JP2001031660A - Thyroid hormone-like action substance - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new thyroid hormone-like action substance which acts on a thyroid hormone receptor to exhibit a thyroid hormone-like action and is useful as an active ingredient for medicines used for treating and/or preventing diseases such as obesity, hypercholesterolemia and atherosclerosis. SOLUTION: A compound of formula I (R1 is H or a 1 to 6C alkyl; R2 to R5 are each H, a halogen or a 1 to 6C alkyl; X is O, S or the like) or its salt. For example, a compound of formula II. The compound of formula I is obtained by reacting 4-hydroxybenzoic acid ethyl ester with KI/I2 in an ammonia aqueous solution to introduce I, reacting the product with a compound of formula III to produce the compound of formula IV, converting the CO2Et of the compound of formula IV into CHO, reacting the CHO with thiazolidinedione in a pyridine solution, and then suitably subjecting the reaction product to a modification reaction, and so on. The compound of formula I or its salt, hydrate or solvate may be used as an active ingredient for medicines. The compound of formula I as an active ingredient is preferably compounded with additives such as a vehicle and a disintegrator to prepare a medicinal composition, such as tablets or capsules, which is administered.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel compound having a thyroid hormone-like action.

[0002]

BACKGROUND OF THE INVENTION Thyroid hormone has 3,5,3'-triiodothyronine as its main active ingredient and plays an important role in regulating vertebrate metabolism, development and differentiation. Thyroid hormones
Nuclear receptor superfamily (Evans, RM,
Science, 240, p. 889, 1988) and exerts an effect by binding as a ligand to a thyroid hormone receptor (TR) belonging to the group and causing transcriptional activation or suppression of a target gene. Thyroid hormone regulates, for example, effects on the cardiovascular system, energy metabolism, lipid metabolism, etc., and may be clinically used as a therapeutic agent for obesity, hypercholesterolemia, and atherosclerosis. is there. However, since it has various side effects due to various physiological actions, such as angina pectoris and myocardial infarction, development of a novel thyroid hormone-like active substance is desired.

[0003]

An object of the present invention is to provide a compound having a thyroid hormone-like action by acting on a thyroid hormone receptor. The present inventors have made intensive efforts to solve the above problems, and as a result, have found that a novel compound represented by the following general formula (I) has a thyroid hormone-like action, and have completed the present invention.

That is, according to the present invention, the following general formula
(I):

Embedded image Wherein, R ¹ represents a hydrogen atom or a C _1-6 alkyl group; R ^2,
R ³ , R ⁴ , and R ⁵ each independently represent a hydrogen atom, a halogen atom, or a C _1-6 alkyl group; X represents —O—, —S—, —NR ⁶ —,
-C (R ⁷ ) (R ⁸ )-, -CH (OR ⁹ )-, or -CO- (wherein R ⁶ , R ⁷ ,
R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-6 alkyl group), and ---- represents a single bond or a double bond.
Or a salt thereof.

In another aspect, the present invention provides a compound of the general formula
There is provided a medicament comprising (I) or a physiologically acceptable salt thereof as an active ingredient. This medicament is, for example, obesity,
It is useful for treating and / or preventing diseases such as hypercholesterolemia and atherosclerosis. Further, according to the present invention, there is provided a thyroid hormone-like agent containing the above general formula (I) or a physiologically acceptable salt thereof as an active ingredient. Further, the above general formula for the production of the above medicament
(I) or a physiologically acceptable salt thereof, and a method for treating and / or preventing a disease such as obesity, hypercholesterolemia, or atherosclerosis, wherein the compound has the general formula (I) Or a method comprising administering to a mammal, including a human, a therapeutically and / or prophylactically effective amount of a physiologically acceptable salt thereof.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, a C _1-6 alkyl group may be linear, branched, cyclic, or a combination thereof. For example, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group,
A cyclopropylmethyl group, n-pentyl group, isopentyl group, neopentyl group, cyclobutylmethyl group, n-hexyl group, cyclohexyl group, and the like can be used. Further, in the present specification, a halogen atom may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

X is preferably an oxygen atom. R ² , R
^The halogen atom represented by ⁴ and R ⁵ is preferably an iodine atom, and the halogen atom represented by R ³ is preferably a bromine atom or an iodine atom. As the alkyl group represented by R ² or R ^3, a bulky alkyl group such as an isopropyl group, an isobutyl group, and a tert-butyl group is preferable. R ¹ , R ⁴ , and R ⁵
The alkyl group represented by is preferably a methyl group.

