JP2024010252A - Combination medicament for treatment of parkinson's disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a combination medicament useful for treatment of Parkinson's disease.

SOLUTION: The present invention provides a prophylactic or therapeutic agent for Parkinson's disease, the agent containing a combination medicament containing a levodopa prodrug compound and a carbidopa prodrug compound.

SELECTED DRAWING: None

COPYRIGHT: (C)2024,JPO&INPIT

Description

The present invention relates to (a) a pharmaceutical combination 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.

Parkinson's disease is a progressive neurodegenerative disease characterized by a deficiency of the neurotransmitter dopamine in the brain. Levodopa, the first-choice drug for this disease, is a direct precursor of dopamine, and unlike dopamine, it can cross the blood-brain barrier and move 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 obtain a high therapeutic effect.

As prodrugs aimed at treating Parkinson's disease, prodrugs with amino acids added (Patent Document 1) and prodrugs with a phosphate ester having a different structure (Patent Document 2) are known.

U.S. Patent Application Publication No. 3,803,120 International Publication No. 2017/184871

In the early stages of treatment for Parkinson's disease, the drug's efficacy can be maintained for a relatively long period simply by taking oral levodopa. However, with long-term administration of levodopa and disease progression, the effective therapeutic range gradually narrows, and many patients develop motor complications such as diurnal fluctuations in motor symptoms (on-off phenomenon) and involuntary movements (dyskinesia). become. In order to avoid motor complications and maintain effective blood levels of levodopa in the brain during the advanced stages of this disease, continuous administration into the body is necessary, and formulations suitable for this administration form must be developed. Is required.

For sustained administration into the body, administration in a liquid composition may be considered. Since levodopa and carbidopa exhibit poor solubility, means are required to increase the solubility of each compound. One effective method is to add a solubilizing agent to the formulation, but it may not be possible to dissolve the desired amount of the active ingredient in some cases. On the other hand, creating a new compound exhibiting high solubility by converting an active ingredient into a prodrug is a more effective means for obtaining a liquid composition with a desired concentration.

An object of the present invention is to provide prodrugs that improve the solubility of levodopa and carbidopa, have high stability in solution, and are converted into active forms in the body.

The present inventors conducted intensive studies to solve the above problems, and found that a levodopa prodrug compound represented by formula (I) or formula (II) and any one of formulas (III) to (IX) The present invention was completed based on the discovery that the represented carbidopa prodrug compounds are converted into active forms in the body and have high solubility and high solution stability, respectively. That is, the present invention is as follows.

（式中、Ｒ^１０ａは、アミノ酸側鎖またはそのＯ－リン酸化アミノ酸側鎖であり、
Ｒ^１１ａおよびＲ^１２ａは、同一または異なって、それぞれ、水素、アルキル、シクロアルキル、フェニル、Ｐ（＝Ｏ）（ＯＲ’）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^１３ａおよびＲ^１４ａは、同一または異なって、それぞれ、水素、アルキル、アルケニル、アルキニル、シクロアルキル、フェニル、－Ｏ－Ｃ（＝Ｏ）－Ｒ’、－Ｃ（＝Ｏ）－ＯＲ’、－Ｃ（＝Ｏ）－Ｒ’、－Ｃ（＝Ｓ）－Ｒ’、－Ｏ－Ｃ（＝Ｏ）－ＮＲ’ Ｒ’’ 、－Ｏ－Ｃ（＝Ｓ）－ＮＲ’ Ｒ’’、またはＯ－Ｃ（＝Ｏ）－Ｒ’’ ’であり、
Ｒ^１５ａは、水素、アルキル、シクロアルキルまたはフェニルであり、
Ｒ’およびＲ’’は、同一または異なって、それぞれ、水素、アルキル、アルケニル、シクロアルキルもしくはフェニルであるか、またはＲ’およびＲ’’が隣接する窒素原子と一緒になって、ヘテロアリールを形成する基であり、
Ｒ’’ ’は、水素、アルキル、アルケニルまたはアルキニルである。）で表される化合物、および 1. A pharmaceutical combination comprising one compound each selected from Group A and Group B below or a pharmacologically acceptable salt thereof.
<Group A> A compound selected from the group consisting of a compound represented by formula (I) and a compound represented by formula (II), or a pharmaceutically acceptable salt thereof, formula (I);

(wherein R ^10a is an amino acid side chain or its O-phosphorylated amino acid side chain,
R ^11a and R ^12a are the same or different and each represents hydrogen, alkyl, cycloalkyl, phenyl, P(=O)(OR') ₂ , S(=O)(OH), or optionally substituted glycosyl and
R ^13a and R ^14a are the same or different and each represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, -O-C(=O)-R', -C(=O)-OR', - C(=O)-R', -C(=S)-R', -OC(=O)-NR'R'',-OC(=S)-NR'R'', or OC(=O)-R''',
R ^15a is hydrogen, alkyl, cycloalkyl or phenyl;
R' and R'' are the same or different and are each hydrogen, alkyl, alkenyl, cycloalkyl or phenyl, or R' and R'' taken together with the adjacent nitrogen atoms form a heteroaryl. is a group that forms
R'' is hydrogen, alkyl, alkenyl or alkynyl. ), and

（式中、Ｒ^２０ａは、置換されていてもよいアミノ酸側鎖であり、
Ｒ^２１ａおよびＲ^２２ａは、同一または異なって、それぞれ水素、アルキル、アルカノイル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^２３ａ、Ｒ^２４ａ、Ｒ^２５ａは、同一または異なって、それぞれ水素またはアルキルである。）で表される化合物 Formula (II);

(wherein R ^20a is an optionally substituted amino acid side chain,
R ^21a and R ^22a are the same or different and each is hydrogen, alkyl, alkanoyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^23a , R ^24a and R ^25a are the same or different and each is hydrogen or alkyl. ) compound represented by

（式中、Ｒ^１０ｂは、アミノ酸側鎖であり、
Ｒ^１１ｂおよびＲ^１２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^１３ｂは、水素またはアルキルである。）で表される化合物、 <Group B> A compound selected from the group consisting of compounds represented by any one of formula (III) to formula (IX) or a pharmaceutically acceptable salt thereof formula (III);

(wherein R ^10b is an amino acid side chain,
R ^11b and R ^12b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^13b is hydrogen or alkyl. ),

（式中、Ｒ^２０ｂは、アミノ酸側鎖であり、
Ｒ^２１ｂおよびＲ^２２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^２３ｂは、水素またはアルキルである。）で表される化合物、 Formula (IV);

(wherein R ^20b is an amino acid side chain,
R ^21b and R ^22b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^23b is hydrogen or alkyl. ),

（式中、Ｒ^３０ｂは、アミノ酸側鎖であり、
Ｒ^３１ｂおよびＲ^３２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^３３ｂは、水素またはアルキルである。）で表される化合物、 Formula (V);

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

（式中、Ｒ^４１ｂおよびＲ^４２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^４３ｂおよびＲ^４４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^４３ｂおよびＲ^４４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^４５ｂは、水素またはアルキルである。）で表される化合物、 Formula (VI);

(wherein R ^41b and R ^42b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^43b and R ^44b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^43b and R ^44b are a group that together form an optionally substituted alkylene,
R ^45b is hydrogen or alkyl. ),

（式中、Ｒ^５１ｂおよびＲ^５２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^５３ｂおよびＲ^５４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^５３ｂおよびＲ^５４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^５５ｂは、水素またはアルキルである。）で表される化合物、 Formula (VII);

(wherein R ^51b and R ^52b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^53b and R ^54b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^53b and R ^54b are a group that together form an optionally substituted alkylene,
R ^55b is hydrogen or alkyl. ),

（式中、Ｒ^６１ｂおよびＲ^６２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^６３ｂおよびＲ^６４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^６３ｂおよびＲ^６４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^６５ｂは、水素またはアルキルである。）で表される化合物、および Formula (VIII);

(wherein R ^61b and R ^62b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^63b and R ^64b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^63b and R ^64b are a group that together form an optionally substituted alkylene,
R ^65b is hydrogen or alkyl. ), and

（式中、Ｒ^７１ｂおよびＲ^７２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^７３ｂおよびＲ^７４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^７３ｂおよびＲ^７４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^７５ｂは、水素またはアルキルである。）で表される化合物。 Formula (IX);

(wherein R ^71b and R ^72b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^73b and R ^74b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^73b and R ^74b are a group that together form an optionally substituted alkylene,
R ^75b is hydrogen or alkyl. ).

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

3. 2. The pharmaceutical combination as described in 1 above, wherein the compound of Group A is a compound represented by formula (II) or a pharmacologically acceptable salt thereof.

4. 4. The pharmaceutical combination according to any one of 1 to 3 above, wherein the compound of Group B is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

5. 4. The pharmaceutical combination according to any one of 1 to 3 above, wherein the compound of Group B is a compound represented by formula (IV) or a pharmacologically acceptable salt thereof.

6. 4. The pharmaceutical combination according to any one of 1 to 3 above, wherein the compound of Group B is a compound represented by formula (V) or a pharmacologically acceptable salt thereof.

7. 4. The pharmaceutical combination according to any one of 1 to 3 above, wherein the compound of Group B is a compound represented by formula (VI) or a pharmacologically acceptable salt thereof.

8. 4. The pharmaceutical combination according to any one of 1 to 3 above, wherein the compound of Group B is a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof.

9. 4. The pharmaceutical combination according to any one of 1 to 3 above, wherein the compound of Group B is a compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof.

10. 4. The pharmaceutical combination according to any one of 1 to 3 above, wherein the compound of Group B is a compound represented by formula (IX) or a pharmacologically acceptable salt thereof.

11. R ^10a in formula (I) is 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 1 or 2 O-phosphorylated 3,4-dihydroxyphenylalanine. 3. The pharmaceutical combination according to 1 or 2 above, which is a side chain or an O-phosphorylated amino acid side chain.

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

13. R ^11a and R ^12a of formula (I) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
^13. The pharmaceutical combination according to 1, 2, 11 or 12 above, wherein R ^13a , R 14a and R ^15a are hydrogen.

14. R ^11a and R ^12a of formula (I) are one hydrogen and one P(=O)(OH) ₂ ,
^13. The pharmaceutical combination according to 1, 2, 11 or 12 above, wherein R ^13a , R 14a and R ^15a are hydrogen.

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

16. R ^21a and R ^22a of formula (II) are the same or different and are each hydrogen, acetyl or P(=O)(OH) ₂ , and R ^23a and R ^24a are hydrogen, 15. The combination medicine according to 15.

17. R ^21a and R ^22a of formula (II) are one hydrogen and one -P(=O)(OH) ₂ ,
16. The pharmaceutical combination according to 1, 3 or 15 above, wherein R ^23a , R ^24a and R ^25a are hydrogen.

18. R ^11b and R ^12b of formula (III) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
5. The pharmaceutical combination according to 1 or 4 above, wherein R ^13b is hydrogen.

19. R ^21b and R ^22b of formula (IV) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
6. The pharmaceutical combination according to 1 or 5 above, wherein R ^23b is hydrogen.

20. R ^31b and R ^32b of formula (V) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
7. The pharmaceutical combination according to 1 or 6 above, wherein R ^33b is hydrogen.

21. R ^41b and R ^42b of formula (VI) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
8. The pharmaceutical combination according to 1 or 7 above, wherein R ^45b is hydrogen.

22. R ^51b and R ^52b of formula (VII) are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
9. The pharmaceutical combination according to 1 or 8 above, wherein R ^55b is hydrogen.

23. R ^61b and R ^62b of formula (VIII) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
10. The pharmaceutical combination according to 1 or 9 above, wherein R ^65b is hydrogen.

24. R ^71b and R ^72b of formula (IX) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
11. The pharmaceutical combination according to 1 or 10 above, wherein R ^75b is hydrogen.

（式中、Ｒ^１０ｂは、アミノ酸側鎖であり、
Ｒ^１１ｂおよびＲ^１２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^１３ｂは、水素またはアルキルである。）で表される化合物またはその薬理的に許容し得る塩。 25. Formula (III);

(wherein R ^10b is an amino acid side chain,
R ^11b and R ^12b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^13b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof.

26. R ^11b and R ^12b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
26. The compound or a pharmacologically acceptable salt thereof as described in 25 above, wherein R ^13b is hydrogen.

（式中、Ｒ^２０ｂは、アミノ酸側鎖であり、
Ｒ^２１ｂおよびＲ^２２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^２３ｂは、水素またはアルキルである。）で表される化合物またはその薬理的に許容し得る塩。 27. Formula (IV);

(wherein R ^20b is an amino acid side chain,
R ^21b and R ^22b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^23b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof.

28. R ^21b and R ^22b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
28. The compound or a pharmaceutically acceptable salt thereof as described in 27 above, wherein R ^23b is hydrogen.

（式中、Ｒ^３０ｂは、アミノ酸側鎖であり、
Ｒ^３１ｂおよびＲ^３２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＲ’）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^３３ｂは、水素またはアルキルである。）で表される化合物またはその薬理的に許容し得る塩。 29. Formula (V);

(wherein R ^30b is an amino acid side chain,
R ^31b and R ^32b are the same or different, and each is hydrogen, alkyl, P(=O)(OR') ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^33b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof.

30. R ^31b and R ^32b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
29. The compound or a pharmacologically acceptable salt thereof as described in 29 above, wherein R ^33b is hydrogen.

（式中、Ｒ^４１ｂおよびＲ^４２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^４３ｂおよびＲ^４４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^４３ｂおよびＲ^４４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^４５ｂは、水素またはアルキルである。）で表される化合物またはその薬理的に許容し得る塩。 31. Formula (VI);

(wherein R ^41b and R ^42b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^43b and R ^44b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^43b and R ^44b are a group that together form an optionally substituted alkylene,
R ^45b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof.

32. R ^41b and R ^42b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
32. The compound or a pharmaceutically acceptable salt thereof as described in 31 above, wherein R ^45b is hydrogen.

（式中、Ｒ^５１ｂおよびＲ^５２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^５３ｂおよびＲ^５４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^５３ｂおよびＲ^５４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^５５ｂは、水素またはアルキルである。）で表される化合物またはその薬理的に許容し得る塩。 33. Formula (VII);

(wherein R ^51b and R ^52b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^53b and R ^54b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^53b and R ^54b are a group that together form an optionally substituted alkylene,
R ^55b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof.

34. R ^51b and R ^52b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
34. The compound or a pharmaceutically acceptable salt thereof as described in 33 above, wherein R ^55b is hydrogen.

（式中、Ｒ^６１ｂおよびＲ^６２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^６３ｂおよびＲ^６４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^６３ｂおよびＲ^６４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^６５ｂは、水素またはアルキルである。）で表される化合物またはその薬理的に許容し得る塩。 35. Formula (VIII);

(wherein R ^61b and R ^62b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^63b and R ^64b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^63b and R ^64b are a group that together form an optionally substituted alkylene,
R ^65b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof.

36. R ^61b and R ^62b are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
36. The compound or a pharmaceutically acceptable salt thereof as described in 35 above, wherein R ^65b is hydrogen.

（式中、Ｒ^７１ｂおよびＲ^７２ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
Ｒ^７３ｂおよびＲ^７４ｂは、同一または異なって、それぞれ水素、アルキル、Ｐ（＝Ｏ）（ＯＨ）_２、Ｓ（＝Ｏ）（ＯＨ）もしくは置換されていてもよいグリコシルであるか、またはＲ^７３ｂおよびＲ^７４ｂが一緒になって、置換されていてもよいアルキレンを形成する基であり、
Ｒ^７５ｂは、水素またはアルキルである。）で表される化合物またはその薬理的に許容し得る塩。 37. Formula (IX);

(wherein R ^71b and R ^72b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^73b and R ^74b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^73b and R ^74b are a group that together form an optionally substituted alkylene,
R ^75b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof.

38. R ^71b and R ^72b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
38. The compound or a pharmacologically acceptable salt thereof as described in 37 above, wherein R ^75b is hydrogen.

（式中、Ｒ^１０ａは、アミノ酸側鎖であり、
Ｒ^１１ａおよびＲ^１２ａは、同一または異なって、それぞれ、水素、Ｓ（＝Ｏ）（ＯＨ）または置換されていてもよいグリコシルであり、
ただし、Ｒ^１１ａおよびＲ^１２ａは、同時に水素ではない。）で表される化合物またはその薬理的に許容し得る塩。 39. Formula (I-1);

(wherein R ^10a is an amino acid side chain,
R ^11a and R ^12a are the same or different and each is hydrogen, S(=O)(OH) or optionally substituted glycosyl,
However, R ^11a and R ^12a are not hydrogen at the same time. ) or a pharmacologically acceptable salt thereof.

