area ratio of the substance measured using an area percentage method of high performance liquid chromatography (HPLC) immediately after the preparation of the solution is compared to a peak area ratio of the substance after being left at 25 °C for about 1 day, a decrease in peak area ratio is not observed or the degree of the decrease in peak area ratio is low.

[0094]

The term “liquid” as used herein, unless specifically mentioned otherwise, means any type of fluid, including gels, aqueous and non-aqueous compositions, and the like.

[0095]

The term “use in combination” as used herein, unless specifically mentioned otherwise, means administration of two or more active ingredients in combination, including administration of these active ingredients at the same time, either separately or in the same composition, and also includes administration of two or more active ingredients consecutively on the same day, and administration of the active ingredients separated from each other for a predetermined time period, and further includes administration of two or more active ingredients on different days.

[0096] The term “continuous” as used herein, unless specifically mentioned otherwise, refer to a time period during which a composition is administered over the entire time period, with intermissions of less than about 24 hours, for example, about 12 hours, about five hours, about three hours, about one hour, about 30 minutes, about 15 minutes, about five minutes or about one minute. A time period during which this drug is administered can be at least about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, three days, seven days, two weeks, one month, three months, six months, one year, two years, three years, five years, ten years, or the like.

[0097]

In the present invention, an alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (C_{1 - 6}). In particular, a group having 1 to 4 carbon atoms (C_{1 - 4}) is preferable. Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, t- butyl, n-pentyl, i-pentyl, n-hexyl, and the like.

Here, examples of substituent groups of the alkyl that may be substituted in R^33a, the alkyl that may be substituted in R^43a, the alkyl that may be substituted in R^83b and R^86b, the alkyl that may be substituted in R^93b and R^96b, the alkyl that may be substituted in R^103b, and the alkyl that may be substituted in R^114b include an alkyl, an alkoxy, a hydroxy, an amino, a carboxyl, a sulfo, and the like, and it may be substituted with 1 to 3 identical or different substituent groups.

[0098]

In the present invention, an alkoxy means a monovalent group in which the above alkyl is bonded to one oxygen atom, and examples thereof include linear or branched alkyl-O- having 1 to 6 carbon atoms (C_{1 - 6}). Specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, and the like.

[0099]

In the present invention, an alkenyl means a linear or branched unsaturated hydrocarbon chain having 2 to 6 carbon atoms having one carbon-carbon double bond, and examples thereof include vinyl, propenyl, butenyl, and various branched chain isomers of these. Preferably, an alkenyl means a linear or branched unsaturated hydrocarbon chain having 2 to 4 carbon atoms. [0100]

In the present invention, an alkynyl refers to a monovalent group of a linear or branched hydrocarbon chain having one or more triple bonds, and, for example, means a linear or branched alkynyl having 2 to 6 carbon atoms. Specific examples thereof include 2-propynyl,

3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,

4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl, and the like.

[0101]

In the present invention, an alkylene refers to a linear or branched saturated hydrocarbon divalent group having 1 to 6 carbon atoms (C_{1 - 6}), and specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, and the like.

Here, examples of the alkylene in R^45a, the alkylene in R^43b and R^44b, the alkylene in R^53b and R^54b, the alkylene in R^63b and R^64b, the alkylene in R^73b and R^74b, the alkylene that may be substituted in R^85b, the alkylene that may be substituted in R^95b, and the alkylene that may be substituted in R^115b preferably include methylene and ethylene, and the alkylenes may each be substituted. Examples of such substituent groups include alkyl, alkoxy, and the like, and it may be substituted with 1 - 3 identical or different substituent groups.

[0102]

In the present invention, an alkanoyl refers to a monovalent group in which the above- described alkyl is bonded to a carbonyl, and examples thereof include a linear or branched alkyl-CO- having 1 to 6 carbon atoms (C_{1 - 6}). Specific examples thereof include acetyl, propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, heptanoyle, and the like.

[0103]

In the present invention, a cycloalkyl refers to a monocyclic saturated hydrocarbon group having 3 to 8 carbon atoms (C_{3 - 8}). Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0104]

In the present invention, specific examples of a 5-membered heterocyclyl containing at least one nitrogen atom refers to pyrrolidine, imidazolidine, pyrazolidine, and the like.

[0105] In the present invention, an aryl refers to a monocyclic or polycyclic (fused) hydrocarbon group that exhibits aromatic properties. Specific examples thereof include a C_6-14 aryl such as phenyl, 1 -naphthyl, 2-naphthyl, biphenylyl, and 2-anthryl. Among them, a C_6-10 aryl is preferred.

Here, examples of substituent groups in the aryl that may be substituted in R^83b and the aryl that may be substituted in R^116b include an alkyl, an alkoxy, a hydroxy, an amino, a carboxyl, and the like, and it may be substituted with 1 to 3 identical or different substituent groups.

[0106]

In the present invention, an amino acid side chain refers to an amino acid side chain of a natural, synthetic, non-natural or non-protein-producing amino acid, and examples of the amino acid include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, lanthionine, selenocysteine, pyrrolidine, ADDA amino acid ((2S, 3S, 4E, 6E, 8S, 9S)-3-amino-9-methoxy-2, 6,8- trimethyl- 10-phenyldeca-4,6-dienoic acid), b-alanine, 4-aminobenzoic acid, g-aminobutyric acid, S-aminoethyl-L-cysteine, 2-aminoisobutyric acid, aminolevulinic acid, azetidine-2- carboxylic acid, canalin, canavanine, carboxyglutamic acid, chloroalanine, cystine, dehydroalanine, diaminopimelic acid, dihydroxyphenylglycine, endouracidine, homoserine, 4-phenylglycine, hydroxyproline, hypusine, b-Leucine, norleucine, norvaline, ornithine, penicillamine, placohipaphorin, pyroglutamic acid, quisqualic acid, sarcosine, theanine, tranexamic acid, trichromic acid, 3,4-dihydroxyphenylalanine, and the like. Examples of R^10a preferably include an amino acid side chain of arginine, lysine, alanine, valine, tyrosine and 3,4-dihydroxyphenylalanine. Examples of R^20a preferably include an amino acid side chain of glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine and tyrosine. Examples of R^10b preferably include an amino acid side chain of tyrosine and lysine. Examples of R^20b preferably include an amino acid side chain of alanine and lysine. Examples of R^30b preferably include an amino acid side chain of alanine and lysine.

[0107]

For example, amino acid side chains represented by R^10a, R^20a, R^10b, R^20b, and R^30b are represented by the following.

(An amino acid side chain of proline, wherein, R^10a, R^20a, R^10b, R^20b, R^30b each form a ring together with a nitrogen atom of the adjacent peptide bond of each compound)

[0108]

Here, the amino acid side chain in the present invention may be substituted, and examples thereof include -P(0)(OR6)₂ (where R.6 is a hydrogen, an alkyl, or the like), a glucosyl group (such as [(2R, 3S, 4R, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]), a group that bonds to another adjacent group to form an alkyl ene group that may be substituted (examples of substituent groups include an alkyl group, an alkoxy group, and the like), and the like. Examples of substituted amino acid side chains include those in which a tyrosine side chain, a serine side chain, a threonine side chain, or an amino acid side chain having a hydroxy such as (3,4-dihydroxyphenyl)methyl is substituted, and specific examples thereof include phosphonooxymethyl, (4-phosphonooxyphenyl)methyl, [4-[(2S, 3R, 4S, 5S, 6R)- 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]methyl, (2,2-dimethyl- l,3-benzodioxol-5-yl)methyl, (2-ethoxy-2-methyl-l,3-benzodioxol-5-yl)methyl, and the like. [0109]

In the present invention, monosaccharides that are the source of glycosyl include aldoses such as glucose (dextrose), ribose, erythrose, xylose, arabinose, mannose, and galactose, as well as ketoses such as ribulose, psicose, fructose, sorbose, and tagatose. These monosaccharides may be of d-form, 1-form or dl-form.

Here, a monosaccharides in the present invention may be substituted, and examples of substituent groups include a carbonyl group, an acetylamino group, a sulfmooxy group, a phosphonooxy group, and the like. Specific examples of substituted monosaccharides include glucuronic acid, N-acetylglucosamine, α-D-Glucopyranose-6-(hydrogen sulfate), and the like.

[0110]

In the present invention, the group in which R’ and R” together, and together with a nitrogen atom, form a heteroaryl, and a heteroaryl refer to a 5 to 10-membered aromatic heterocycle group containing 1 to 4 heteroatoms independently selected from a group consisting of a sulfur atom, an oxygen atom, and a nitrogen atom, and a monocyclic or bicyclic heteroaryl is preferable. A 5 to 10-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from a group consisting of a sulfur atom, an oxygen atom, and a nitrogen atom is more preferable. Specific examples thereof include pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridil, pyrazinyl, pyrimidinyl, pyridadinyl, thiazinyl, triazinyl, indrill, isoindrill, indazolyl, benzoimidazolyl, benthiazolyl, benzofuranyl, quinolyl, isoquinolyl, imidazopyridyl, benzopyranyl, and the like. Pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridil, pyrazinyl, pyrimidinyl, pyridadinyl, thiazinyl, triazinyl, and the like are preferable. In particular, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyridil, pyrazinyl, pyrimidinel, pyridadinyl, and the like are preferable.

[0111]

When a compound of the present invention has an asymmetric carbon atom in the molecule thereof, the compound of the present invention can exist as multiple stereoisomers (that is, diastereomeric isomers, and optical isomers) based on the asymmetric carbon atoms. The present invention includes any one of these stereoisomers and mixtures thereof. [0112]

The compounds of the present invention include compounds labeled with isotopes (for example, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³²P, ³⁵S, ¹²⁵I, and the like) and include deuterium converters.

[0113]

Examples of pharmacologically acceptable salts of the compounds of the present invention include inorganic acid addition salts (such as salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like), organic acid addition salts (such as salts of methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartrate acid, succinic acid, mandelic acid, malic acid, pantothenic acid, methyl sulfuric acid, and the like), inorganic base addition salts (such as salts of sodium, potassium, calcium, magnesium, and the like), salts of amino acids (such as salts of glutamic acid, aspartic acid, arginine, lysine, and the like), and the like.

The compounds of the present invention or pharmacologically acceptable salts thereof include any of intramolecular salts or adducts thereof, solvates or hydrates thereof, and the like.

[0114]

Preferred compounds of the general formula (I) or formula (1-1) are listed below.

Table 1

[0115] Preferred compounds of the general formula (II) are listed below.

Table 2

[0116]

Preferred compounds of any of the general formulae (III) to (XIV) are listed below.

Table 2-2

[Oi l 7]

The compounds represented by the general formula (I) of the present invention or pharmacologically acceptable salts thereof can be produced, for example, as follows.

Synthesis Method (A)

[wherein, Bn indicates a benzyl, Cbz indicates a carbobenzoxy, and the other symbols have the same meaning as above]

[Oi l 8]

Among the target compounds [I] of the present invention, the compound represented by the general formula [la] can be produced, for example, as follows. The compound [a] and the compound [b] are subjected to a condensation reaction to obtain the compound [c], and then, the compound [c] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [f] is obtained. On the other hand, the compound [f] can also be obtained by condensing the compound [e] and the compound [b]. The compound [la] can be produced by deprotecting the compound [f] thus obtained.

[Oi l 9]

Step l

The condensation reaction between the compound [a] or a salt thereof and the compound [b] or a salt thereof can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base, in the presence of a condensing agent, and in the presence or absence of an activating agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N,N-dimethylformamide and N-methylpyrrolidone; nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, diazabicycloundecene and the like. Examples of the condensing agent include O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and the like. Examples of the activating agent include 1 - hydroxy-7-azabenzotriazole (HO At), 1 -hydroxybenzotriazole (HOBt), 4- dimethylaminopyridine and the like.

[0120]

An amount of the compound [b] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [a],

[0121]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0to 2.0 equivalents, in molar ratio with respect to the compound [a].

[0122]

An amount of the condensing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [a].

[0123]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [a].

The present reaction can be carried out at room temperature to under heating, for example, at room temperature to 80 °C, preferably at room temperature to 50 °C.

[0124]

Step 2 The condensation reaction between the compound [c] and a phosphite esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence of an activating agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds.

An example of the phosphite esterifying agent is dibenzyl N,N-diisopropyl phosphoramidite. An example of the activating agent is 1-tetrazole.

[0125]

An amount of the phosphite esterifying agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [c].

[0126]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [c],

[0127]

The present reaction can be carried out under ice-cooling to under heating, for example, at 0 °C to 80 °C, preferably at room temperature to 50 °C.

[0128]

Step 3

The oxidation reaction of the compound [d] can be carried out according to a conventional method in a suitable solvent in the presence of an oxidizing agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the oxidizing agent include a hydrogen peroxide solution, tert-butyl hydroperoxide, metachloroperbenzoic acid, and the like.

[0129]

An amount of the oxidizing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [d].

[0130] The present reaction can be carried out under ice cooling to at room temperature, preferably under ice cooling.

[0131]

Step 4

The condensation reaction between the compound [c] and a phosphate esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence of a base. As the solvent, any solvent that does affect the present reaction may be used.

Examples of the solvent include: halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the phosphate esterifying agent include dibenzylphosphoryl chloride, tetrabenzyl pyrophosphate, and the like.

Examples of the base include: alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide; alkylamines such as triethylamine and diisopropylethylamine; and the like.

[0132]

An amount of the phosphate esterifying agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [c].

[0133]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [c].

[0134]

The present reaction can be carried out at room temperature to under heating, for example, at room temperature to 100 °C, preferably at room temperature to 70 °C.

[0135]

Step 5

The condensation reaction between the compound [e] or a salt thereof and the compound [b] or a salt thereof can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base, in the presence of a condensing agent, and in the presence or absence of an activating agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N,N-dimethylformamide and N-methylpyrrolidone; nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, diazabicycloundecene and the like. Examples of the condensing agent include O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and the like. Examples of the activating agent include 1- hydroxy-7-azabenzotriazole (HOAt), 1 -hydroxybenzotriazole (HOBt), 4- dimethylaminopyridine and the like.

[0136]

An amount of the compound [b] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [e].

[0137]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [e].

[0138]

An amount of the condensing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [e].

[0139]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [e].

[0140]

[0141]

Step 6

The deprotection of the compound [f] can be carried out according to a conventional method by a treatment with a catalyst in a suitable solvent in a hydrogen atmosphere. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol and isopropanol; water; or a mixture of these compounds; and the like.

[0142]

Examples of the catalyst include palladium carbon and the like.

[0143]

[0144]

Synthesis Method (B)

[wherein, R-OH is an amino acid side chain such as serine or tyrosine, and other symbols have the same meaning as above]

[0145]

Among the target compounds [I] of the present invention, the compound represented by the general formula [lb] can be produced, for example, as follows. The compound [g] and the compound [b-1] are subjected to a condensation reaction to obtain the compound [h]. The compound [h] is subjected to phosphite esterification to obtain the compound [i], which is then subjected to oxidation to obtain the compound [j], or, the compound [h] is subjected to phosphate esterification to obtain the compound [j]. After that, the compound [lb] can be produced by deprotecting the compound [j]. [0146]

Step 1

The condensation reaction between the compound [g] or a salt thereof and the compound [b- 1] or a salt thereof can be carried out in the same manner as the reaction between the compound [a] or a salt thereof and the compound [b] or a salt thereof in the synthesis method (A).

[0147]

Step 2

The condensation reaction between the compound [h] and a phosphite esterifying agent can be carried out in the same manner as the reaction between the compound [c] and a phosphite esterifying agent in the synthesis method (A).

[0148]

Step 3

The oxidation reaction of the compound [i] can be carried out in the same manner as the reaction of the compound [d] in the synthesis method (A).

[0149]

Step 4

The condensation reaction between the compound [h] and a phosphate esterifying agent can be carried out in the same manner as the reaction between the compound [c] and a phosphate esterifying agent in the synthesis method (A).

[0150]

Step 5

The deprotection of the compound [j] can be carried out in the same manner as the reaction of the compound [f] in the synthesis method (A).

[0151]

The compounds represented by the general formula (II) of the present invention or pharmacologically acceptable salts thereof can be produced, for example, as follows. Synthesis Method (C)

[wherein the symbols have the same meaning as above]

[0152]

Among the target compounds [II] of the present invention, the compound represented by the general formula [Ila] can be produced, for example, as follows. The compound [k-1] and the compound [1-1] are subjected to a condensation reaction to obtain the compound [m], and then, the compound [m] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [p] is obtained. On the other hand, the compound [p] can also be obtained by condensing the compound [o] and the compound [1-1], The compound [Ila] can be produced by subjecting the compound [p] thus obtained to deprotection or to hydrolysis and then deprotection.

[0153]

Step 1

The condensation reaction between the compound [k-1] or a salt thereof and the compound [1-1] or a salt thereof can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base, in the presence or absence of a condensing agent, and in the presence or absence of an activating agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1 ,4-dioxane; amides such as N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidone; nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, and the like. Examples of the condensing agent include O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide hydrochloride, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the like. Examples of the activating agent include l-hydroxy-7-azabenzotriazole (HOAt), 1- hydroxybenzotriazole (HOBt), 4-dimethylaminopyridine and the like.

[0154]

An amount of the compound [1-1] or [1-2] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [k- 1 ] .

[0155]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [k-1],

[0156]

An amount of the condensing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [k-1].

[0157]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [k-1],

[0158]

[0159]

Step 2 The condensation reaction between the compound [m] and a phosphite esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence of an activating agent. As the solvent, any solvent that does not affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds.

[0160]

An amount of the phosphite esterifying agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [m],

[0161]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [m],

[0162]

[0163]

Step 3

The oxidation reaction of the compound [n] can be carried out according to a conventional method in a suitable solvent in the presence of an oxidizing agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the oxidizing agent include a hydrogen peroxide solution, tert-butyl hydroperoxide, metachloroperbenzoic acid, and the like.

[0164]

An amount of the oxidizing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [n],

[0165] The present reaction can be carried out under ice-cooling to under heating, for example, at 0 °C to 80 °C, preferably at room temperature to 50 °C.

Step 4

[0166]

Step 4

The condensation reaction between the compound [m] and a phosphate esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence of a base. As the solvent, any solvent that does not affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the phosphate esterifying agent include dibenzylphosphoryl chloride, tetrabenzyl pyrophosphate, and the like. Examples of the base include: alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide; alkylamines such as triethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7-ene; and the like.

[0167]

An amount of the phosphate esterifying agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [m],

[0168]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [m].

[0169]

[0170]

Step 5

The condensation reaction between the compound [o] or a salt thereof and the compound [1- 1] or a salt thereof can be carried out in the same manner as the condensation of the compound [k-1] or a salt thereof and the compound [1-1] or a salt thereof in the synthesis method (C). [0171]

Step 6

The deprotection of the compound [p] can be carried out according to a conventional method by a treatment with a catalyst in a suitable solvent in a hydrogen atmosphere.

As the solvent, any solvent that does not affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; alcohols such . as methanol, ethanol and isopropanol; water; or a mixture of these compounds; and the like.

Examples of the catalyst include palladium/carbon, and the like.

[0172]

Step 7

The hydrolysis of the compound [q] can be carried out according to a conventional method in a suitable solvent in the presence of a base and water. As the solvent, any solvent that does not affect the present reaction may be used. Examples of the solvent include: alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran, 1,4-dioxane and 1,2- dimethoxyethane; water; or a mixture of these compounds; and the like. Examples of the base include: alkali metal hydroxides such as sodium hydroxide and lithium hydroxide; and the like. The present reaction can be carried out under ice-cooling to under heating, for example, at 0 °C to 50 °C, preferably at a room temperature.

[0173]

An amount of the base to be used can be 1.0 to 10.0 equivalents, preferably 1.0 to 4.0 equivalents, with respect to the compound [q],

[0174]

Step 8

The deprotection of the compound [q] can be carried out in the same manner as the deprotection of the compound [p] in the synthesis method (C).

[0175] Synthesis Method (D)

[wherein the symbols have the same meaning as above]

[0176]

Among the target compounds [II] of the present invention, the compound represented by the general formula [lib] can be produced, for example, as follows. The compound [k-2] and the compound [1-3] are subjected to a condensation reaction to obtain the compound [r], and then, the compound [r] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [t] is obtained. The compound [lib] can be produced by deprotecting the compound [t],

[0177]

Step 1

The condensation reaction between the compound [k-2] or a salt thereof and the compound [1-3] or a salt thereof can be carried out in the same manner as the condensation reaction between the compound [k-1] or a salt thereof and the compound [1-1] or a salt thereof in the synthesis method (C).