The compounds of the present invention may exist as salts. In addition, depending on the type of the substituent, the compound may have one or more asymmetric carbons, but the configuration of any asymmetric carbon is not particularly limited. Any salts, stereoisomers such as optically active isomers and diastereoisomers based on asymmetric carbon, any mixtures of stereoisomers, racemates and the like are all included in the scope of the present invention. Hydrates or solvates of the above compounds or salts thereof are also included in the scope of the present invention.

Among the compounds of the present invention represented by the general formula (I), preferred compounds include the following compounds wherein X is -O-, but the scope of the present invention is limited to these compounds. Never.

[0010]

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[0011]

[Table 1]

As a typical example of the compound of the present invention, the following scheme shows a method for producing compounds 1 to 15 represented by the above chemical formulas. In addition, methods for producing these compounds are described in detail and specifically in Examples of the present specification. However, the method for producing the compound of the present invention is not limited to the method described in the following scheme. Those skilled in the art, referring to the specific description of the production method and examples shown in the following scheme,
By appropriately selecting starting compounds, reaction conditions, reagents, and the like, and appropriately modifying or modifying these methods as necessary, any of the compounds of the present invention encompassed by the general formula (I) can be produced. Is possible.

[0013]

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[0014]

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[0015]

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[0016]

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[0017]

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[0018]

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[0019]

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[0020]

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[0021]

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The compound represented by the formula (I) can bind to and activate the thyroid hormone receptor in the nucleus to exert a thyroid hormone-like action. As a result, the compounds of the present invention are useful for treating and / or preventing diseases such as obesity, hypercholesterolemia, and atherosclerosis. As the active ingredient of the medicament of the present invention, in addition to the compound represented by the above formula (I) or a physiologically acceptable salt thereof, a hydrate or a solvate thereof may be used. As the medicament of the present invention, the above-mentioned active ingredient may be administered as it is, but generally, a pharmaceutical composition containing the above-mentioned active ingredient and one or more pharmaceutical additives is prepared and administered. It is desirable to do. The administration route of the medicament of the present invention is not particularly limited, and it can be administered orally or parenterally.

Pharmaceutical compositions suitable for oral administration include:
For example, tablets, capsules, powders, fine granules, granules, solutions, syrups and the like can be mentioned. Examples of the pharmaceutical composition suitable for parenteral administration include injections, drops, suppositories, Examples include inhalants, eye drops, nasal drops, transdermal absorbents, ointments, creams, patches, and the like.
Pharmaceutical additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments,
Diluent, base, solubilizer or solubilizer, tonicity agent, pH
A regulator, a stabilizer, a propellant, an adhesive, and the like can be used, and an appropriate one can be selected and used according to the form of the pharmaceutical composition. The dosage of the medicament of the present invention is not particularly limited, and may be appropriately determined depending on conditions such as the type of the compound as the active ingredient, the purpose of prevention or treatment, the type of disease to be applied, the age and symptoms of the patient, and the administration route. It is possible to select a dose.

[0024]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples. The compound numbers and production steps in the examples are the same as those described in the above scheme. Example 1: Synthesis of Compound 1 4-Hydroxybenzoic acid ethyl ester 10.00 g (60.2
4 mmol) in 180 ml of aqueous ammonia, and 124 g (747 mmol) of potassium iodide, 36.7 g (145 mmol) of iodine
Was dissolved in 120 ml of water, and the mixture was stirred. 24 hours later
The mixture was acidified with concentrated hydrochloric acid and extracted with ether. The organic phase was dried washed MgSO ₄ water, brine. After evaporating the solvent,
The residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 1: 1) to give compound I-1.
3.26 g (92%) were obtained. Compound I-1: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.36 (s, 2 H),
6.12 (s, 1 H), 4.35 (q, J = 8.1 Hz, 2 H), 1.39
(t, J = 7.2 Hz, 3H).