40. A liquid pharmaceutical composition containing a combination drug comprising a compound selected from Group A and a compound selected from Group B.

41. A therapeutic agent for a neurodegenerative disease and/or a disease or symptom caused by a decrease in brain dopamine concentration, comprising a pharmaceutical combination comprising a compound selected from Group A and a compound selected from Group B.

42. 42. The therapeutic agent according to 41 above, wherein the disease or symptom caused by a neurodegenerative disease and/or a decrease in brain dopamine concentration is Parkinson's disease.

The pharmaceutical combination containing prodrugs of levodopa and carbidopa of the present invention is useful as a prophylactic or therapeutic agent for neurodegenerative diseases and/or diseases or conditions caused by decreased brain dopamine concentration, such as Parkinson's disease.
Furthermore, the compounds (I) to (IX) of the present invention described in Groups A and B and their pharmaceutical combinations exhibit high solubility and high solution stability, and therefore can be used in the form of liquid compositions. For example, it is useful as a minimally invasive, sustained subcutaneous administration preparation suitable for the prevention or treatment of the aforementioned neurodegenerative diseases.

The features of the present disclosure will be described in detail below. The definitions of each group in this specification can be freely combined unless otherwise specified.

The term "treatment" as used herein generally refers to obtaining a desired pharmacological and/or physiological effect. The term treatment as used herein includes the treatment of a disease in a mammal, particularly a human, including (a) suppressing the disease, i.e., preventing an increase in the severity or extent of the disease; (b) (c) alleviation of a disease, including partial or complete amelioration of the disease; or (c) prevention of recurrence of a disease, meaning preventing relapse after successful treatment of the disease or condition.

As used herein, the term "prophylaxis" refers to delaying the onset of clinical symptoms, complications, or biochemical indicators of a condition, disorder, disease, or condition to which a subject is susceptible or susceptible. but does not include not yet experiencing or exhibiting clinical or subclinical symptoms of those conditions, disorders, diseases, or conditions. "Prevention" includes prophylactic treatment for a condition, disorder, disease or condition in a subject and includes prophylactic treatment for clinical symptoms, complications, or biochemical indicators for a condition, disorder, disease or condition in a subject; It will be done.

As used herein, the term "patient" or "subject" refers to any mammal, mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or non-human primate; Includes all animals including humans. In some embodiments, the mammal treated with the methods of the invention is a human suffering from a neurodegenerative disease, such as Parkinson's disease, and/or a disease or condition caused by decreased brain dopamine levels.

As used herein, the term "about" is intended to include a range of ±10% of the stated value, unless otherwise stated. In some cases, a presented value may be considered to cover a range of ±10% of that value, even if the term "about" is not used.

The term "stable" as used herein, unless otherwise stated, refers to the state of a substance that does not or is not susceptible to decomposition in solution. Therefore, the term "stable" in this specification refers to, for example, the peak area ratio of a substance when a solution of the substance is prepared and measured by the area percentage method of high performance liquid chromatography (HPLC) immediately after preparing the solution; This means that when comparing the peak area ratios of substances after being left at 25°C for about 1 day, no decrease in the peak area ratio is observed or the degree of decrease is low.

The term "liquid" as used herein means all types of liquids, including gels, aqueous and non-aqueous compositions, and the like, unless otherwise stated.

As used herein, the term "combination" refers to the administration of two or more active ingredients in combination, including the administration of these active ingredients simultaneously, either in separate or in the same composition, unless otherwise stated. It also includes administering two or more active ingredients consecutively on the same day, administering the active ingredients a predetermined time apart from each other, and further including administering two or more active ingredients on different days. It also includes administering to

As used herein, the term "sustained", unless otherwise stated, refers to a period in which the composition is administered for an entire period of time, less than about 24 hours, such as about 12 hours, about 5 hours, about 3 hours, with breaks of about 1 hour, about 30 minutes, about 15 minutes, about 5 minutes, or about 1 minute. The period of administration of this drug is at least about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, 3 days, 7 days, 2 weeks, 1 month, 3 days. It can be for 1 year, 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, etc.

In the present invention, alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (C _{1 to 6} ). Particularly preferred are groups having 1 to 4 carbon atoms (C _1-4 ). Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl and the like.

In the present invention, alkoxy refers to a monovalent group in which the above-mentioned alkyl is bonded to one oxygen atom, and a straight or branched alkyl-O- having 1 to 6 carbon atoms (C _{1 to 6} ) is Can be mentioned. Specific examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.

In the present invention, alkenyl means a straight or branched unsaturated hydrocarbon chain having 2 to 6 carbon atoms and having one carbon-carbon double bond, such as vinyl, propenyl, butenyl, and various branched chain isomers thereof, preferably a straight or branched unsaturated hydrocarbon chain having 2 to 4 carbon atoms.

In the present invention, alkynyl refers to a monovalent group of a straight or branched hydrocarbon chain having one or more triple bonds, such as a straight or branched alkynyl group having 2 to 6 carbon atoms. means. Specifically, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3- Examples include nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like.

In the present invention, alkylene refers to a linear or branched saturated hydrocarbon divalent group having 1 to 6 carbon atoms (C _{1 to 6} ), and specifically includes methylene, ethylene, trimethylene, and tetramethylene. Examples include.
Here, the alkylene for R ^43b and R ^44b , the alkylene for R ^53b and R ^54b , the alkylene for R ^63b and R ^64b , and the alkylene for R ^73b and R ^74b preferably include methylene and ethylene, and the alkylene is Each may be replaced. Examples of such substituents include alkyl, alkoxy, and the like, which may be substituted with 1 to 3 substituents that are the same or different.

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

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

In the present invention, amino acid side chains refer to amino acid side chains of natural, synthetic, non-natural or non-proteinogenic amino acids, such as 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 acids ((2S, 3S, 4E, 6E, 8S, 9S) )-3-amino-9-methoxy-2,6,8trimethyl-10-phenyldec-4,6-dienoic acid), β-alanine, 4-aminobenzoic acid, γ-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, enduracidin, homoserine, 4-phenyl Examples include glycine, hydroxyproline, hypusine, β-leucine, norleucine, norvaline, ornithine, penicillamine, placohypaforin, pyroglutamic acid, quisqualic acid, sarcosine, theanine, tranexamic acid, trichromic acid, and 3,4-dihydroxyphenylalanine. R ^10a preferably includes the amino acid side chain of arginine, lysine, alanine, valine, tyrosine or 3,4-dihydroxyphenylalanine. R ^20a preferably includes the amino acid side chain of glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine or tyrosine. R ^10b preferably includes the amino acid side chain of tyrosine or lysine. R ^20b preferably includes an amino acid side chain of alanine or lysine. R ^30b preferably includes an amino acid side chain of alanine or lysine.

（プロリンのアミノ酸側鎖であって、式中、Ｒ^１０ａ、Ｒ^２０ａ、Ｒ^１０ｂ、Ｒ^２０ｂ、Ｒ^３０ｂの各々は、各化合物の隣接するペプチド結合の窒素原子と一緒になって環を形成している）；

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

(The amino acid side chain of proline, in which each of R ^10a , R ^20a , R ^10b , R ^20b , and R ^30b forms a ring together with the nitrogen atom of the adjacent peptide bond of each compound. ing);

Here, the amino acid side chain in the present invention may be substituted, such as -P(O)(OR ⁶ ) ₂ (R ⁶ represents hydrogen or alkyl, etc.) or a glucosyl group ([(2R, 3S, 4R, (5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl], etc.) or with other adjacent groups to form an optionally substituted alkylene group (Substituents include alkyl groups, alkoxy groups, etc.). Examples of the substituted amino acid side chain include those in which a hydroxy-containing amino acid side chain such as a tyrosine side chain, a serine side chain, a threonine side chain, and (3,4-dihydroxyphenyl)methyl are substituted. Specifically, phosphonooxymethyl, (4-phosphonooxyphenyl)methyl, [4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) Tetrahydropyran-2-yl]oxyphenyl]methyl, (2,2-dimethyl-1,3-benzodioxol-5-yl)methyl, (2-ethoxy-2-methyl-1,3-benzodioxol-5-yl) Examples include methyl.

In the present invention, the monosaccharides that form the basis of glycosyl include aldoses such as glucose, ribose, erythrose, xylose, arabinose, mannose, and galactose, as well as ketoses such as ribulose, psicose, fructose, sorbose, and tagatose. It will be done. These monosaccharides may be d-form, l-form or dl-form.
Here, the monosaccharide in the present invention may be substituted, and examples of the substituent include a carbonyl group, an acetylamino group, a sulfinooxy group, a phosphonooxy group, and specifically, glucuronic acid, N-acetyl Examples include glucosamine and glucopyranoside-6-(hydrogen sulfate).

In the present invention, the group in which R' and R'' are taken together to form a heteroaryl with a nitrogen atom refers to 1 to 4 groups independently selected from the group consisting of a sulfur atom, an oxygen atom, and a nitrogen atom. It refers to a 5- to 10-membered aromatic heterocyclic group containing a heteroatom, and monocyclic or bicyclic heteroaryl is preferred. More preferred is a 5- to 10-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen atoms. Specifically, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl. , isoquinolyl, imidazopyridyl, benzopyranyl and the like. Preferred are pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazinyl, triazinyl, and especially pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl. , triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like are preferred.

When the compound of the present invention has an asymmetric carbon atom in the molecule, it may exist as multiple stereoisomers (i.e., diastereoisomers, optical isomers) based on the asymmetric carbon atom, but the present invention includes any one of these stereoisomers and mixtures thereof.

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

Pharmaceutically acceptable salts of the compounds of the present invention include inorganic acid addition salts (e.g., salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts (e.g., 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, tartaric acid, succinic acid, mandelic acid , malic acid, pantothenic acid, methyl sulfate, etc.), inorganic base addition salts (e.g., salts with sodium, potassium, calcium, magnesium, etc.), salts with amino acids (e.g., glutamic acid, aspartic acid, arginine, lysine, etc.) etc.).
The compound of the present invention or a pharmacologically acceptable salt thereof includes any of its inner salts, adducts, solvates or hydrates thereof, and the like.

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

Preferred compounds of general formula (II) are listed below.

［式中、Ｂｎはベンジルを、Ｃｂｚはカルボベンゾキシを示し、他の記号は前記と同一意味を表す。］ The compound represented by general formula (I) of the present invention or a pharmacologically acceptable salt thereof can be produced, for example, as follows.
Synthesis method A

[Wherein, Bn represents benzyl, Cbz represents carbobenzoxy, and other symbols have the same meanings as above. ]

Among the target compounds [I] of the present invention, the compound represented by the general formula [Ia] can be produced, for example, as follows. Compound [a] and compound [b] are subjected to a condensation reaction to obtain compound [c], and then compound [f] is obtained by phosphorous acid esterification and oxidation or phosphoric acid esterification. It will be done. On the other hand, compound [f] can also be obtained by condensing compound [e] and compound [b]. Compound [Ia] can be produced by deprotecting compound [f] thus obtained.

Process 1
The condensation reaction of compound [a] or a salt thereof and compound [b] or a salt thereof is carried out according to a conventional method in an appropriate solvent, in the presence or absence of a base, in the presence of a condensing agent, and in the presence of an activating agent. Or it can be carried out in the absence. The solvent may be any solvent as long as it does not affect this reaction, such as ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N,N-dimethylformamide and N-methylpyrrolidone, and acetonitrile. Examples include nitriles, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as toluene, or mixtures thereof. Examples of the base include triethylamine, diisopropylethylamine, and diazabicycloundecene. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3- Examples include (3-dimethylaminopropyl)carbodiimide hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Examples of the activator include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of compound [b] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [a].

The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [a].

The amount of the condensing agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [a] in molar ratio.

The amount of the activator used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [a].
This reaction can be carried out at room temperature to heating, for example room temperature to 80°C, preferably room temperature to 50°C.

Process 2
The condensation reaction between compound [c] and the phosphite esterifying agent can be carried out in a suitable solvent in the presence of an activator according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the phosphite forming agent include dibenzyl N,N-diisopropyl phosphoramidite. Examples of the activator include 1-tetrazole.

The amount of the phosphite esterifying agent used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [c].

The amount of the activator to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [c].

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

Process 3
The oxidation reaction of compound [d] can be carried out in a suitable solvent in the presence of an oxidizing agent according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the oxidizing agent include hydrogen peroxide, tert-butyl hydroperoxide, and metachloroperbenzoic acid.

The amount of the oxidizing agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [d].

This reaction can be carried out under ice-cooling to room temperature, preferably under ice-cooling.

Process 4
The condensation reaction between compound [c] and the phosphoric acid esterifying agent can be carried out in a suitable solvent in the presence of a base according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and examples thereof include halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, and mixtures thereof. Examples of the phosphoric acid esterification agent include dibenzylphosphoryl chloride and tetrabenzyl pyrophosphate. Examples of the base include alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide, and alkylamines such as triethylamine and diisopropylethylamine.

The amount of the phosphoric acid esterifying agent used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [c].

The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [c].

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

Process 5
The condensation reaction between compound [e] or a salt thereof and compound [b] or a salt thereof is carried out according to a conventional method in an appropriate solvent, in the presence or absence of a base, in the presence of a condensing agent, and in the presence of an activating agent. Or it can be carried out in the absence. The solvent may be any solvent as long as it does not affect this reaction, such as ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N,N-dimethylformamide and N-methylpyrrolidone, and acetonitrile. Examples include nitriles, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as toluene, or mixtures thereof. Examples of the base include triethylamine, diisopropylethylamine, and diazabicycloundecene. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3- Examples include (3-dimethylaminopropyl)carbodiimide hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Examples of the activator include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of compound [b] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [e].

The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [e].

The amount of the condensing agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [e].

The amount of the activator used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [e].

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

Process 6
Deprotection of compound [f] can be carried out by treatment with a catalyst in a suitable solvent in a hydrogen atmosphere according to a conventional method.
The solvent may be any solvent as long as it does not affect this reaction, and examples thereof include ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol, ethanol, and isopropanol, water, and mixtures thereof. It will be done.

Examples of the catalyst include palladium on carbon.

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

［式中、Ｒ－ＯＨは、セリン、チロシン等のアミノ酸側鎖であり、他の記号は前記と同一意味を表す。］ Synthesis method B

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

Among the target compounds [I] of the present invention, the compound represented by the general formula [Ib] can be produced, for example, as follows. Compound [g] and compound [b-1] are subjected to a condensation reaction to obtain compound [h]. Compound [h] is phosphorous-esterified to form compound [i], and then oxidized to obtain compound [j], or compound [h] is phosphoric-esterified to obtain compound [j] After obtaining, compound [Ib] can be produced by deprotecting.

Process 1
The condensation reaction of compound [g] or a salt thereof and compound [b-1] or a salt thereof may be carried out in the same manner as the reaction of compound [a] or a salt thereof and compound [b] or a salt thereof in synthesis method A. Can be done.

Process 2
The condensation reaction between the compound [h] and the phosphite esterifying agent can be carried out in the same manner as the reaction between the compound [c] and the phosphite esterifying agent in synthesis method A.

Process 3
The oxidation reaction of compound [i] can be carried out in the same manner as the reaction of compound [d] in synthesis method A.

Process 4
The condensation reaction between the compound [h] and the phosphoric acid esterifying agent can be carried out in the same manner as the reaction between the compound [c] and the phosphoric acid esterifying agent in synthesis method A.

Process 5
Deprotection of compound [j] can be carried out in the same manner as the reaction of compound [f] in synthesis method A.

〔式中、各記号は前記と同一意味を有する。〕 The compound represented by general formula (II) of the present invention or a pharmacologically acceptable salt thereof can be produced, for example, as follows.
Synthesis method C

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

Among the target compounds [II] of the present invention, the compound represented by the general formula [IIa] can be produced, for example, as follows. Compound [k-1] and compound [l-1] are subjected to a condensation reaction to obtain compound [m], and then phosphorous acid esterification and oxidation or phosphoric acid esterification is performed to obtain compound [m]. p] is obtained. On the other hand, compound [p] can also be obtained by condensing compound [o] and compound [l-1]. Compound [IIa] can be produced by deprotecting compound [p] thus obtained, or by deprotecting it after hydrolysis.