[0178]

Step 2

The condensation reaction between the compound [r] and a phosphite esterifying agent can be carried out in the same manner as the condensation reaction between the compound [m] and a phosphite esterifying agent in the synthesis method (C). [0179]

Step 3

The oxidation reaction of the compound [s] can be carried out in the same manner as the oxidation reaction of the compound [n] in the synthesis method (C).

[0180]

Step 4

The condensation reaction between the compound [r] and a phosphate esterifying agent can be carried out in the same manner as the condensation reaction between the compound [m] and a phosphate esterifying agent in the synthesis method (C).

[0181]

Step 5

The deprotection of the compound [t] can be carried out in the same manner as the deprotection of the compound [p] in the synthesis method (C).

[0182]

Synthesis Method (Έ1

[wherein, Ac indicates an acetyl, and the other symbols have the same meaning as above]

Among the target compounds [II] of the present invention, the compound represented by the general formula [lie] can be produced, for example, as follows. The compound [k-3] and the compound [I-1] are subjected to a condensation reaction to obtain the compound [u], and then, the compound [u] is subjected to deprotection, and thereby, the compound [lie] can be produced.

[0183]

Step 1 The condensation reaction between the compound [k-3] or a salt thereof and the compound [1-1] or a salt thereof can be carried out in the same manner as the condensation reaction between the compound [k-1] or a salt thereof and the compound [1-1] or a salt thereof in the synthesis method (C).

[0184]

Step 2

The deprotection of the compound [u] can be carried out in the same manner as the deprotection of the compound [p] in the synthesis method (C).

[0185]

Synthesis Method (F)

[wherein the symbols have the same meaning as above]

Among the target compounds [II] of the present invention, the compound represented by the general formula [lid] can be produced, for example, as follows. The compound [k-2] and the compound [1-1] are subjected to a condensation reaction to obtain the compound [v], and then, the compound [v] is subjected to deprotection, and thereby, the compound [lId] can be produced.

[0186]

Step 1

The condensation reaction between the compound [k-2] or a salt thereof and the compound [1-1] or a salt thereof can be carried out in the same manner as the condensation reaction between the compound [k-1] and the compound [1-1] or a salt thereof in the synthesis method (C).

[0187]

Step 2 The deprotection of the compound [v] can be carried out in the same manner as the deprotection of the compound [p] in the synthesis method (C).

[0188]

The compounds represented by the general formula (III) of the present invention or pharmacologically acceptable salts thereof can be produced, for example, as follows.

[0189]

Synthesis Method (G)

[wherein the symbols have the same meaning as above]

Among the target compounds [III] of the present invention, the compound represented by the general formula [Ilia] can be produced, for example, as follows. The compound [w] and the compound [x-1] are subjected to a condensation reaction to obtain the compound [y], and then, the compound [y] is subjected to deprotection, and thereby, the compound [Ilia] can be produced.

[0190]

Step 1

The condensation reaction between the compound [w] and the compound [x-1] or a salt thereof can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base, in the presence of a condensing agent, and in the presence or absence of an activating agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N,N-dimethylformamide and N-methylpyrrolidone; nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazobicyclo[5.4.0]undec-7-ene, and the like. Examples of the condensing agent include O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), 1 -ethyl -3-(3- dimethylaminopropyl)carbodiimide hydrochloride, 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and the like. Examples of the activating agent include 1- hydroxy-7-azabenzotriazole (HO At), 1 -hydroxybenzotriazole (HOBt), 4- dimethylaminopyridine and the like.

[0191]

An amount of the compound [x-1] to be Used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [w].

[0192]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [w],

[0193]

An amount of the condensing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [w].

[0194]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [w].

[0195]

[0196]

Step 2

The deprotection of the compound [y] can be carried out according to a conventional method by a treatment with a catalyst in a suitable solvent in a hydrogen atmosphere.

As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol and isopropanol; water; or a mixture of these compounds; and the like.

Examples of the catalyst include palladium/carbon, and the like.

[0197] The present reaction can be carried out at room temperature to under heating, for example, at room temperature to 80 °C, preferably at room temperature to 50 °C.

[0198]

Synthesis Method (H)

[wherein the symbols have the same meaning as above]

Among the target compounds [III] of the present invention, the compound represented by the general formula [Illb] can be produced, for example, as follows. The compound [z] and the compound [x-1] are subjected to a condensation reaction to obtain the compound [aa], and then, the compound [aa] is subjected to deprotection, and thereby, the compound [Illb] can be produced.

[0199]

Step 1

The condensation reaction between the compound [z] and [x-1] or a salt thereof can be carried out in the same manner as the condensation reaction between the compound [w] and the compound [x-1] or a salt thereof in the synthesis method (G).

[0200]

Step 2

The deprotection reaction of the compound [aa] can be carried out in the same manner as the deprotection reaction of the compound [y] in the synthesis method (G).

[0201]

Synthesis Method (I)

[wherein, t-Bu indicates a tert-butyl, and the other symbols have the same meaning as above]

Among the target compounds [IV] of the present invention, the compound represented by the general formula [I Va] can be produced, for example, as follows. The compound [bb] and the compound [x-2] are subjected to a condensation reaction to obtain the compound [cc], and then, the compound [cc] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [ee] is obtained. The compound [IV c] can be produced by deprotecting the compound [ee]. Alternatively, the compound [gg] can be obtained by condensing the compound [ff] and the compound [x-2]. After a two-step deprotection, the compound [IVa] can also be produced.

[0202]

Step 1

The condensation reaction between the compound [bb] or a salt thereof and the compound [x- 1] or a salt thereof can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base, in the presence of a condensing agent, and in the presence or absence of an activating agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N,N-dimethylformamide and N- methylpyrrolidone; nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, 1,8- diazobicyclo[5.4.0]undec-7-ene, and the like. Examples of the condensing agent include O- (7-azabenzotriazol-l-yI)-N,N,N',N'-tetramethyIuronium hexafluorophosphate (HATU), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and the like. Examples of the activating agent include 1- hydroxy-7-azabenzotriazole (HO At), 1 -hydroxybenzotriazole (HOBt), 4- dimethylaminopyridine and the like.

[0203]

An amount of the compound [x-1] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to- 2.0 equivalents, in molar ratio with respect to the compound [bb].

[0204]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [bb].

[0205]

An amount of the condensing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [bb],

[0206]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in molar ratio with respect to the compound [bb].

[0207]

[0208]

Step 2

The condensation reaction between the compound [cc] and a phosphite esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence of an activating agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds.

[0209]

An amount of the phosphite esterifying agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [cc].

[0210]

An amount of the activating agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [cc].

[0211]

[0212]

Step 3

The oxidation reaction of the compound [dd] can be carried out according to a conventional method in a suitable solvent in the presence of an oxidizing agent. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the oxidizing agent include a hydrogen peroxide solution, tert-butyl hydroperoxide, metachloroperbenzoic acid, and the like.

[0213]

An amount of the oxidizing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [dd].

[0214]

[0215] Step 4

The condensation reaction between the compound [cc] and a phosphate esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the phosphate esterifying agent include dibenzylphosphoryl chloride, tetrabenzyl pyrophosphate, and the like. Examples of the base include: alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide; alkylamines such as triethylamine, diisopropylethylamine and l,8-diazobicyclo[5.4.0]undec-7-ene; and the like.

[0216]

An amount of the phosphate esterifying agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [y].

[0217]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio with respect to the compound [y].

[0218]

[0219]

Step 5

The deprotection reaction of the compound [ee] can be carried out in the same manner as the deprotection reaction of the compound [y] in the synthesis method (G).

[0220]

Step 6

The condensation reaction between the compound [ff] or a salt thereof and “x-2” or a salt thereof can be carried out in the same manner as the condensation reaction between the compound [bb] or a salt thereof and the compound [x-2] or a salt thereof in the synthesis method (G). [0221]

Step 7

The deprotection of the compound [gg] can be carried out according to a conventional method in a suitable solvent in the presence or absence of an additive and in the presence of an acid or Lewis acid. As the solvent, any solvent that does affect the present reaction may be used. Examples of the solvent include: ethers such as methyl acetate, ethyl acetate, isopropyl acetate; ethers such as 1,4-dioxane and tetrahydrofuran; halogenated aliphatic hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons such as toluene; acetonitrile; or a mixture of these compounds. Examples of the additive include water, tetraethylsilane, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid, and the like. Examples of the Lewis acid include triethylsilyl trifluoromethanesulfonate, and the like.

[0222]

An amount of the additive to be used can be 1.0 to 10.0 equivalents, preferably 1.0 to 2.0 equivalents, with respect to the compound [gg].

[0223]

An amount of the acid or Lewis acid to be used can be 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, with respect to the compound [gg].

[0224]

The present reaction can be carried out under 0 °C to heating, for example, at room temperature to 80 °C, preferably at room temperature to 60 °C.

[0225]

Step 8

The deprotection reaction of the compound [hh] can be carried out in the same manner as the deprotection reaction of the compound [y] in the synthesis method (G).

[0226]

Synthesis Method (T)

[wherein the symbols have the same meaning as above]

Among the target compounds [V] of the present invention, the compound represented by the general formula [Va] can be produced, for example, as follows. The compound [ii] and the compound [x-1] are subjected to a condensation reaction to obtain the compound [jj]. The compound [jj] is subjected to phosphite esterification to obtain the compound [kk], which is then subjected to oxidation to obtain the compound [ll], or, the compound [jj] is subjected to phosphate esterification to obtain the compound [ll]. After that, the compound [Va] can be produced by deprotecting the compound [ll].

[0227]

Step 1

The condensation reaction between the compound [ii] or a salt thereof and the compound [x- 3] or a salt thereof can be carried out in the same manner as the reaction between the compound [k-1] and the compound [l-1] in the synthesis method (C).

[0228]

Step 2

The condensation reaction between the compound [jj] and a phosphite esterifying agent can be carried out in the same manner as the reaction between the compound [c] and a phosphite esterifying agent in the synthesis method (A).

[0229]

Step 3 The oxidation reaction of the compound [kk] can be carried out in the same manner as the reaction of the compound [d] in the synthesis method (A).

[0230]

Step 4

The condensation reaction between the compound [jj] and a phosphate esterifying agent can be carried out in the same manner as the reaction between the compound [c] and a phosphate esterifying agent in the synthesis method (A).

[0231]

Step 5

The deprotection of the compound [11] can be carried out in the same manner as the reaction of the compound [f] in the synthesis method (A).

[0232]

Synthesis Method (K)

[wherein the symbols have the same meaning as above]

Among the target compounds [VI] of the present invention, the compound represented by the general formula [Via] can be produced, for example, as follows. The compound [w] and the compound [x-4] are subjected to a condensation reaction to obtain the compound [mm], and then, the compound [mm] is subjected to deprotection, and thereby, the compound [Via] can be produced.

[0233]

Step 1

The condensation reaction between the compound [w] or a salt thereof and the compound [x- 4] or a salt thereof can be carried out in the same manner as the reaction between the compound [w] or a salt thereof and the compound [x-1] or a salt thereof in the synthesis method (G).

[0234]

Step 2

The deprotection of the compound [mm] can be carried out in the same manner as the reaction of the compound [f] in the synthesis method (A).

[0235]

Synthesis Method (L)

[wherein the symbols have the same meaning as above]

Among the target compounds [VII] of the present invention, the compound represented by the general formula [Vila] can be produced, for example, as follows. The compound [w] and the compound [x-5] are subjected to a condensation reaction to obtain the compound [nn], and then, the compound [nn] is subjected to deprotection, and thereby, the compound [Vila] can be produced.

[0236]

Step 1

The condensation reaction between the compound [w] or a salt thereof and the compound [x- 5] or a salt thereof can be carried out in the same manner as the reaction between the compound [w] or a salt thereof and the compound [x-1] or a salt thereof in the synthesis method (G).

[0237]

Step 2 The deprotection of the compound [nn] can be carried out in the same manner as the reaction of the compound [f] in the synthesis method (A).

[0238]

Synthesis Method (M)

[wherein the symbols have the same meaning as above]

Among the target compounds [VIII] of the present invention, the compound represented by the general formula [Villa] can be produced, for example, as follows. The compound [oo] and the compound [x-6] are subjected to a condensation reaction to obtain the compound [pp]. The compound [pp] is subjected to phosphite esterification to obtain the compound [qq], which is then subjected to oxidation to obtain the compound [rr], or, the compound [pp] is subjected to phosphate esterification to obtain the compound [rr]. After that, the compound [Vllla] can be produced by deprotecting the compound [rr].

[0239]

Step 1

The condensation reaction between the compound [oo] or a salt thereof and the compound [x- 6] or a salt thereof can be carried out in the same manner as the reaction between the compound [k-1] or a salt thereof and the compound [1-1] or a salt thereof in the synthesis method (C).

[0240]

Step 2

The condensation reaction between the compound [pp] and a phosphite esterifying agent can be carried out in the same manner as the reaction between the compound [c] and a phosphite esterifying agent in the synthesis method (A).

[0241]

Step 3

The oxidation reaction of the compound [qq] can be carried out in the same manner as the reaction of the compound [d] in the synthesis method (A).

[0242]

Step 4

The condensation reaction between the compound [pp] and a phosphate esterifying agent can be carried out in the same manner as the reaction between the compound [c] and a phosphate esterifying agent in the synthesis method (A).

[0243]

Step 5

The deprotection of the compound [rr] can be carried out in the same manner as the reaction of the compound [f] in the synthesis method (A).

[0244]

Synthesis Method (N)

[wherein the symbols have the same meaning as above]

Among the target compounds [IX] of the present invention, the compound represented by the general formula [IXa] can be produced, for example, as follows. The compound [ss] and the compound [x-7] are subjected to a condensation reaction to obtain the compound [tt]. The compound [tt] is subjected to phosphite esterification to obtain the compound [uu], which is then subjected to oxidation to obtain the compound [vv], or, the compound [tt] is subjected to phosphate esterification to obtain the compound [vv]. After that, the compound [IXa] can be produced by deprotecting the compound [vv].

[0245]

Step 1

The condensation reaction between the compound [ss] or a salt thereof and the compound [x- 7] or a salt thereof can be carried out in the same manner as the reaction between the compound [k-1] or a salt thereof and the compound [l-1] or a salt thereof in the synthesis method (C). _.

[0246]

Step 2 The condensation reaction between the compound [tt] and a phosphite esterifying agent can be carried out in the same manner as the reaction between the compound [c] and a phosphite esterifying agent in the synthesis method (A).

[0247]

Step 3

The oxidation reaction of the compound [uu] can be carried out in the same manner as the reaction of the compound [d] in the synthesis method (A).

[0248]

Step 4

[0249]

Step 5

The deprotection of the compound [vv] can be carried out in the same manner as the reaction of the compound [f] in the synthesis method (A).

[0250]

Synthesis Method (O)

[wherein the symbols have the same meaning as above]

[0251]

Among the target compounds [X] of the present invention, the compound represented by the general formula [Xa] can be produced, for example, as follows. The compound [ww] or a salt thereof and the compound [x-8] are subjected to a condensation reaction to obtain the compound [xx], and then, the compound [xx] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [zz] is obtained. The compound [Xa] can be produced by deprotecting the compound [zz]. Alternatively, the compound [bbb] can be obtained by condensing the compound [aaa] or a salt thereof and the compound [x-8]. After deprotection of the compound [bbb], the compound [Xa] can also be produced.

[0252]

Step 1

The condensation reaction between the compound [ww] or a salt thereof and the compound [x-8] can be carried out in the same manner as the condensation reaction between the compound [bb] or a salt thereof and the compound [x-2] in the synthesis method (I).

[0253] Step 2

The condensation reaction between the compound [xx] and a phosphite esterifying agent can be carried out in the same manner as the condensation reaction between the compound [cc] and a phosphite esterifying agent in the synthesis method (I).

[0254]

Step 3

The oxidation reaction of the compound [yy] can be carried out in the same manner as the oxidation reaction of the compound [dd] in the synthesis method (I).

[0255]

Step 4

The condensation reaction between the compound [xx] and a phosphate esterifying agent can be carried out in the same manner as the condensation reaction between the compound [cc] and a phosphate esterifying agent in the synthesis method (I).

Step 5

The deprotection reaction of the compound [zz] can be carried out in the same manner as the deprotection reaction of the compound [ee] in the synthesis method (I).

[0256]

Step 6

The condensation reaction between the compound [aaa] or a salt thereof and the compound [x-8] can be carried out in the same manner as the condensation reaction between the compound [ff] or a salt thereof and the compound [x-8] in the synthesis method (I).

[0257]

Step 7

The deprotection of the compound [bbb] can be carried out in the same manner as the deprotection of the compound [gg] in the synthesis method (I).

[0258]

Synthesis Method (P)

[wherein the symbols have the same meaning as above] [0259]

Among the target compounds [XI] of the present invention, the compound represented by the general formula [XIa] can be produced, for example, as follows. The compound [ww] or a salt thereof and the compound [x-9] are subjected to a condensation reaction to obtain the compound [ccc], and then, the compound [ccc] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [eee] is obtained. The compound [XIa] can be produced by deprotecting the compound [eee].

[0260]

Step 1

The condensation reaction between the compound [ww] or a salt thereof and the compound [x-9] can be carried out according to a conventional method in a suitable solvent in the presence of a base, and in the presence or absence of an additive. As the solvent, any solvent that does not affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, and the like. Examples of the additive include 1-hydroxy-7- azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and the like.

[0261] An amount of the compound [x-9] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio with respect to the compound [ww],

[0262]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 2.0 to 3.0 equivalents, in molar ratio with respect to the compound [ww].

[0263]

An amount of the additive to be used can be 1.0 to- 5.0 equivalents, preferably 1.0 to- 2.0 equivalents, in molar ratio with respect to the compound [ww].

[0264]

Step 2

The condensation reaction between the compound [ccc] and a phosphite esterifying agent can be carried out in the same manner as the condensation reaction between the compound [cc] and a phosphite esterifying agent in the synthesis method (I).

[0265]

Step 3

The oxidation reaction of the compound [ddd] can be carried out in the same manner as the oxidation reaction of the compound [dd] in the synthesis method (I).

[0266]

Step 4

The condensation reaction between the compound [ccc] and a phosphate esterifying agent can be carried out in the same manner as the condensation reaction between the compound [cc] and a phosphate esterifying agent in the synthesis method (I).

[0267]

Step 5 The deprotection reaction of the compound [eee] can be carried out in the same manner as the deprotection reaction of the compound [ee] in the synthesis method (I).

[0268]

Synthesis Method (Q)

[wherein the symbols have the same meaning as above]

[0269]

Among the target compounds [XII] of the present invention, the compound represented by the general formula [Xlla] can be produced, for example, as follows. The compound [ww] or a salt thereof and the compound [x-10] are subjected to a condensation reaction to obtain the compound [fff], and then, the compound [fff] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [hhh] is obtained. The compound [Xlla] can be produced by deprotecting the compound [hhh].

[0270]

Step 1

The condensation reaction between the compound [ww] or a salt thereof and the compound [x-10] can be carried out according to a conventional method in a suitable solvent in the presence of a base in the presence or absence of an additive. As the solvent, any solvent that does not affect the present reaction may be used. Examples of the solvent include: ethers such as tetrahydrofuran and 1 ,4-dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, and the like.

[0271]

An amount of the compound [x- 10] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, in molar ratio with respect to the compound [ww],

[0272]

An amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, in molar ratio with respect to the compound [ww].

[0273]

[0274]

Step 2

The condensation reaction between the compound [fff] and a phosphite esterifying agent can be carried out in the same manner as the condensation reaction between the compound [cc] and a phosphite esterifying agent in the synthesis method (I).

[0275]

Step 3

The oxidation reaction of the compound [ggg] can be carried out in the same manner as the oxidation reaction of the compound [dd] in the synthesis method (I).

[0276]

Step 4

The condensation reaction between the compound [fff] and a phosphate esterifying agent can be carried out in the same manner as the condensation reaction between the compound [cc] and a phosphate esterifying agent in the synthesis method (I).

[0277]

Step 5 The deprotection reaction of the compound [hhh] can be carried out in the same manner as the deprotection reaction of the compound [ee] in the synthesis method (I).

