# US 8,772,290 B2 · Alpha-arylmethoxyacrylate derivative, preparation method thereof, and pharmaceutical composition containing same

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- Number: US 8,772,290 B2
- Document ID: US8772290B2
- Status: Granted
- Kind: B2
- Application number: 13/392,024
- Filed: 2011-04-21
- Published: 2012-06-14
- Granted: 2014-07-08
- Earliest claimed: 2010-04-21
- Assignees: Oscotech Inc.
- Applicants: Se-Won Kim; Jung Ho Kim; Se-Nyum Kim; Dae-Pil Kang; Youn Ho Han; Guo Fan Jin; Dong-Sik Jung; Sung-Ho Park; Ji Min Kim; Jhi Zheng
- Inventors: Se-Won Kim; Jung Ho Kim; Se-Nyum Kim; Dae-Pil Kang; Youn Ho Han; Guo Fan Jin; Dong-Sik Jung; Sung-Ho Park; Ji Min Kim; Jhi Zheng
- Web page: https://patentgrep.com/patent/US8772290B2

## CPC

- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 31/24: having an amino or nitro group
- A61K 31/336: having three-membered rings, e.g. oxirane, fumagillin
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/415: 1,2-Diazoles
- A61K 31/421: 1,3-Oxazoles, e.g. pemoline, trimethadione
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/4453: only substituted in position 1, e.g. propipocaine, diperodon
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07C 69/736: the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
- C07C 217/20: by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
- C07C 251/48: with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
- C07C 251/86: having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
- C07D 213/30: Oxygen atoms
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 295/088: to an acyclic saturated chain
- C07D 295/30: non-acylated
- C07D 303/12: with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07C 2601/02: with a three-membered ring
- C07C 2601/08: the ring being saturated
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to an alpha-arylmethoxyacrylate derivative, a preparation method thereof and a pharmaceutical composition comprising the same, and the alpha-arylmethoxyacrylate derivative is inhibitory of HIF, which plays an important role in the regulation of genes associated with energy metabolism, vasomotion, angiogenesis and apoptosis and in the response of cells under hypoxic conditions, so that it can be used for preventing or treating of diseases such as cancer, arthritis, psoriasis, diabetic retinopathy and macular degeneration.

## Claims

### Claim 1

A method for treating pancreatic cancer, psoriasis, diabetic retinopathy, or macular degeneration in a subject in need thereof, comprising administering to the subject an alpha-arylmethoxyacrylate of the following formula 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof:
wherein
R1 and R5 are each independently H, hydroxy, halogen, C1-6alkyl, or C1-6alkoxy;
R2, R3 and R4 are each independently H, hydroxy, halogen, formyl, C1-6alkyl, C1-6alkoxy, C3-6 heteroaryl, or any one of formulae A to C:
wherein
n is an integer of 0 to 4;
R11 is H, hydroxy, cyano, C1-4alkyl, C2-6alkenyl, C1-6alkoxy, C1-4alkoxyC1-4alkyl, C3-8cycloalkylC1-4alkyl, or C2-7heterocycloalkylC1-4alkyl, C1-4alkylamino, or diC1-4alkylamino;
R12 and R13 are each independently H, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8cycloalkylC1-4alkyl, C2-7heterocycloalkylC1-4alkyl, C6-12aryl, C6-12arylC1-4alkyl, C6-12aryloxyC1-4alkyl, or C3-6heteroarylC1-4alkyl, or combine together to form C2-7heterocycloalkyl; and
R14 is H, hydroxy, C3-8cycloalkyl, C2-7heterocycloalkyl, C6-12aryl, C6-12 arylC1-4alkyl, C6-12aryloxy, C3-6heteroaryl, C1-4alkylamino, diC1-4alkylamino, or
said alkyl, alkenyl and alkoxy each independently being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro and cyano;
said cycloalkyl, heterocycloalkyl, aryl and heteroaryl each independently being optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-4alkyl and C1-4alkoxy; and
said heterocycloalkyl and heteroaryl each independently comprising at least one atom of N or O.

### Claim 2 (depends on 1)

The method of claim 1, wherein at least one of R2, R3 and R4 is selected from formulae A to C.