Process 1
The condensation reaction between compound [k-1] or a salt thereof and compound [l-1] or a salt thereof is carried out in an appropriate solvent, in the presence or absence of a base, in the presence or absence of a condensing agent, according to a conventional method. It can be carried out in the presence or absence of an activator. The solvent may be any solvent as long as it does not affect this reaction, such as tetrahydrofuran, ethers such as 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc. Examples include amides of , nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as toluene, and mixtures thereof. Examples of the base include triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3- Examples include (3-dimethylaminopropyl)carbodiimide hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Examples of the activator include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of compound [l-1] or [l-2] to be used is 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [k-1]. can do.

The amount of the base used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [k-1].

The amount of the condensing agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [k-1].

The amount of the activator used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [k-1].

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

Process 2
The condensation reaction between the compound [m] and the phosphite esterifying agent can be carried out in a suitable solvent in the presence of an activator according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the phosphite forming agent include dibenzyl N,N-diisopropyl phosphoramidite. Examples of the activator include 1-tetrazole.

The amount of the phosphite esterifying agent to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on the compound [m].

The amount of the activator used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [m] in molar ratio.

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

Process 3
The oxidation reaction of compound [n] can be carried out in a suitable solvent in the presence of an oxidizing agent according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the oxidizing agent include hydrogen peroxide, tert-butyl hydroperoxide, and metachloroperbenzoic acid.

The amount of the oxidizing agent used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [n].

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

Process 4
The condensation reaction between the compound [m] and the phosphoric acid esterifying agent can be carried out in a suitable solvent in the presence of a base according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the phosphoric acid esterification agent include dibenzylphosphoryl chloride and tetrabenzyl pyrophosphate. Examples of the base include alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide, and alkylamines such as triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. Can be mentioned.

The amount of the phosphoric acid esterifying agent used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on the compound [m].

The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [m].

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

Process 5
The condensation reaction of compound [o] or its salt and compound [l-1] or its salt is the same as the condensation reaction of compound [k-1] or its salt and compound [l-1] or its salt in synthesis method C. It can be carried out as follows.

Process 6
Deprotection of compound [p] can be carried out by treatment with a catalyst in a suitable solvent in a hydrogen atmosphere according to a conventional method.
The solvent may be any solvent as long as it does not affect this reaction, and examples thereof include ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol, ethanol, and isopropanol, water, and mixtures thereof. It will be done.
Examples of the catalyst include palladium/carbon.
This reaction can be carried out at room temperature to heating, for example room temperature to 80°C, preferably room temperature to 50°C.

Process 7
Hydrolysis of compound [q] can be carried out in a suitable solvent in the presence of a base and water according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, such as alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, water, or Examples include mixtures of these. Examples of the base include alkali metal hydroxides such as sodium hydroxide and lithium hydroxide. This reaction can be carried out under ice-cooling to heating, for example at 0°C to 50°C, preferably at room temperature.

The amount of the base used can be 1.0 to 10.0 equivalents, preferably 1.0 to 4.0 equivalents, relative to compound [q].

Process 8
Deprotection of compound [q] can be carried out in the same manner as the deprotection of compound [p] in Synthesis Method C.

〔式中、各記号は前記と同一意味を有する。〕 Synthesis method D

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

Among the target compounds [II] of the present invention, the compound represented by the general formula [IIb] can be produced, for example, as follows. Compound [k-2] and compound [l-3] are subjected to a condensation reaction to obtain compound [r], and then phosphorous acid esterification and oxidation or phosphoric acid esterification is performed to obtain compound [r]. t] is obtained. Compound [IIb] can be produced by deprotecting this.

Process 1
The condensation reaction of compound [k-2] or a salt thereof and compound [l-3] or a salt thereof is the condensation reaction of compound [k-1] or a salt thereof and compound [l-1] or a salt thereof in synthesis method C. It can be implemented in the same manner as .

Process 2
The condensation reaction between the compound [r] and the phosphite esterifying agent can be carried out in the same manner as the condensation reaction between the compound [m] and the phosphite esterifying agent in synthesis method C.

Process 3
The oxidation reaction of compound [s] can be carried out in the same manner as the oxidation reaction of compound [n] in synthesis method C.

Process 4
The condensation reaction between the compound [r] and the phosphoric acid esterifying agent can be carried out in the same manner as the condensation reaction between the compound [m] and the phosphoric acid esterifying agent in Synthesis Method C.

Process 5
Deprotection of compound [t] can be carried out in the same manner as the deprotection of compound [p] in Synthesis Method C.

〔式中、Ａｃはアセチルを示し、他の記号は前記と同一意味を有する。〕
本発明の目的化合物［ＩＩ］のうち、一般式［ＩＩｃ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｋ－３］と化合物［ｌ－１］を縮合反応に付し、化合物［ｕ］を得た後，これを脱保護することにより、化合物［ＩＩｃ］を製造することができる。 Synthesis method E

[In the formula, Ac represents acetyl, and the other symbols have the same meanings as above. ]
Among the target compounds [II] of the present invention, the compound represented by the general formula [IIc] can be produced, for example, as follows. Compound [k-3] and compound [l-1] are subjected to a condensation reaction to obtain compound [u], which is then deprotected to produce compound [IIc].

Process 1
The condensation reaction of compound [k-3] or a salt thereof and compound [l-1] or a salt thereof is the condensation reaction of compound [k-1] or a salt thereof and compound [l-1] or a salt thereof in synthesis method C. It can be implemented in the same manner as .

Process 2
Deprotection of compound [u] can be carried out in the same manner as the deprotection of compound [p] in Synthesis Method C.

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［ＩＩ］のうち、一般式［ＩＩｄ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｋ－２］と化合物［ｌ－１］を縮合反応に付し、化合物［ｖ］を得た後、これを脱保護することにより、化合物［ＩＩｄ］を製造することができる。 Synthesis method F

[In the formula, each symbol has the same meaning as above. ]
Among the target compounds [II] of the present invention, the compound represented by the general formula [IId] can be produced, for example, as follows. Compound [k-2] and compound [l-1] are subjected to a condensation reaction to obtain compound [v], which is then deprotected to produce compound [IId].

Process 1
The condensation reaction of compound [k-2] or its salt and compound [l-1] or its salt is carried out in the same manner as the condensation reaction of compound [k-1] and compound [l-1] or its salt in synthesis method C. It can be implemented by

Process 2
Deprotection of compound [v] can be carried out in the same manner as the deprotection of compound [p] in Synthesis Method C.

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

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［ＩＩＩ］のうち、一般式［ＩＩＩａ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｗ］と化合物［ｘ－１］を縮合反応に付し、化合物［ｙ］を得た後，脱保護することにより、化合物［ＩＩＩａ］を製造することができる。 Synthesis method G

[In the formula, each symbol has the same meaning as above. ]
Among the target compounds [III] of the present invention, the compound represented by the general formula [IIIa] can be produced, for example, as follows. Compound [IIIa] can be produced by subjecting compound [w] and compound [x-1] to a condensation reaction to obtain compound [y], followed by deprotection.

Process 1
The condensation reaction between compound [w] and compound [x-1] or a salt thereof can be carried out in a suitable solvent, in the presence or absence of a base, in the presence of a condensing agent, in the presence of an activating agent, or in the presence or absence of a base, according to a conventional method. It can be carried out in the absence. The solvent may be any solvent as long as it does not affect this reaction, such as ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N,N-dimethylformamide and N-methylpyrrolidone, and acetonitrile. Examples include nitriles, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as toluene, or mixtures thereof. Examples of the base include triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3- Examples include (3-dimethylaminopropyl)carbodiimide hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Examples of the activator include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of compound [x-1] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [w].

The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on the compound [w].

The amount of the condensing agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on the compound [w].

The amount of the activator to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on the compound [w].

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

Process 2
Deprotection of compound [y] can be carried out by treatment with a catalyst in a suitable solvent in a hydrogen atmosphere according to a conventional method.
The solvent may be any solvent as long as it does not affect this reaction, and examples thereof include ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol, ethanol, and isopropanol, water, and mixtures thereof. It will be done.
Examples of the catalyst include palladium/carbon.

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

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［ＩＩＩ］のうち、一般式［ＩＩＩｂ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｚ］と化合物［ｘ－１］を縮合反応に付し、化合物［ａａ］を得た後，脱保護することにより、化合物［ＩＩＩｂ］を製造することができる。 Synthesis method H

[In the formula, each symbol has the same meaning as above. ]
Among the target compounds [III] of the present invention, the compound represented by the general formula [IIIb] can be produced, for example, as follows. Compound [IIIb] can be produced by subjecting compound [z] and compound [x-1] to a condensation reaction to obtain compound [aa], followed by deprotection.

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

Process 2
The deprotection reaction of compound [aa] can be carried out in the same manner as the deprotection reaction of compound [y] in Synthesis Method G.

〔式中、ｔ－Ｂｕはｔｅｒｔ－ブチルを示し、他の記号は前記と同一意味を有する。〕
本発明の目的化合物［ＩＶ］のうち、一般式［ＩＶａ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｂｂ］と化合物［ｘ－２］を縮合反応に付し、化合物［ｃｃ］を得た後，亜リン酸エステル化および酸化するか、またはリン酸エステル化することにより、化合物［ｅｅ］が得られる。これを脱保護することにより、化合物［ＩＶｃ］を製造することができる。別法として，化合物［ｆｆ］と化合物［ｘ－２］あるいはその塩を縮合することにより、化合物［ｇｇ］を得ることができる。二段階の脱保護ののち，化合物［ＩＶａ］を製造することもできる。 Synthesis method I

[In the formula, t-Bu represents tert-butyl, and other symbols have the same meanings as above. ]
Among the target compounds [IV] of the present invention, the compound represented by the general formula [IVa] can be produced, for example, as follows. After subjecting compound [bb] and compound [x-2] to a condensation reaction to obtain compound [cc], compound [ee] is obtained by phosphorous acid esterification and oxidation or phosphoric acid esterification. is obtained. Compound [IVc] can be produced by deprotecting this. Alternatively, compound [gg] can be obtained by condensing compound [ff] and compound [x-2] or a salt thereof. Compound [IVa] can also be produced after two steps of deprotection.

Process 1
The condensation reaction between compound [bb] or a salt thereof and compound [x-1] or a salt thereof is carried out in a suitable solvent in the presence or absence of a base, in the presence of a condensing agent, and in the presence of an activating agent. It can be carried out in the presence or absence. The solvent may be any solvent as long as it does not affect this reaction, such as ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N,N-dimethylformamide and N-methylpyrrolidone, and acetonitrile. Examples include nitriles, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as toluene, or mixtures thereof. Examples of the base include triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3- Examples include (3-dimethylaminopropyl)carbodiimide hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Examples of the activator include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of compound [x-1] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on the molar ratio of compound [bb].

The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [bb].

The amount of the condensing agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [bb] in molar ratio.

The amount of the activator used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, based on compound [bb] in molar ratio.

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

Process 2
The condensation reaction between the compound [cc] and the phosphite esterifying agent can be carried out in a suitable solvent in the presence of an activator according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the phosphite forming agent include dibenzyl N,N-diisopropyl phosphoramidite. Examples of the activator include 1-tetrazole.

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

The amount of the activator used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on the compound [cc].

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

Process 3
The oxidation reaction of compound [dd] can be carried out in a suitable solvent in the presence of an oxidizing agent according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the oxidizing agent include hydrogen peroxide, tert-butyl hydroperoxide, and metachloroperbenzoic acid.

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

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

Process 4
The condensation reaction between the compound [cc] and the phosphoric acid esterifying agent can be carried out in a suitable solvent in the presence or absence of a base according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, and includes, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, or mixtures thereof. Examples of the phosphoric acid esterification agent include dibenzylphosphoryl chloride and tetrabenzyl pyrophosphate. Examples of the base include alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide, and alkylamines such as triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. It will be done.

The amount of the phosphoric acid esterifying agent used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [y].

The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on compound [y].

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

Process 5
The deprotection reaction of compound [ee] can be carried out in the same manner as the deprotection reaction of compound [y] in Synthesis Method G.

Process 6
The condensation reaction of compound [ff] or a salt thereof and "x-2" or a salt thereof is carried out in the same manner as the condensation reaction of compound [bb] or a salt thereof and compound [x-2] or a salt thereof in Synthesis Method G. be able to.

Process 7
Deprotection of compound [gg] can be carried out in a suitable solvent in the presence or absence of an additive in the presence of an acid or Lewis acid according to a conventional method. The solvent may be any solvent as long as it does not affect this reaction, such as esters such as methyl acetate, ethyl acetate, and isopropyl acetate, ethers such as 1,4-dioxane and tetrahydrofuran, and halogens such as dichloromethane and chloroform. Examples include aliphatic hydrocarbons, aromatic hydrocarbons such as toluene, acetonitrile, and mixtures thereof. Examples of additives include water, tetraethylsilane, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid. Examples of the Lewis acid include triethylsilyl trifluoromethanesulfonate.

The amount of the additive used can be 1.0 to 10.0 equivalents, preferably 1.0 to 2.0 equivalents, based on compound [gg].

The amount of acid or Lewis acid used can be 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, based on compound [gg].

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

Process 8
The deprotection reaction of compound [hh] can be carried out in the same manner as the deprotection reaction of compound [y] in Synthesis Method G.

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［Ｖ］のうち、一般式［Ｖａ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｉｉ］と化合物［ｘ－１］を縮合反応に付し、化合物［ｊｊ］が得られる。化合物［ｊｊ］を亜リン酸エステル化して、化合物［ｋｋ］とした後、酸化することにより化合物［ｌｌ］を得るか、または化合物［ｊｊ］をリン酸エステル化することにより、化合物［ｌｌ］を得た後、脱保護することにより、化合物［Ｖａ］を製造することができる。 Synthesis method J

[In the formula, each symbol has 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. Compound [ii] and compound [x-1] are subjected to a condensation reaction to obtain compound [jj]. Compound [ll] is obtained by phosphorous acid esterifying compound [jj] to obtain compound [kk], and then oxidizing it, or by phosphoric acid esterifying compound [jj] to obtain compound [ll] After obtaining, compound [Va] can be produced by deprotecting.

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

Process 2
The condensation reaction between compound [jj] and the phosphite esterifying agent can be carried out in the same manner as the reaction between compound [c] and the phosphite esterifying agent in synthesis method A.

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

Process 4
The condensation reaction between the compound [jj] and the phosphoric acid esterifying agent can be carried out in the same manner as the reaction between the compound [c] and the phosphoric acid esterifying agent in synthesis method A.

Process 5
Deprotection of compound [ll] can be carried out in the same manner as the reaction of compound [f] in synthetic method A.

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［ＶＩ］のうち、一般式［ＶＩａ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｗ］と化合物［ｘ－４］を縮合反応に付し、化合物［ｍｍ］を得た後、脱保護することにより、化合物［ＶＩａ］を製造することができる。 Synthesis method K

[In the formula, each symbol has 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. Compound [VIa] can be produced by subjecting compound [w] and compound [x-4] to a condensation reaction to obtain compound [mm], followed by deprotection.

Process 1
The condensation reaction of compound [w] or a salt thereof and compound [x-4] or a salt thereof is carried out in the same manner as the reaction of compound [w] or a salt thereof and compound [x-1] or a salt thereof in synthesis method G. can do.

Process 2
Deprotection of compound [mm] can be carried out in the same manner as the reaction of compound [f] in synthesis method A.

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［ＶＩＩ］のうち、一般式［ＶＩＩａ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｗ］と化合物［ｘ－５］を縮合反応に付し、化合物［ｎｎ］を得た後、脱保護することにより、化合物［ＶＩＩａ］を製造することができる。 Synthesis method L

[In the formula, each symbol has the same meaning as above. ]
Among the target compounds [VII] of the present invention, the compound represented by the general formula [VIIa] can be produced, for example, as follows. Compound [VIIa] can be produced by subjecting compound [w] and compound [x-5] to a condensation reaction to obtain compound [nn], followed by deprotection.

Process 1
The condensation reaction of compound [w] or a salt thereof and compound [x-5] or a salt thereof is carried out in the same manner as the reaction of compound [w] or a salt thereof and compound [x-1] or a salt thereof in synthesis method G. can do.

Process 2
Deprotection of compound [nn] can be carried out in the same manner as the reaction of compound [f] in synthesis method A.

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［ＶＩＩＩ］のうち、一般式［ＶＩＩＩａ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｏｏ］と化合物［ｘ－６］を縮合反応に付し、化合物［ｐｐ］が得られる。化合物［ｐｐ］を亜リン酸エステル化して、化合物［ｑｑ］とした後、酸化することにより化合物［ｒｒ］を得るか、または化合物［ｐｐ］をリン酸エステル化することにより、化合物［ｒｒ］を得た後、脱保護することにより、化合物［ＶＩＩＩａ］を製造することができる。 Synthesis method M

[In the formula, each symbol has the same meaning as above. ]
Among the target compounds [VIII] of the present invention, the compound represented by the general formula [VIIIa] can be produced, for example, as follows. Compound [oo] and compound [x-6] are subjected to a condensation reaction to obtain compound [pp]. Compound [rr] can be obtained by phosphorous acid esterifying compound [pp] to obtain compound [qq], and then oxidizing it to obtain compound [rr], or by phosphoric acid esterifying compound [pp]. After obtaining, compound [VIIIa] can be produced by deprotecting.