[0278]

Synthesis Method (R)

[0279]

Among the target compounds [XIV] of the present invention, the compound represented by the general formula [XlVa] can be produced, for example, as follows. Compound [iii] is phosphorylated to give compound [jjj], which is then hydrazinated to give compound [kkk]. This can be oxidized to obtain compound [lll], which is then deprotected to produce compound [XlVa].

The detailed reaction conditions for each step are the same as in Example 267, but can be modified as necessary according to the usual methods.

[0280]

The starting compounds in the above methods can be produced in the same manner as in known methods and/or in methods described in Examples described' later.

Introduction of a protecting group into a functional group and removal of a protecting group of a functional group can be carried out with reference to known methods (PROTECTIVE GROUPS in ORGANIC SYNTHESIS (by Theodora W. Greene, Peter G. M. Wuts), and the like).

[0281] A compound of the present invention or a starting compound thereof produced as described above is isolated and purified in a free form thereof or as a salt thereof. A salt can be produced by a commonly used salt preparation process. Isolation and purification can be carried out by applying conventional chemical procedures such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.

[0282]

When a compound of the present invention or a pharmacologically acceptable salt thereof exists as optical isomers based on asymmetric carbon atoms, it can be separated into individual optical isomers by ordinary optical resolution means (for example, a fractional crystallization method, and a separation method using a chiral column). Further, an optical isomer can also be synthesized using an optically pure starting material. Further, an optical isomer can also be synthesized by stereoselectively performing each reaction using an asymmetric auxiliary group or an asymmetric catalyst.

[0283]

The compound [I] or [II] of the present invention or a pharmacologically acceptable salt thereof can be orally or parenterally administered alone or as a pharmaceutical composition that contains the compound or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. Further, a combination of the compound [I] or [II] of the present invention or a pharmacologically acceptable salt thereof and any one of the compounds [III] to [XIV] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally by itself or as a pharmaceutical composition that contains the combination and a pharmacologically acceptable carrier.

[0284]

When a liquid pharmaceutical composition such as an injection or an infusion is produced, such a pharmacologically acceptable carrier may be a carrier commonly used in the art. Examples thereof include aqueous solvents (such as water for injection, and purified water), isotonizing agents (such as sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, and propylene glycol), buffers (such as a phosphoric acid buffer, an acetic acid buffer, a boric acid buffer, a carbonic acid buffer, a citric acid buffer, a tris buffer, a glutamic acid buffer, and an epsilon aminocaproic acid buffer), preservatives (such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, benzyl alcohol, benzalconium chloride, sodium dehydroacetate, sodium edetate, boric acid, and borax), soothing agents (such as lidocaine hydrochloride, procaine hydrochloride, benzyl alcohol, and chlorobutanol), viscous agents (such as hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene glycol), stabilizers (such as sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, and dibutylhydroxytoluene), pH adjusting agents (such as hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid), and the like. The liquid pharmaceutical composition can be produced by dissolving or dispersing the compound or combination medicament of the present invention described above in a solution to which these carriers are appropriately added. Such pharmaceutically acceptable additives can be appropriately selected by a person skilled in the art according to a purpose, and a condition such as an additive amount can also be appropriately set. Further, when necessary, a solubilizing agent or the like may be used.

Further, such a liquid pharmaceutical composition can also be applied to a device (pump) for subcutaneous delivery.

[0285]

A dosage amount of the compound [I] or [II] of the present invention or a pharmacologically acceptable salt thereof varies depending on an administration method, and age, body weight, condition and the like of a patient. However, when administered as a liquid pharmaceutical composition, it is usually 1 to 200 mg/kg per day.

A dosage amount of any one of the compounds [III] to [XIV] of the present invention or a pharmacologically acceptable salt thereof varies depending on an administration method, and age, body weight, condition and the like of a patient. However, when administered as a liquid pharmaceutical composition, it is usually 0.02 to 100 mg/kg per day.

[0286]

In some embodiments, a liquid pharmaceutical composition disclosed herein comprises between about 10 to about 45 % w/v, at least about 30 % w/v, or between about 30 to about 45 % w/v of the compound (I) or (II) or (XV) or (XVI) of the invention, or an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof. According to some embodiments, the liquid pharmaceutical composition comprises between about 2.5 to about 5 % w/v, between about 5 to about 10 % w/v, between about 10 to about 15 % w/v, between about 15 to about 20 % w/v, between about 20 to about 25 % w/v, between about 25 to about 30 % w/v, at least about 30%, between about 30 to about 35 % w/v, between about 35 to about 40 % w/v, between about 30 to about 45 % w/v, between about 30 to about 50 % w/v, between about 30 to about 55 % w/v, between about 30 to about 60 % w/v, between about 30 to about 65 % w/v, between about 30 to about 70 % w/v, between about 40 to about 45 % w/v, between about 45 to about 50 % w/v, between about 50 to about 55 % w/v, between about 55 to about 60 % w/v, between about 60 to about 65 % w/v, between about 65 to about 70 % w/v, between about 10 to about 12.5 % w/v, between about 12.5 to about 17.5 % w/v, between about 17.5 to about 22.5 % w/v, between about 22.5 to about 27.5 % w/v, between about 27.5 to about 32.5 % w/v, between about 32.5 to about 37.5 % w/v, between about 37.5 to about 42.5 % w/v, between about 42.5 to about 45 % w/v, about 10 % w/v, about

12.5 % w/v, about 15 % w/v, about 17.5 % w/v, about 20 % w/v, about 22.5 % w/v, about 25 % w/v, about 27.5 % w/v, about 30 % w/v, about 32.5 % w/v, about 35 % w/v, about 37.5 % w/v, about 40 % w/v, about 42.5 % w/v, about 45 % w/v, about 47.5 % w/v, about 50 % w/v, about

52.5 % w/v, about 55 % w/v, about 57.5 % w/v, about 60 % w/v, about 62.5 % w/v, about 65 % w/v, about 67.5 % w/v, about 70 % w/v of the compound (I) or (II) or (XV) or (XVI) of the invention, an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof.

[0287]

In some embodiments, a liquid pharmaceutical composition of the invention may comprise between about 0.25 to about 3.0 % w/v of any one of the compounds (III) to (XIV) or a pharmaceutically acceptable salt thereof. According to some embodiments, the liquid pharmaceutical compositions comprises between about 0.25 to about 0.5 % w/v, between about 0.5 to about 0.75 % w/v, between about 0.75 to about 1.0 % w/v, between about 1.0 to about

1.25 % w/v, between about 1.25 to about 1.5 % w/v, between about 1.5 to about 1.75 % w/v, between about 1.75 to about 2.0 % w/v, between about 2.0 to about 2.25 % w/v, between about

2.25 to about 2.5 % w/v, between about 2.5 to about 2.75 % w/v, between about 2.75 to about 3.0 % w/v, between about 0.5 to about 1.0 % w/v, between about 1.0 to about 1.5 % w/v, between about 0.75 to about 1.4 % w/v, between about 0.6 to about 0.9 % w/v, between about 0.7 to about 0.8 % w/v, about 0.5 % w/v, about 0.55% w/v, about 0.6 % w/v, about 0.65 % w/v, about 0.7 % w/v, about 0.75 % w/v, about 0.8 % w/v, about 0.85 % w/v, about 0.9 % w/v, about 0.95 % w/v, about 1.0 % w/v, about 1.05 % w/v, about 1.1 % w/v, about 1.15 % w/v, about 1.2 % w/v, about 1.25 % w/v, about 1.3 % w/v, about 1.35 % w/v, about 1.4 % w/v, about 1.45 % w/v, about 1.5 % w/v, of any one of the compounds (III) to (XIV) or a pharmaceutically acceptable salt thereof.

[0288]

In some embodiments, the stabilizer is present in an amount of about 0.1 to about 30 % w/v. [0289]

In some embodiments, the stabilizer comprises a base. In some embodiments, the base is selected from the group consisting of arginine, NaOH, NH₄OH, tris(hydroxymethyl)aminomethane (TRIS), ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. In some embodiments, the base is selected from the group consisting of arginine, NH₄OH, ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. In some embodiments, the base is selected from the group consisting of L-Arg, diethylamine, and a combination thereof. In some embodiments, the base is selected from the group consisting of L-Arg, ethanolamine, and a combination thereof.

[0290]

In some embodiments, the liquid pharmaceutical composition comprises between about 0.1 to about 30 % w/v of the base. In some embodiments, the liquid pharmaceutical composition comprises between about 1.5 to about 20 % w/v of the base.

[0291]

In some embodiments, a liquid pharmaceutical composition disclosed herein has a pH in the range of between about 5 to about 10 at about 25°C. In some embodiments, a liquid pharmaceutical composition disclosed herein has a pH in the range of between about 8 to about 10. In some embodiments, a liquid pharmaceutical composition disclosed herein has a pH in the range of between about 8 to about 9.

[0292]

In some embodiments, a liquid pharmaceutical composition disclosed herein can include a free base of the compound (I) or (II) or (XV) or (XVI) or any one of the compounds (III) to (XIV) and a counterion.

[0293] Any of the aforementioned liquid pharmaceutical compositions described herein can further include an antioxidant or a combination of two or more antioxidants. For example, in some embodiments, a liquid pharmaceutical composition described herein can include an antioxidant selected from the group consisting of ascorbic acid or a salt thereof, a cysteine, e.g., N-acetyl cysteine (NAC), a bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a Cu²⁺ chelator, and any combination thereof. In some embodiments, a liquid pharmaceutical composition described herein can include between about 0.05 to about 1.5 % w/v of an antioxidant or a combination of antioxidants. In some embodiments, the liquid pharmaceutical composition comprises a combination of ascorbic acid and NAC.

[0294]

Any of the aforementioned liquid pharmaceutical composition described herein can further include at least one of: a catechol-O-methyltransferase (COMT) inhibitor, a monoamine oxidase (MAO) inhibitor, a surfactant, a buffer, an acid, a base, a solvent, or any combination thereof. In some embodiments, the liquid pharmaceutical composition comprises between about 5.0 to about 40.0 % w/v of a buffer, base, or solvent. For example, in some embodiments, a liquid pharmaceutical composition described herein can include a solvent, wherein the solvent may be N-methylpyrrolidone (NMP), tris(hydroxymethyl)aminomethane (tromethamine, TRIS), an ether such as tetrahydrofuran and 1,4-dioxane an amide, such as N,N-dimethylformamide and N-methylpyrrolidone, a nitrile, such as acetonitrile, a halogenated aliphatic hydrocarbon, such as chloroform and dichloromethane, an aromatic hydrocarbon, such as toluene or any combination thereof. It is noted that certain materials, such as tromethamine (TRIS) may be added to the composition and function, e.g., as a base, buffer, solvent, or any combination thereof. In some embodiments, a liquid pharmaceutical composition described herein can include a surfactant, wherein the surfactant is Tween-80. In some embodiments, a liquid pharmaceutical composition described herein can include a solvent and a surfactant, where the solvent is NMP and the surfactant is Tween-80. In some embodiments, the liquid pharmaceutical composition can include between about 0.1 to about 1.0 % w/v of the surfactant, for example, 0.1 to about 1.0 % w/v of Tween-80. In some embodiments, the liquid pharmaceutical composition can include between about 5.0 to about 40.0 % w/v of the solvent, for example, between about 5.0 to about 40.0 % w/v of NMP.

[0295] In certain embodiments, the solvent is TRIS. In certain embodiments, the stabilizer includes polyethylene glycol.

[0296]

The compounds of the present invention or pharmacologically acceptable salts thereof and the combination medicament of the present invention can each be formulated in a form of a liquid pharmaceutical composition, for example, as a formulation applicable to all appropriate routes of administration by parenteral administration such as bolus administration or continuous administration. Specifically, the liquid pharmaceutical composition of the present invention can be formulated for subcutaneous administration, transdermal administration, intradermal administration, transmucosal administration, intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, intratracheal administration, intrathecal administration, intraduodenal administration, intrapleural administration, intranasal administration, sublingual administration, buccal administration, intestinal administration, intraduodenal administration, rectal administration, intraocular administration or oral administration. Further, the composition can also be formulated for inhalation or direct absorption through mucosal tissues.

[0297]

The present invention provides a method for treating a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain, for example, Parkinson's disease and related symptoms, including administration of a combination medicament containing effective amounts of a levodopa prodrug compound of the formula (I) or (II) or (XV) or (XVI), or a pharmacologically acceptable salt thereof, and a carbidopa prodrug compound of the any of formulas (III) to (XIV), or a pharmacologically acceptable salt thereof, to a patient. Further, in the present invention, effective amounts of a levodopa prodrug compound of the formula (I) or (II) or (XV) or (XVI), or a pharmacologically acceptable salt thereof, and a carbidopa prodrug compound of the any of formulas (III) to (XIV), or a pharmacologically acceptable salt thereof, can be formulated together, or formulated separately and administered to a patient in forms of pharmaceutical compositions. Such pharmaceutical compositions can be administered to a patient at the same time or administered separately to a patient. Accordingly, the term “combination medicament” as used herein may comprise effective amounts of a levodopa prodrug compound of the formula (I) or (II) or (XV) or (XVI), or a pharmacologically acceptable salt thereof, and a carbidopa prodrug compound of the any of formulas (III) to (XIV), or a pharmacologically acceptable salt thereof, wherein the levodopa prodrug, or a pharmacologically acceptable salt thereof, and the carbidopa prodrug, or a pharmacologically acceptable salt thereof, may be formulated in a single formulation or in separate formulations. The separate formulations may be administered to the patient at the same time or at different times, e.g., within certain predefined time intervals, or at time intervals as required, possibly defined by the patient, a caregiver or a physician, e.g., based on the condition of the patient.

[0298]

In the present invention, in addition to the levodopa prodrug compound of the formula (I) or (II) or (XV) or (XVI), or a pharmacologically acceptable salt thereof, and the carbidopa prodrug compound of any of formulas (III) to (XIV), or a pharmacologically acceptable salt thereof, one or more additional therapeutic agents (for example, an anti-Parkinson's disease drug) can be used in combination for treatment of Parkinson's disease. Specific examples of such therapeutic agents include decarboxylase inhibitors (such as benserazide), catechol-O- methyltransferase (“COMT”) inhibitors (such as entacapone and tolcapone), monoamine oxidase A (“MAO-A”) or monoamine oxidase B (“MAO-B”) inhibitors (such as moclobemide, rasagiline, selegiline and safinamide), and the like.

[0299]

The combination medicament of the present invention can be administered at the same time as the above-described additional therapeutic agents that can be used in combination, or can be administered separately. Further, when the combination medicament of the present invention is used therapeutically together with the above-described additional therapeutic agents that can be used in combination, the combination medicament of the present invention and the additional therapeutic agents can be administered in the same dosage form such as parenteral administration, and may be administered in different dosage forms such as parenteral administration for one and oral administration for the other.

[0300] The compounds and the combination medicament of the present invention are useful for prevention or treatment of a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain. Specifically, the compounds and the combination medicament of the present invention are useful for prevention or treatment of Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's disease-like syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome, dystonia, Alzheimer's disease, Lewy body dementias (LBD), akinesia, bradykinesia, and hypokinesia, and are preferably useful for prevention or treatment of Parkinson's disease. Further, the compounds and the combination medicament of the present invention are useful for prevention or treatment of diseases or symptoms caused by a brain damage including carbon monoxide poisoning or manganese poisoning, or diseases or symptoms associated with neurological diseases or neurological disorders including alcoholism, drug addiction or erectile dysfunction.

[0301]

According to some embodiments, the method of the invention comprises administering the liquid pharmaceutical composition substantially continuously. According to some embodiments, the liquid pharmaceutical composition is administered subcutaneously. According to some embodiments, the liquid pharmaceutical composition is administered subcutaneously via a designated pump device.

[0302]

Embodiments of a designated pump may be, for example, any of the pump embodiments disclosed in US 62/529784, US 62/576362, PCT/IB2018/054962, US 16/027804, US 16/027710, US 16/351072, US 16/351076, US 16/351061, USD 29/655583, USD 29/655587, USD 29/655589, USD 29/655591, USD 29/655592, USD 29/655594, USD 29/655597, US 62/851903, and US 29/723714, all of which are incorporated herein by reference in their entirety.

[0303]

According to some embodiments, the method of the invention comprises administering the liquid pharmaceutical composition at one site, two sites, or three or more sites, wherein the position of the sites may be changed at any appropriate, possibly pre-determined, intervals. Once administered via a specific site, according to some embodiments, the administration via the same site, or the vicinity of that site, may be only after a, possibly predefined, period of time. According to some embodiments, the position of any one of the sites is changed after 12, 24, 36, 48, 60 or 72 hours. According to some embodiments, the position of the site is changed after 4, 5, 6 or 7 days. According to some embodiments, the position of the site is changed after two, three or four weeks. According to some embodiments, the position of the site is changed when required or desired, e.g., according to subjective data received from the patient and/or according to objective data received, e.g., from sensors located at, or in the vicinity of, the injection site(s).

[0304]

According to some embodiments, the administrated volume and/or the administration rate is identical in all or at least two of the sites. According to other embodiments, the administration rate and/or administrated volume differ from site to site. Each site may be controlled independently or otherwise, all sites may be controlled dependently on one another.

[0305]

According to some embodiments, the method of the invention comprises subcutaneously administrating between about 1 to about 15 ml of the liquid pharmaceutical composition of the invention over the course of 24 hours. According to some embodiments, the method of invention comprises subcutaneously administrating between about 1 to about 2, between about 2 to about 3, between about 3 to about 4, between about 4 to about 5, between about 5 to about 6, between about 6 to about 7, between about 7 to about 8, between about 8 to about 9, between about 9 to about 10, between about 10 to about 11, between about 11 to about 12, between about 12 to about 13, between about 13 to about 14, between about 14 to about 15 ml over the course of 24 hours.

[0306]

It is noted that the administration rate may be constant over the course of 24 hours or may change over the course of 24 hours. For instance, according to some embodiments, there may be a certain rate for high activity/day hours and a different rate for low activity/night hours. The high activity/day hours may be, e.g., about 15, about 16, about 17, about 18 or about 19 hours, while the low activity night hours may be about 9, about 8, about 7, about 6 or about 5 hours, respectively. According to some embodiments, the high activity/day rate is implemented for about 18 hours, while the low activity/night rate is implemented for about 6 hours. According to some embodiments, the high activity /day rate is implemented for about 16 hours, while the low activity/night rate is implemented for about 8 hours.

[0307]

According to some embodiments, the administration rate is constant over the course of 24 hours. According to some embodiments, the liquid pharmaceutical formulation is administered for a certain period of time in each 24 hours, e.g., 8 hours a day, 9 hours a day, 10 hours a day, 11 hours a day, 12 hours a day, 13 hours a day, 14 hours a day, 15 hours a day , 16 hours a day, 17 hours a day, 18 hours a day, 19 hours a day, 20 hours a day, 21 hours a day, 22 hours a day, or 23 hours a day. According to some embodiments, the number of hours of administration per day may be constant over the course of a certain number of days, e.g., 7 days, 14 days, 21 days, 28 days, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, or more. According to some embodiments, the number of hours of administration per day may vary from day to day, according to the patient’s condition, aa caregiver’s or physician’s decision, input from sensors, and the like. It is further noted that while only whole hours are specifically mentioned, any parts of hours, days, months, etc., are possible for administration, e.g., 16.5 hours a day, 7.5 days, and the like.