### Claim 3 (depends on 1)

The method of claim 1, wherein R12 and R13 are each independently H, methyl, ethyl, propyl, cyclopropylmethyl, cyclopentyl, oxirane-2-ylmethyl, pyrrolidinylethyl, piperidinylethyl, phenyl, benzyl, 4-methylbenzyl, 3-methoxybenzyl, phenoxyethyl, phenethyl, pyridin-2-ylmethyl or pyridin-4-ylmethyl, or combine together to form morpholino.

### Claim 4 (depends on 1)

The method of claim 1, wherein n is 1 or 2; and R14 is hydroxy, morpholino, phenyl, phenoxy, pyridin-2-yl, pyridin-4-yl, 4-nitrophenyl,
or hydroxyethylamino.

### Claim 5 (depends on 1)

The method of claim 1, wherein R1 and R5 are each independently H, methyl, methoxy, or fluoro.

### Claim 6 (depends on 1)

The method of claim 1, wherein the alpha-arylmethoxyacrylate of formula 1 is selected from the group consisting of the following compounds 1) to 82):
1) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)propyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
2) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
3) (E)-methyl 2-(2-((3-(benzyloxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
4) (E)-methyl 2-(2((3-((E)-(ethoxyimino)methyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
5) (E)-methyl 2-(2-((5-hydroxyphenoxy)methyl)phenyl)-3-methoxyacrylate;
6) (E)-methyl 2-(2-((5-formyl-2-methoxyphenoxy)methyl)phenyl)-3-methoxyacrylate;
7) (E)-methyl 2-(2-((3-((E)-1-(propoxyimino)propyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
8) (E)-methyl 2-(2-((4-((E)-1-(propoxyimino)ethyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
9) (E)-methyl 2-(2-((4-((E)-1-(2-(piperidin-1-yl)ethoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
10) (E)-methyl 2-(2-((3-((E)-(2-(piperidin-1-yl)ethoxyimino)methyl)-phenoxy)methyl)phenyl)-3-methoxyacrylate;
11) (E)-methyl 2-(2-((3-(2-(2-hydroxyethylamino)ethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
12) (E)-methyl 2-(2-((3-(2-hydroxyethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
13) (E)-4-(2-(3-(2-(1,3-dimethoxy-3-oxoprop-1-en-2-yl)benzyloxy)phenoxy)ethyl)-morpholine 4-oxide;
14) (E)-methyl 2-(2-((3-((E)-(propoxyimino)methyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
15) (E)-methyl 2-(2-((3-fluoro-5-hydroxyphenoxy)methyl)phenyl)-3-methoxyacrylate;
16) (E)-methyl 2-(2-((3-phenethoxyphenoxy)methyl)phenyl)-3-methoxyacrylate;
17) (E)-methyl 2-(2-((4-((E)-1-(benzyloxyimino)ethyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
18) (E)-methyl 2-(2-((4-((E)-1-(phenethoxyimino)ethyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
19) (E)-methyl 2-(2-((4-fluorophenoxy)methyl)phenyl)-3-methoxyacrylate;
20) (E)-methyl 2-(2-((3-hydroxy-5-(2-phenoxyethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
21) (E)-methyl 2-(2-((3-(benzyloxy)-5-fluorophenoxy)methyl)phenyl)-3-methoxyacrylate;
22) (E)-methyl 2-(2-((3-fluoro-5-(2-phenoxyethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
23) (E)-methyl 2-(2-((3-fluoro-5-(pyridin-2-ylmethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
24) (E)-methyl 2-(2-((3-fluoro-5-(4-nitrobenzyloxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
25) (E)-methyl 2-(2-((3-((E)-(morpholinoimino)methyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
26) (E)-methyl 2-(2-((3-(pyridin-2-ylmethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
27) (E)-methyl 2-(2-((3-(pyridin-4-ylmethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
28) (E)-methyl 2-(2-((3-hydroxy-5-(pyridin-2-ylmethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
29) (E)-methyl 2-(2-((3-hydroxy-5-(pyridin-4-ylmethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
30) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(morpholinoimino)propyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
31) (E)-methyl 2-(2-((4-((E)-(hydroxyimino)methyl)-2-methylphenoxy)methyl)phenyl)-3-methoxyacrylate;
32) (E)-methyl 2-(2-((2-methyl-4-((E)-(propoxyimino)methyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
33) (E)-methyl 2-(2-((4-((E)-(benzyloxyimino)methyl)-2-methylphenoxy)methyl)-phenyl)-3-methoxyacrylate;
34) (E)-methyl 2-(2-((4-((E)-1-(hydroxyimino)ethyl)-2-methoxyphenoxy)methyl)-phenyl)-3-methoxyacrylate;
35) (E)-methyl 2-(2-((4-((E)-1-(propoxyimino)ethyl)-2-methoxyphenoxy)methyl)-phenyl)-3-methoxyacrylate;
36) (E)-methyl 2-(2-((4-((E)-1-(benzyloxyimino)ethyl)-2-methoxyphenoxy)methyl)-phenyl)-3-methoxyacrylate;
37) (E)-methyl 2-(2-((5-((E)-1-(hydroxyimino)ethyl)-2-methoxyphenoxy)methyl)-phenyl)-3-methoxyacrylate;
38) (E)-methyl 2-(2-((5-((E)-1-(benzyloxyimino)ethyl)-2-methoxyphenoxy)methyl)-phenyl)-3-methoxyacrylate;
39) (E)-methyl 2-(2-((5-((E)-(benzyloxyimino)methyl)-2-methoxyphenoxy)methyl)-phenyl)-3-methoxyacrylate;
40) (E)-methyl 2-(2-((2,5-dimethyl-3-propoxyphenoxy)methyl)phenyl)-3-methoxyacrylate;
41) (E)-methyl 2-(2-((3-(benzyloxy)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate;