Process 1
The condensation reaction of compound [oo] or its salt and compound [x-6] or its salt is carried out in the same manner as the reaction of compound [k-1] or its salt and compound [l-1] or its salt in synthesis method C. It can be implemented by

Process 2
The condensation reaction between the compound [pp] and the phosphite esterifying agent can be carried out in the same manner as the reaction between the compound [c] and the phosphite esterifying agent in synthesis method A.

Process 3
The oxidation reaction of compound [qq] can be carried out in the same manner as the reaction of compound [d] in synthesis method A.

Process 4
The condensation reaction between the compound [pp] and the phosphoric acid esterifying agent can be carried out in the same manner as the reaction between the compound [c] and the phosphoric acid esterifying agent in synthesis method A.

Process 5
Deprotection of compound [rr] can be carried out in the same manner as the reaction of compound [f] in synthesis method A.

〔式中、各記号は前記と同一意味を有する。〕
本発明の目的化合物［ＩＸ］のうち、一般式［ＩＸａ］で示される化合物は、例えば、以下のようにして製造することができる。化合物［ｓｓ］と化合物［ｘ－７］を縮合反応に付し、化合物［ｔｔ］が得られる。化合物［ｔｔ］を亜リン酸エステル化して、化合物［ｕｕ］とした後、酸化することにより化合物［ｖｖ］を得るか、または化合物［ｔｔ］をリン酸エステル化することにより、化合物［ｖｖ］を得た後、脱保護することにより、化合物［ＩＸａ］を製造することができる。 Synthesis method N

[In the formula, each symbol has 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. Compound [ss] and compound [x-7] are subjected to a condensation reaction to obtain compound [tt]. Compound [vv] can be obtained by phosphorous acid esterifying compound [tt] to obtain compound [uu], and then oxidizing it to obtain compound [vv], or by phosphoric acid esterifying compound [tt]. After obtaining, compound [IXa] can be produced by deprotecting.

Process 1
The condensation reaction of compound [ss] or its salt and compound [x-7] or its salt is carried out in the same manner as the reaction of compound [k-1] or its salt and compound [l-1] or its salt in synthesis method C. It can be implemented by

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

Process 3
The oxidation reaction of compound [uu] can be carried out in the same manner as the reaction of compound [d] in synthesis method A.

Process 4
The condensation reaction between the compound [pp] and the phosphoric acid esterifying agent can be carried out in the same manner as the reaction between the compound [c] and the phosphoric acid esterifying agent in synthesis method A.

Process 5
Deprotection of compound [vv] can be carried out in the same manner as the reaction of compound [f] in synthetic method A.

The raw material compounds in the above method can be produced in the same manner as known methods and/or methods described in Examples below.
Note that the introduction of a protecting group to a functional group and the removal of a functional group protecting group can be carried out with reference to a known method (PROTECTIVE GROUPS in ORGANIC SYNTHESIS (authored by Theodora W. Greene, Peter GMWuts), etc.).

The compound of the present invention or its raw material compound produced as described above is isolated and purified in its free form or as a salt thereof. Salt can be produced by subjecting it to a commonly used salt-forming treatment. Isolation and purification can be carried out by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various chromatography.

When the compound of the present invention or a pharmacologically acceptable salt thereof exists as an optical isomer based on an asymmetric carbon, the individual optical Can be separated into isomers. Optical isomers can also be synthesized using optically pure starting materials. Furthermore, optical isomers can also be synthesized by performing each reaction stereoselectively using an asymmetric auxiliary group or an asymmetric catalyst.

The compound [I] or [II] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, alone or as a pharmaceutical composition containing it and a pharmaceutically acceptable carrier. It can be administered to Furthermore, 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 [IX] of the present invention or a pharmacologically acceptable salt thereof can be administered either orally or parenterally, either by itself or as a pharmaceutical composition containing a pharmaceutically acceptable carrier.

When producing a liquid pharmaceutical composition such as an injection or an infusion, such a pharmacologically acceptable carrier may be a carrier commonly used in the art, such as an aqueous solvent (water for injection, purified water, etc.). , isotonic agents (sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, propylene glycol, etc.), buffers (phosphate buffer, acetate buffer, borate buffer, carbonate buffer) liquid, citrate buffer, Tris buffer, glutamate buffer, epsilon aminocaproate buffer, etc.), preservatives (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, benzyl alcohol, benzalcochloride) sodium dehydroacetate, sodium edetate, boric acid, borax, etc.), soothing agents (lidocaine hydrochloride, procaine hydrochloride, benzyl alcohol, chlorobutanol, etc.), viscosity agents (hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, etc.), stabilizers (sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxytoluene, etc.) or pH adjusters (hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc.) etc., and can be produced by dissolving or dispersing the aforementioned compound or combination drug of the present invention in a solution to which these are appropriately added. Such pharmaceutically acceptable additives can be appropriately selected by those skilled in the art depending on the purpose, and conditions such as the amount added can also be appropriately set. Further, a solubilizing agent or the like may be used if necessary.
Such liquid pharmaceutical compositions can also be applied to devices (pumps) for subcutaneous delivery.

The dosage of the compound [I] or [II] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient's age, weight, condition, etc., but when administered as a liquid pharmaceutical composition, it is usually , 1-200 mg/kg per day.
On the other hand, the dosage of any one of the compounds [III] to [IX] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient's age, body weight, condition, etc., but is administered as a liquid pharmaceutical composition. When administered, it is usually 0.02 to 100 mg/kg per day.

The compound of the present invention or a pharmaceutically acceptable salt thereof and the pharmaceutical combination of the present invention can be administered in the form of a liquid pharmaceutical composition for any suitable route of administration, e.g. by parenteral administration, such as bolus administration or continuous administration. It can be formulated as an applicable formulation. Specifically, the liquid pharmaceutical composition of the present invention can be used for subcutaneous administration, transdermal administration, intradermal administration, transmucosal administration, intravenous administration, intraarterial administration, intramuscular administration, and intraperitoneal administration. For administration, intratracheal administration, intrathecal administration, intraduodenal administration, intrapleural administration, intranasal administration, sublingual administration, buccal administration, intestinal administration, intraduodenal administration, rectal administration. They can be formulated for internal, ocular or oral administration. The compositions can also be formulated for inhalation or direct absorption through mucosal tissues.

The present invention provides an effective amount of a levodopa prodrug compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and a carbidopa prodrug compound of any of formulas (III) to formula (IX) or its A method for treating neurodegenerative diseases and/or diseases or conditions caused by decreased brain dopamine levels, such as Parkinson's disease and related conditions, comprising administering to a patient a pharmaceutical combination comprising a pharmacologically acceptable salt. provide. The present invention also provides an effective amount of a levodopa prodrug compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and a carbidopa prodrug compound of any one of formulas (III) to formula (IX). or a pharmaceutically acceptable salt thereof can be formulated together or separately and administered to a patient in the form of a pharmaceutical composition. Such pharmaceutical compositions can be administered to a patient simultaneously or separately.
Accordingly, the term "medicinal combination" includes an effective amount of a levodopa prodrug compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and any of formulas (III) to (IX). The carbidopa prodrug compound or a pharmaceutically acceptable salt thereof can be a levodopa prodrug compound or a pharmaceutically acceptable salt thereof, and the levodopa prodrug or a pharmaceutically acceptable salt thereof and the carbidopa prodrug or a pharmaceutically acceptable salt thereof are a single compound. It can be prepared in formulations or separate formulations. The separate formulations may be administered to the patient at the same time or at different times, such as within defined time intervals, e.g., at intervals prescribed by the patient, caregiver, or physician based on the patient's condition. Also good.

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

The pharmaceutical combination of the present invention can be administered simultaneously with the above-mentioned additional therapeutic agents that can be used in combination, or can be administered separately. Furthermore, when the combination drug of the present invention is used for treatment together with the above-mentioned additional therapeutic agents that can be used in combination, they can be administered in the same dosage form, such as parenteral administration, or one can be administered parenterally and the other can be administered orally. The administration may take different forms of administration, such as administration.

The compounds and pharmaceutical combinations of the present invention are useful for the prevention or treatment of neurodegenerative diseases and/or diseases or conditions caused by decreased brain dopamine levels. Specifically, 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 dementia (LBD), akinesia, bradykinesia, and hypokinesia, preferably for the prevention or treatment of Parkinson's disease. Useful. The compounds and pharmaceutical combinations of the present invention may also be used to treat diseases or conditions resulting from brain damage, including carbon monoxide poisoning or manganese poisoning, or diseases or conditions associated with neurological diseases or disorders, including alcoholism, drug dependence, or erectile dysfunction. Useful in preventing or treating symptoms.

The present invention also includes a pharmaceutical combination containing a compound of levodopa prodrug 1 or 2 or a pharmaceutically acceptable salt thereof and a compound of carbidopa prodrug or a pharmaceutically acceptable salt thereof described in the Examples below. be done.

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.
Note that the mass spectrum (MS) was measured in positive ion mode using liquid chromatography mass spectrometry.
[Levodopa prodrug 1] (compound of formula (I))

Example 1: Preparation of levodopa amino acid (LDAA) Ten LDAA conjugates were prepared as trifluoroacetic acid (TFA) salts for initial screening.
Preparation of levodopa arginine TFA salt (LD-Arg TFA salt)

Preparation of levodopaglycin TFA salt (LD-Gly TFA salt)

Preparation of levodoparidine TFA salt (LD-Lys TFA salt)

Preparation of levodopa aspartate TFA salt (LD-Asp TFA salt)

Preparation of levodopa glutamate TFA salt (LD-Glu TFA salt)

Preparation of levodopa glutamine TFA salt (LD-Gln TFA salt)

Preparation of levodopa asparagine TFA salt (LD-Asn TFA salt)

Preparation of levodopatyrosin TFA salt (LD-Tyr TFA salt)

Preparation of levodopatryptophan TFA salt (LD-Trp TFA salt)

Preparation step 1 of levodopa-lanthionine TFA salt (LD-LA TFA salt): Halogenation

Step 2: Hydrolysis

Step 3: Deprotection

Process 4: Coupling

Step 5: Coupling with protected levodopa

Step 6: Deprotection (Fmoc removal) and diastereomer separation

Step 7a: Deprotection of LD and isolation of levodoparathionine peak 1 TFA salt (LD-LA1 TFA salt)

Step 7b: Deprotection of LD and isolation of levodoparathionine peak 2 TFA salt (LD-LA2 TFA salt)

It should be noted that throughout this text it has been demonstrated that LD-LA 1 (also referred to as levodoparathionine peak 1 or levodoparathionine 1) is the (S)(S)(R) isomer, and that LD-LA 2 Although it has been demonstrated that (also referred to as levodoparathionine peak 1 or levodoparathionine 1) is the (S)(R)(R) isomer, the two prepared isomers have not been completely identified. Therefore, these isomers may be opposite to those demonstrated and depicted throughout this text.

Example 2: Preparation of levodopa amino acid (LDAA) free base form
CBz Protection of L-DOPA Synthesis was performed using CBz-Cl and NaOH as bases. 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)/water (600 mL) was added at 0 °C, and a mixture of CBz-Cl (211.4 g, 1.239 mol)/dioxane (800 mL) was added at 0 °C. Added over an hour. The mixture was allowed to warm to room temperature. After about 1 hour, 73% conversion was observed. Separate portions of NaOH (4.9 g, 0.123 mol)/water (60 mL) and CBz-Cl (20.8 g, 0.122 mol)/dioxane (80 mL) were added. The reaction mixture was stirred at room temperature overnight. A conversion of 83% was observed. Separate portions of NaOH (8.1 g, 0.203 mol)/water (50 mL) and CBz-Cl (35 g, 0.205 mol)/dioxane (50 mL) were added. Once 94% conversion was obtained (1.5 h after addition), the pH was adjusted to 10 with 3M NaOH and the mixture was washed with MTBE (1 L). The pH of the aqueous phase was adjusted to 2 using 6M HCl and the aqueous phase was extracted with MTBE (2 x 1 L). The combined organic phases were washed with water (1 L) and 25% aqueous NaCl (1 L). The organic phase was dried over sodium sulfate, filtered, evaporated under reduced pressure and dried in vacuo to yield 448.3 g (135%) as a brown viscous product (purity (280 nm) 82.3 g (135%)). 5%).

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 to nitrogen (3 times) then 10% palladium on carbon (18.8 g) was added and the atmosphere was exchanged again to nitrogen (2 times) followed by hydrogen (3 times). The reaction vessel was evacuated/filled with hydrogen. After 4.5 hours, the reaction was estimated to be complete by HPLC analysis. The reaction mixture was filtered through Celite® and evaporated under reduced pressure at a water bath temperature of 40°C. When approximately 400 mL remained, the suspension was filtered and the filter residue was washed with methanol (50 mL). The solid was dried in vacuo at 25° C. overnight to yield 33.1 g (75%) of LD-Lys free base as an off-white solid (purity was 99.0%).

Example 2.2: Preparation of LD-Tyr free base form
Coupling with H-Tyr-OBzl EDC-Cl (46.3 g, 242 mmol) was coupled with BnO-Tyr (64.9 g, 242 mmol) in DMF (863.2 g, 0.9 L) at 0 °C. 239 mmol), HOBt (36.8 g, 88 w/w%, 240 mmol) and CBz-L-DOPA (363.1 g, 20.1 w/w% in DMF, 220 mmol) for 10 min. I added it little by little. After stirring the reaction at 0° C. for 4 hours, water (1.7 kg) was added over 30 minutes and the reaction mixture was allowed to warm to room temperature. EtOAc (2.6 kg, 2.8 L) was charged to the reaction vessel and the phases were separated. The organic phase was washed three times with water (1.5L, 1.4L and 1.4L). The crude residue was purified by flash column chromatography (silica gel column, packed with 3.2 kg EtOAc/dichloromethane 1:1 (v/v)), Celite® mixture was loaded onto the column, and EtOAc/dichloromethane 1:1 (v/v) was loaded onto the column. :1 (v/v). The resulting fraction (12 L) was concentrated under reduced pressure at a water bath temperature of 45°C and further dried in vacuo overnight. L-DOPA-BnOTyr was isolated as a slightly brown solid (44.7 g, 35%) with a purity of 96.4%. Fractionation was performed using flash column chromatography (solvent: 20% methanol/CH ₂ Cl ₂ (10 L)), and all fractions containing L-DOPA-Bn-OTyr were collected. The obtained fractions were concentrated under reduced pressure at a water bath temperature of 45°C. The crude material (60.2 g) was dissolved in 2-PrOH (432.1 g, 550 mL) by heating the mixture to 75°C. The solution was filtered hot, allowed to cool to room temperature, and stirred overnight to obtain a precipitate. The suspension was filtered and the filtrate was washed with 2-PrOH (166 g, 211 mL) and dried in vacuo at 30 °C overnight to give CBz-L-DOPA-Tyr (OBn) as a white solid ( 34.9 g, 27%) with a purity of 95.1%.

Deprotection of CBz-L-DOPA-Tyr (OBn) A solution of L-DOPA-BnOTyr (60.4 g, 103 mmol) in methanol (2051 g, 2.6 L) was purged with nitrogen three times (vacuum). (<250 mbar) followed by nitrogen filling). 10% palladium/carbon (12.0 g) was added to the reaction vessel followed by filling with hydrogen (vacuum (>250 mbar) followed by filling with hydrogen). The reaction vessel was evacuated/filled with hydrogen after 1 hour and 20 minutes and allowed to stand for an additional 30 minutes before being evacuated/filled with nitrogen and filtered through Celite®. The filtrate was washed with methanol (418.9 g, 529 mL), and the combined filtrates were concentrated under reduced pressure. The solution in a volume of about 500 mL was filtered through a filter with a pore size of 0.45 μm, and the filtrate was concentrated to dryness under reduced pressure. The oily solid was dried in vacuo overnight to yield LD-Tyr free base as an off-white solid (36.5 g, 98%) with 95.4% purity.