[0308]

The administration rate may be between about 0.01 mL/site/hour to about 1 mL/site/hour. According to some embodiments, the administration rate is between about 0.01-0.02 mL/site/hour. According to some embodiments, the administration rate is between about 0.02- 0.03 mL/site/hour. According to some embodiments, the administration rate is between about 0.03-0.04 mL/site/hour. According to some embodiments, the administration rate is between about 0.04-0.05 mL/site/hour. According to some embodiments, the administration rate is between about 0.05-0.06 mL/site/hour. According to some embodiments, the administration rate is between about 0.06-0.07 mL/site/hour. According to some embodiments, the administration rate is between about 0.07-0.08 mL/site/hour. According to some embodiments, the administration rate is between about 0.08-0.09 mL/site/hour. According to some embodiments, the administration rate is between about 0.09-0.1 mL/site/hour. According to some embodiments, the administration rate is between about 0.1-0.15 mL/site/hour. According to some embodiments, the administration rate is between about 0.15-0.2 mL/site/hour. According to some embodiments, the administration rate is between about 0.2-0.25 mL/site/hour. According to some embodiments, the administration rate is between about 0.25- 0.3 mL/site/hour. According to some embodiments, the administration rate is between about 0.3-0.35 mL/site/hour. According to some embodiments, the administration rate is between about 0.35-0.4 mL/site/hour. According to some embodiments, the administration rate is between about 0.4-0.45 mL/site/hour. According to some embodiments, the administration rate is between about 0.45-0.5 mL/site/hour. According to some embodiments, the administration rate is between about 0.5-0.55 mL/site/hour. According to some embodiments, the administration rate is between about 0.55-0.6 mL/site/hour. According to some embodiments, the administration rate is between about 0.6-0.65 mL/site/hour. According to some embodiments, the administration rate is between about 0.65-0.7 mL/site/hour. According to some embodiments, the administration rate is between about 0.7-0.75 mL/site/hour. According to some embodiments, the administration rate is between about 0.75-0.8 mL/site/hour. According to some embodiments, the administration rate is between about 0.8-0.85 mL/site/hour. According to some embodiments, the administration rate is between about 0.85- 0.9 mL/site/hour. According to some embodiments, the administration rate is between about 0.9-0.95 mL/site/hour. According to some embodiments, the administration rate is between about 0.95-1.0 mL/site/hour.

[0309]

According to some embodiments, the administration rate in the low activity/night hours is between about 0.01-0.15 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.01-0.02 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.02-0.03 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.03-0.04 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.04-0.05 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.05-0.06 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.06-0.07 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.07-0.08 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.08-0.09 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.09-0.1 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.1-0.11 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.11-0.12 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.12- 0.13 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.13-0.14 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.14-0.15 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is about 0.04 mL/site/hour.

[0310]

According to some embodiments, the administration rate in the high activity/day hours is between about 0.15-1.0 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.15-0.2 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.2-0.25 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.25-0.3 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.3-0.35 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.35-0.4 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.4-0.45 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.45-0.5 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.5-0.55 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.55-0.6 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.6-0.65 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.65-0.7 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.7-0.75 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.75-0.8 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.8-0.85 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.85-0.9 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.9-0.95 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.95-1.0 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is about 0.32 mL/site/hour.

[0311]

It is further noted that the administrated volume and/or administration rate may be constant throughout the treatment, or may vary during different hours of the day, between different days, weeks or months of treatment, and the like. According to some embodiments, the patient is monitored, e.g., independently, by a caretaker, or electronically, e.g., by sensors, possibly found in a dedicated device, e.g., a watch-like device, the administration pump, and the like. According to such embodiments, the administration volume and/or rate are determined according to data received from such monitoring.

[0312]

Some embodiments are directed to a method for administering a bolus subcutaneous injection of the liquid pharmaceutical composition of the invention. According to some embodiments, the bolus injection comprises between about 0.5 to about 2.0 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.5 to about 0.75 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 to about 1.0 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.0 to about 1.25 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.25 to about 1.5 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.5 to about 1.75 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.75 to about 2.0 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 to about 1.25 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.0 mL/Kg of the liquid pharmaceutical composition. [0313]

The bolus subcutaneous injection may be administered at any time point in relation to any possible continuous subcutaneous administrations, e.g., prior to, during, or after the continuous administration.

[0314]

According to some embodiments, the administered dose may be doubled, tripled or more, by using more than one pump, more than one injection site for each pump, and the like.

[0315]

According to some embodiments, the liquid pharmaceutical compositions are administered for a defined period of time, e.g., days, weeks, months, or years. According to some embodiments, the liquid pharmaceutical compositions are administered endlessly, for the treatment of a chronic condition.

[0316]

A combination medicament containing a compound of Levodopa Prodrug lor 2 or a pharmacologically acceptable salt thereof and a compound of Carbidopa Prodrug or a pharmacologically acceptable salt thereof described in the following examples is also included in the present invention.

Examples

[0317]

In the following, the present invention is described in more detail with reference to Examples. However, the present invention is not limited to these Examples.

A mass spectrum (MS) was measured in a positive ion mode using liquid chromatography- mass spectrometry.

[Levodopa Prodrug 1] (a compound of formula (I) or (XV) )

[0318]

Example 1: Preparation of levodopa amino acids (LDAA)

Ten LDAA conjugates were prepared for initial screening as trifluoroacetic acid (TFA) salts.

Preparation of Levodopa Arginine TFA salt (LD-Arg TFA salt)

[0319]

Preparation of Levodopa Glycine TFA salt (LD-Gly TFA salt)

Preparation of Levodopa Lysine TFA salt (LD-Lys TFA salt)

[0321]

Preparation of Levodopa Aspartic Acid TFA salt (LD-Asp TFA salt)

[0322]

Preparation of Levodopa Glutamic Acid TFA salt (LD-Glu TFA salt)

[0323]

Preparation of Levodopa Glutamine TFA salt (LD-Gln TFA salt)

Preparation of Levodopa Asparagine TFA salt (LD-Asn TFA salt)

[0325]

Preparation of Levodopa Tyrosine TFA salt (LD-Tyr TFA salt)

[0326]

Preparation of Levodopa Tryptophan TFA salt (LD-Trp TFA salt)

[0327]

Preparation of Levodopa-Lanthionine TFA salt (LD-LA TFA salt) Step 1: Halogenation

[0328]

Step 2: Hydrolysis

[0329]

Step 3: Deprotection

[0330]

Step 4: Coupling

[0331]

Step 5: Coupling with protected Levodopa

[0332]

Step 6: Deprotection (Fmoc removal) and diastereomers separation

[0333]

Step 7a: Deprotection of LD and isolation of Levodopa Lanthionine peak 1 TFA salt (LD-LA 1 TFA salt)

[0334]

Step 7b: Deprotection of LD and isolation of Levodopa Lanthionine peak 2 TFA salt (LD-LA 2 TFA salt)

[0335]

It is noted that, throughout this document, although LD-LA 1 (referred to also as levodopa lanthionine peak 1 or levodopa lanthionine 1) is demonstrated as being the (S) (S) (R) isomer, and LD-LA 2 (referred to also as levodopa lanthionine peak 1 or levodopa lanthionine 1) is demonstrated as being the (S) (R) (R) isomer, the two prepared isomers were not fully identified and therefore, the isomers may be opposite to what is demonstrated and depicted throughout this document.

[0336]

Example 2: Preparation of levodopa amino acids (LDAA) free base forms

CBz protection of L-DOPA

The synthesis was performed using CBz-chloride and NaOH as the base. L-DOPA (200 g,

1.014 mol,) was suspended in water (600 mL) and cooled to 0°C under nitrogen. A mixture of NaOH (81.3 g, 2.033 mol) in water (600 mL) was added at 0°C. CBz-chloride (211.4 g,

1.239 mol) in dioxane (800 mL) was added at 0°C over the course of 1 h. The mixture was allowed to warm to room temperature. After approximately 1 hour, a conversion of 73% was observed. Another portion of NaOH (4.9 g, 0.123 mol) in water (60 mL) and CBz-chloride (20.8 g, 0.122 mol) in dioxane (80 mL) was added. The reaction mixture was stirred overnight at room temperature. A conversion of 83% was observed. Another portion of NaOH (8.1 g, 0.203 mol) in water (50 mL) and CBz-chloride (35 g, 0.205 mol) in dioxane (50 mL) was added. When a conversion of 94% was obtained (1.5 h after addition) the pH was adjusted to 10 with 3 M NaOH, and the mixture was washed with MTBE (1 L). The pH of the aqueous phase was adjusted to 2 using 6 M HC1, and the aqueous phase was extracted with MTBE (2 x 1L). The combined organic phases were washed with water (1 L) and 25% NaCl, aq. (1 L). The organic phase was dried over sodium sulphate, filtered, evaporated under a reduced pressure and dried in vacuum to give 448.3 g (135%) as a sticky, brown mass (purity (280 nm) was 82.5%).

[0337]

Deprotection of CBz-L-DOPA- (CBz/Bn) -Lys

CBz-L-DOPA- (CBz/Bn) -Lys (93.4 g) was dissolved in methanol (4.2 L). The atmosphere was exchanged for nitrogen (3 times), after which 10% Pd/C (18.8 g) was added and the atmosphere was again exchanged for nitrogen (2 times) and, subsequently, hydrogen (3 times). The reactor was evacuated/filled with hydrogen. After 4.5 h it was estimated by HPLC analysis that the reaction was complete. The reaction mixture was filtered through Celite® and evaporated under a reduced pressure at a water bath temperature of 40°C. The compound precipitated during evaporation. When approximately 400 mL was left, the suspension was filtered, and the filter cake was washed with methanol (50 mL). The solid was dried in vacuum at 25°C overnight to provide 33.1 g (75%) of LD-Lys free base as an off-white solid (purity was 99.0%).

[0338]

Example 2.2; Preparation of the free base form of LD-Tyr

Coupling with H-Tyr-OBzl

EDC-C1 (46.3 g, 242 mmol) was added in portions, over the course of 10 min, to a solution of BnO-Tyr (64.9 g, 239 mmol), HOBt (36.8 g, 88 w/w%, 240 mmol) and CBz-L-DOPA (363.1 g, 20.1 w/w% solution in DMF, 220 mmol) in DMF (863.2 g, 0.9 L), at 0 °C. The reaction was stirred at 0 °C for 4 hours before water (1.7 kg) was added over the course of 30 min, and the reaction mixture was allowed to heat to ambient temperature. EtOAc (2.6 kg, 2.8 L) was charged to the reactor and the phases separated. The organic phase was washed with water three times (1.5 L, 1.4L and 1.4L). Celite® (450 g) was added to the crude organic phase, and the mixture was concentrated to dryness. The crude residue was purified by flash column chromatography (silica gel column, 3.2 kg packed with EtOAc/dichloromethane 1:1 (v/v)), by loading the Celite®-mixture onto the column and eluting with EtOAc/dichloromethane 1:1 (v/v). Selected fractions (12 L) were concentrated under a reduced pressure at a water bath having a temperature of 45°C. The selected fractions were further dried in vacuum overnight. L-DOPA-BnOTyr was isolated as a slightly brown solid (44.7 g, 35%) with a purity of 96.4%. The column was flushed with 20% MeOH in CH2C12 (10 L) and all fractions containing L-DOPA-Bn-OTyr were collected and concentrated under a reduced pressure at a water bath with temperature of 45°C. The crude residue (60.2 g) was dissolved in 2-PrOH (432.1 g, 550 mL) by heating the mixture to 75 °C. The solution was filtered while hot and allowed to cool to ambient temperature and stirred overnight to give a precipitate. The suspension was filtered, and the filter cake washed with 2-PrOH (166 g, 211 mL) and dried in vacuum at 30 °C overnight to yield CBz-L-DOPA-Tyr (OBn) as a white solid (34.9 g, 27%) with a purity of 95.1 %.

[0339]

Deprotection of CBz-L-DOPA-Tyr (OBn) A solution of L-DOPA-BnOTyr (60.4 g, 103 mmol) in MeOH (2051 g, 2.6 L) was purged with nitrogen three times (vacuum (<250 mbar) followed by filling with N2). 10% Pd/C (12.0 g) was added to the reactor, which was subsequently purged with hydrogen (vacuum (>250 mbar) followed by filling with H2). The reactor was evacuated/filled with H2 after 1 hour and 20 minutes and left an additional 30 min before being evacuated/filled with N2 and filtered through Celite®. The filter cake was washed with MeOH (418.9 g, 529 mL), and the combined filtrates were concentrated under a reduced pressure. At approximately a volume of 500 mL the solution was filtered through a 0.45 pm pore filter and the filtrate concentrated to dryness under a reduced pressure. The oily solid was dried overnight at vacuum to yield LD-Tyr free base as an off-white solid (36.5 g, 98%) with a purity of 95.4%.

[0340]

Example 3: Synthesis of LD-Lys HCl, LD-Tyr HCl and LD-Arg HCl salts Example 3.1: Synthesis of LD-Arg HCl salt - method #1

Coupling with H-Arginine (NO2) -OBn

CBz-L-DOPA (342.9 g, 20.1 w/w% solution in DMF, 208 mmol) was dissolved in DMF (690 mL). HOBt.H20 (35.2 g, 228 mmol (88% w/w)) and H-Arg (N02) OBn, p-tosylate (110.0 g, 228 mmol) were added. The solution was cooled to 0°C. Triethylamine (23.2 g, 228 mmol) was added, and then EDC. HC1 (43.7 g, 228 mmol) was added in portions, while the temperature was kept at 0°C. The coupling mixture was stirred for 2.5 h and then quenched with water (1400 mL). The mixture was extracted with EtOAc three times (1400 mL and 2 x 700 mL). The organic phases were combined.

The organic phase was evaporated under a reduced pressure at a water bath temperature of 40°C. The residue was dissolved in 8 vol distilled THF, 8 volumes water was added, resulting in an emulsion. The emulsion was applied to a reverse phase column (26 equivalents of Phenomenex Sepra C-18-T (50 pm, 135 A) packed with THF and conditioned with 700 mL 20% distilled THF/water). The column was eluted with 40% distilled THF in water. The pure fractions were evaporated under a reduced pressure until mainly water was left. The suspension was cooled and filtered. The filter cake was dried to provide a solid (259 g) that was not dried; rather, it was placed in a freezer until further processing.

[0341] CBz-L-DOPA-Arg (NQ2V(OBn)

CBz-L-DOPA-Arg (N02)-(0Bn) (230.4 g wet, approximately 68.6 g dry, 110 mmol) was suspended in methanol (6.45 L) and water (1.29 L), and HC1 (36%, aq., 43 mL) was added. The reaction flask was evacuated to 250 mbar, and the atmosphere was exchanged for nitrogen three times. The mixture was heated to 40°C.

10% Pd/C (14.0 g) was added and the atmosphere was exchanged for nitrogen (3 times) and then hydrogen (3 times). The reaction mixture was protected from light. The atmosphere was exchanged for hydrogen. After 3 h, the atmosphere was exchanged for nitrogen (3 times). The suspension was filtered through Celite®, and the filter cake was washed with 20% water/methanol (600 mL). The pH of the filtrate was adjusted to pH 6 using an ion exchange resin (Dowex 1x8 chloride form, pre-activated with 1 M NaOH and washed with water to pH 7). The pH was adjusted in four portions, each of which was filtered and washed with 20% water/methanol (250 mL). The filtrates were evaporated under a reduced pressure at a water bath temperature of 50°C to a volume of approximately 500 mL. The residue was treated with activated carbon (5.0 g) for 40 minutes. The suspension was filtered over Celite®, the filter cake was washed with water (150 mL), and the combined filtrate and wash were concentrated to dryness under a reduced pressure at a water bath temperature of 50°C. The solid residue was dried overnight in vacuum to provide 48.1 g as a light brown solid (purity 95.6%). The prepared LD-Arg HC1 salt comprises one equivalent of HC1.

[0342]

Example 3.2: Synthesis of LD-Arg HCI salt - method #2

Synthesis of N-Boc-L-Dopa

[0343]

Synthesis of 2, 5-dioxopyrrolidin-l-yl (2S)-2-[(tert-butoxycarbonyl) aminol-3-(3,4- dihydroxyphenyl) propanoate

[0344]

Synthesis of (2S)-2-[(2S)-2-[Ytert-butoxycarbonyl) aminol-3-(3.4-dihydroxyphenyl) propanamidol-5-carbamimidamidopentanoic acid

[0345]

Synthesis of LD-Arg HC1

Example 3.3: Synthesis of LD-Tyr HC1 salt

Synthesis of benzyl (2S)-2-[(2S)-2-[(tert-butoxycarbonyl ) aminol-3-(3.4-dihydroxyphenyl) propanamidol -3-(4-hydroxyphenyl) propanoate

[0347]

Synthesis of (2SV2-[(2SV2-[(tert-butoxycarbonyl) aminol-3-(3,4-dihydroxyphenyl) propanamidol 3-(4-hydroxyphenyl) propanoic acid

[0348]

Synthesis of LD-Tyr HC1

[0349]

Example 3.4; Synthesis of LD-Lys HC1 salt

Synthesis of benzyl (2S)-6-[(tert-butoxycarbonyl) aminol-2-[(2S)-2-[(tert-butoxycarbonyl) amino] -3-(3.4-dihydroxyphenyl) propanamidol hexanoate

[0350]

Synthesis of (2S)-6-[(tert-butoxycarbonyl) amino]-2-[(2S)-2-[(tert-butoxycarbonyl) aminol- 3 -(3.4- dihydroxyphenyl) propanamidolhexanoic acid

[0351]

Synthesis of LD-Lys HC1

[0352]

Example 4:

Production of (2S)-6-amino-2-[[(2S)-2-amino-3-(3-hydroxy-4- phosphonooxyphenyl)propanoyl] amino] hexanoic acid

Benzyl (2S)-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2- (phenylmethoxycarbonylamino)propanoyl]amino]-6-

(phenylmethoxycarbonylamino)hexanoato (3.29 g) was dissolved in a mixed solvent of tetrahydrofuran (13 mL), ethanol (13 mL) and water (13 mL), and palladium/carbon (hydrous) (106 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. Tetrahydrofuran (20 mL) and water (26 mL) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. Water (57 mL) was added to the reaction mixture, precipitate was dissolved at 65 °C, and insoluble matter was removed by celite filtration. Insoluble matter was washed with water, and the filtrate was distilled under a reduced pressure until the volume thereof was reduced to about half, and freeze-drying was performed, and then, the title compound (1.41 g) as a crude product was obtained.

MS (ESI); m/z 406.2 [M+H]+

[0353]

Examples 5 to 18:

The corresponding starting compounds were respectively treated in the same manner as in Example 4 to obtain the compounds shown in Table 3 below.

Table 3

[0354]

Example 19;

Production of (2S)-2-[[(2S)-2-amino-3-(3-hydroxy-4- phosphonooxyphenyl)propanoyl]amino]-3-(3-hydroxy-4-phosphonooxyphenyl) propanoic acid

(1) A suspension of dibenzyl N,N-diisopropyl phosphoramidite (615 uL) and 1H-tetrazole (115 mg) in acetonitrile (3 mL) was added to a solution of benzyl (2S)-3-(4-hydroxy-3- phenylmethoxyphenyl)-2-[[(2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2- (phenylmethoxycarbonylamino)propanoyl]amino]propanoate (430 mg) in dichloromethane (9 mL), and the mixture was stirred at room temperature for 13.5 hours. Dibenzyl N,N- diisopropyl phosphoramidite (205 uL) and 1H-tetrazole (35 mg) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, a tert-butyl hydroperoxide aqueous solution (70%) (0.39 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform, an organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 60/40 - 35/65), and thereby, a crude product of benzyl (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3- phenylmethoxyphenyl] -2- [[(2 S)-3 - [4-bis(phenylmethoxy)phosphoryloxy-3 -phenylmethoxy phenyl] -2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoate (565 mg) was obtained.

[0355]

(2) The crude product of benzyl (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3- phenylmethoxyphenyl]-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxy phenyl] -2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoate (290 mg) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), acetic acid (1 mL) and water (0.5 mL), and palladium/carbon (hydrous) (50 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 25.5 hours. Water (10 mL) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble matter. The insoluble matter was washed with water (20 mL). After freeze-drying, the title compound (112 mg) was obtained.

MS (ESI); m/z 537.3 [M+H]+

[0356]

Examples 20 and 21: The corresponding starting compounds were respectively treated in the same manner as in Example 4 to obtain the compounds shown in Table 4 below.

[0357]

[Levodopa Prodrug 2] (a compound of formula (II) or (XVI))

Example 22:

Production of (2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-(3-hydroxy-4- phosphonooxyphenyl) propanoic acid

(2S)-3 - [4-bis (phenylmethoxy)phosphoryloxy-3 -phenylmethoxyphenyl] -2- [ [(2S)-2- (phenylmethoxycarbonylamino)propanoyl]amino] benzyl propanoate (551 mg) was dissolved in a mixed solvent of ethanol (2 mL) and tetrahydrofuran (2 mL), and palladium/carbon (hydrous) (69 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 7 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble matter. The insoluble matter was washed with water/ethanol (2:1, 12 mL), and the filtrate was distilled under a reduced pressure until the filtrate was reduced to about 1 mL, and freeze-drying was performed, and then, the title compound (214 mg, yield: 100%) as a white powder was obtained.