42) (E)-methyl 2-(2-((2-methoxy-5-((E)-1-(propoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
43) (E)-methyl 2-(2-((2-methoxy-5-((E)-(propoxyimino)methyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
44) (E)-methyl 2-(2-((2-methoxy-5-((E)-1-(phenylethoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
45) (E)-methyl 2-(2-((2-methoxy-5-((E)-1-(phenylethoxyimino)methyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
46) (E)-methyl 2-(2-((2-methoxy-5-((E)-1-(phenoxyimino)methyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
47) (E)-methyl 2-(2-((3-((E)-1-(phenoxyimino)methyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
48) (E)-methyl 2-(2-((2-methoxy-5-((E)-1-(phenylhydrazono)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
49) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-(propoxyimino)methyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
50) (E)-methyl 2-(2-((4-((E)-(benzyloxyimino)methyl)-2,5-dimethylphenoxy)methyl)-phenyl)-3-methoxyacrylate;
51) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-(2-phenoxyethoxyimino)methyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
52) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-(oxirane-2-ylmethoxyimino)methyl)-phenoxy)methyl)phenyl)-3-methoxyacrylate;
53) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-(2-(pyrrolidin-1-yl)ethoxyimino)methyl)-phenoxy)methyl)phenyl)-3-methoxyacrylate;
54) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-(2-(piperidin-1-yl)ethoxyimino)methyl)-phenoxy)methyl)phenyl)-3-methoxyacrylate;
55) (E)-methyl 2-(2-((3-hydroxy-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate;
56) (E)-methyl 2-(2-((2,5-dimethyl-3-(2-phenoxyethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
57) (E)-methyl 2-(2-((2-methoxy-5-((E)-1-(4-methylbenzyloxyimino)ethyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
58) (E)-methyl 2-(2-((2-methoxy-5-((E)-1-(4-methylbenzyloxyimino)methyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
59) (E)-methyl 2-(2-((2-methyl-4-((E)-(phenylethoxyimino)methyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
60) (E)-methyl 2-(2-((2-methyl-4-((E)-(4-methylbenzyloxyimino)methyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
61) (E)-methyl 2-(2-((4-((E)-(benzyloxyimino)methyl)-2-fluoro-6-methoxyphenoxy)-methyl)phenyl)-3-methoxyacrylate;
62) (E)-methyl 2-(2-((3-(benzyloxy)-2,4-difluorophenoxy)methyl)phenyl)-3-methoxyacrylate;
63) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-(phenoxyimino)methyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
64) (E)-methyl 2-(2-((2-fluoro-6-methoxy-4-((E)-(propoxyimino)methyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
65) (E)-methyl 2-(2-((2,4-difluoro-3-propoxyphenoxy)methyl)phenyl)-3-methoxyacrylate;
66) (E)-methyl 2-(2-((2-fluoro-6-methoxy-4-((E)-(phenethoxyimino)methyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
67) (E)-methyl 2-(2-((4-((E)-(cyclopropylmethoxyimino)methyl)-2-methylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
68) (E)-methyl 2-(2-((4-((E)-(cyclopropylmethoxyimino)methyl)-2,5-dimethylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
69) (E)-methyl 2-(2-((4-((E)-(cyclopentyloxyimino)methyl)-2,5-dimethylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
70) (E)-methyl 2-(2-((4-((E)-(cyclopentyloxyimino)methyl)-2-methylphenoxy)methyl)-phenyl)-3-methoxyacrylate;
71) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-(3-phenoxypropyloxyimino)methyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
72) (E)-methyl 2-(2-((4-((E)-(3-methoxybenzyloxyimino)methyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate;
73) (E)-methyl 2-(2-((4-((E)-(pyridin-2-ylmethoxyimino)methyl)-2,5-dimethylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
74) (E)-methyl 2-(2-((4-((E)-(pyridin-4-ylmethoxyimino)methyl)-2,5-dimethylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
75) (E)-methyl 2-(2-((3-((E)-(2-phenoxyethoxyimino)methyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
76) (E)-methyl 2-(2-((3-(2-morpholinoethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
77) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(methoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
78) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(ethoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
79) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(pyridin-2-ylmethoxyimino)ethyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
80) (E)-methyl 2-(2-((4-((Z)-2-methoxy-1-(methoxyimino)ethyl)2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate;
81) (E)-methyl 2-(2-((2,5-dimethyl-4-(oxazol-5-yl)phenoxy)methyl)phenyl)-3-methoxyacrylate; and
82) (E)-methyl 2-(2-((2,5-dimethyl-4-(1-methyl-1H-pyrazol-3-yl)phenoxy)-methyl)phenyl)-3-methoxyacrylate.