Example 3: Synthesis of LD-Lys HCl salt, LD-Tyr HCl salt and LD-Arg HCl salt
Example 3.1: Synthesis of LD-Arg HCl salt - Method 1
Coupling with H-Arginine (NO ₂ )-OBn CBz-L-DOPA (342.9 g, 20.1 w/w% solution in DMF, 208 mmol) was dissolved in DMF (690 mL). HOBt. H ₂ O (35.2 g, 228 mmol (88% w/w)) and H-Arg(NO2)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 treated with EDC. while maintaining the temperature at 0°C. HCl (43.7 g, 228 mmol) was added portionwise. The reaction was stirred for 2.5 hours and then quenched with water (1400 mL). The mixture was extracted with EtOAc three times (1400 mL and 2x700 mL).
After the organic phase was distilled off under reduced pressure at a water bath temperature of 40° C., the residue was dissolved in 8 times the amount of distilled THF, and 8 times the amount of water was added to form an emulsion. The emulsion was applied to a reverse phase column (26 equivalents of Phenomenex Sepra C-18-T (50 μm, 135A) packed with THF and adjusted with 700 mL of 20% distilled THF/water). The column was eluted with 40% distilled aqueous THF. The pure fractions were evaporated under reduced pressure until mainly water remained. The suspension was cooled and filtered. The filter material was dried to obtain a wet solid (259 g). The solid was stored in the freezer until the next processing step.

CBz-L-DOPA-Arg(NO2 ₎ -(OBn)
CBz-L-DOPA-Arg(NO ₂ )-(OBn) (230.4 g wet solid, ~68.6 g dry, 110 mmol) was dissolved in methanol (6.45 L) and water (1.29 L). ) and HCl (36% aqueous solution, 43 mL) was added. The inside of the reaction flask was depressurized to 250 mbar, filled with nitrogen, and the same operation was repeated three times. The mixture was heated to 40°C.
10% palladium on carbon (14.0 g) was added and the atmosphere was exchanged to nitrogen (3 times) then hydrogen (3 times). The reaction mixture was protected from light. The atmosphere was exchanged to hydrogen. After 3 hours, the atmosphere was exchanged to nitrogen (3 times). The suspension was filtered through Celite® and the filtrate was washed with 20% water/methanol (600 mL). The filtrate was adjusted to pH 6 using an ion exchange resin (Dowex 1x8 chloride form, preactivated with 1M NaOH and washed with water to pH 7). Each of the four filtrates was filtered, washed with 20% water/methanol (250 mL), and then the pH was adjusted. The filtrate was distilled off under reduced pressure at a water bath temperature of 50°C to a volume of about 500 mL. The residue was treated with activated carbon (5.0 g) for 40 minutes. The suspension was filtered through Celite®, the filtrate was washed with water (150 mL), and the combined filtrate and washings were concentrated to dryness under reduced pressure at a water bath temperature of 50°C. The solid residue was dried in vacuo overnight to yield 48.1 g as a light brown solid (95.6% purity). The prepared LD-Arg HCl salt contains 1 equivalent of HCl.

Example 3.2: Synthesis of LD-Arg HCl salt - Method 2
Synthesis of N-Boc-L-Dopa

Synthesis of 2,5-dioxopyrrolidin-1-yl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanoate

Synthesis of (2S)-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanamido]-5-carbamimidamidopentanoic acid

Synthesis of LD-Arg HCl

Example 3.3: Synthesis of LD-Tyr HCl salt
Synthesis of benzyl (2S)-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanamide]-3-(4-hydroxyphenyl)propanoate

Synthesis of (2S)-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanamide]3-(4-hydroxyphenyl)propanoic acid

Synthesis of LD-Tyr HCl

Example 3.4: Synthesis of LD-Lys HCl salt
Benzyl (2S)-6-[(tert-butoxycarbonyl)amino]-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanamide]hexa Synthesis of Noart

(2S)-6-[(tert-butoxycarbonyl)amino]-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanamido]hexanoic acid synthesis of

Synthesis of LD-Lys HCl

ベンジル （２Ｓ）－２－［［（２Ｓ）－３－［４－ビス（フェニルメトキシ）ホスホリルオキシ－３－フェニルメトキシフェニル］－２－（フェニルメトキシカルボニルアミノ）プロパノイル］アミノ］－６－（フェニルメトキシカルボニルアミノ）ヘキサノアト（３．２９ ｇ）をテトラヒドロフラン（１３ ｍＬ），エタノール（１３ ｍＬ），水（１３ ｍＬ）の混合溶媒に溶解し、パラジウム／炭素（含水）（１０６ ｍｇ）を加え、水素雰囲気下室温で１８時間撹拌した。テトラヒドロフラン（２０ ｍＬ），水（２６ ｍＬ）を追加し、水素雰囲気下室温で４時間撹拌した。反応混合物に水（５７ ｍＬ）を加え，６５℃で析出物を溶解させ，セライトろ過により不溶物を除いた。不溶物を水で洗浄し、ろ液の体積がおよそ半分になるまで減圧下留去し，凍結乾燥した後、粗精製物の標題化合物（１．４１ ｇ）を得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ４０６．２［Ｍ＋Ｈ］＋ 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-(phenyl Methoxycarbonylamino)hexanoate (3.29 g) was dissolved in a mixed solvent of tetrahydrofuran (13 mL), ethanol (13 mL), and water (13 mL), palladium/carbon (hydrated) (106 mg) was added, and hydrogen was added. Stirred at room temperature under atmosphere for 18 hours. Tetrahydrofuran (20 mL) and water (26 mL) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. Water (57 mL) was added to the reaction mixture, the precipitate was dissolved at 65°C, and insoluble matter was removed by filtration through Celite. Insoluble matter was washed with water, the filtrate was distilled off under reduced pressure until the volume was reduced to approximately half, and the filtrate was lyophilized to obtain the title compound (1.41 g) as a crude product.
MS (ESI); m/z 406.2 [M+H]+

Examples 5-18:
The corresponding raw material compounds were treated in the same manner as in Example 4 to obtain the compounds listed in Table 3 below.

（１）ベンジル (2S)-3-(4-ヒドロキシ-3-フェニルメトキシフェニル)-2-[[(2S)-3-(4-ヒドロキシ-3-フェニルメトキシフェニル)-2-(フェニルメトキシカルボニルアミノ)プロパノイル]アミノ]プロパノエート（４３０ ｍｇ）のジクロロメタン（９ ｍＬ）溶液に、ジベンジル Ｎ，Ｎ－ジイソプロピルホスホロアミダイト（６１５ ｕＬ）、１Ｈ－テトラゾール（１１５ ｍｇ）のアセトニトリル（３ ｍＬ）懸濁液を加え、室温で１３．５時間攪拌した。ジベンジル Ｎ，Ｎ－ジイソプロピルホスホロアミダイト（２０５ ｕＬ）、１Ｈ－テトラゾール（３５ ｍｇ）を追加し、室温で１時間攪拌した。反応混合物を氷冷し，ｔｅｒｔ－ブチル ヒドロペルオキシド水溶液（７０％）（０．３９ ｍＬ）を加え、室温で１時間攪拌した。反応混合物をクロロホルムで希釈し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝６０／４０～３５／６５）で精製することにより、ベンジル (2S)-3-[4-ビス(フェニルメトキシ)ホスホリルオキシ-3-フェニルメトキシフェニル]-2-[[(2S)-3-[4-ビス(フェニルメトキシ)ホスホリルオキシ-3-フェニルメトキシフェニル]-2-(フェニルメトキシカルボニルアミノ)プロパノイル]アミノ]プロパノエートの粗精製物（５６５ ｍｇ）を得た。 Example 19:
(2S)-2-[[(2S)-2-amino-3-(3-hydroxy-4-phosphonooxyphenyl)propanoyl]amino]-3-(3-hydroxy-4-phosphonooxyphenyl)propane acid production

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

(2) Benzyl(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3 -Phenylmethoxyphenyl]-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). Palladium/carbon (hydrated) (50 mg) was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 25.5 hours. Water (10 mL) was added and stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble materials. Insoluble matter was washed with water (20 mL). After lyophilization, the title compound (112 mg) was obtained.
MS (ESI); m/z 537.3 [M+H]+

Examples 20 and 21:
The corresponding raw material compounds were treated in the same manner as in Example 4 to obtain the compounds listed in Table 4 below.

（2S)-3-[4-ビス(フェニルメトキシ)ホスホリルオキシ-3-フェニルメトキシフェニル]-2-[[(2S)-2-(フェニルメトキシカルボニルアミノ)プロパノイル]アミノ]プロパン酸ベンジル（５５１ mｇ）をエタノール（２ ｍＬ），テトラヒドロフラン（２ ｍＬ）の混合溶媒に溶解させ，パラジウム／炭素（含水）（６９ ｍｇ）を加え，水素雰囲気下室温で７時間撹拌した。反応混合物をメンブレンフィルター（セルロースアセテート）でろ過し，不溶物を除いた。不溶物を水/エタノール（２：１，１２ ｍＬ）で洗浄し，ろ液がおよそ１ｍＬになるまで減圧下留去し，凍結乾燥した後，標題化合物（２１４ ｍｇ，収率１００％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ３４９．１ ［Ｍ＋Ｈ］＋ [Levodopa prodrug 2] (compound of formula (II))
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), palladium/carbon (hydrated) (69 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble matter. The insoluble material was washed with water/ethanol (2:1, 12 mL), and the filtrate was distilled off under reduced pressure until the volume was approximately 1 mL. After lyophilization, the title compound (214 mg, yield 100%) was obtained as a white product. Obtained as a powder.
MS (ESI); m/z 349.1 [M+H]+

Examples 23-40:
The corresponding raw material compounds were treated in the same manner as in Example 21 to obtain the compounds listed in Table 5 below.

(2S)-3-[3,4-ビス(フェニルメトキシ)フェニル]-2-[[(2S)-5-[(N-ニトロカルバムイミドイル)アミノ]-2-(フェニルメトキシカルボニルアミノ)ペンタノイル]アミノ]プロパン酸ベンジル（２５７ ｍｇ）をテトラヒドロフラン（２ ｍＬ），２－プロパノール（３ ｍＬ）および２Ｍ 塩酸（０．８０ ｍＬ）の混合溶媒に溶解し，パラジウム／炭素（含水）（３４１ ｍｇ）を加え，水素雰囲気下室温で２４時間撹拌した。反応混合物に２－プロパノール（４ ｍＬ），水（６ ｍＬ）を加え，メンブレンフィルターにより不溶物を除いた。不溶物を水（６ ｍＬ）で洗浄し，２－プロパノール（２５ ｍＬ）を加えて減圧下留去した。残渣にジイソプロピルエーテルを加え，析出した固体をろ取し，減圧乾燥し，標題化合物（１４４ ｍｇ，収率１００％）を黄茶色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ３５４．２［Ｍ＋Ｈ］＋ Example 41:
(2S)-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid; production of hydrochloride

(2S)-3-[3,4-bis(phenylmethoxy)phenyl]-2-[[(2S)-5-[(N-nitrocarbamimidoyl)amino]-2-(phenylmethoxycarbonylamino) Benzyl 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 (hydrated) (341 mg) was dissolved. ) and stirred at room temperature under hydrogen atmosphere for 24 hours. 2-propanol (4 mL) and water (6 mL) were added to the reaction mixture, and insoluble materials were removed using a membrane filter. Insoluble materials were washed with water (6 mL), 2-propanol (25 mL) was added, and the mixture was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (144 mg, yield 100%) as a yellowish brown powder.
MS (ESI); m/z 354.2 [M+H]+

（２Ｓ）－２－［［（２Ｓ）－３－［４－ビス（フェニルメトキシ）ホスホリルオキシ－３－フェニルメトキシフェニル］－２－メチル－２－［フェニルメトキシカルボニル（フェニルメトキシカルボニルアミノ）アミノ］プロパノイル］アミノ］－６－（フェニルメトキシカルボニルアミノ）ヘキサン酸ベンジル（８９ ｍｇ）をテトラヒドロフラン（１ ｍＬ），水（０．２ ｍＬ）の混合溶媒に溶解させ，パラジウム／炭素（含水）（１０ ｍｇ）を加え，水素雰囲気下，室温で２．５時間撹拌した。水（０．２ ｍＬ）を追加し，水素雰囲気下室温で２．５時間撹拌した。反応混合物をメンブレンフィルター（セルロースアセテート）でろ過し，不溶物を除いた。不溶物を水（４ ｍＬ）で洗浄し，ろ液の体積がおよそ３／４になるまで減圧下留去し，凍結乾燥した後，標題化合物（３０ ｍｇ， 収率９７％）を得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ４３５．４［Ｍ＋Ｈ］＋ [Carbidopa prodrugs] (compounds of formula (III) to formula (IX))
Example 42:
Production of (2S)-6-amino-2-[[(2S)-2-hydrazinyl-3-(3-hydroxy-4-phosphonooxyphenyl)-2-methylpropanoyl]amino]hexanoic acid

(2S)-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino] Benzyl 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 (hydrated) (10 mg) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (0.2 mL). ) and stirred for 2.5 hours at room temperature under a hydrogen atmosphere. Water (0.2 mL) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble materials. The insoluble material was washed with water (4 mL), and the filtrate was distilled off under reduced pressure until the volume became approximately 3/4, and after freeze-drying, the title compound (30 mg, yield 97%) was obtained.
MS (ESI); m/z 435.4 [M+H]+

Examples 43-45:
The corresponding raw material compounds were treated in the same manner as in Example 42 to obtain the compounds listed in Table 6 below.

（１）（２Ｓ）－２－［［（２Ｓ）－３－［４－ビス（フェニルメトキシ）ホスホリルオキシ－３－フェニルメトキシフェニル］－２－メチル－２－［フェニルメトキシカルボニル（フェニルメトキシカルボニルアミノ）アミノ］プロパノイル］アミノ］－３－（４－フェニルメトキシフェニル）プロパン酸ベンジル（２０９ ｍｇ）とＮ，Ｎ－ジメチルホルムアミド（２ ｍＬ）の混合物に，１－ヒドロキシ－７－アザベンゾトリアゾール（ＨＯＡｔ）（４０ ｍｇ），１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣＩ）（５７ ｍｇ），（２Ｓ）－２－アミノ－３－（４－ベンジルオキシフェニル）プロパン酸ベンジル；ヒドロクロリド（１０８ ｍｇ）およびＮ，Ｎ－ジイソプロピルエチルアミン（０．０４７ ｍＬ）を加えて，室温で２５.５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液，水を加え，酢酸エチルで抽出した。有機層を水，飽和食塩水で洗浄し，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝７５／２５～５０／５０）で精製することにより，（２Ｓ）－２－［［（２Ｓ）－３－［４－ビス（フェニルメトキシ）ホスホリルオキシ－３－フェニルメトキシフェニル］－２－メチル－２－［フェニルメトキシカルボニル（フェニルメトキシカルボニルアミノ）アミノ］プロパノイル］アミノ］－３－（４－フェニルメトキシフェニル）プロパン酸ベンジルの粗精製物（１６８ ｍｇ）を得た。 Example 46:
(2S)-2-[[(2S)-2-hydrazinyl-3-(3-hydroxy-4-phosphonooxyphenyl)-2-methylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Manufacturing of

(1)(2S)-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino) 1-Hydroxy-7-azabenzotriazole (HOAt ) (40 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI) (57 mg), (2S)-2-amino-3-(4-benzyloxyphenyl)benzyl 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. Saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 75/25 to 50/50) to obtain (2S)-2-[[(2S)-3-[4-bis( Crude benzyl phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino]propanoyl]amino]-3-(4-phenylmethoxyphenyl)propanoate A purified product (168 mg) was obtained.

(2) The crude product obtained in (1) (168 mg) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and water (0.5 mL), and palladium/carbon (hydrated) (20 mg) was added. , and stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite to remove insoluble materials. The insoluble material was washed with water (15 mL), the solvent was distilled off under reduced pressure until the volume of the filtrate was reduced to approximately 7/8, and after freeze-drying, the title compound (67 mg, yield 57% in 2 steps) was obtained. I got it.
MS (ESI); m/z 470.1 [M+H]+

Examples 47-82:
The following compounds can be obtained in the same manner as in the above examples.