MS (ESI); m/z 349.1 [M+H]+

[0358]

Example 23 to 40 and 101 to 112:

The corresponding starting compounds were respectively treated in the same manner as in Example 21 to obtain the compounds shown in Table 5 below. Some of the compounds shown in Table 5 below can be obtained in the same manner as above example.

Table 5

[0359]

Example 41;

Production of (2S)-2-[[(2S)-2-amino-5-carbamimidamide pentanoyl]amino]-3-(3,4- dihydroxyphenyl) propanoic acid; hydrochloride

benzyl (2S)-3-[3,4-bis(phenylmethoxy)phenyl]-2-[[(2S)-5-[(N-Nitrocarbamimideyl)amino]- 2-(phenylmethoxycarbonylamino)pentanoyl]amino] propanoate (257 mg) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), 2-propanol (3 mL) and 2M hydrochloric acid (0.80 mL), and palladium/carbon (hydrous) (341 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. 2-propanol (4 mL) and water (6 mL) were added to the reaction mixture, and insoluble matter was removed using a membrane filter. The insoluble matter was washed with water (6 mL), 2-propanol (25 mL) was added, and the mixture was distilled under a reduced pressure. Diisopropyl ether was added to the residue, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the title compound (144 mg, yield: 100%) as a yellow-brown powder was obtained.

MS (ESI); m/z 354.2 [M+H]+

[0360]

Examples 113 to 120

The compounds shown in Table 5-6 below can be obtained in the same manner as above example.

Table 5-6

[0361]

[Carbidopa Prodrug] ( a compound of any one of formulas (III) to (XIV))

Example 42:

Production of (2S)-6-amino-2-[[(2S)-2-hydrazinyl-3-(3-hydroxy-4- phosphonooxyphenyl)-2-methylpropanoyl]amino] hexanoic acid

benzyl (2S -2-[[(2S)-3- [4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2- methyl-2-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino]propanoyl]amino]- 6-(phenylmethoxycarbonylamino) hexanoate (89 mg) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (0.2 mL), and palladium/carbon (hydrous) (10 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. Water (0.2 mL) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble matter. The insoluble matter was washed with water (4 mL), and the filtrate was distilled under a reduced pressure until the volume of the filtrate was reduced to about 3/4, and freeze-drying was performed, and then, the title compound (30 mg, yield: 97%) was obtained.

MS (ESI); m/z 435.4 [M+H]+

[0362]

Examples 43 to 45 and 201 to 254: The corresponding starting compounds were respectively treated in the same manner as in Example 42 to obtain the compounds shown in Table 6 below.

Table 6

[0363]

Example 255: Production of (2S)-2-[2-[(2S)-2-amino-3-(3-hydroxy-4- phosphonooxyphenyl)propanoyl]hydrazinyl]-3-(3-hydroxy-4-phosphonooxyphenyl)-2- methylpropanoic acid

(1) 1H-Tetrazole (41 mg) and dibenzyl N,N-diisopropylphosphoroamidite (0.20 mL) were added under ice-cooling to a mixture of benzyl (2S)-2-[2-[(2S)-2-(benzyloxycarbonylamino)- 3-(3-benzyloxy-4-hydroxy-phenyl)propanoyl]hydrazinyl]-3-(3-benzyloxy-4-hydroxy-phenyl) -2-methylpropanoate (181 mg), dichloromethane (1.8 mL), and acetonitrile (0.68 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was ice- cooled, a tert-butyl hydroperoxide decane solution (5.5 M) (0.092 mL) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and then, extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 50/50 to 25/75), and thereby, a crude product of benzyl (2S)-2-[2-[(2S)-2-(benzyloxycarbonylamino)- 3 -(3-benzyloxy-4-dibenzyloxyphosphoryloxy-phenyl)propanoyl]hydrazinyl] -3 -(3 -benzyloxy- 4-dibenzyloxyphosphoryloxy-phenyl)-2-methylpropanoate (130 mg) as a colorless viscous substance was obtained.

[0364]

(2) The crude product (128 mg) obtained in (1) was dissolved in a mixed solvent of tetrahydrofuran (0.48 mL), methanol (0.48 mL) and water (0.64 mL), and palladium/carbon (hydrous 50 wt%) (11 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered through Celite® to remove insoluble matter. The organic solvent was distilled away under a reduced pressure, and freeze-drying was performed, and then, the title compound (44 mg, 2-step yield: 36%) was obtained.

MS (ESI); m/z 564.2 [M-H]-

[0365]

Examples 256 to 258:

The corresponding starting compounds were respectively treated in the same manner as in Example 255 to obtain the compounds shown in Table 6-3 below.

Table 6-3

[0366]

Example 259:

Production of (2S)-3-(3-hydroxy-4-phosphonooxyphenyl)-2-methyI-2-[2-(pyridin-3- carbonyl)hydrazinyl] propanoic acid

A 4M hydrogen chloride ethyl acetate solution (0.40 mL) and triethylsilane (0.051 mL) were added at room temperature to a mixture of tert-butyl (2S)-3-[4-[bis[(2-methylpropan-2- yl)oxy]phosphoryloxy] -3 -hydroxyphenyl] -2-methyl-2- [2-(pyridine-3 -carbonyl)hydrazinyl] propanoate (46.6 mg) and ethyl acetate (2 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was distilled under a reduced pressure, a 4M hydrogen chloride ethyl acetate solution (0.40 mL) and triethylsilane (0.051 mL) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was distilled under a reduced pressure. The obtained residue was suspended and washed twice with ethyl acetate. A precipitated solid was collected by filtration and was dried under a reduced pressure, and the title compound (16.6 mg, yield: 46%) was obtained.

MS (ESI); m/z 412.1 [M+H]+

[0367]

Examples 260-261;

The corresponding starting compound was treated in the same manner as in Example 259 to obtain the compound shown in Table 6-4 below.

Table 6-4

Examples 262 to 266

[0368]

The compounds shown in Table 6-5 below can be obtained in the same manner as above example.

Table 6-5

[0369]

Example 267:

Production of azane;(2S)-2-hydrazinyl-2-methyl-3-(4-phosphonooxyphenyl)propanoic acid

X-4 (1) To a mixture of compound X-1 (3000 mg) and acetonitrile (30 mL) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (2.5 mL) and tetrabenzyl diphosphate (8.91 g) under ice cooling, and the mixture was gradually raised to room temperature and stirred for 16 hours. l,8-diazabicyclo[5.4.0]undec-7-ene (1.17 mL) and tetrabenzyl diphosphate (4.08 g) were added and the mixture was stirred at room temperature for 15 min. The solvent in the reaction mixture was removed under a reduced pressure. The mixture was diluted in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (200 mL x2), 1M hydrochloric acid (150 mL), and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, and the solvent was removed under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 50/50) to afford compound X-2 (6609 mg, yield: 94%) as a colorless viscous substance.

MS (ESI); m/z 425.1 [M+H]+

[0370]

(2) To a mixture of compound X-2 (6609 mg) and acetonitrile (28 mL) was added benzyl-N benzyloxycarbonyliminocarbamate (5.57 g), (2R,4S)-4 -[tert- butyl(diphenyl)silyl]oxypyrrolidine-2 -carboxylic acid (258 mg), and trifluoroacetic acid (0.054 mL), and the mixture was stirred at room temperature for 17 hours 30 minutes. The reaction mixture was passed through silica gel column chromatography (solvent: hexane/ethyl acetate = 50/50, 80 mL), and the filtrate was washed with saturated sodium bicarbonate solution (200 mL). The organic layer was washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, and the solvent was removed under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 67/33 to 45/55) to afford compound X-3 (4125 mg, yield: 39%) as a white powder.

MS (ESI); m/z 721.2 [M-H]-

[0371]

(3) To a mixture of compound X-3 (2021 mg) and acetonitrile (20 mL) was added sodium dihydrogen phosphate (668 mg), water (9 mL) and dimethyl sulfoxide (0.94 mL), and then sodium chlorite (1291 mg) was added under ice cooling, and the mixture was stirred at 0°C for 3 hours. Sodium sulfite (1458 mg) was added to the reaction mixture under ice cooling and the mixture was stirred. The solvent in the reaction mixture was removed under a reduced pressure. Ethyl acetate and water were added and the mixture was separated. The organic layer was washed three times with water/saturated aqueous sodium chloride solution (1:1), dried over magnesium sulfate, and the solvent was removed under a reduced pressure to afford compound X-4 (2089 mg, yield quant.) as a colorless viscous substance.

MS (ESI); m/z 737.2 [M-H]-

[0372]

(4) Compound X-4 (1159 mg) was dissolved in a mixture of tetrahydrofuran (8 mL) and water (4 mL), and ammonium carbonate (431 mg) and palladium/carbon (hydrous) (108 mg) were added. The mixture was stirred for 6 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite® to remove insoluble material. The insoluble material was washed with water (8 mL) and lyophilized to give the title compound (527 mg, yield quant.).

MS (ESI); m/z 291.1[M+H]+

[0373]

Example 46:

Production of (2S)-2-[[(2S)-2-hydrazinyl-3-(3-hydroxy-4-phosphonooxyphenyl)-2- methylpropanoyl]amino]-3-(4-hydroxyphenyl) propanoic acid

(1) To a mixture of benzyl (2S)-2-[[(2S)-3-[4-bis (phenylmethoxy) phosphoryloxy-3- phenylmethoxyphenyl] -2 -methyl-2 - [phenylmethoxycarbonyl

(phenylmethoxycarbonylamino)amino]propanoyl] amino] -3 -(4-phenylmethoxyphenyl) propanoate (209 mg) and N,N-dimethylformamide (2 mL), l-hydroxy-7-azabenzotriazole (HO At) (40 mg), 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (WSCI) (57 mg), benzyl (2S)-2-amino-3-(4-benzyloxyphenyl) propanoate; hydrochloride (108 mg) and N,N-diisopropylethylamine (0.047 mL) were added, and the mixture was stirred at room temperature for 25.5 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution, and the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 75/25 to 50/50), and thereby, a crude product of benzyl (2S)-2-[[(2S)-3-[4-bis (phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2- [phenylmethoxycarbonyl (phenylmethoxycarbonylamino)amino]propanoyl]amino]-3-(4- phenylmethoxyphenyl) propanoate (168 mg) was obtained.

[0374]

(2) The crude product (168 mg) obtained in (1) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and water (0.5 mL), and palladium/carbon (hydrous) (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was filtered through Celite® to remove insoluble matter. The insoluble matter was washed with water (15 mL), and the filtrate was distilled under a reduced pressure until the volume of the filtrate was reduced to about 7/8, and freeze-drying was performed, and then, the title compound (67 mg, 2-step yield: 57%) was obtained.

MS (ESI); m/z 470.1 [M+H]+

[0375]

Examples 47 - 82:

In the same manner as in the above examples, the following compounds can be obtained.

Table 7

[0376]

[Levodopa Prodrug 1] (a compound of formula (I) or (XV) )

Reference Example 1 :

Production of benzyl (2S)-2-[ [(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3- phenylmethoxyphenyl]-2-(phenylmethoxycarbonylamino)propanoyl]amino]-6-

(phenylmethoxycarbonylamino) hexanoato

Dibenzyl N,N-diisopropyl phosphoramidite (3.28 mL) and 1H-tetrazole (0.62 g) were added to a suspension of benzyl (2S)-2-[[(2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2- (phenylmethoxycarbonylamino)propanoyl]amino]-6-

(phenylmethoxycarbonylamino)hexanoato (4.57 g) in dichloromethane (45 mL) and acetonitrile (18 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, a tert-butyl hydroperoxide aqueous solution (70%) (1.2 mL) was added, and the mixture was stirred at room temperature for 19 hours. The solvent of the reaction mixture was distilled away under a reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and water were added, and extraction with ethyl acetate was performed. An organic layer was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 67/33 to 40/60), and thereby, the title compound (5.38 g, 85%) as a white powder was obtained.

MS (ESI); m/z 1034.4 [M+H]+

[0377]

Reference Examples 2 to 13;

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 8 below.

Table 8

[0378]

Reference Example 101;

Production of benzyl (2S)-3-14-bis(phenylmethoxy)phosphoryloxy-3- phenylmethoxyphenyl] -2- [ [(2S)-4-methyI-2- (phenylmethoxycarbonylamino)pentanoyl] amino] propanoato

l,8-diazabicyclo[5.4.0]undec-7-ene (223 uL) and tetrabenzyl diphosphate (805 mg) were added to a mixuture of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[[(2S)-4- methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]propanoato (623 mg) and acetonitrile (5 mL) under ice cooling, and the temperature was gradually raised to room temperature, and the mixture was stirred for 21 hours. l,8-diazabicyclo[5.4.0]undec-7-ene (74 uL) and tetrabenzyl diphosphate (266 mg) were added to the mixture, and the mixture was stirred for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and the solvent was removed under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 67/33 to 40/60), and thereby, the title compound (702 mg, yield: 80%) as a colorless viscous substance was obtained.

MS (ESI); m/z 885.3 [M+H]+

[0379]

Reference Examples 102 to 112:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 101 to obtain the compounds shown in Table 8-5 below. Some of the compounds shown in Table 8-2 below can be obtained in the same manner as above example.

[0380]

Reference Example 2’ :

Production of benzyl (2S)-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3- pheny]methoxyphenyl]-2-(phenylmethoxycarbonylamino)propanoyl]aminol-3-(4 - phenylmethoxyphenyl) propanoate

Benzyl(2S)-2-amino-3-(4-benzyloxyphenyl)propanoate; hydrochloride (277 mg), N,N- diisopropylethylamine (0.35 mL), l-ethyl-3-(3-dimethylarninopropyl)carbodiimide hydrochloride (WSCI) (115 mg) and l-hydroxy-7-azabenzotriazole (HOAt) (82 mg) were added to a mixture of (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3- phenylmethoxyphenyl]-2-(phenylmethoxycarbonylamino)propanoic acid (352 mg) and N,N- dimethylformamide (4 mL), and the mixture was stirred at room temperature for 16 hours. An organic layer was washed with water and a saturated aqueous sodium chloride solution, and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 75/25 to 45/55), and thereby, the title compound (250 mg, 52%) as a white powder was obtained.

MS (ESI); m/z 1025.6 [M+H]+

[0381]

Reference Examples 14 to 29 and 113 to 124:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 2' to obtain the compounds shown in Table 9 below.

[0382]

Reference Example 30: Production of (2S)-2-(benzyloxycarbonyIamino)-3-(3-benzyloxy- 4-hydroxyphenyl) propanoic acid

(1) The compound A-1 (8.0 g, 74 wt%) was dissolved in dichloromethane (75 mL), and, under ice cooling, N-carbobenzoxy-2-phosphonoglycine trimethyl (7.98 g) and 1, 1,3,3- tetramethylguanidine (3.6 mL) were added, and the mixture was stirred at room temperature for 16.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with chloroform was performed. An organic layer was dried over sodium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 85/15 to 65/35), and thereby, the compound A-2 (8.58 g, 82%) as a white powder was obtained.

MS (ESI); m/z 476.4 [M+H]+

[0383] (2) The compound A-2 (5.90 g, 92 wt%) was dissolved in tetrahydrofuran (80 mL), and (+)- 1 ,2-bis((2S,5S)-2,5-diethylphosphorano)benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate ((S,S)-Et-DUPHOS-Rh) (295 mg) was added, and the mixture was stirred under a pressurized hydrogen atmosphere (600 kPa) at room temperature for 4 hours. The solvent of the reaction mixture was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 85/15 - 55/45), and thereby, the compound A-3 (5.71 g, 78%) as a white powder was obtained.

MS (ESI); m/z 478.4 [M+H]+

[0384]

(3) The compound A-3 (1.73 g) was dissolved in tetrahydrofuran (18 mL), methanol (9 mL) and distilled water (7 mL), and lithium hydroxide monohydrate (608 mg) was added, and the mixture was stirred at room temperature for 30 min. 1M hydrochloric acid (30 mL) was added to the reaction mixture, and extraction with chloroform (50 mL) was performed. An organic layer was dried, over sodium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure, and the title compound (1.69 g, 100%) as a white powder was obtained.

MS (ESI); m/z 422.4 [M+H]+ [0385]

Reference Example 31: Production of (2S)-2-(benzyloxycarbonylamino)-3-(3-benzyloxy-

4-dibenzyIoxyphosphoryloxyphenyl) propanoic acid

(1) The compound B-l (R = Me, 2.30 g) was dissolved in a mixed solvent of tetrahydrofuran (36 mL) and methanol (4 mL), and a 2M aqueous lithium hydroxide solution (4.0 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled, an 0.5 M aqueous potassium hydrogen sulfate solution (20 mL) was added, and extraction with chloroform was performed. An organic layer was washed with a saturated aqueous sodium chloride solution and was dried over sodium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The residue was suspended in methyl tert-butyl ether, and a precipitated solid was collected by filtration and dried under a reduced pressure, and thereby, the title compound (2.30 g, 100%) as a white powder was obtained.

MS (ESI); m/z 682.6 [M+H]+

[0386]

(1)’ The compound B-l (R = Bn, 0.57 g) was dissolved in methanol (2 mL), and an 1M aqueous sodium hydroxide solution (0.37 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified by adding an 1M hydrochloric acid, and then, extraction with ethyl acetate was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over sodium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure, and thereby, the title compound (0.53 g, 104%) as a white powder was obtained.

MS (ESI); m/z 638.1 [M+H-C02]+

[0387]

Reference Example 32: Production of benzyl (2S)-2-amino-3-(3-benzyloxy-4- hydroxyphenyl) propanoate; hydrochloride

(1) Iodine (153 mg) was added to a suspension of activated zinc (923 mg) in N,N- dimethylformamide (7 mL) at 5 °C under a nitrogen atmosphere. The temperature was raised to 20 °C and the mixture was stirred for 10 minutes. The reaction mixture was cooled again to 6 °C, and N-(tert-butoxycarbonyl)-3-iodo-L-alanine benzyl ester (1890 mg) was added in portions at 20 °C or below, and the mixture was stirred at 20 °C for 30 minutes, and thereby, a solution of the compound C-2 was obtained.

Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (31 mg), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyldicyclohexyl(2',6'-dimethoxy-[1,1'- biphenyl]-2-yl)phosphine (30 mg), and the compound C-l (1309 mg) were sequentially added, and the mixture was stirred at room temperature for 16 hours. Hexane/(ethyl acetate) (1:1) was added to the reaction mixture, and insoluble matter was removed by celite filtration. The insoluble matter was washed with hexane/(ethyl acetate) (1:1) and water, and the filtrate was washed sequentially with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. An organic layer was dried over anhydrous magnesium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 - 67/33), and thereby, the compound C-3 (1733 mg, 90%) as a white powder was obtained.

MS (ESI); m/z 378.2 [M+H-Boc]

[0388]

(2) A 4M hydrogen chloride dioxane solution (6 mL) was added to a solution of the compound C-3 (1.625 g) in 1,4-dioxane (15 mL) at 3°C, and the mixture was stirred at room temperature for 1 hour. A 4M hydrogen chloride dioxane solution (6 mL) was added, and the mixture was stirred for 17 hours. The reaction mixture was concentrated under a reduced pressure until the volume thereof was reduced to about 1/10. The residue was suspended in ethyl acetate, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the title compound (1271 mg, 90%) as a white powder was obtained.

MS (ESI); m/z 378.4 [M+H]+

[0389]

[Levodopa Prodrug 2] (a compound of formula (II) or (XVI))

Reference Example 33: Production of (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenyImethoxyphenyl]-2-

[[(2S)-3-(2-ethoxy-2-methyl-1,3-benzodioxol-5)-yl)-2- (phenylmethoxycarbonylamino)propanoyl] amino] proanoic acid

benzyl (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-3-(2- ethoxy-2-methyl-l,3-benzodioxol-5-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino] propanoate (208 mg) was dissolved in a mixed solvent of water (0.41 mL) and tetrahydrofuran (1.0 mL), and lithium hydroxide monohydrate (9.4 mg) was added under an ice bath, and then, the mixture was stirred at room temperature for 2 hours. After adding ethyl acetate to the reaction mixture, a saturated aqueous citric acid solution was added until the pH of the mixture reached 6, and extraction with ethyl acetate was performed. An organic layer was dried over magnesium sulfate and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 70/30 - 0/100, (ethyl acetate)/methanol = 100/0 - 85/15), and thereby, the title compound (179 mg, yield: 94%) as a colorless viscous substance was obtained.