Compound I-1 2.00 g (4.78 mmol) and compound
Compound I-2 4.03 g (9.57 mmol) in triethylamine 1 m
l, 0.7 g of copper powder and 20 ml of anhydrous methanol
Stirred for 24 hours. Filter off the copper and concentrate the filtrate
After that, the mixture was extracted with ethyl acetate. The organic phase is 1N hydrochloric acid,
Wash with water, 1 N aqueous sodium hydroxide solution, water, and brine MgS
O_Four And dehydrated. After evaporation of the solvent, the residue is
Chromatography (ethyl acetate: n-hexane = 1: 6)
The compound I-3 and p-dimethoxybenzene were purified by
1.14 g (43%) of the mixture of 1 were obtained. Compound I-3:¹ H-NMR (400 MHz, CDCl_Three) 8.51 (s, 2 H), 6.83 (d, J
= 6.4 Hz, 2 H), 6.70 (d, J = 6.8 Hz, 2 H), 4.39
(q, J = 7.1 Hz, 2 H), 3.78 (s, 3 H), 1.40 (t, J =
7.2 Hz, 3 H).

Compound I-3 1.13 g (2.16 mmol) was dissolved in tetrahydrofuran (THF) 6 ml, and DIBAL (1 M
(Toluene solution) 6.47 ml (6.47 mmol) was gradually added thereto, followed by stirring. After 20 minutes, the reaction solution was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried washed MgSO ₄ brine. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain 951 mg (99.5%) of compound I-4. Compound I-4: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.86 (s, 2 H), 6.82 (d, J
= 8.2 Hz, 2 H), 6.71 (d, J = 9.3 Hz, 2 H), 4.66
(s, 2H), 3.77 (s, 3H), 1.83 (brs, 1H).

Compound I-4 880 mg (1.83 mmol) was dissolved in methanol-free methylene chloride (8 ml), and PCC (1.18 g) was dissolved.
(5.48 mmol) was added and the mixture was stirred at room temperature. After 1 hour, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give 838 mg of compound I-5 (9
6%). Compound I-5: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.87 (s, 1 H), 8.35 (s, 2
H), 6.84 (d, J = 9.2 Hz, 2 H), 6.71 (d, J = 9.2 H
z, 2 H), 3.78 (s, 3 H)

596 mg (1.72 mmol) of TiCl _{4 was} added to carbon tetrachloride
The mixture was dissolved in 1 ml and gradually added to 3 ml of ice-cooled THF under argon over 15 minutes. When a yellow precipitate was formed, compound I-5 200 mg (0.42 mmol), thiazolidinedione 58.5 mg (0.5 mmol), anhydrous pyridine 1 ml (12.
A solution of 4 mmol) in 3 ml of THF was added at 0 ° C., and the mixture was stirred at room temperature for 23 hours. Ethyl acetate was added to the reaction solution, and solid matter was removed by filtration. The filtrate was washed with water, 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 → 1: 1) to obtain 158 mg of compound I-6 (6 mg).
6%). Compound I-6: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.14 (br s, 1 H),
8.12 (s, 2 H), 7.75 (s, 1 H), 6.89 (d, J = 9.3 H
z, 2 H), 6.69 (d, J = 9.0 Hz, 2 H), 3.72 (s, 3 H)

Compound I-6 140 mg (0.24 mmol) was suspended in methanol-free methylene chloride (4 ml), and BBr was added at 0 ° C.
₃ (1 M methylene chloride solution) 0.97 ml (0.97 mmol) was added, and the mixture was stirred at 0 ° C for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . The solvent was distilled off to obtain 136 mg (quantitative) of a crude product of compound I-7. Compound I-7: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.70 (br s, 1 H),
9.11 (s, 1 H), 8.10 (s, 2 H), 7.63 (s, 1 H), 6.70
(d, J = 9.0 Hz, 2 H), 6.57 (d, J = 9.0 Hz, 2 H)