ベンジル （２Ｓ）－２－［［（２Ｓ）－３－（４－ヒドロキシ－３－フェニルメトキシフェニル）－２－（フェニルメトキシカルボニルアミノ）プロパノイル］アミノ］－６－（フェニルメトキシカルボニルアミノ）ヘキサノアト（４．５７ ｇ）のジクロロメタン（４５ ｍＬ）とアセトニトリル（１８ ｍＬ）の懸濁液に，氷冷下でジベンジル Ｎ，Ｎ－ジイソプロピルホスホロアミダイト（３．２８ ｍＬ），１Ｈ－テトラゾール（０．６２ ｇ）を加え，室温で１時間攪拌した。反応混合物を氷冷し，ｔｅｒｔ－ブチル ヒドロペルオキシド水溶液（７０％）（１．２ｍＬ）を加え、室温で１９時間攪拌した。反応混合物の溶媒を減圧下留去し、飽和炭酸水素ナトリウム水溶液と水を加え、酢酸エチルで抽出した。有機層を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝６７／３３～４０／６０）で精製することにより、標題化合物（５．３８ ｇ， ８５％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ １０３４．４［Ｍ＋Ｈ］＋ [Levodopa prodrug 1] (compound of formula (I))
Reference example 1:
Benzyl (2S)-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-(phenylmethoxycarbonylamino)propanoyl]amino]-6-(phenyl Production of methoxycarbonylamino)hexanoate

Benzyl (2S)-2-[[(2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-6-(phenylmethoxycarbonylamino)hexanoate ( 4.57 g) in dichloromethane (45 mL) and acetonitrile (18 mL), dibenzyl N,N-diisopropyl phosphoramidite (3.28 mL), 1H-tetrazole (0.62 g) was added and stirred at room temperature for 1 hour. The reaction mixture was cooled with ice, and tert-butyl hydroperoxide aqueous solution (70%) (1.2 mL) was added, followed by stirring at room temperature for 19 hours. The solvent of the reaction mixture was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 67/33 to 40/60) to obtain the title compound (5.38 g, 85%) as a white powder.
MS (ESI); m/z 1034.4 [M+H]+

Reference examples 2 to 9:
The corresponding raw material compounds were treated in the same manner as in Reference Example 1 to obtain the compounds listed in Table 8 below.

（２Ｓ）－３－［４－ビス（フェニルメトキシ）ホスホリルオキシ－３－フェニルメトキシフェニル］－２－（フェニルメトキシカルボニルアミノ）プロパン酸（３５２ ｍｇ）とＮ，Ｎ－ジメチルホルムアミド（４ ｍＬ）の混合物に、ベンジル（２Ｓ）－２－アミノ－３－（４－ベンジルオキシフェニル）プロパン酸；ヒドロクロリド（２７７ ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３５ ｍＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣＩ）（１１５ ｍｇ）及び１－ヒドロキシ－７－アザベンゾトリアゾール（ＨＯＡｔ）（８２ ｍｇ）を加え室温で１６時間撹拌した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝７５／２５～４５／５５）で精製することにより、標題化合物（２５０ ｍｇ， ５２％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ １０２５．６ ［Ｍ＋Ｈ］＋ Reference example 2':
Benzyl (2S)-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-(4 -Production of phenylmethoxyphenyl)propanoate

(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-(phenylmethoxycarbonylamino)propanoic acid (352 mg) and N,N-dimethylformamide (4 mL). To the mixture were added benzyl (2S)-2-amino-3-(4-benzyloxyphenyl)propanoic acid; hydrochloride (277 mg), N,N-diisopropylethylamine (0.35 mL), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (WSCI) (115 mg) and 1-hydroxy-7-azabenzotriazole (HOAt) (82 mg) were added and stirred at room temperature for 16 hours. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 75/25 to 45/55) to obtain the title compound (250 mg, 52%) as a white powder.
MS (ESI); m/z 1025.6 [M+H]+

Reference examples 14 to 29:
The corresponding raw material compounds were treated in the same manner as in Reference Example 2' to obtain the compounds listed in Table 9 below.

（１）化合物A－１（８．０ ｇ， ７４ｗｔ％）をジクロロメタン（７５ ｍＬ）に溶解し、氷冷下でN-カルボベンゾキシ-2-ホスホノグリシントリメチル（７．９８ ｇ）、1,1,3,3-テトラメチルグアニジン（３．６ｍＬ）を加え、室温で１６．５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥し不溶物をろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝８５／１５～６５／３５）で精製することにより、化合物A-２（８．５８ ｇ， ８２％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ４７６．４ ［Ｍ＋Ｈ］＋ Reference Example 30: Production of (2S)-2-(benzyloxycarbonylamino)-3-(3-benzyloxy-4-hydroxyphenyl)propanoic acid

(1) Compound A-1 (8.0 g, 74 wt%) was dissolved in dichloromethane (75 mL), and N-carbobenzoxy-2-phosphonoglycine trimethyl (7.98 g), 1 ,1,3,3-tetramethylguanidine (3.6 mL) was 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 the mixture was extracted with chloroform. After drying the organic layer with sodium sulfate and filtering off insoluble matter, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 85/15 to 65/35) to obtain compound A-2 (8.58 g, 82%) as a white powder. Ta.
MS (ESI); m/z 476.4 [M+H]+

(2) 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 stirred at room temperature under pressurized hydrogen atmosphere (600 kPa) for 4 hours. did. The solvent of the reaction mixture was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 85/15 to 55/45) to obtain compound A-3 (5.71 g, 78%) as a white powder. Ta.
MS (ESI); m/z 478.4 [M+H]+

(3) 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. The mixture was stirred at room temperature for 30 minutes. 1M hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (50 mL). After drying the organic layer over sodium sulfate and filtering off insoluble matter, the solvent was distilled off under reduced pressure to obtain the title compound (1.69 g, 100%) as a white powder.
MS (ESI); m/z 422.4 [M+H]+

（１）化合物B-１（Ｒ＝Ｍｅ、２．３０ ｇ）をテトラヒドロフラン（３６ ｍＬ）、メタノール（４ ｍＬ）の混合溶媒に溶解し、２Ｍ水酸化リチウム水溶液（４．０ ｍL）を加え、室温で１０分撹拌した。反応混合物を氷冷し、０．５M硫酸水素カリウム水溶液（２０ ｍL）を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し不溶物をろ過後、溶媒を減圧下留去した。残渣をメチルtert-ブチルエーテルに懸濁させ、析出した固体をろ取し、減圧乾燥し、標題化合物（２．３０ ｇ、１００％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ６８２．６ ［Ｍ＋Ｈ］＋ Reference Example 31: Production of (2S)-2-(benzyloxycarbonylamino)-3-(3-benzyloxy-4-dibenzyloxyphosphoryloxyphenyl)propanoic acid

(1) Compound B-1 (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. Stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled, 0.5M aqueous potassium hydrogen sulfate solution (20 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove insoluble materials, and then the solvent was distilled off under reduced pressure. The residue was suspended in methyl tert-butyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (2.30 g, 100%) as a white powder.
MS (ESI); m/z 682.6 [M+H]+

(1)' Compound B-1 (R=Bn, 0.57 g) was dissolved in methanol (2 mL), 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 made acidic by adding 1M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over sodium sulfate, filtered to remove insoluble materials, and the solvent was distilled off under reduced pressure to obtain the title compound (0.53 g, 104%) as a white powder. Ta.
MS (ESI); m/z 638.1 [M+H-CO2]+

（１）活性化した亜鉛 （９２３ ｍｇ） のＮ，Ｎ－ジメチルホルムアミド（７ ｍＬ）懸濁液に，窒素雰囲気下５℃でヨウ素（１５３ ｍｇ）を加えた。２０℃まで昇温し、１０分間撹拌した。反応混合物を再度６℃に冷却し、Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－３－ヨード－Ｌ－アラニン ベンジルエステル（１８９０ ｍｇ）を２０℃以下で分割添加し、２０℃で３０分間撹拌し、化合物C-２の溶液を得た。
トリス(ジベンジリデンアセトン)ジパラジウム(0)-クロロホルム付加体（３１ ｍｇ），２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニルジシクロヘキシル（２’，６’－ジメトキシ－［１，１’－ビフェニル］－２－イル）ホスフィン（３０ ｍｇ），化合物C-１（１３０９ ｍｇ）を順次加え室温で１６時間撹拌した．反応混合物にヘキサン／酢酸エチル（１：１）を加え、セライトろ過により不溶物を除いた。不溶物をヘキサン／酢酸エチル（１：１）と水で洗浄し、ろ液を飽和塩化アンモニウム水溶液、飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥し不溶物をろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝８０／２０～６７／３３）で精製することにより、化合物C-３（１７３３ ｍｇ， ９０％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ３７８．２［Ｍ＋Ｈ－Ｂｏｃ］ 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) under a nitrogen atmosphere at 5°C. The temperature was raised to 20°C and stirred for 10 minutes. The reaction mixture was cooled to 6°C again, and N-(tert-butoxycarbonyl)-3-iodo-L-alanine benzyl ester (1890 mg) was added in portions at 20°C or below, stirred at 20°C for 30 minutes, and the compound A solution of 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 Compound C-1 (1309 mg) were added sequentially, and the mixture was stirred at room temperature for 16 hours. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and insoluble materials were removed by filtration through Celite. The insoluble matter was washed with hexane/ethyl acetate (1:1) and water, and the filtrate was washed successively with a saturated aqueous ammonium chloride solution and a saturated saline solution. After drying the organic layer over anhydrous magnesium sulfate and filtering off insoluble matter, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 67/33) to obtain compound C-3 (1733 mg, 90%) as a white powder.
MS (ESI); m/z 378.2 [M+H-Boc]

(2) A 4M hydrogen chloride dioxane solution (6 mL) was added to a solution of 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 reduced pressure until the volume was reduced to approximately 1/10. The residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (1271 mg, 90%) as a white powder.
MS (ESI); m/z 378.4 [M+H]+

（2S)-3-[4-ビス(フェニルメトキシ)ホスホリルオキシ-3-フェニルメトキシフェニル]-2-[[(2S)-3-(2-エトキシ-2-メチル-1,3-ベンゾジオキソル-5-イル)-2-(フェニルメトキシカルボニルアミノ)プロパノイル]アミノ]プロパン酸ベンジル（２０８ ｍｇ）を水（０．４１ ｍＬ），テトラヒドロフラン（１．０ ｍＬ）の混合溶媒に溶解させ，氷浴下で水酸化リチウム一水和物（９．４ ｍｇ）を加えた後，室温で２時間撹拌した。反応混合物に酢酸エチルを加えた後、飽和クエン酸水溶液をｐＨ６になるまで加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し，不溶物をろ過後、溶媒を減圧下留去し，残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝７０／３０～０／１００，酢酸エチル／メタノール＝１００／０～８５／１５）で精製することにより，標題化合物（１７９ ｍｇ， 収率９４％）を無色粘体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ９２９．３ ［Ｍ－Ｈ］－ [Levodopa prodrug 2] (compound of formula (II))
Reference example 33:
(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-3-(2-ethoxy-2-methyl-1,3-benzodioxol-5 -yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoic acid production

(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-3-(2-ethoxy-2-methyl-1,3-benzodioxol-5 Benzyl -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 the solution was dissolved in an ice bath. After adding lithium hydroxide monohydrate (9.4 mg), 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 reached 6, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the insoluble materials were filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: hexane/ethyl acetate = 70/30 to 0/100, ethyl acetate/methanol = The title compound (179 mg, yield 94%) was obtained as a colorless viscous substance.
MS (ESI); m/z 929.3 [MH]-

（2S)-3-(4-ヒドロキシ-3-フェニルメトキシフェニル)-2-[[(2S)-2-(フェニルメトキシカルボニルアミノ)プロパノイル]アミノ]プロパン酸ベンジル（３８７ ｍｇ）とジクロロメタン（４ ｍＬ）とアセトニトリル（１.６ ｍＬ）の混合物に，氷冷下で１Ｈ－テトラゾール（７２ ｍｇ）とジベンジル Ｎ，Ｎ－ジイソプロピルホスホロアミダイト（０．３８ ｍＬ）を加え，室温で３時間攪拌した。反応混合物を氷冷し，tert-ブチル ヒドロペルオキシド デカン溶液（５．５ Ｍ）（０．１８ ｍＬ）を加え，室温で１時間攪拌した。反応混合物の溶媒を減圧下留去した後，トルエンを加えて不溶物をＰｈａｓｅ－ｓｅｐａｒａｔｏｒ（登録商標）で除いた。ろ液をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝６７／３３～４０／６０）で精製することにより，標題化合物（５５１ ｍｇ， 収率９０％）を無色粘体として得た。
MS(ESI);m/z 843.7[M+H]+ Reference example 34:
Production of benzyl (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoate

Benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoate (387 mg) and dichloromethane (4 mL) ) and acetonitrile (1.6 mL) were added 1H-tetrazole (72 mg) and dibenzyl N,N-diisopropylphosphoramidite (0.38 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled with ice, and tert-butyl hydroperoxide decane solution (5.5 M) (0.18 mL) was added, followed by stirring at room temperature for 1 hour. After the solvent of the reaction mixture was distilled off under reduced pressure, toluene was added and insoluble materials were removed using a Phase-separator (registered trademark). The filtrate was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 67/33 to 40/60) to obtain the title compound (551 mg, yield 90%) as a colorless viscous substance.
MS(ESI);m/z 843.7[M+H]+

Reference examples 35 to 48:
The corresponding raw material compounds were treated in the same manner as in Reference Example 34 to obtain the compounds listed in Table 10 below.

（2S)-2-アミノ-3-(4-ヒドロキシ-3-フェニルメトキシフェニル)プロパン酸ベンジル；ヒドロクロリド（1.87 g）とＮ，Ｎ－ジメチルホルムアミド（１８ ｍＬ）の混合物に，（２Ｓ）－２－（ベンジルオキシカルボニルアミノ）プロパン酸（１.02 ｇ），１－ヒドロキシ－７－アザベンゾトリアゾール（ＨＯＡｔ）（７１２ ｍｇ），１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣＩ）（１．０３ ｇ）およびＮ，Ｎ－ジイソプロピルエチルアミン（０．７５０ ｍＬ）を加えて，室温で１８時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液，水を加え，酢酸エチルで抽出した。有機層を水，飽和食塩水で洗浄し，硫酸マグネシウムで乾燥し，不溶物をろ過後、溶媒を減圧下留去し，残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝６７／３３～４５／５５）で精製することにより，標題化合物（２．５６ ｇ， 収率９９％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ５８３．６［Ｍ＋Ｈ］＋ Reference example 49:
Production of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoate

Benzyl (2S)-2-amino-3-(4-hydroxy-3-phenylmethoxyphenyl)propanoate; (2S)- 2-(benzyloxycarbonylamino)propanoic acid (1.02 g), 1-hydroxy-7-azabenzotriazole (HOAt) (712 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI) (1.03 g) and N,N-diisopropylethylamine (0.750 mL) were added, 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 the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered to remove insoluble matter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: hexane/ethyl acetate = 67/33~ 45/55) to obtain the title compound (2.56 g, yield 99%) as a white powder.
MS (ESI); m/z 583.6 [M+H]+

Reference examples 50 to 66:
The corresponding raw material compounds were treated in the same manner as in Reference Example 49 to obtain the compounds listed in Table 11 below.

（2S)-2-アミノ-3-(3,4-ジヒドロキシフェニル)プロパン酸ベンジル; ヒドロクロリド（２５３ ｍｇ）のピリジン（１ ｍＬ）の混合物に，氷冷下で無水酢酸（０．２９１ ｍＬ）を加え，室温で１８時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え，クロロホルムで抽出した。有機層を飽和食塩水で洗浄し，硫酸ナトリウムで乾燥し，不溶物をろ過後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝８０／２０～０／１００）で精製することにより，標題化合物（２８０ ｍｇ， 収率７２％）を無色粘体として得た。
MS(ESI);m/z 414.2 [M+H]+ Reference example 67:
Production of benzyl (2S)-2-acetamido-3-(3,4-diacetyloxyphenyl)propanoate

Benzyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; Acetic anhydride (0.291 mL) was added to a mixture of hydrochloride (253 mg) and pyridine (1 mL) under ice cooling. was added and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and after filtering off insoluble matter, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (280 mg, yield 72%) as a colorless viscous substance.
MS(ESI);m/z 414.2 [M+H]+

Reference examples 68 and 69:
The corresponding raw material compounds were treated in the same manner as in Reference Example 67 to obtain the compounds listed in Table 12 below.