MS (ESI); m/z 929.3 [M-H]- [0390]

Reference Example 34:

Production of benzyl (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3- phenylmethoxyphenyI]-2-[[(2S)-2-(phenylmethoxycarbonyIamino)propanoyl]amino] propanoate

1H-tetrazole (72 mg) and dibenzyl N,N-diisopropylphosphoroamidite (0.38 mL) were added under ice-cooling to a mixture of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2- [[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino] propanoate (387 mg), dichloromethane (4 mL) and acetonitrile (1.6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled, a tert-butyl hydroperoxide decane solution (5.5 M) (0.18 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled away under a reduced pressure, and then, toluene was added, and insoluble matter was removed with Phase-separator®. The filtrate was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 67/33 to 40/60), and thereby, the title compound (551 mg, yield: 90%) as a colorless viscous substance was obtained.

MS (ESI); m/z 843.7 [M+H]+

[0391]

Reference Examples 35 to 48:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 34 to obtain the compounds shown in Table 10 below.

Table 10

[0392]

Reference Example 49:

Production of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[ [(2S)-2- (phenylmethoxycarbonylamino)propanoyl] amino] propanoate

(2S)-2-(benzyloxycarbonylamino) propanoic acid (1.02 g), 1 -hydroxy-7-azabenzotriazole (HOAt) (712 mg), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI)

(1.03 g), and N,N-diisopropylethylamine (0.750 mL) were added to a mixture of benzyl (2S)- 2-amino-3-(4-hydroxy-3-phenylmethoxyphenyl) propanoate; hydrochloride (1.87 g) and N,N-dimethylformamide (18 mL), and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer is washed with water and a saturated aqueous sodium chloride solution and was dried over magnesium sulfate. Insoluble matter was filtered, and the solvent was distilled away under a reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 67/33 - 45/55), and thereby, the title compound (2.56 g, yield: 99%) as a white powder was obtained.

MS (ESI); m/z 583.6 [M+H]+

[0393]

Reference Examples 50 - 66:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 49 to obtain the compounds shown in Table 11 below.

Table 11

[0394]

Reference Example 67:

Production of benzyl (2S)-2-acetamido-3-(3,4-diacetyIoxyphenyl) propanoate

Acetic anhydride (0.291 mL) was added under ice-cooling to a mixture of benzyl (2S)-2- amino-3-(3,4-dihydroxyphenyl) propanoate; hydrochloride (253 mg) and pyridine (1 mL), and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with chloroform was performed. An organic layer was washed with a saturated aqueous sodium chloride solution and was dried over sodium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 - 0/100), and thereby, the title compound (280 mg, yield: 72%) as a colorless viscous substance was obtained.

MS (ESI); m/z 414.2 [M+H]+

[0395]

Reference Examples 68 and 69:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 67 to obtain the compounds shown in Table 12 below.

Table 12

[0396]

Reference Example 70:

Production of benzyl (2S)-2-amino-3-[3,4-bis(phenylmethoxy)phenyl] propanoate; hydrochloride

A 4M hydrogen chloride dioxane solution (43 mL) was added under ice cooling to benzyl (2S)-3 - [3 ,4-bis(phenylmethoxy)phenyl] -2- [(2-methylpropan-2-yl)oxycarbonylamino] propanoate (13.2 g), and the mixture was stirred at room temperature for 3 hours. A 4M hydrogen chloride ethyl acetate solution (3 mL) was added, and the mixture was stirred for 2 hours. The solvent of the reaction mixture was distilled away under a reduced pressure. The residue was suspended in diisopropyl ether, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the title compound (10.4 mg, yield: 96%) as a white powder was obtained.

MS (ESI); m/z 468.3 [M+H]+

[0397]

Reference Example 71:

The corresponding starting compound was treated in the same manner as in Reference Example 70 to obtain the compound shown in Table 13 below.

Table 13

[0398]

Reference Example 72: Production of benzyl (2S)-2-amino-3-(3-benzyloxy-4- hydroxyphenyl) propanoate; hydrochloride

(1) N-(tert-butoxycarbonyl)-phosphonoglycine trimethyl ester (10 g) and 1,1, 3, 3- tetramethylguanidine (5 mL) were added under ice-cooling to a mixture of the compound D- 1 (8.31 g) and dichloromethane (90 mL), and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was passed through silica gel column chromatography (solvent: ethyl acetate), and the solvent of the filtrate was distilled away under a reduced pressure. The residue was suspended in ethanol, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and the compound D-2 (10.7 g, yield: 79%) as a white powder was obtained.

MS (ESI); m/z 440.3 [M-H]-

[0399]

(2) (+)-1 ,2-bis((2S,5S)-2,5-diethylphosphorano)benzene(l ,5-cyclooctadiene)rhodium(I) tetrafluoroborate ((S,S)-Et-DUPHOS-Rh) (144 mg) was added to a mixture of the compound D-2 (9.65 g) and tetrahydrofuran (80 mL), and the mixture was stirred under a pressurized hydrogen atmosphere (800 kPa) at 35 °C for 3 hours. The reaction mixture was passed through silica gel column chromatography (solvent: hexane/(ethyl acetate) = 50/50), and the solvent of the filtrate was distilled away under a reduced pressure. The residue was suspended in ethanol, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and the compound D-3 (9.00 g, yield: 93%) as a white powder was obtained.

MS (ESI); m/z 442.2 [M-H]- [0400]

(3) The compound D-3 (7.52 g) was dissolved in a mixed solvent of tetrahydrofuran (40 mL), methanol (20 mL) and distilled water (15 mL), and a 4M aqueous lithium hydroxide solution (20 mL) was added under ice-cooling, and the mixture was stirred at 0 °C for 7 hours. 1M hydrochloric acid (60 mL) was added to the reaction mixture, and extraction with ethyl acetate (100 mL) was performed. An organic layer was washed with a saturated aqueous sodium chloride solution, and was dried over magnesium sulfate, and insoluble matter was filtered, and the solvent was distilled away under a reduced pressure, and thereby, the compound D-4 (7.52 g, 88 wt%, yield: 100%) as a yellow viscous substance was obtained.

MS (ESI); m/z 386.2 [M-H]- [0401]

(4)-l Cesium carbonate (3.97 g) and benzyl bromide (2.40 mL) were added at room temperature to a mixture of the compound D-4 (7.46 g, 88 wt%) and N,N- dimethylformamide (4 mL), and the mixture was stirred at the same temperature for 4 hours. A saturated aqueous sodium chloride solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution, and the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 - 67/33), and thereby, the compound D-5 (8.81 g, 90 wt%, 98%) as a white powder was obtained.

MS (ESI); m/z 476.2 [M-H]-

[0402]

(4)-2 (Another synthesis method of the compound D-5) Iodine (153 mg) was added to a mixture of activated zinc (923 mg) and N,N-dimethylformamide (7 mL) at 5 °C under a nitrogen atmosphere. The temperature was raised to 20 °C and the mixture was stirred for 10 minutes. The reaction mixture was cooled again to 6 °C, and the compound D-6 (1890 mg) was added in portions at 20 °C or lower, and the mixture was stirred at 20 °C for 30 minutes, and thereby, a solution of the compound D-7 was obtained. Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (31 mg), 2- dicyclohexylphosphino-2^,,6’-dimethoxybiphenyldicyclohexyl(2',6’-dimethoxy-[1,1'- biphenyl] -2-yl)phosphine (30 mg), and the compound D-8 (1309 mg) were sequentially added, and the mixture was stirred at room temperature for 16 hours. Hexane/(ethyl acetate) (1:1) was added to the reaction mixture, and insoluble matter was removed by celite filtration. The insoluble matter was washed with hexane/(ethyl acetate) (1:1) and water, and the filtrate was washed sequentially with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. An organic layer was dried over anhydrous magnesium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 - 67/33), and thereby, the compound D-5 (1.84 g, yield: 90%) as a yellow viscous substance was obtained.

MS (ESI); m/z 378.2 [M+H-Boc]+

[0403]

(5) A 4M hydrogen chloride dioxane solution (6 mL) was added under ice-cooling to a mixture of the compound D-5 (1.63 g) and 1,4-dioxane (15 mL), and the mixture was stirred at room temperature for 1 hour. A 4M hydrogen chloride dioxane solution (6 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under a reduced pressure until the volume thereof was about 1/10. The residue was suspended in ethyl acetate, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the title compound (1288 mg, yield: 90%) as a white powder was obtained.

MS (ESI); m/z 378.4 [M+H]+

[0404]

Reference Example 73: Production of benzyl (2S)-2-amino-3-(3,4-diacetoxyphenyl) propanoate; hydrochloride

(1) Cesium carbonate (1.43 g) and benzyl bromide (0.58 mL) were added to a mixture of the compound E-l (2.0 g) and N,N-dimethylformamide (19 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium chloride solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution and was dried over magnesium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography, and thereby, the Compound E-2 (1.68 g, yield: 75%) as a colorless viscous substance was obtained.

MS (ESI); m/z 372.1 [M+H-Boc]+

[0405]

(2) A 4M hydrogen chloride ethyl acetate solution (0.5 mL) was added under ice-cooling to a solution of the compound E-2 (515 mg) in ethyl acetate (5 mL), and the mixture was stirred at room temperature for 4 hours. A 4M hydrogen chloride ethyl acetate solution (3 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent of the reaction mixture was distilled away under a reduced pressure. The residue was suspended in ethyl acetate, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the title compound (409 mg, yield: 98%) as a white powder was obtained.

MS (ESI); m/z 372.1 [M+H]+

[0406]

Reference Example 74; Production of (2S)-2-(benzyloxycarbonylamino)-3-(2,2- dimethyl-l,3-benzodioxol-5-yl) propanoic acid

(1) p-toluenesulfonic acid (175 mg) and 2,2-dimethoxypropane (12.5 mL) were added to a mixture of the compound F-l (3.66 g) and toluene (102 mL), and the mixture was heated to reflux using a Dean-Stark apparatus for 14 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was dried over magnesium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure, and a crude product of the compound F-2 as a yellow viscous substance was obtained.

[0407]

(2) The crude product of the compound F-2 was dissolved in a mixed solvent of methanol (25 mL), water (20 mL) and tetrahydrofuran (51 mL), and lithium hydroxide monohydrate (855 mg) was added under an ice bath, and the mixture was stirred at the same temperature for 40 minutes, and then, the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and was washed with diethyl ether. Ethyl acetate was added to an aqueous layer, and a saturated aqueous citric acid solution was added until the pH of the mixture reached 6, and extraction with ethyl acetate was performed. An organic layer was dried over magnesium sulfate and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate), and thereby, the title compound (2.40 g, 2-step yield: 63%) as a yellow viscous substance was obtained.

MS (ESI); m/z 370.2 [M-H]-

[0408]

Reference Example 75: Production of (2S)-2-(benzyloxycarbonylamino)-3-(2-ethoxy-2- m ethyl-1,3-benzodioxol-5-yl) propanoic acid

(1) The compound G-1 (1.35 g) was dissolved in 1 -butyl-3 -methylimidazolium hexafluorophosphate (7.51 mL), and triethyl orthoacetate (1.38 mL) was added, and the mixture was stirred at 80 °C for 3 hours. Water was added to the reaction mixture, and then, extraction with ethyl acetate was performed. An organic layer was dried over magnesium sulfate and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 85/15 - 70/30), and thereby, the compound G-2 (1.41 g, yield: 87%) as a colorless viscous substance was obtained. MS (ESI); m/z 430.0 [M+H]+

[0409]

(2) The compound G-2 (1.35 g) was dissolved in a mixed solvent of methanol (3.9 mL), water (6.3 mL) and tetrahydrofuran (6.3 mL), and lithium hydroxide monohydrate (264 mg) was added under an ice bath, and then, the mixture was stirred at room temperature for 10 hours. After adding ethyl acetate to the reaction mixture, a saturated aqueous ammonium chloride solution was added until the pH of the mixture reached 6, and extraction with ethyl acetate was performed. An organic layer was dried over magnesium sulfate and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure, and the residue was purified by silica gel column chromatography (solvent: (ethyl acetate)/methanol = 100/0 - 95/5), and thereby, the title compound (816 mg, yield: 65%) as a colorless solid was obtained.

MS (ESI); m/z 400.2 [M-H]- [0410]

[Carbidopa Prodrug] (a compound of any one of formulas (III) - (XIV))

Reference Example 76;

Production of benzyl (2S)-3-[4-bis(phenylmethoxy)phosphoryIoxy-3- nhenylmethoxyphenyl]-2-methyl-2-[2-[(2S)-2- (phenylmethoxycarbonylamino)propanoyl]hydrazinyl] propanoate

1,8-diazabicyclo [5.4.0]undec-7-ene (0.036 mL) and tetrabenzyldiphosphate (123 mg) were added under ice-cooling to a mixture of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)- 2-methyl-2-[2-[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]hydrazinyl] propanoate (190 mg) and acetonitrile (2 mL), and the temperature was gradually raised to room temperature, and the mixtured was stirred for 9 hours. 1,8-diazabicyclo [5.4.0]undec-7-ene (0.017 mL) and tetrabenzyldiphosphate (57 mg) were added, and the mixture was stirred at room temperature for 14.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was dried over magnesium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 55/45 - 34/66), and thereby, the title compound (172 mg, yield: 71%) as a colorless viscous substance was obtained.

MS (ESI); m/z 870.5 [M-H]-

[0411]

Reference Examples 201 to 231:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 76 to obtain the compounds shown in Table 13-2 below.

Table 13-2

[0412]

Reference Example 232;

Production of dibenzyl 3-[[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3- phenyImethoxyphenyl]-2-methyl-l-oxo-l-phenylmethoxypropan-2- yl] amino] carbamoyl] -3-hydroxypentanedioate

1H-Tetrazole (13 mg) and dibenzyl N,N-diisopropylphosphoroamidite (0.065 mL) were added under ice-cooling to a mixture of dibenzyl 3-hydroxy-3-[[[(2S)-3-(4-hydroxy-3- phenylmethoxyphenyl)-2-methyl- 1 -oxo- 1 -phenylmethoxypropan-2- yl]amino]carbamoyl]pentanedioate (110 mg), dichloromethane (1.20 mL), and acetonitrile (0.44 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was ice-cooled, a tert-butyl hydroperoxide decane solution (5.5 M) (0.030 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and then, extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution, and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 67/33 to 34/66), and thereby, the title compound (134 mg, yield: 90%) as a colorless viscous substance was obtained.

MS (ESI); m/z 1021.4 [M+H]+

[0413]

Reference Examples 233 to 236:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 232 to obtain the compounds shown in Table 13-3 below.

Table 13-3

[0414] Reference Example 77: Production of (2S)-2-[2-[(2S)-2,6- bis(phenylmethoxycarbonylamino) hexanoyl]hydrazinyl]-3-(3-hydroxy-4- phosphonooxyphenyl)-2-methyIpropanoic acid; 2,2,2-trifluoroacetic acid

Trifluoroacetic acid (0.20 mL) was added to a mixture of (2S)-3-[4-[bis[(2-methylpropan-2- yl)oxy]phosphoryloxy]-3-hydroxyphenyl]-2-[2-[(2S)-2,6-bis(phenylmethoxycarbonylamino) hexanoyl]hydradinyl]-2-methylpropanoic acid tert-butyl (137 mg) and dichloromethane (2 mL), and the mixture was stirred at room temperature for 16 hours. Trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction mixture was distilled away under a reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and washing with ethyl acetate was performed. 1M hydrochloric acid was added to an aqueous layer until the pH of the mixture reached.1 , and extraction with ethyl acetate was performed. An organic layer was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The residue was suspended in diisopropyl ether, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the title compound (113 mg, yield: 88%) as a white powder was obtained.

MS (ESI); m/z 703.2 [M+H]+

[0415]

Reference Example 78; Production of benzyl (2S)-2- -3-[4-bis(phenylmethoxy)phosphoryloxy-3-

phenylmethoxyphenyl]-2-methyl-2-[phenylmethoxycarbonyl

( phenylmethoxycarbonylamino) amino] propanoyl] amino] -6-

(phenylmethoxycarbonylamino) hexanoate

l-hydroxy-7-azabenzotriazole (HOAt) (20 mg), 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (WSCI) (33 mg), benzyl (2S)-2-amino-6- (benzyloxycarbonylamino) hexanoate; hydrochloride (56 mg) andN,N- diisopropylethylamine (0.023 mL) were added to a mixture of (2S)-3-[4- bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2- [phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino] propanoic acid (105 mg) and N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution, and the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 67/33 - 45/55), and thereby, the title compound (89 mg, yield: 57%) as a colorless viscous substance was obtained.

MS (ESI); m/z 1215.1 [M+H+H20]+

[0416]

Reference Examples 79 to 81 and 237 to 282:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 78 to obtain the compounds shown in Table 14 below.

Table 14

[0417]

Reference Example 283:

Production of benzyl (2S)-2-[2-[[(lS)-2-benzyloxy-l-(benzyloxymethyl)-2-oxo- ethyl] carbamoyl] hydrazino]-3-(3-benzyloxy-4-hydroxy-phenyl)-2-methyI-propanoate

Pyridine (0.18 mL) and triphosgene (114 mg) were added under ice-cooling to a mixture of benzyl (2S)-2-amino-3-benzyloxypropanoate; hydrochloride (315 mg) and dichloromethane (3.5 mL), and the mixture was stirred at 0 °C for 1 hour. 1M hydrochloric acid was added to the reaction mixture, and extraction with dichloromethane was performed. An organic layer was distilled away under a reduced pressure to obtain benzyl (2S)-3-benzyloxy-2-isocyanate- propanoate. Benzyl (2S)-3-benzyloxy-2-isocyanate-propanoate and triethylamine (0.055 mL) were added under ice-cooling to a mixture of benzyl (2S)-2-hydrazinyl-3-(4-hydroxy-3- phenylmethoxyphenyl)-2-methylpropanoate; hydrochloride (175 mg) and dichloromethane (4 mL), the temperature was gradually raised from 0 °C to room temperature, and the mixture was stirred for 20 hours. The solvent of the reaction mixture was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 75/25 to 50/50), and thereby, the title compound (442 mg, yield: 59%) as a colorless viscous substance was obtained.

MS (ESI); m/z 718.5 [M+H]+

[0418] Reference Examples 284 to 286:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 283 to obtain the compounds shown in Table 14-3 below.

Table 14-3

[0419]

Reference Example 287:

Production of (2-benzyIoxy-l-methyl-2-oxoethyl) (2S)-3-[4- bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2-

[phenylmethoxycarbonyl(phenylmethoxycarbonyIamino)amino]propanoate

Cesium hydrogencarbonate (40 mg) and benzyl 2-bromopropanoate (47 mg) were added to a mixture of (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2 -methyl- 2-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino] propanoic acid (120 mg) and N,N-dimethylacetamide (2 mL), and the mixture was stirred at room temperature for 15 hours. Insoluble matter was filtered off, and the filtrate was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 to 60/40), and thereby, the title compound (131 mg, yield: 92%) as a colorless viscous substance was obtained.

MS (ESI); m/z 1007.0 [M+H]+

[0420]

Reference Example 288:

Production of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-methyl-2-[2-

[(2S,3R,4S,5S,6R)-3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2- yl]oxycarbonylhydrazinyl]propanoate

1-Hydroxybenzotriazole monohydrate (62 mg), (4-nitrophenyl) [(2S,3R,4S,5S,6R)-3,4,5- tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-yl]carbonate (310 mg) and N,N- diisopropylethylamine (0.21 mL) were added to a mixture of benzyl (2S)-2-hydrazinyl-3-(4- hydroxy-3-phenylmethoxyphenyl)-2-methylpropanoate; hydrochloride (177 mg) and tetrahydrofiiran (2.0 mL), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution and was dried over sodium sulfate, insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 to 60/40), and thereby, the title compound (299 mg, yield: 77%) as a pale yellow viscous substance was obtained.

MS (ESI); m/z 972.0 [M-H]-

[0421]

Reference Examples 289 to 297:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 288 to obtain the compounds shown in Table 14-4 below.