Compound I-7 140 mg (0.25 mmol) was dissolved in aqueous ammonia 10 ml, and potassium iodide 255 mg (1.54
mmol) and 75.5 mg (0.30 mmol) of iodine were dissolved in 5 ml of water, and the mixture was stirred at room temperature. After 7 hours, the mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. Wash the organic phase with saline,
Dehydrated with MgSO ₄ . After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1).
Purification in 1) gave 55 mg (32%) of compound 1. Compound 1: yellow needles (ethyl acetate / n-hexane); melting point 261 ° C .; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.76 (br s, 1 H),
10.00 (s, 1 H), 8.11 (s, 1 H), 7.75 (s, 1 H), 7.08
(d, J = 2.9 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 1 H),
6.60 (dd, J = 8.8, 2.9 Hz, 1 H); Anal.calcd for C ₁₆ H ₈ NO ₄ SI ₃ C: 27.81%, H: 1.17
%, N: 2.03%, Found C: 27.95%, H: 1.40%, N: 2.20
%

Example 2: Synthesis of compound 2 300 mg (0.53 mmol) of compound I-7 was added to 10 ml of aqueous ammonia.
Toka, potassium iodide 1.09 g (6.58 mmol), iodine
297 mg (1.17 mmol) was dissolved in 8 ml of water, and the mixture was stirred at room temperature. After 2.5 hours, the reaction solution was acidified by adding 2 N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane =
Purification by 3: 2) gave 185 mg (50%) of compound 2. Compound 2: pale yellow powder (DMF / ethyl acetate / n-hexane); melting point> 300 ° C .; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.72 (br s, 1 H),
9.56 (s, 1 H), 8.12 (s, 2 H), 7.75 (s, 1 H), 7.14
(s, 2 H); Anal. Calcd for C ₁₆ H ₇ NO ₄ SI ₄ C: 23.52%, H: 0.86
%, N: 1.71%, Found C: 23.46%, H: 1.11%, N: 1.77
%

Example 3 Synthesis of Compound 3 989 mg (1.89 mmol) of Compound I-3 was dissolved in 10 ml of anhydrous methylene chloride, and 5.7 ml (5.7 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C. The mixture was further stirred for 2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent,
The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 8) to give compound II-1 1.
02 g (quantitative) were obtained. Compound II-1: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.51 (s, 2 H), 6.77 (d, J
= 8.7 Hz, 2 H), 6.66 (d, J = 8.9 Hz, 2 H), 4.59
(s, 1 H), 4.39 (q, J = 6.7 Hz, 2 H), 1.41 (t, J =
(7.0 Hz, 3 H)

Compound II-1 393 mg (0.77 mmol) was dissolved in methanol 10 ml, ammonia water 10 ml, potassium iodide 793 mg (4.78 mmol) and iodine 234 mg (0.92 mmol).
was dissolved in 5 ml of water, and the mixture was stirred at room temperature for 40 minutes. The mixture was acidified by adding concentrated hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydrogen sulfite, brine and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 1: 1) to obtain 263 mg (45%) of compound II-2.
I got Compound II-2: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.51 (s, 2 H), 7.11 (s, 2
H), 5.50 (s, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 1.4
2 (t, J = 7.1 Hz, 3 H)

NaH (60% in oil) 21 mg (0.51 mmol)
Wash with n-hexane, dry, suspend in 1 ml of DMF, and add compound
II-2 260 mg (0.34 mmol) dissolved in DMF (3 ml) was added, and the mixture was stirred at room temperature for 15 minutes. 0.03 ml of CH ₃ I in the reaction solution
(0.68 mmol) and stirred for 30 minutes. Water was added to the reaction solution, which was extracted with ether. Wash the organic phase with saline, Mg
And dried over SO _4. Evaporate the solvent to obtain the crude product of compound II-3.
162 mg (61%) were obtained. Compound II-3: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.51 (s, 2 H), 7.16 (s, 2
H), 4.41 (q, J = 7.2 Hz, 2 H), 3.84 (s, 3 H), 1.42
(t, J = 7.1 Hz, 3 H)