（2S)-3-[3,4-ビス(フェニルメトキシ)フェニル]-2-[(2-メチルプロパン-2-イル)オキシカルボニルアミノ]プロパン酸ベンジル（１３．２ ｇ）に，氷冷下で４M 塩化水素ジオキサン溶液（４３ ｍＬ）を加え，室温で３時間撹拌した。４M 塩化水素酢酸エチル溶液（３ ｍＬ）を追加し，２時間撹拌した。反応混合物の溶媒を減圧下留去した。残渣をジイソプロピルエーテルに懸濁させ，析出した固体をろ取し，減圧乾燥し，標題化合物（１０．４ ｍｇ， 収率９６％）を白色粉体として得た。
MS(ESI);m/z 468.3 [M+H]+ Reference example 70:
Benzyl (2S)-2-amino-3-[3,4-bis(phenylmethoxy)phenyl]propanoate; production of hydrochloride

(2S)-3-[3,4-bis(phenylmethoxy)phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (13.2 g) was added under ice cooling. A 4M hydrogen chloride dioxane solution (43 mL) was added thereto, 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 off under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (10.4 mg, yield 96%) as a white powder.
MS(ESI);m/z 468.3 [M+H]+

Reference example 71:
The corresponding raw material compounds were treated in the same manner as in Reference Example 70 to obtain the compounds listed in Table 13 below.

（１）化合物D-１（８．３１ ｇ）とジクロロメタン（９０ ｍＬ）の混合物に，氷冷下でN－（tert-ブトキシカルボニル）-ホスホノグリシントリメチルエステル（１０ ｇ）および１，１，３，３－テトラメチルグアニジン（５ ｍＬ）を加えて，室温で２４時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液，水を加え，酢酸エチルで抽出した。有機層をシリカゲルカラムクロマトグラフィー（溶媒：酢酸エチル）に通し，ろ液の溶媒を減圧下留去した。残渣をエタノールに懸濁させ，析出した固体をろ取し，減圧乾燥し，化合物D-２（１０．７ ｇ， 収率７９％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ４４０．３ ［Ｍ－Ｈ］－ Reference Example 72: Production of benzyl (2S)-2-amino-3-(3-benzyloxy-4-hydroxyphenyl)propanoate; hydrochloride

(1) To a mixture of Compound D-1 (8.31 g) and dichloromethane (90 mL), N-(tert-butoxycarbonyl)-phosphonoglycine trimethyl ester (10 g) and 1,1, 3,3-tetramethylguanidine (5 mL) was added and stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was passed through silica gel column chromatography (solvent: ethyl acetate), and the solvent of the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain Compound D-2 (10.7 g, yield 79%) as a white powder.
MS (ESI); m/z 440.3 [MH]-

(2) Add (+)-1,2-bis((2S,5S)-2,5-diethylphosphorano)benzene (1) to a mixture of compound D-2 (9.65 g) and tetrahydrofuran (80 mL). ,5-cyclooctadiene) rhodium (I) tetrafluoroborate ((S,S)-Et-DUPHOS-Rh) (144 mg) was added, and the mixture was stirred at 35°C under a pressurized hydrogen atmosphere (800 kPa) 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 off under reduced pressure. The residue was suspended in ethanol, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain Compound D-3 (9.00 g, yield 93%) as a white powder.
MS (ESI); m/z 442.2 [MH]-

(3) 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 4M lithium hydroxide aqueous solution (20 mL) and stirred at 0°C for 7 hours. 1M hydrochloric acid (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove insoluble materials, and the solvent was distilled off under reduced pressure to give compound D-4 (7.52 g, 88 wt%, yield 100%) as a yellow compound. Obtained as a viscous substance.
MS (ESI); m/z 386.2 [MH]-

(4)-1 To a mixture of Compound D-4 (7.46 g, 88 wt%) and N,N-dimethylformamide (4 mL) were added cesium carbonate (3.97 g) and benzyl bromide (2. 40 mL) and stirred at the same temperature for 4 hours. Saturated brine and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 67/33) to obtain compound D-5 (8.81 g, 90 wt%, 98%) as a white powder. I got it as a body.
MS (ESI); m/z 476.2 [MH]-

(4)-2 (Alternative synthesis method for 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. added. The temperature was raised to 20°C and stirred for 10 minutes. The reaction mixture was cooled to 6° C. again, and Compound D-6 (1890 mg) was added in portions at 20° C. or below, followed by stirring at 20° C. for 30 minutes to obtain a solution of Compound D-7.
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 Compound D-8 (1309 mg) were added sequentially, and the mixture was stirred at room temperature for 16 hours. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and insoluble materials were removed by filtration through Celite. Insoluble matter was washed with hexane/ethyl acetate (1:1) and water, and the filtrate was washed successively with saturated ammonium chloride aqueous solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and after filtering off insoluble matter, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 67/33) to obtain compound D-5 (1.84 g, yield 90%) as a yellow viscous substance. Ta.
MS (ESI); m/z 378.2 [M+H-Boc]+

(5) A 4M hydrogen chloride dioxane solution (6 mL) was added to a mixture of Compound D-5 (1.63 g) and 1,4-dioxane (15 mL) under ice cooling, 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 reduced pressure until the volume was reduced to approximately 1/10. The residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (1288 mg, yield 90%) as a white powder.
MS (ESI); m/z 378.4 [M+H]+

（１）化合物E-１（２．０ ｇ）とＮ，Ｎ－ジメチルホルムアミド（１９ ｍＬ）の混合物に，炭酸セシウム（１．４３ ｇ）と臭化ベンジル（０．５８ ｍＬ）を加え，室温で２時間撹拌した。反応混合物に飽和食塩水，水を加え，酢酸エチルで抽出した。有機層を水，飽和食塩水で洗浄し，硫酸マグネシウムで乾燥し，不溶物をろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより，化合物E-２（１．６８ ｇ， 収率７５％）を無色粘体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ３７２．１ ［Ｍ＋Ｈ－Ｂｏｃ］＋ 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 compound E-1 (2.0 g) and N,N-dimethylformamide (19 mL), and the mixture was heated to room temperature. The mixture was stirred for 2 hours. Saturated brine and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and after filtering off insoluble matter, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound E-2 (1.68 g, yield 75%) as a colorless viscous substance.
MS (ESI); m/z 372.1 [M+H-Boc]+

(2) A 4M hydrogen chloride ethyl acetate solution (0.5 mL) was added to a solution of compound E-2 (515 mg) in ethyl acetate (5 mL) under ice cooling, 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 off under reduced pressure. The residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (409 mg, yield 98%) as a white powder.
MS (ESI); m/z 372.1 [M+H]+

（１）化合物Ｆ―１（３．６６ ｇ）とトルエン（１０２ ｍＬ）の混合物に，ｐ－トルエンスルホン酸（１７５ ｍｇ）と２，２－ジメトキシプロパン（１２．５ ｍＬ）を加え，ディーン・スターク装置で１４時間加熱還流した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え，酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し，不溶物をろ過後、溶媒を減圧下留去し，化合物２の粗精製物を黄色粘体として得た。 Reference Example 74: Production of (2S)-2-(benzyloxycarbonylamino)-3-(2,2-dimethyl-1,3-benzodioxol-5-yl)propanoic acid

(1) To a mixture of compound F-1 (3.66 g) and toluene (102 mL), p-toluenesulfonic acid (175 mg) and 2,2-dimethoxypropane (12.5 mL) were added, and Dean The mixture was heated under reflux in a Stark apparatus for 14 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and after filtering off insoluble materials, the solvent was distilled off under reduced pressure to obtain a crude product of Compound 2 as a yellow viscous substance.

(2) The crude product of 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 dissolved in an ice bath. ) and stirred at the same temperature for 40 minutes, then at room temperature for 1 hour. The reaction mixture was diluted with water and washed with diethyl ether. Ethyl acetate was added to the aqueous layer, saturated aqueous citric acid solution was added until the pH reached 6, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the insoluble matter was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate) to give the title compound (2.40 g, yield). (2-step yield: 63%) was obtained as a yellow viscous substance.
MS (ESI); m/z 370.2 [MH]-

（１）化合物Ｇ―１（１．３５ ｇ）を１－ブチル－３－メチルイミダゾリウムヘキサフルオロリン酸塩（７．５１ ｍＬ）に溶解させ，オルト酢酸トリエチル（１．３８ ｍＬ）を加え，８０℃で３時間撹拌した。反応混合物に水を加えた後，酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し，不溶物をろ過後、溶媒を減圧下留去し，残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝８５／１５～７０／３０）で精製することにより，化合物Ｇ―２（１．４１ ｇ， 収率８７％）を無色粘体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ４３０．０ ［Ｍ＋Ｈ］＋ Reference Example 75: Production of (2S)-2-(benzyloxycarbonylamino)-3-(2-ethoxy-2-methyl-1,3-benzodioxol-5-yl)propanoic acid

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

(2) 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 dissolved in lithium hydroxide in an ice bath. After adding the monohydrate (264 mg), 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 reached 6, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the insoluble matter was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate/methanol = 100/0 to 95/5). , the title compound (816 mg, yield 65%) was obtained as a colorless solid.
MS (ESI); m/z 400.2 [MH]-

（２Ｓ）－３－（４－ヒドロキシ－３－フェニルメトキシフェニル）－２－メチル－２－［２－［（２Ｓ）－２－（フェニルメトキシカルボニルアミノ）プロパノイル］ヒドラジニル］プロパン酸ベンジル（１９０ ｍｇ）とアセトニトリル（２ ｍＬ）の混合物に，氷冷下，１，８ージアザビシクロ［5.4.0］ウンデカ-7-エン（０．０３６ ｍＬ），テトラベンジルジホスフェイト（１２３ ｍｇ）を加えて徐々に室温に昇温し，９時間撹拌した。１，８ージアザビシクロ［5.4.0］ウンデカ-7-エン（０．０１７ ｍＬ），テトラベンジルジホスフェイト（５７ ｍｇ）を追加し，室温で１４．５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え，酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝５５／４５～３４／６６）で精製することにより，標題化合物（１７２ ｍｇ， 収率７１％）を無色粘体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ８７０．５［Ｍ－Ｈ］－ [Carbidopa prodrug] (compounds of formula (III) to formula (IX))
Reference example 76:
(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2-[2-[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]hydrazinyl] Production of benzyl propanoate

Benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-methyl-2-[2-[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]hydrazinyl]propanoate (190 mg ) and acetonitrile (2 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL) and tetrabenzyl diphosphate (123 mg) were gradually added under ice cooling. The temperature was raised to room temperature and stirred for 9 hours. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.017 mL) and tetrabenzyl diphosphate (57 mg) were added, and the mixture was stirred at room temperature for 14.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 55/45 to 34/66) to obtain the title compound (172 mg, yield 71%) as a colorless viscous substance.
MS (ESI); m/z 870.5 [MH]-

(2S)-3-[4-[ビス[(2-メチルプロパン-2-イル)オキシ]ホスホリルオキシ]-3-ヒドロキシフェニル]-2-[2-[(2S)-2,6-ビス(フェニルメトキシカルボニルアミノ)ヘキサノイル]ヒドラジニル]-2-メチルプロパン酸tert-ブチル（１３７ ｍｇ）とジクロロメタン（２ ｍＬ）の混合物に，トリフルオロ酢酸 （０．２０ ｍＬ）を加え室温で１６時間撹拌した。トリフルオロ酢酸 （２．０ ｍＬ）を追加し，室温で４時間撹拌した。反応混合物の溶媒を減圧下留去した。残渣に飽和炭酸水素ナトリウム水溶液を加え，酢酸エチルで洗浄した。水層に１Ｍ
塩酸をｐＨ１になるまで加えた後，酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。残渣をジイソプロピルエーテルに懸濁させ，析出した固体をろ取し，減圧乾燥し，標題化合物（113 ｍｇ、収率88％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ７０３．２［Ｍ＋Ｈ］＋ Reference Example 77: (2S)-2-[2-[(2S)-2,6-bis(phenylmethoxycarbonylamino)hexanoyl]hydrazinyl]-3-(3-hydroxy-4-phosphonooxyphenyl)-2 -Methylpropanoic acid; Production of 2,2,2-trifluoroacetic acid

(2S)-3-[4-[bis[(2-methylpropan-2-yl)oxy]phosphoryloxy]-3-hydroxyphenyl]-2-[2-[(2S)-2,6-bis( Trifluoroacetic acid (0.20 mL) was added to a mixture of tert-butyl phenylmethoxycarbonylamino)hexanoyl]hydrazinyl]-2-methylpropanoate (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 stirred at room temperature for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was washed with ethyl acetate. 1M in water layer
After adding hydrochloric acid until the pH reached 1, the mixture was extracted with ethyl acetate. After drying the organic layer over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (113 mg, yield 88%) as a white powder.
MS (ESI); m/z 703.2 [M+H]+

（２Ｓ）－３－［４－ビス（フェニルメトキシ）ホスホリルオキシ－３－フェニルメトキシフェニル］－２－メチル－２－［フェニルメトキシカルボニル（フェニルメトキシカルボニルアミノ）アミノ］プロパン酸（１０５ ｍｇ）とＮ，Ｎ－ジメチルホルムアミド（１ ｍＬ）の混合物に，１－ヒドロキシ－７－アザベンゾトリアゾール（ＨＯＡｔ）（２０ ｍｇ），１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣＩ）（３３ ｍｇ），（２Ｓ）－２－アミノ－６－（ベンジルオキシカルボニルアミノ）ヘキサン酸ベンジル；ヒドロクロリド（５６ ｍｇ）およびＮ，Ｎ－ジイソプロピルエチルアミン（０．０２３ ｍＬ）を加えて室温で２．５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液，水を加え，酢酸エチルで抽出した。有機層を水，飽和食塩水で洗浄し，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝６７／３３～４５／５５）で精製することにより，標題化合物（８９ ｍｇ， 収率５７％）を無色粘体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ １２１５．１［Ｍ＋Ｈ＋Ｈ２Ｏ］＋ Reference example 78:
(2S)-2-[[(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino] Production of benzyl propanoyl]amino]-6-(phenylmethoxycarbonylamino)hexanoate

(2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-methyl-2-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino]propanoic acid (105 mg) and N , N-dimethylformamide (1 mL), 1-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) and N,N-diisopropylethylamine (0.023 mL) were added at room temperature. Stirred for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 67/33 to 45/55) to obtain the title compound (89 mg, yield 57%) as a colorless viscous substance.
MS (ESI); m/z 1215.1 [M+H+H2O]+

Reference examples 79-81:
The corresponding raw material compounds were treated in the same manner as in Reference Example 78 to obtain the compounds listed in Table 14 below.