Table 14-4

[0422]

Reference Example 298: Production of (4-nitrophenyl) [(2S,3R,4S,5S,6R)-3,4,5-tris(phenylmethoxy)-6- (phenylmethoxymethyl)oxan-2-yI] carbonate

l,4-Diazabicyclo[2.2.2]octane (804 mg) was added under ice-cooling to a mixture of 2, 3,4,6- tetra-O-benzyl-D-galactopyranose (2.50 g) and tetrahydrofuran (15.4 mL). After stirring for 3 minutes, 1-hydroxybenzotriazole monohydrate (142 mg) and 4-nitrophenyl chloroformate (1.12 g) were added, and the mixture was stirred under ice-cooling for 2 hours. Insoluble matter in the reaction mixture was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 95/5 to 85/15), and thereby, the title compound (1.62 g, yield: 50%) as a colorless viscous substance was obtained.

MS (ESI); m/z 540.3 [M+H-(p-N02Ph0C02H)+NH3]+

[0423]

Reference Examples 299 to 300:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 298 to obtain the compounds shown in Table 14-5 below.

Table 14-5

[0424]

Reference Example 301:

Production of (4-ditert-butoxyphosphoryloxyphenyl)methyl (4-nitrophenyl) carbonate

Bis(4-nitrophenyl)carbonate (531 mg) and diisopropylethylamine (0.277 mL) were added to a mixture of di-tert-butyl[4-(hydroxymethyl)phenyl]phosphate (276 mg) and tetrahydrofuran (6 mL), and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 to 60/40, and thereby, the title compound (33.3 mg, yield: 79%) as a white powder was obtained.

MS(ESI);m/z 371.0 [M+H-2(C₄H₈)]+ [0425]

Reference Example 302:

Production of (4-nitrophenoxy)carbonyloxymethyl (2S)-2-(benzyloxycarbonylamino)-3- methylbutanoate

(1) Cesium carbonate (389 mg) was added to a mixture of N-benzyloxycarbonyl-L-valine (500 mg) and methanol (13.3 mL), and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was distilled away under a reduced pressure to obtain a crude product of cesium; (2S)-2-(benzyloxycarbonylamino)-3-methyl-butanoate.

[0426]

(2) A mixture of the crude product obtained in (1) and N,N-dimethylformamide (4.0 mL) was added under ice-cooling to a mixture of iodomethyl(4-nitrophenyl)carbonate (643 mg) and N,N-dimethylformamide (10.0 mL), and the mixture was stirred under an ice bath for 2 hours. Ethyl acetate, water, and a saturated aqueous citric acid solution were added to the reaction mixture, the pH of an aqueous layer was adjusted to about 6, and then extraction with ethyl acetate was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution and was dried over sodium sulfate, insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 85/15 to 70/30), and thereby, the title compound (284 mg, yield: 32%) as a colorless viscous substance was obtained.

MS (ESI); m/z 447.3 [M+H]+

[0427]

Reference Examples 303 to 304:

The corresponding starting compounds were respectively treated in the same manner as in Reference Example 302 to obtain the compounds shown in Table 14-6 below. Table 14-6

[0428]

Reference Example 82: Production of (2S)-2-(2-benzyIoxycarbonylhydrazino)-3-(3.,4- dibenzyloxyphenyl)-2-methylpropanoic acid

(1) The compound H-2 (13.6 g) as a pale yellow viscous substance was obtained from the compound H-1 (10.0 g) according to WO 2004052841.

MS (ESI); m/z 241.0 [M+H]+

[0429] (2) The compound H-3 (13.8 g, 2-step yield: 93%) as a white powder was obtained from the compound H-2 (13.6 g) of WO 2004052841.

MS (ESI); m/z 339.1 [M-H]-

[0430]

(3) The compound H-4 (15.4 g, yield: 73%) as a colorless viscous substance was obtained from the compound H-3 (13.8 g) according to WO 2020115753.

MS (ESI); m/z 465.0 [M+H-C4H8]+

[0431]

(4) Triethylsilane (10.3 g) and a 4M hydrogen chloride dioxane solution (150 mL) were added under ice-cooling to a solution of the compound H-4 (15.4 g) in methanol (75 mL), and the mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was distilled away under a reduced pressure, and thereby, a crude product of the compound H-5 (17.5 g) as a beige powder was obtained.

MS (ESI); m/z 421.1 [M+H]+

[0432]

(5) The compound H-5 (18.0 g) was suspended in dichloromethane (340 mL), and benzyl chloroformate (5.76 g) and triethylamine (13.7 g) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction was performed. An organic layer was washed with a saturated aqueous sodium chloride solution, and was dried over magnesium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 - 60/40), and thereby, the compound H-6 (12.6 g, 2-step yield: 74%) as a yellow viscous substance was obtained.

MS (ESI); m/z 555.1 [M+H]+

[0433]

(6) The compound H-6 (3.0 g) was dissolved in tetrahydrofuran (41 mL) and distilled water (4 mL), a 4M aqueous lithium hydroxide solution (4.1 mL) was added, and the mixture was stirred at 60 °C for 4 hours. 1M hydrochloric acid (17 mL) was added to the reaction mixture, and extraction with ethyl acetate (200 mL x 1, 100 mL x 1) was performed. An organic layer was washed with a saturated aqueous sodium chloride solution (30 mL), and was dried over magnesium sulfate, and then, the solvent was distilled away under a reduced pressure. The residue was suspended in diisopropyl ether, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the title compound (2.27 mg, yield: 77%) as a white powder was obtained.

MS (ESI); m/z 541.1 [M+H]+

[0434]

Reference Example 83: Production of benzyl (2S)-3-(3-benzyloxy-4-hydroxyphenyl)-2- hydrazide-2-methylpropanoate: hydrochloride

(1) The compound 1-2 (30.2 g, yield 80%) as a white powder was obtained from the compound 1-1 (25.0 g) with reference to WO 2004052841.

MS (ESI); m/z 325.2 [M-H]-

[0435]

(2)-l Cesium carbonate (2.23 g) was added to a mixture of the compound 1-2 (8.0 g) and N,N-dimethylformamide (40 mL). The reaction mixture was ice-cooled, and benzyl bromide (4.04 g) dissolved in N,N-dimethylformamide (40 mL) was added, and the mixture was stirred at room temperature for 94 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with 0.5 N hydrochloric acid, and was washed with water and a saturated aqueous sodium chloride solution, and was dried over magnesium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 65/35 - 45/55), and thereby, the compound 1-3 (2.89 g, yield: 28%) as a pale yellow powder was obtained. MS (ESI); m/z 415.3 [M-H]- [0436]

(2)-2 (Alternative Method for synthesizing the compound 1-3)

Cesium hydrogencarbonate (9.81 g) was added to a mixture of the compound 1-2 (15.0 g) and N,N-dimethylformamide (230 mL). The reaction mixture was ice-cooled, benzyl bromide (6.01 mL) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 75/25 to 50/50), and thereby, the compound 1-3 (12.5 g, yield: 65%) as a white powder was obtained.

MS (ESI); m/z 417.2 [M+H]+

[0437]

(3)-l The compound 1-3 (2.59 g) was dissolved in N,N-dimethylformamide (20 mL), and cesium carbonate (2.23 g) was added. Benzyl bromide (1.07 g) dissolved inN,N- dimethylformamide (1 mL) was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution, and was dried over magnesium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 70/30 to 45/55), and thereby, the compound 1-4 (738 g, yield: 23%) as a pale yellow viscous substance was obtained.

MS (ESI); m/z 507.0 [M+H]+

[0438]

(3)-2 (K2C03 condition) To a mixture of compound 1-3 (35.5 g) and N,N- dimethylformamide were added potassium carbonate (9.74 g) and benzyl bromide (8.38 mL) under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite®, insoluble material was removed, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was removed under a reduced pressure. The residue obtained was purified by NH silica gel column chromatography (solvent: hexane/ethyl acetate = 75/25 to 0/100). Then, by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 60/4 (solvent: hexane/ethyl acetate = 80/20 to 60/4/0), the compound 1-4 (8.67 g, 26% yield) was obtained as a white viscous substance.

[0439]

(4) A 4M hydrogen chloride ethyl acetate solution (1.9 mL) was added to a mixture of the compound 1-4 (415 mg) and ethyl acetate (2 mL), and the mixture was stirred at room temperature for 18.5 hours. The solvent of the reaction mixture was distilled away under a reduced pressure. The residue was dissolved in ethyl acetate, and the solvent was distilled away under a reduced pressure again, and drying under a reduced pressure was performed, and thereby, the title compound (385 mg, yield 97%) as a red viscous substance was obtained.

MS (ESI) z; m/z 407.1 [M+H]+

[0440]

Reference Example 305: Production of benzyl (2S)-3-(3-benzyloxy-4-hydroxyphenyl)-2- methyl-2-[2-[(2-methylpropan-2-yl)oxycarbonyl]hydrazinyl] propanoate (Alternative M ethod)

(1) Potassium carbonate (14.7 g) was added under ice cooling to a mixture of the compound J-1 (23.2 g) and dichloromethane (200 mL), and the mixture was stirred. Acetic anhydride (10 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 15 hours. Acetic anhydride (3 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Potassium carbonate (3.40 g) was added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite®, and then a saturated aqueous sodium hydrogen carbonate solution (175 mL) was added, and extraction with ethyl acetate (200 mL) was performed. An aqueous layer was re-extracted with ethyl acetate and was dried over magnesium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 90/10 to 67/33), and thereby, the compound 1-5 (25.6 g, yield: 93%) as a white powder was obtained.

MS (ESI); m/z 330.2 [M+H+NH3]+

[0441]

(2) Benzyl-N-benzyloxycarbonyliminocarbamate (13.1 g), (2R,4S)-4-[tert- butyl(diphenyl)silyl]oxypyrrolidine-2-carboxylic acid (664 mg), and trifluoroacetic acid (0.137 mL) were added to a mixture of the compound 1-5 (12.0 g) and acetonitrile (70 mL), and the mixture was stirred at room temperature for 17 hours and 30 minutes. After concentrating the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (80 mL) was added, and extraction with ethyl acetate (200 mL) was performed. An organic layer was washed with a saturated aqueous sodium chloride solution. An aqueous layer was re-extracted with ethyl acetate (100 mL), the organic layers were combined and were dried over sodium sulfate, and then the organic layers were passed through silica gel column chromatography (solvent: ethyl acetate), and the solvent of the filtrate was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 to 55/45). Ethanol (100 mL) was added to the obtained powder, and the mixture was heated and stirred at 80°C. After completely dissolving the powder, the solution was allowed to cool with stirring at room temperature. A precipitated solid was collected by filtration and was dried under a reduced pressure, and the compound 1-6 (10.4 g, yield: 54%) as a white powder was obtained.

MS (ESI); m/z 609.3 [M-H]-

[0442]

(3) Sodium dihydrogen phosphate (5.20 g), water (50 mL), and dimethylsulfoxide (7.3 mL) were added to a mixture of the compound 1-6 (12.6 g) and acetonitrile (120 mL), and then sodium chlorite (10.2 g) was added in two portions under ice cooling, and the mixture was stirred at 0°C for 3 hours. Sodium sulfite (11.5 g) and water (150 mL) were added under ice cooling to the reaction mixture, the mixture was stirred, and extraction with ethyl acetate (200 mL) was performed. An organic layer was washed with water and a saturated aqueous sodium chloride solution. The aqueous layer was re-extracted with ethyl acetate (100 mL), the organic layers were combined and were dried over magnesium sulfate, and then the solvent was distilled away under a reduced pressure. Ethanol (65 mL) was added to the obtained powder, and the mixture was heated and stirred at 80°C. After completely dissolving the powder, heating was stopped, seed crystals were added, and the mixture was stirred at room temperature. A precipitated solid was collected by filtration and was dried under a reduced pressure, and the compound 1-7 (10.8 g, yield: 84%) as a white powder was obtained.

MS (ESI); m/z 625.2 [M-H]- [0443]

(4) 2,2-Bipyridine (1.21 g) was added to a mixture of the compound 1-7 (9.68 g) and methanol (180 mL), palladium/carbon (hydrous) (1.00 g) was added under a nitrogen atmosphere, then the reactor was purged with hydrogen, and the mixture was stirred at room temperature for 18 hours. A solution of di-tert-butyl dicarbonate (3.55 g) in methanol (4 mL) and a solution of triethylamine (2.25 mL) in methanol (6 mL) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was filtered through Celite® to remove insoluble matter. The solvent was distilled away under a reduced pressure, and then the residue was diluted with ethyl acetate (200 mL), washed with IN hydrochloric acid (200 mL) twice and with a saturated aqueous sodium chloride solution (100 mL) once, and dried over magnesium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained powder was suspended and washed with diisopropyl ether (25 mL). A precipitated solid was collected by filtration and was dried under a reduced pressure, and thereby, the compound 1-8 (5.30 g, yield: 70%) as a yellow powder was obtained.

MS (ESI); m/z 457.2 [M-H]- [0444]

(5) Triphenylphosphine (3.70 g) was added under a nitrogen atmosphere to a mixture of the compound 1-8 (4.98 g) and tetrahydrofuran (35 mL), diisopropylazodicarboxylate (7.50 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was distilled under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 to 55/45), and thereby, the compound 1-9 (5.74 g, yield: 83%) as a yellow viscous substance was obtained.

MS (ESI); m/z 547.3 [M-H]- [0445]

(6) Acetic acid (1.03 mL) was added to a mixture of the compound 1-9 (5.74 g) and tetrahydrofuran (30 mL), hydrazine monohydrate (0.88 mL) was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was distilled under a reduced pressure, then diluted with ethyl acetate (200 mL), washed with IN hydrochloric acid (100 mL) and a saturated aqueous sodium hydrogen carbonate solution (100 mL), and dried over magnesium sulfate, and then the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 to 55/45), and thereby, the compound 1-4 (4.65 g, yield: 94%) as a yellow viscous substance was obtained.

MS (ESI); m/z 507.3 [M+H]+

[0446]

Reference Example 84: Production of tert-butyl (2S)-3-(4-ditert-butoxyphosphoryloxy- 3-hydroxyphenyl)-2-hydrazino-2-methylpropanoate

(1) Dibenzylazocarboxylate (7.82 g), (R)-5-(pyrrolidine-2-yl)-1H-tetrazole (380 mg) and trifluoroacetic acid (0.206 mL) were added at room temperature to a mixture of the compound J-1 (4.91 g) and acetonitrile (35 mL), and the mixture was stirred at room temperature for 18 hours. Dibenzylazocarboxylate (3.02 g), (R)-5-(pyrrolidine-2-yl)-1H- tetrazole (105 mg) and trifluoroacetic acid (0.070 mL) were added, and the mixture was stirred at room temperature for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution, and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 80/20 - 60/40), and thereby, the compound 2 (6.87 g, yield: 64%,

51 ,2%ee) as a white powder was obtained.

MS (ESI); m/z 569.3 [M+H]+ [0447]

(2) 1H-tetrazole (679 mg) and dibenzyl N,N-diisopropylphosphoroamidite (2.00 mL) were added at room temperature toa mixture of the compound J-2 (2.74 g), dichloromethane (24 mL) and acetonitrile (6 mL), and the mixture was stirred at room temperature for 3 hours. A tert-butyl hydroperoxide decane solution (5.5 M) (1.10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours and 30 minutes. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution, and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 75/25 - 50/50), and thereby, the compound J-3 (2.69 g, yield: 70%) as a yellow viscous substance was obtained.

MS (ESI); m/z 759.3 [M+H]+

[0448]

(3) An aqueous solution (2 mL) of dimethylsulfoxide (0.577 mL) and sodium dihydrogen phosphate (891 mg) and an aqueous solution of sodium chlorite (1.76 g) (2.5 mL) were added at room temperature to a mixture of the compound J-3 (2.69 g) and acetonitrile (35 mL), and the mixture was stirred at room temperature for 2 hours. Sodium sulfite (939 mg) and water were added to the reaction mixture, and the mixture was stirred, and extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution, and was dried over sodium sulfate, and then, the solvent was distilled away under a reduced pressure. Drying under a reduced pressure was performed, and the compound J-4 (2.78 g, yield: 97%) as a yellow viscous substance was obtained.

MS (ESI); m/z 775.2[M-H]-

[0449]

(4) 2-tert-butyl 1,3-diisopropylisourea (2.1 mL) was added to a mixture of the compound J-4 (1.71 g) and dichloromethane (10 mL) at room temperature, and the mixture was stirred at room temperature for 20 hours. Insoluble matter was filtered off, and the filtrate was distilled under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 75/25 - 50/50), and thereby, the compound J-5 (1.35 g, yield: 83%) as a yellow viscous substance was obtained.

MS (ESI); m/z 833.3 [M+H]+

[0450]

(5) Palladium/carbon (hydrous) (487 mg) was added to a mixture of the compound J-5 (1.35 g) and tetrahydrofuran (8 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered through Celite® to remove insoluble matter. Insoluble matter was washed with tetrahydrofuran, and the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol = 100/0 - 95/5), and thereby, the title compound (0.513 g, yield: 64%) as a yellow viscous substance was obtained.

MS (ESI); m/z 475.3 [M+H]+

[0451]

Reference Example 306: tert-butyl (2S)-3-(4-ditert-butoxyphosphoryloxy-3- hydroxyphenyl)-2-hydrazino-2-methyIpropanoate (Alternative Method)

(1) 2-tert-Butyl 1,3-diisopropylisourea (4.23 mL) was added at room temperature to a mixture of the compound 1-7 (2.78 g) and dichloromethane (20 mL), and the mixture was stirred at room temperature for 24 hours. 2-tert-Butyl 1,3-diisopropylisourea (1.06 mL) was added, and the mixture was stirred at room temperature for 5 hours. Insoluble matter was filtered off, and the filtrate was distilled under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) = 90/10 to 70/30), and thereby, the compound J-6 (2.61 g, yield: 97%) as a colorless powder was obtained.

MS (ESI); m/z 681.4 [M-H]- [0452]

(2) Potassium carbonate (1.05 g) was added at room temperature to a mixture of the compound J-6 (2.61 g) and methanol (20 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution and was dried over sodium sulfate, then the solvent was distilled away under a reduced pressure, and the compound J-7 (2.67 g, yield: 100%) was obtained.

MS (ESI); m/z 639.3 [M-H]-

[0453]

(3) 1H-Tetrazole (484 mg) and tert-butyl N,N-diisopropylphosphoramidite (2.24 mL) were added at room temperature to a mixture of the compound J-7 (2.67 g), dichloromethane (20 mL), and acetonitrile (5 mL), and the mixture was stirred at room temperature for 1 hour and 30 minutes. A tert-butyl hydroperoxide decane solution (5.5 M) (1.30 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. An organic layer was washed with a saturated aqueous sodium chloride solution and was dried over sodium sulfate, and then the solvent was distilled away under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 60/40), and thereby, the compound J-5 (2.62 g, yield: 76%) as a colorless powder was obtained.

MS (ESI); m/z 831.5 [M-H]-

[0454]

(4) Palladium/carbon (hydrous) (153 mg) was added to a mixture of the compound J-5 (465 mg) and ethanol (3 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through a membrane filter to remove insoluble matter. The insoluble matter was washed with ethanol, and the solvent was distilled away under a reduced pressure, and thereby the compound J was obtained. MS (ESI); m/z 475.3 [M+H]+

[0455]

Experimental Example 1: Evaluation of in vitro conversion efficiency using human hepatocytes (Levodopa prodrug)

Conversion efficiency from a prodrug to levodopa was evaluated with a metabolic study using human hepatocytes. A prodrug was incubated with human hepatocytes at 37 °C for 4 hours. A part of the reaction solution was sampled at each predetermined time and mixed with an to stop the reaction. The reaction-stopped solution was centrifuged, and the obtained supernatant was analyzed using a liquid chromatography/tandem mass spectrometry method. The conversion efficiency to levodopa was evaluated as a levodopa production amount after 4 hours of incubation. Tables 15 and 16 show the levodopa production amounts of the compounds as some of the examples of the present invention.

[0456]

Table 15

[0457]

Table 16

[0458]

As shown in the results of the above tests, it was confirmed that all the compounds produced levodopa. From these results, efficient levodopa production in vivo is expected, and it is considered to be particularly useful as a therapeutic medicament for Parkinson's disease.