Compound II-3 160 mg (0.21 mmol) was added to TH
After dissolving in 5 ml of F, 0.62 ml (0.62 mmol) of DIBAL (1 M toluene solution) was gradually added at 0 ° C., followed by stirring. After 30 minutes, the mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. The solvent was distilled off to obtain 173 mg (quantitative) of a crude product of compound II-4. Compound II-4: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.87 (s, 2 H), 7.17 (s, 2
H), 4.69 (s, 2 H), 3.84 (s, 3 H)

Compound II-4 150 mg (20.4 mmol) was dissolved in methanol-free methylene chloride (2 ml).
mg (0.61 mmol) was added, and the mixture was stirred at room temperature. Two hours later,
Silica gel column chromatography (ethyl acetate: n-
Hexane = 1: 4) to give Compound II-5 139
mg (93%). Compound II-5: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.90 (s, 1 H), 8.36 (s, 2
H), 7.17 (s, 2 H), 3.85 (s, 3 H)

107 mg (0.56 mmol) of TiCl _{4 was} added to carbon tetrachloride
The solution was dissolved in 0.8 ml of ice-cold THF2 under argon.
It was slowly added into the ml. When a yellow precipitate was formed, compound II-5 137 mg (0.19 mmol), thiazolidinedione 26 mg (0.22 mmol), anhydrous pyridine 0.2 ml (2.
(5 mmol) in THF at 0 ° C.
Stirred for hours. The reaction solution was extracted with ethyl acetate, the solid was removed by filtration, and the filtrate was washed successively with water, 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was subjected to silica gel column chromatography (ethyl acetate:
n-hexane = 1: 4 → 1: 2) to give compound 3
63 mg (40%, raw material recovery 35 mg) was obtained. Compound 3: colorless powder (DMF / ethyl acetate / n-hexane); melting point> 300 ° C .; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.73 (b, 1 H), 8.
13 (s, 2 H), 7.74 (s, 1 H), 7.23 (s, 2 H), 3.73 (s,
3 H); Anal.Calcd for C ₁₇ H ₉ NO ₄ SI ₄ C: 24.57%, H: 1.69
%, N: 1.09%, Found C: 24.60%, H: 1.49%, N: 1.39
%

Example 4: Synthesis of Compound 4 431 mg (0.82 mmol) of Compound I-3 (Scheme I) was dissolved in 8 ml of carbon tetrachloride, and 55 mg (0.99 mmol) of iron powder was added. 0.055 ml (1.07 mmol) of bromine was added at room temperature, and the mixture was stirred at 60 ° C for 1 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen sulfite, and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain 362 mg of compound III-1 (73 mg).
%). Compound III-1: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.51 (s, 2 H), 7.03 (d, J
= 2.9 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 6.65 (d
d, J = 9.0, 3.0 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 2
H), 3.86 (s, 3 H), 1.39 (t, J = 7.1 Hz, 3 H)

Compound III-1 355 mg (0.59 mmol) was added to THF
After dissolving in 5 ml, DIBAL (1 M toluene solution) (1.77 ml, 1.77 mmol) was gradually added at 0 ° C., followed by stirring for 30 minutes. The reaction solution was poured into 2N hydrochloric acid and extracted with ethyl acetate.
The organic phase, washed with brine, dried over MgSO _4. The solvent was distilled off to obtain 360 mg (quantitative) of compound III-2. Compound III-2: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.86 (s, 2 H), 7.02 (d, J
= 2.9 Hz, 1 H), 6.82 (d, J = 9.1 Hz, 1 H), 6.69 (d
d, J = 9.0, 3.0 Hz, 1 H), 4.68 (s, 2 H), 3.86 (s,
3 H)

Compound III-2 320 mg (0.57 mmol) was dissolved in methanol-free methylene chloride (6 ml).
mg (1.14 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (ethyl acetate; n-hexane = 1: 4) to give compound III-330.
8 mg (97%) were obtained. Compound III-3: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.89 (s, 1 H), 8.35 (s, 2
H), 7.05 (d, J = 2.9 Hz, 1 H), 6.82 (d, J = 9.1 H
z, 1 H), 6.66 (dd, J = 9.0, 3.1 Hz, 1 H), 3.87 (s,
3 H)