（１）ＷＯ ２００４／０５２８４１に従い，化合物H-１（１０．０ ｇ）から化合物H-２（１３．６ ｇ）を淡黄色粘体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ２４１．０ ［Ｍ＋Ｈ］＋ Reference Example 82: Production of (2S)-2-(2-benzyloxycarbonylhydrazino)-3-(3,4-dibenzyloxyphenyl)-2-methylpropanoic acid

(1) According to WO 2004/052841, compound H-2 (13.6 g) was obtained as a pale yellow viscous substance from compound H-1 (10.0 g).
MS (ESI); m/z 241.0 [M+H]+

(2) WO 2004/052841 Compound H-3 (13.8 g, yield 93% over two steps) was obtained as a white powder from compound H-2 (13.6 g).
MS (ESI); m/z 339.1 [MH]-

(3) Compound H-4 (15.4 g, yield 73%) was obtained as a colorless viscous substance from compound H-3 (13.8 g) according to WO 2020/115753.
MS (ESI); m/z 465.0 [M+H-C4H8]+

(4) To a solution of Compound H-4 (15.4 g) in methanol (75 mL) were added triethylsilane (10.3 g) and 4M hydrogen chloride dioxane solution (150 mL) under ice cooling, and the mixture was diluted at room temperature for 2 hours. Stir for hours. The solvent of the reaction mixture was distilled off under reduced pressure to obtain a crude product (17.5 g) of compound H-5 as a beige powder.
MS (ESI); m/z 421.1 [M+H]+

(5) Compound H-5 (18.0 g) was suspended in dichloromethane (340 mL), benzyl chloroformate (5.76 g) and triethylamine (13.7 g) were added under ice cooling, and the mixture was stirred at room temperature. Stirred for 1 hour. Water was added to the reaction mixture for extraction. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 60/40) to give compound H-6 (12.6 g, yield 74% in 2 steps) as a yellow color. Obtained as a viscous substance.
MS (ESI); m/z 555.1 [M+H]+

(6) Compound H-6 (3.0 g) was dissolved in tetrahydrofuran (41 mL) and distilled water (4 mL), 4M lithium hydroxide aqueous solution (4.1 mL) was added, and the mixture was incubated at 60°C for 4 hours. Stirred. 1M hydrochloric acid (17 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL x 1,100 mL x 1). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (2.27 g, yield 77%) as a white powder.
MS (ESI); m/z 541.1 [M+H]+

（１）ＷＯ ２００４／０５２８４１を参考に，化合物I-１（２５．０ ｇ）から化合物I-２（３０．２ ｇ，収率８０％）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ３２５．２ ［Ｍ－Ｈ］－ Reference Example 83: Production of benzyl (2S)-3-(3-benzyloxy-4-hydroxyphenyl)-2-hydrazide-2-methylpropanoate; hydrochloride

(1) Compound I-2 (30.2 g, yield 80%) was obtained as a white powder from compound I-1 (25.0 g) with reference to WO 2004/052841.
MS (ESI); m/z 325.2 [MH]-

(2) Cesium carbonate (2.23 g) was added to a mixture of Compound I-2 (8.0 g) and N,N-dimethylformamide (40 mL). The reaction mixture was cooled with ice, and benzyl bromide (4.04 g) dissolved in N,N-dimethylformamide (40 mL) was added, followed by stirring at room temperature for 94 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 65/35 to 45/55) to obtain compound I-3 (2.89 g, yield 28%) as a pale yellow powder. I got it as a body.
MS (ESI); m/z 415.3 [MH]-

(3) Compound I-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 in N,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 the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 70/30 to 45/55) to obtain compound I-4 (738 mg, yield 23%) as a pale yellow viscous substance. Ta.
MS (ESI); m/z 507.0 [M+H]+

(4) A 4M hydrogen chloride ethyl acetate solution (1.9 mL) was added to a mixture of Compound I-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 off under reduced pressure. The residue was dissolved in ethyl acetate, the solvent was distilled off again under reduced pressure, and the residue was dried under reduced pressure to obtain the title compound (385 mg, yield 97%) as a red viscous substance.
MS(ESI)z; m/z 407.1 [M+H]+

（１）化合物J-１（４．９１ ｇ）とアセトニトリル（３５ ｍＬ）混合物に，室温でジベンジルアゾカルボキシレート（７．８２ ｇ）と（Ｒ）‐５‐（ピロリジン‐２‐イル）‐１Ｈ‐テトラゾール（３８０ ｍｇ）とトリフルオロ酢酸（０．２０６ ｍＬ）を加え，室温で１８時間撹拌した。ジベンジルアゾカルボキシレート（３．０２ ｇ）と（Ｒ）‐５‐（ピロリジン‐２‐イル）‐１Ｈ‐テトラゾール（１０５ ｍｇ）とトリフルオロ酢酸（０．０７０ ｍＬ）を加え，室温で１０時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え，酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し，硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶媒：ヘキサン／酢酸エチル＝８０／２０～６０／４０）で精製することにより，化合物Ｊ－２（６．８７ ｇ， 収率６４％， ５１．２％ｅｅ）を白色粉体として得た。
ＭＳ（ＥＳＩ）；ｍ／ｚ ５６９．３ ［Ｍ＋Ｈ］＋ Reference Example 84: tert-butyl (2S)-3-(4-di-tert-butoxyphosphoryloxy-3-hydroxyphenyl)-2-hydrazino-2-methylpropanoate
Manufacturing of

(1) Dibenzyl azocarboxylate (7.82 g) and (R)-5-(pyrrolidin-2-yl)- were added to a mixture of compound J-1 (4.91 g) and acetonitrile (35 mL) at room temperature. 1H-tetrazole (380 mg) and trifluoroacetic acid (0.206 mL) were added, and the mixture was stirred at room temperature for 18 hours. Dibenzylazocarboxylate (3.02 g), (R)-5-(pyrrolidin-2-yl)-1H-tetrazole (105 mg) and trifluoroacetic acid (0.070 mL) were added, and the mixture was incubated at room temperature for 10 hours. Stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 60/40) to obtain compound J-2 (6.87 g, yield 64%, 51.2%). ee) was obtained as a white powder.
MS (ESI); m/z 569.3 [M+H]+

(2) In a mixture of compound J-2 (2.74 g), dichloromethane (24 mL), and acetonitrile (6 mL), 1H-tetrazole (679 mg) and dibenzyl N,N-diisopropyl phosphoramidite (2 .00 mL) and 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 the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 75/25 to 50/50) to obtain compound J-3 (2.69 g, yield 70%) as a yellow viscous substance. Obtained.
MS (ESI); m/z 759.3 [M+H]+

(3) Add an aqueous solution (2 mL) of dimethyl sulfoxide (0.577 mL) and sodium dihydrogen phosphate (891 mg) to a mixture of Compound J-3 (2.69 g) and acetonitrile (35 mL) at room temperature. An aqueous solution (2.5 mL) of sodium chlorite (1.76 g) was added, and the mixture was stirred at room temperature for 2 hours. Sodium sulfite (939 mg) and water were added to the reaction mixture, stirred, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. It was dried under reduced pressure to obtain Compound J- 4 (2.78 g, yield 97%) as a yellow viscous substance.
MS (ESI); m/z 775.2 [MH]-

(4) Add 2-tert-butyl 1,3-diisopropylisourea (2.1 mL) to a mixture of compound J-4 (1.71 g) and dichloromethane (10 mL) at room temperature, and stir at room temperature for 20 hours. did. Insoluble matter was filtered off, and the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 75/25 to 50/50) to obtain compound J-5 (1.35 g, yield 83%) as a yellow viscous substance. Obtained.
MS (ESI); m/z 833.3 [M+H]+

(5) Palladium/carbon (hydrated) (487 mg) was added to a mixture of Compound J-5 (1.35 g) and tetrahydrofuran (8 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere 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 off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol = 100/0 to 95/5) to obtain the title compound (0.513 g, yield 64%) as a yellow viscous substance.
MS (ESI); m/z 475.3 [M+H]+

Test Example 1: Evaluation of in vitro conversion efficiency using human hepatocytes The conversion efficiency of prodrugs to levodopa was evaluated in a metabolic test using human hepatocytes. Prodrugs were incubated with human hepatocytes for 4 hours at 37°C. A portion of the reaction solution was taken at each predetermined time and mixed with an organic solvent to stop the reaction. The reaction stop solution was centrifuged, and the resulting supernatant was measured by LC-MS/MS. The conversion efficiency to levodopa was evaluated as the amount of levodopa produced 4 hours after the start of the reaction. The levodopa production amounts of some example compounds of the present invention are shown in Tables 15 and 16.

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

Test Example 2: Evaluation of Solution Stability Phosphate buffer, pH 7.4, was added to each compound to dissolve it, and if necessary, a NaOH solution was added to adjust the pH to prepare a solution of about 1 mg/mL. After storing this solution at 25° C. for about 1 day, the HPLC purity (area percentage, %) was measured. The HPLC purity of the solution immediately after 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 the HPLC purity difference. The solution stability of some example compounds of the present invention is shown in Table 17, Table 18 and Table 19.

As shown in the results in Tables 17 to 19, it was confirmed that the compounds of the present invention are stable in near-neutral aqueous solutions, and among them, Examples 4, 5, 22, 29, Example 42 and Example 44 were stable.
From the above results, the compound of the present invention is expected to have high solution stability at pH 6 to 8, and the combination drug of the present invention, which combines these compounds, is considered to be useful as a solution preparation with high solution stability. .

Test Example 3: Evaluation of Solubility Water was added to each compound to prepare a suspension, which was shaken at 25°C overnight and filtered to obtain a filtrate. The concentration of the compound in this filtrate was determined using HPLC and was defined as the solubility. Additionally, the pH of the filtrate was measured. Tables 20 and 21 show the solubility of some example compounds of the present invention.

As shown in the results of the above test, it was confirmed that all the compounds exhibited good solubility at pH around the isoelectric point.
From the above results, high solubility at pH 6 to 8 was expected, and it was considered to be particularly useful as a solution formulation.

The present invention provides that a pharmaceutical combination comprising a levodopa prodrug compound and a carbidopa prodrug compound is useful for the prevention or treatment of neurodegenerative diseases and/or diseases or conditions caused by decreased brain dopamine levels, such as Parkinson's disease and related symptoms. Therefore, it has high utility value in the pharmaceutical industry.

Claims (42)

A pharmaceutical combination comprising one compound each selected from Group A and Group B below or a pharmacologically acceptable salt thereof.
<Group A> A compound selected from the group consisting of a compound represented by formula (I) and a compound represented by formula (II) or a pharmaceutically acceptable salt thereof Formula (I);

(wherein R ^10a is an amino acid side chain or its O-phosphorylated amino acid side chain,
R ^11a and R ^12a are the same or different and each is hydrogen, alkyl, cycloalkyl, phenyl, P(=O)(OR') ₂ , S(=O)(OH) or optionally substituted glycosyl and
R ^13a and R ^14a are the same or different and each represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, -O-C(=O)-R', -C(=O)-OR', - C(=O)-R', -C(=S)-R', -OC(=O)-NR'R'', -OC(=S)-NR'R'', or OC(=O)-R''',
R ^15a is hydrogen, alkyl, cycloalkyl or phenyl;
R' and R'' are the same or different and are each hydrogen, alkyl, alkenyl, cycloalkyl or phenyl, or R' and R'' taken together with the adjacent nitrogen atoms form a heteroaryl. is a group that forms
R'' is hydrogen, alkyl, alkenyl or alkynyl. ), and a compound represented by formula (II);

(wherein R ^20a is an optionally substituted amino acid side chain,
R ^21a and R ^22a are the same or different and each is hydrogen, alkyl, alkanoyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^23a , R ^24a and R ^25a are the same or different and each is hydrogen or alkyl. ) A compound represented by <Group B> A compound selected from the group consisting of compounds represented by any one of formulas (III) to formula (IX) or a pharmaceutically acceptable salt thereof Formula (III);

(wherein R ^10b is an amino acid side chain,
R ^11b and R ^12b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^13b is hydrogen or alkyl. ),
Formula (IV);

(wherein R ^20b is an amino acid side chain,
R ^21b and R ^22b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^23b is hydrogen or alkyl. ),
Formula (V);

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

(wherein R ^41b and R ^42b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^43b and R ^44b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^43b and R ^44b are a group that together form an optionally substituted alkylene,
R ^45b is hydrogen or alkyl. ),
Formula (VII);

(wherein R ^51b and R ^52b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^53b and R ^54b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^53b and R ^54b are a group that together form an optionally substituted alkylene,
R ^55b is hydrogen or alkyl. ),
Formula (VIII);

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

(wherein R ^71b and R ^72b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^73b and R ^74b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^73b and R ^74b are a group that together form an optionally substituted alkylene,
R ^75b is hydrogen or alkyl. ). The pharmaceutical combination according to claim 1, wherein the compound of Group A is a compound represented by formula (I) or a pharmacologically acceptable salt thereof. The pharmaceutical combination according to claim 1, wherein the compound of Group A is a compound represented by formula (II) or a pharmacologically acceptable salt thereof. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of Group B is a compound represented by formula (III) or a pharmacologically acceptable salt thereof. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of Group B is a compound represented by formula (IV) or a pharmacologically acceptable salt thereof. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of Group B is a compound represented by formula (V) or a pharmacologically acceptable salt thereof. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of Group B is a compound represented by formula (VI) or a pharmacologically acceptable salt thereof. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of Group B is a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of group B is a compound represented by formula (VIII) or a pharmacologically acceptable salt thereof. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of Group B is a compound represented by formula (IX) or a pharmacologically acceptable salt thereof. R ^10a in formula (I) is 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 1 or 2 O-phosphorylated 3,4-dihydroxyphenylalanine. The pharmaceutical combination according to claim 1 or 2, which is a side chain or an O-phosphorylated amino acid side chain. R ^10a in formula (I) is an amino acid side chain or an O-phosphorylated amino acid side chain of an amino acid selected from the group consisting of lysine, valine, tyrosine, O-phosphorylated tyrosine and 3,4-dihydroxyphenylalanine; The pharmaceutical combination according to claim 1 or 2. R ^11a and R ^12a of formula (I) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1, 2, 11 or 12, wherein R ^13a , R ^14a , R ^15a are hydrogen. R ^11a and R ^12a of formula (I) are one hydrogen and one P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1, 2, 11 or 12, wherein R ^13a , R ^14a , R ^15a are hydrogen. The pharmaceutical combination according to claim 1 or 3, wherein R ^20a of formula (II) is an amino acid side chain of an amino acid selected from the group consisting of glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine and tyrosine. . R ^21a and R ^22a of formula (II) are the same or different and are each hydrogen, acetyl or P(=O)(OH) ₂ ,
16. The pharmaceutical combination according to claim 1, 3 or 15, wherein ^R23a , ^R24a , ^R25a are hydrogen. R ^21a and R ^22a of formula (II) are one hydrogen and one -P(=O)(OH) ₂ ,
16. The pharmaceutical combination according to claim 1, 3 or 15, wherein ^R23a , ^R24a , ^R25a are hydrogen. R ^11b and R ^12b of formula (III) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1 or 4, wherein R ^13b is hydrogen. R ^21b and R ^22b of formula (IV) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1 or 5, wherein R ^23b is hydrogen. R ^31b and R ^32b of formula (V) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1 or 6, wherein R ^33b is hydrogen. R ^41b and R ^42b of formula (VI) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1 or 7, wherein R ^45b is hydrogen. R ^51b and R ^52b of formula (VII) are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1 or 8, wherein R ^55b is hydrogen. R ^61b and R ^62b of formula (VIII) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1 or 9, wherein R ^65b is hydrogen. R ^71b and R ^72b of formula (IX) are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
The pharmaceutical combination according to claim 1 or 10, wherein R ^75b is hydrogen. Formula (III);

(wherein R ^10b is an amino acid side chain,
R ^11b and R ^12b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^13b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof. R ^11b and R ^12b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
26. The compound or a pharmaceutically acceptable salt thereof according to claim 25, wherein R ^13b is hydrogen. Formula (IV);

(wherein R ^20b is an amino acid side chain,
R ^21b and R ^22b are the same or different and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^23b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof. R ^21b and R ^22b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
28. The compound or a pharmaceutically acceptable salt thereof according to claim 27, wherein ^R23b is hydrogen. Formula (V);

(wherein R ^30b is an amino acid side chain,
R ^31b and R ^32b are the same or different, and each is hydrogen, alkyl, P(=O)(O) ₂ , S(=O)(OH) or optionally substituted glycosyl,
R ^33b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof. R ^31b and R ^32b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
30. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein ^R33b is hydrogen. Formula (VI);

(wherein R ^41b and R ^42b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^43b and R ^44b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^43b and R ^44b are a group that together form an optionally substituted alkylene,
R ^45b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof. R ^41b and R ^42b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
32. The compound or a pharmaceutically acceptable salt thereof according to claim 31, wherein R ^45b is hydrogen. Formula (VII);

(wherein R ^51b and R ^52b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^53b and R ^54b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^53b and R ^54b are a group that together form an optionally substituted alkylene,
R ^55b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof. R ^51b and R ^52b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
34. The compound or a pharmaceutically acceptable salt thereof according to claim 33, wherein ^R55b is hydrogen. Formula (VIII);

(wherein R ^61b and R ^62b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^63b and R ^64b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^63b and R ^64b are a group that together form an optionally substituted alkylene,
R ^65b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof. R ^61b and R ^62b are the same or different and are each hydrogen or P(=O)(OH) ₂ ,
36. The compound or a pharmaceutically acceptable salt thereof according to claim 35, wherein R ^65b is hydrogen. Formula (IX);

(wherein R ^71b and R ^72b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl,
R ^73b and R ^74b are the same or different, and each is hydrogen, alkyl, P(=O)(OH) ₂ , S(=O)(OH), or optionally substituted glycosyl, or R ^73b and R ^74b are a group that together form an optionally substituted alkylene,
R ^75b is hydrogen or alkyl. ) or a pharmacologically acceptable salt thereof. R ^71b and R ^72b are the same or different and each is hydrogen or P(=O)(OH) ₂ ,
38. The compound or a pharmaceutically acceptable salt thereof according to claim 37, wherein ^R75b is hydrogen. Formula (I-1);

(wherein R ^10a is an amino acid side chain,
R ^11a and R ^12a are the same or different and each is hydrogen, S(=O)(OH) or optionally substituted glycosyl,
R ^15a is hydrogen or alkyl;
However, R ^11a and R ^12a are not hydrogen at the same time. ) or a pharmacologically acceptable salt thereof. A liquid pharmaceutical composition containing a combination drug comprising a compound selected from Group A and a compound selected from Group B. A therapeutic agent for a neurodegenerative disease and/or a disease or symptom caused by a decrease in brain dopamine concentration, comprising a combination drug comprising a compound selected from Group A and a compound selected from Group B. 42. The therapeutic agent according to claim 41, wherein the disease or symptom caused by a neurodegenerative disease and/or a decrease in brain dopamine concentration is Parkinson's disease.