### Claim 7 (depends on 1)

The method of claim 1, wherein the alpha-arylmethoxyacrylate of formula 1 is selected from the following 1) to 14):
1) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)propyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
2) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
3) (E)-methyl 2-(2-((3-(benzyloxy)phenoxy)methyl)phenyl)-3-methoxyacrylate (compound 3);
4) (E)-methyl 2-(2-((4-((E)-(cyclopropylmethoxyimino)methyl)-2,5-dimethylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
5) (E)-methyl 2-(2-((4-((E)-(cyclopentyloxyimino)methyl)-2,5-dimethylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
6) (E)-methyl 2-(2-((4-((E)-(pyridin-2-ylmethoxyimino)methyl)-2,5-dimethylphenoxy)-methyl)phenyl)-3-methoxyacrylate;
7) (E)-methyl 2-(2-((3-((E)-(2-phenoxyethoxyimino)methyl)phenoxy)methyl)phenyl)-3-methoxyacrylate;
8) (E)-methyl 2-(2-((3-(2-morpholinoethoxy)phenoxy)methyl)phenyl)-3-methoxyacrylate;
9) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(methoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
10) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(ethoxyimino)ethyl)phenoxy)methyl)-phenyl)-3-methoxyacrylate;
11) (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(pyridin-2-ylmethoxyimino)ethyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate;
12) (E)-methyl 2-(2-((4-((Z)-2-methoxy-1-(methoxyimino)ethyl)2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate;
13) (E)-methyl 2-(2-((2,5-dimethyl-4-(oxazol-5-yl)phenoxy)methyl)phenyl)-3-methoxyacrylate; and
14) (E)-methyl 2-(2-((2,5-dimethyl-4-(1-methyl-1H-pyrazol-3-yl)phenoxy)-methyl)phenyl)-3-methoxyacrylate.

### Claim 8 (depends on 1)

The method of claim 1, wherein the alpha-arylmethoxyacrylate derivative of formula 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof is administered in a pharmaceutical composition formulation, said pharmaceutical composition formulation comprising the alpha-arylmethoxyacrylate derivative of formula 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof and a pharmaceutically acceptable carrier.