308 mg (1.61 mmol) of TiCl _{4 was} added to carbon tetrachloride
The solution dissolved in 2 ml was cooled in ice-cooled THF 5 under argon.
It was added slowly into the ml over 15 minutes. When a yellow precipitate was formed, a solution of 300 mg (0.54 mmol) of compound III-3, 75.3 mg (0.64 mmol) of thiazolidinedione and 0.56 ml (7.1 mmol) of anhydrous pyridine in 7 ml of THF was added at 0 ° C., and the mixture was added at room temperature for 20 hours. Stirred. The reaction was extracted with ethyl acetate, the solids were removed by filtration, and the filtrate was washed with water, 2 N hydrochloric acid,
The extract was washed successively with saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain 246 mg (70%) of compound III-4. Compound III-4: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.71 (b, 1 H), 8.
12 (s, 2 H), 7.75 (s, 1 H), 7.07 (d, J = 2.9 Hz, 1
H), 7.06 (d, J = 9.2 Hz, 1 H), 6.70 (dd, J = 9.1,
2.9 Hz, 1 H), 3.80 (s, 3 H)

187 mg (0.28 mmol) of compound III-3 was suspended in 2 ml of anhydrous methylene chloride, and 0.85 ml (0.85 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C., followed by stirring for 3 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: methylene chloride = 1: 2) to obtain 176 mg (96%) of compound 4. Compound 4: colorless needles (ethyl acetate / n-hexane); melting point 253 ° C; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.68 (br, 1 H),
9.90 (s, 1 H), 8.11 (s, 2 H), 7.73 (s, 1 H), 6.90
(d, J = 2.7 Hz, 1H), 6.89 (d, J = 9.5 Hz, 1H), 6.
59 (dd, J = 9.0, 2.7 Hz, 1 H); Anal. Calcd for C ₁₆ H ₈ NO ₄ SBrI ₂ C: 29.84%, H: 1.25
%, N: 2.17%, Found C: 29.64%, H: 1.42%, N: 1.9
2%

Example 5: Synthesis of Compound 5 Compound I-1 1.00 g (2.39 mmol), Compound IV-1 1.55 g
(2.87 mmol) in triethylamine 1 ml, copper powder 0.70
g and anhydrous methylene chloride (20 ml) were added, and the mixture was stirred at room temperature for 18 hours. The copper was removed by filtration, and the filtrate was concentrated and then extracted with ethyl acetate. The organic phase was washed successively with 1 N hydrochloric acid, water, 1 N aqueous sodium hydroxide solution, water and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 1: 8) to obtain 706 mg (51%) of compound IV-2. Compound IV-2: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.04 (dd, J = 8.8, 2.4 Hz,
1H), 7.96 (d, J = 2.4 Hz, 1 H), 7.10 (d, J = 9.0
Hz, 1 H), 3.85 (s, 3 H), 1.31 (s, 9 H)

Compound IV-2 700 mg (1.21 mmol) was added to 10 m
Then, 3.6 ml (3.6 mmol) of BBr ₃ (1 M methylene chloride solution) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO _4. The solvent was distilled off, and the crude product of compound IV-3 was 693 mg.
(Quantitative) was obtained. Compound IV-3: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.50 (s, 2 H), 6.87 (d, J
= 3.1 Hz, 1 H), 6.54 (d, J = 8.6 Hz, 1 H), 6.31 (d
d, J = 8.6, 3.1 Hz, 1 H), 4.53 (br s, 1 H), 4.39
(q, J = 7.2 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3 H),
1.38 (s, 9 H)