[0459]

Experimental Example 2: Evaluation of solution stability

A phosphate buffer solution at pH 7.4 was added to each of the compounds to dissolve the each of the compounds, and when necessary, a NaOH solution was added to adjust the pH of the mixture to prepare a solution of about 1 mg/mL. After storing this solution at 25 °C for about 1 day, HPLC purity (area percentage, %) was measured. The HPLC purity of the solution immediately after the preparation, or the HPLC purity of the compound, was subtracted from the HPLC purity after storage at 25 °C for about 1 day to obtain a HPLC purity difference. Tables 17 - 19 show the solution stabilities of the compounds of some of the examples of the present invention.

[0460]

Table 17

[0461]

Table 18

[0462]

Table 19

[0463]

As shown in the results of Tables 17 to 19, it was confirmed that the compounds of the present invention were stable in aqueous solutions near neutrality, and among them, the compounds of Example 4, Example 5, Example 22, Example 29, Example 31, Example 42 and Example 44, and Example 201, Example 202, Example 203, Example 205, Example 206, Example 207, Example 208, Example 210, Example 211, Example 212, Example 213, Example 214, Example 215, Example 219, Example 232, Example 233, Example 235, Example 237, Example 239, Example 241, Example 243, Example 246, Example 249, Example 251 and Example 255 were stable.

From the above results, the compounds of the present invention are expected to have high solution stability at pH 6 to 8, and are considered to be useful even in the combination medicament of the present invention, in which these compounds are combined, as a solution formulation having a high solution stability.

[0464]

Experimental Example 3: Evaluation of solubility

Water was added to each of the compounds to prepare a suspension, which was shaken at 25 °C for 24 hours, and then, filtration through a filter was performed to obtain a filtrate. A compound concentration in the filtrate was quantified using HPLC to obtain the solubility. Further, the pH of the filtrate was measured. Tables 20 and 21 show the solubilities of the compounds of some of the examples of the present invention.

[0465]

Table 20

[0466]

Table 21

[0467]

As shown in the results of the above tests, it was confirmed that all the compounds showed good solubility at pH near the isoelectric point.

From the above results, the compounds are expected to have high solubility at pH 6 to 8, and are considered to be particularly useful as a solution formulation.

[0468]

Experimental Example 4: Evaluation of in vitro conversion efficiency using human hepatocytes (Carbidopa prodrug)

Conversion efficiency from a prodrug to carbidopa was evaluated with a metabolic study using human hepatocytes. A prodrug was incubated with human hepatocytes at 37 °C for 4 hours. A part of the reaction solution was sampled 4 hours after the start of the reaction and mixed with an organic solvent to stop the reaction. The reaction-stopped solution was centrifuged, and the obtained supernatant was analyzed using a liquid chromatography/tandem mass spectrometry method. The conversion efficiency to carbidopa was evaluated as a carbidopa production amount after 4 hours of incubation. Table 22 shows the carbidopa production amounts of the compounds as some of the examples of the present invention.

[0469]

Table 22

Industrial Applicability [0470]

In the present invention, the combination medicament containing a levodopa prodrug compound and a carbidopa prodrug compound is useful for the prevention or treatment of neurodegenerative diseases and/or diseases or symptoms caused by a decrease in dopamine concentration in the brain, such as Parkinson's disease and related symptoms. Therefore, the present invention has a high utility value in the pharmaceutical industry.

[0471]

The disclosure of Japanese Patent Application No. 2021-037959 (filing date: March 10,

2021 ) is incorporated herein by reference in its entirety.

All references, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if the individual references, patent applications, and technical standards were specifically and individually noted as being incorporated by reference.

Claims

[Claim 1] A combination medicament comprising a compound or a pharmacologically acceptable salt thereof selected from the following group A and a compound or a pharmacologically acceptable salt thereof selected from the following group B:

<group A> a compound selected from a group consisting of a compound represented by a formula (I), a compound represented by a formula (II), a compound represented by a formula (XV) and a compound represented by a formula (XVI) or a pharmacologically acceptable salt thereof: a compound represented by the formula (I):

R^13a and R^14a are the same or different, and are each a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a phenyl, -O-C(=O)-R’, -C(=O)-OR’, -C(=O)-R’, -C(=S)-R’, -O- C(=O)-NR’R”, -O-C(=S)-NR’R”, or O-C(=O)-R’”;

R^15a is a hydrogen, an alkyl, a cycloalkyl or a phenyl;

R’ and R” are the same or different, and are each a hydrogen, an alkyl, an alkenyl, a cycloalkyl or a phenyl, or R’ and R”, taken together with an adjacent nitrogen atom thereto, form a heteroaryl; and R’” is a hydrogen, an alkyl, an alkenyl or an alkynyl, and a compound represented by the formula (II):

wherein R^20a is an amino acid side chain that may be substituted;

wherein R⁴¹³ and R^42a are the same or different and are each a hydrogen, an alkyl, an alkanoyl, a P(=O)(OH)2, S(=O)(OH) or a glycosyl that may be substituted;

R^43a is an alkyl that may be substituted, -R^45a-O-R^46a or a 5-membered heterocyclyl containing at least one nitrogen atom, wherein R^45a is an alkylene, and R^46a is a hydrogen, an alkyl, P(=O)(OH)2, S(=O)(OH), or a glycosyl that may be substituted; and R⁴⁴³ is a hydrogen or an alkyl,

R^11b and R^12b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)2, S(=O)(OH), or a glycosyl that may be substituted; and R^13b is a hydrogen or an alkyl, a compound represented by the formula (IV):

wherein R^20b is an amino acid side chain;

wherein R^30b is an amino acid side chain;

R^31b and R^32b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^33b is a hydrogen or an alkyl, a compound represented by the formula (VI):

wherein R^51b and R^52b are the same or different and are each a hydrogen, an alkyl,

P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^63b and R^64b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^63b and R^64b taken together form an alkylene that may be substituted; and R^65b is a hydrogen or an alkyl, a compound represented by the formula (IX):

R^93b is an alkyl that may be substituted, -R^95b-OC(=O)-R^96b, -R^95b-OC(=O)-NH-^R96b, -R^95b- 0C(=O)-R^96b, or a benzyl or phenethyl that may be substituted, wherein R^95b is an alkylene, that may be substituted, and R^96b is an alkyl that may be substituted; and R^94b is a hydrogen or an alkyl, a compound represented by the formula (XII):

wherein R^111b and R^112b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted;

R^113b is an amino, -NH- R^115b -SO₃H, -NH-SO₂-R^114b, -O-R^114b, -O-R^115b-NHCO-R' ', or -O- R^115b-NHCO-O-R^114b, wherein R^114b is an alkyl that may be substituted, R^115b is an alkylene that may be substituted, and R^116b is an aryl that may be substituted, or

[Claim 2] A combination medicament comprising a compound or a pharmacologically acceptable salt thereof selected from the following group A and a compound or a pharmacologically acceptable salt thereof selected from the following group B:

R^13a and R^14a are the same or different, and are each a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a phenyl, -O-C(=O)-R’, -C(=O)-OR', -C(=O)-R', -C(=S)-R', -O- C(=O)-NR’R”, -O-C(=S)-NR’R”, or OC(=O)-R’”;

R^15a is a hydrogen, an alkyl, a cycloalkyl or a phenyl; R’ and R” are the same or different, and are each a hydrogen, an alkyl, an alkenyl, a cycloalkyl or a phenyl, or R’ and R”, taken together with an adjacent nitrogen atom thereto, form a heteroaryl; and R”’ is a hydrogen, an alkyl, an alkenyl or an alkynyl, and a compound represented by the formula (II):

wherein R^20a is an amino acid side chain that may be substituted;

R^21a and R^22a are the same or different and are each a hydrogen, an alkyl, an alkanoyl, a P(=O)(OH)₂, S(=O)(OH) or a glycosyl that may be substituted; and R^23a, R^24a, and R^25a are the same or different, and are each a hydrogen or an alkyl,

<group B> a compound selected from a group consisting of compounds represented by formulas (III) to (IX) respectively or a pharmacologically acceptable salt thereof: a compound represented by the formula (III):

wherein R^10b is an amino acid side chain;

R^11b and R^12b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^13b is a hydrogen or an alkyl, a compound represented by the formula (IV):

wherein R^20b is an amino acid side chain;

wherein R^30b is an amino acid side chain;

R^43b and R⁴⁴⁵ are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^43b and R^44b taken together form an alkylene that may be substituted; and R^45b is a hydrogen or an alkyl, a compound represented by the formula (VII):

wherein R^61b and R^62b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; R^63b and R^64b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^63b and R^64b taken together form an alkylene that may be substituted; and R^65b is a hydrogen or an alkyl, and a compound represented by the formula (IX):

[Claim 3] The combination medicament according to claim 1 or 2, wherein the compound of group A is a compound represented by formula (I) or a pharmacologically acceptable salt thereof.

[Claim 4] The combination medicament according to claim 1 or 2, wherein the compound of group A is a compound represented by formula (II) or a pharmacologically acceptable salt thereof.

[Claim 5] The combination medicament according to claim 1 , wherein the compound of group A is a compound represented by formula (XV) or a pharmacologically acceptable salt thereof.

[Claim 6] The combination medicament according to claim 1 , wherein the compound of group A is a compound represented by formula (XVI) or a pharmacologically acceptable salt thereof.

[Claim 7] The combination medicament according to any one of claims 1 to 6, wherein the compound of group B is a compound represented by formula (III) or a pharmacologically acceptable salt thereof.

[Claim 8] The combination medicament according to any one of claims 1 to 6, wherein the compound of group B is a compound represented by formula (IV) or a pharmacologically acceptable salt thereof.

[Claim 9] The combination medicament according to any one of claims 1 to 6, wherein the compound of group B is a compound represented by formula (V) or a pharmacologically acceptable salt thereof.

[Claim 10] The combination medicament according to any one of claims 1 to 6, wherein the compound of group B is a compound represented by formula (VI) or a pharmacologically acceptable salt thereof.

[Claim 11] The combination medicament according to any one of claims 1 to 6, wherein the compound of group B is a compound represented by formula (VII) or a pharmacologically acceptable salt thereof.

[Claim 12] The combination medicament according to any one of claims 1 to 6, wherein the compound of group B is a compound represented by formula (VIII) or a pharmacologically acceptable salt thereof.

[Claim 13] The combination medicament according to any one of claims 1 to 6, wherein the compound of group B is a compound represented by formula (IX) or a pharmacologically acceptable salt thereof.

[Claim 14] The combination medicament according to any one of claims 1 and 3 to 6, wherein the compound of group B is a compound represented by formula (X) or a pharmacologically acceptable salt thereof.

[Claim 15] The combination medicament according to any one of claims 1 and 3 to 6, wherein the compound of group B is a compound represented by formula (XI) or a pharmacologically acceptable salt thereof.

[Claim 16] The combination medicament according to any one of claims 1 and 3 to 6, wherein the compound of group B is a compound represented by formula (XII) or a pharmacologically acceptable salt thereof.

[Claim 17] The combination medicament according to any one of claims 1 and 3 to 6, wherein the compound of group B is a compound represented by formula (XIII) or a pharmacologically acceptable salt thereof.

[Claim 18] The combination medicament according to any one of claims 1 and 3 to 6, wherein the compound of group B is a compound represented by formula (XIV) or a pharmacologically acceptable salt thereof.

[Claim 19] The combination medicament according to any one of claims 1 to 3, wherein in the formula (I), R^10a is an amino acid side chain or an O-phosphorylated amino acid side chain selected from a group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, O-phosphorylated tyrosine, tryptophan, ornithine, lanthionine, 3,4-dihydroxyphenylalanine, and 3,4- dihydroxyphenylalanine in which one or two hydroxy groups are O-phosphorylated.

[Claim 20] The combination medicament according to any one of claims 1 to 3, wherein in the formula (I), R^10a is an amino acid side chain or an O-phosphorylated amino acid side chain selected from a group consisting of lysine, valine, tyrosine, O-phosphorylated tyrosine, and 3,4-dihydroxyphenylalanine.

[Claim 21] The combination medicament according to claim 1, 2, 3, 19 or 20, wherein in the formula (I), R^11a and R^12a are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^13a, R^14a, R^15a are each a hydrogen.

[Claim 22] The combination medicament according to claim 1, 2, 3, 19 or 20, wherein in the formula (I), one of R^11a and R^12a is a hydrogen and the other is P(=O)(OH)₂; and R^13a, R^14a, R^15a are each a hydrogen.

[Claim 23] The combination medicament according to claim 1, 2 or 4, wherein in the formula (II), R^20a is an amino acid side chain selected from a group consisting of a glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine and tyrosine.

[Claim 24] The combination medicament according to claim 1, 2, 4 or 23, wherein in the formula (II), R^21a and R^22a are the same or different and are each a hydrogen, an acetyl, or P(=O)(OH)₂; and R^23a, R^24a and R^25a are each a hydrogen.

[Claim 25] The combination medicament according to claim 1, 2, 4 or 23, wherein in the formula (II), one of R^21a and R^22a is a hydrogen and the other is P(=O)(OH)₂; and R^23a, R^24a, and R^25a are each a hydrogen.

[Claim 26] The combination medicament according to claim 1 or 5, wherein in the formula (XV), R^31a and R^32a are the same or different and are each a hydrogen, an acetyl, or P(=O)(OH)₂.

[Claim 27] The combination medicament according to claim 1 or 5, wherein in the formula (XV), one of R^31a and R^32a is a hydrogen and the other is P(=O)(OH)₂.

[Claim 28] The combination medicament according to claim 1 or 6, wherein in the formula (XVI), R^41a and R^42a are the same or different and are each a hydrogen, an acetyl, or P(=O)(OH)₂, and R^44a is a hydrogen.

[Claim 29] The combination medicament according to claim 1 or 6, wherein in the formula (XVI), one of R^4,a and R^42a is a hydrogen and the other is P(=O)(OH)₂, and R^44a is a hydrogen.

[Claim 30] The combination medicament according to claim 1, 2 or 7, wherein in the formula (III), R^11b and R^12b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^13b is a hydrogen.

[Claim 31] The combination medicament according to claim 1, 2 or 8, wherein in the formula (IV), R^21b and R^22b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^23b is a hydrogen.

[Claim 32] The combination medicament according to claim 1, 2 or 9, wherein in the formula (V), R^31b and R^32b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^33b is a hydrogen.

[Claim 33] The combination medicament according to claim 1, 2 or 10, wherein in the formula (VI), R^41b and R^42b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^45b is a hydrogen.

[Claim 34] The combination medicament according to claim 1, 2 or 11, wherein in the formula (VII), R^51b and R^52b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^55b is a hydrogen.

[Claim 35] The combination medicament according to claim 1, 2 or 12, wherein in the formula (VIII), R^61b and R^62b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^65b is a hydrogen.

[Claim 36] The combination medicament according to claim 1, 2 or 13, wherein in the formula (IX), R^7,b and R^72b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^75b is a hydrogen.

[Claim 37] The combination medicament according to claim 1, or 14, wherein in the formula (X), R^81b and R^82b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^84b is a hydrogen.

[Claim 38] The combination medicament according to claim 1 or 15, wherein in the formula (XI), R^91b and R^92b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^94b is a hydrogen.

[Claim 39] The combination medicament according to claim 1 or 16, wherein in the formula (XII), R^101b and R^102b are the same or different and are each a hydrogen or P(=O)(OH)₂; and R^104b is a hydrogen.

[Claim 40] The combination medicament according to claim 1 or 17, wherein in the formula (XIII), R^111b and R^112b are the same or different and are each a hydrogen or P(=O)(OH)₂.

[Claim 41] The combination medicament according to claim 1 or 18, wherein in the formula (XIV), R^121b is a hydrogen or P(=O)(OH)₂; and R^122b is a hydrogen.

[Claim 42] A compound represented by a formula (III) or a pharmacologically acceptable salt thereof:

wherein R^10b is an amino acid side chain, or R^10b, taken together with the adjacent nitrogen atom, forms a 5-membered heterocyclyl containing at least one nitrogen atom; R^11b and R^12b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^13b is a hydrogen or an alkyl.

[Claim 43] The compound according to claim 42 or a pharmacologically acceptable salt thereof, wherein

R^11b and R^12b are the same or different and are each a hydrogen or P(=O(OH)₂, and R^13b is a hydrogen.

[Claim 44] A compound represented by a formula (IV) or a pharmacologically acceptable salt thereof:

wherein R^20b is an amino acid side chain;

[Claim 45] The compound according to claim 44 or a pharmacologically acceptable salt thereof, wherein

R^21b and R^22b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^23b is a hydrogen.

[Claim 46] A compound represented by a formula (V) or a pharmacologically acceptable salt thereof:

wherein R^30b is an amino acid side chain; R^31b and R^32b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted; and R^33b is a hydrogen or an alkyl.

[Claim 47] The compound according to claim 46 or a pharmacologically acceptable salt thereof, wherein

R^31b and R^32b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^33b is a hydrogen.

[Claim 48] A compound represented by a formula (VI) or a pharmacologically acceptable salt thereof:

[Claim 49] The compound according to claim 48 or a pharmacologically acceptable salt thereof, wherein

R^41b and R^42b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^45b is a hydrogen.

[Claim 50] A compound represented by a formula (VII) or a pharmacologically acceptable salt thereof:

R^53b and R^54b are the same or different and are each a hydrogen, an alkyl, P(=O)(OH)₂, S(=O)(OH), or a glycosyl that may be substituted, or R^53b and R^54b taken together form an alkylene that may be substituted; and R^55b is a hydrogen or an alkyl.

[Claim 51] The compound according to claim 50 or a pharmacologically acceptable salt thereof, wherein

R^51b and R^52b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^55b is a hydrogen.

[Claim 52] A compound represented by a formula (VIII) or a pharmacologically acceptable salt thereof:

[Claim 53] The compound according to claim 52 or a pharmacologically acceptable salt thereof, wherein

R^61b and R^62b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^65b is a hydrogen.

[Claim 54] A compound represented by a formula (IX) or a pharmacologically acceptable salt thereof:

[Claim 55] The compound according to claim 54 or a pharmacologically acceptable salt thereof, wherein

R^71b and R^72b are the same or different and are each a hydrogen or P(=O)(OH)₂, and R^75b is a hydrogen.

[Claim 56] A compound represented by the formula (X) or a pharmacologically acceptable salt thereof:

[Claim 57] The compound according to claim 56 or a pharmacologically acceptable salt thereof, wherein

[Claim 58] A compound represented by the formula (XI) or a pharmacologically acceptable salt thereof:

R^93b is an alkyl that may be substituted, -R^95b-OC(=O)-R^96b, -R^95b-OC(=O)-NH-^R96b, -R^95b- 0C(=O)-R^96b, or a benzyl or phenethyl that may be substituted, wherein R^95b is an alkylene, that may be substituted, and R^96b is an alkyl that may be substituted; and R^94b is a hydrogen or an alkyl.

[Claim 59] The compound according to claim 58 or a pharmacologically acceptable salt thereof, wherein

[Claim 60] A compound represented by the formula (XII) or a pharmacologically acceptable salt thereof:

[Claim 61] The compound according to claim 60 or a pharmacologically acceptable salt thereof, wherein

[Claim 62] A compound represented by the formula (XIII) or a pharmacologically acceptable salt thereof:

R^113b is an amino, -NH-R^115b-SO₃H, -NH-SO₂-R^114b, -O-R^114b, -O-R^115b-NHCO-R^116b, or -O- R^115b-NHCO-O-R^114b, wherein R^114b is an alkyl that may be substituted, R^115b is an alkylene that may be substituted, and R^116b is an aryl that may be substituted, or

[Claim 63] The compound according to claim 62 or a pharmacologically acceptable salt thereof, wherein R^111b and R^112b are the same or different and are each a hydrogen or P(=O)(OH)₂.

[Claim 64] A compound represented by the formula (XIV) or a pharmacologically acceptable salt thereof:

[Claim 65] The compound according to claim 64 or a pharmacologically acceptable salt thereof, wherein R^121b is a hydrogen or P(=O)(OH)₂; and R^122b is a hydrogen.

[Claim 66] A compound represented by a formula (1-1) or a pharmacologically acceptable salt thereof:

[Claim 67] A liquid pharmaceutical composition comprising a combination medicament containing a compound selected from the group A and a compound selected from the group B.

[Claim 68] A therapeutic agent for a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain, the therapeutic agent comprising a combination medicament containing a compound selected from the group A and a compound selected from the group B.

[Claim 69] The therapeutic agent according to claim 68, wherein the neurodegenerative disease and/or the disease or symptom caused by a decrease in dopamine concentration in the brain is Parkinson's disease.