72.9 mg (1.82 mmol) of NaH (60% in oil)
Was washed with n-hexane, and suspended in 1 ml of DMF.
685 mg (1.21 mmol) of IV-3 was dissolved in 3 ml of DMF and added, followed by stirring at room temperature. Twenty minutes later, 0.18 ml (2.43 mmol) of chloromethyl methyl ether was added, and the mixture was stirred at room temperature. After 30 minutes, water was added and extracted with ether. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was subjected to silica gel column chromatography (ethyl acetate: n-ethyl acetate).
Purification by hexane = 1: 9) gave 397 mg of compound IV-4 and 173 mg of its MOM ester. Compound IV-4: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.50 (s, 2 H), 6.97 (d, J
= 9.0 Hz, 1 H), 6.89 (d, J = 3.1 Hz, 1 H), 6.37 (d
d, J = 8.8, 3.1 Hz, 1 H), 5.17 (s, 2 H), 4.39 (q,
J = 7.1 Hz, 2 H), 3.49 (s, 3 H), 1.41 (t, J = 7.1
Hz, 3 H), 1.36 (s, 9 H)

Compound 395 mg (0.65 mmol) of compound IV-4 was added to TH
After dissolving in 3 ml of F, 1.95 ml (1.95 mmol) of DIBAL (1 M toluene solution) was gradually added at 0 ° C., followed by stirring. Two
After 0 minutes, the mixture was poured into water and extracted with ether. 2N organic phase
It was washed with hydrochloric acid and brine, and dried over MgSO ₄ . The solvent was distilled off to obtain 347 mg (94%) of a crude product of compound IV-5. Compound IV-5: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.85 (s, 2 H), 6.96 (d, J
= 9.0 Hz, 1 H), 6.91 (d, J = 3.1 Hz, 1 H), 6.36 (d
d, J = 8.8, 3.1 Hz, 1 H), 5.16 (s, 2 H), 4.66 (s,
2 H), 3.49 (s, 3 H), 1.37 (s, 9 H)

Compound 488 mg (0.86 mmol) of compound IV-5 was dissolved in methanol-free methylene chloride (6 ml), and PCC 557 was dissolved.
mg (2.59 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was purified by silica gel column chromatography (ethyl acetate; n-hexane = 1: 4) to give compound IV-644.
5 mg (92%) were obtained. Compound IV-6: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.88 (s, 1 H), 8.35 (s, 2
H), 6.99 (d, J = 9.1 Hz, 1 H), 6.90 (d, J = 3.1 H
z, 1 H), 6.38 (dd, J = 9.1, 3.1 Hz, 1 H), 5.18 (s,
2 H), 3.80 (s, 3 H), 1.37 (s, 9 H)

445 mg (2.34 mmol) of TiCl _{4 was} added to carbon tetrachloride
The solution dissolved in 2 ml was cooled in ice-cooled THF 6 under argon.
to the ml over 15 minutes. If a yellow precipitate forms, compound IV-6 440 mg (0.78 mmol), thiazolidinedione
110 mg (0.94 mmol), anhydrous pyridine 0.8 ml (10.5 mmo
A solution of l) in 5 ml of THF was added at 0 ° C, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was extracted with ethyl acetate, the solid was removed by filtration, and the filtrate was washed with water, 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain 377 mg of compound IV-7 (73 mg).
%). Compound IV-7: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.70 (b, 1 H), 8.
12 (s, 2 H), 7.75 (s, 1 H), 6.96 (d, J = 9.0 Hz, 1
H), 6.81 (d, J = 3.2 Hz, 1 H), 6.39 (dd, J = 9.0,
3.1 Hz, 1 H), 5.19 (s, 2 H), 3.41 (s, 3 H), 1.34
(s, 9 H)

Compound IV-7 97 mg (0.15 mmol) was added to THF
The solution was dissolved in 4 ml, 1 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 40 ° C for 2 hours. Water and ethyl acetate were added to the reaction solution. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to obtain 95 mg of compound 5 (quantitative). Compound 5: yellow needles (ethyl acetate / n-hexane); melting point 283 ° C .; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.70 (b, 1 H), 9.
08 (s, 1 H), 8.11 (s, 2 H), 7.74 (s, 1 H), 6.71 (d,
J = 3.0 Hz, 1 H), 6.66 (d, J = 8.5 Hz, 1 H), 6.25
(dd, J = 8.5, 2.9 Hz, 1 H), 1.31 (s, 9 H); Anal.Calcd for C ₂₀ H ₁₇ NO ₄ SI ₂ C: 38.67%, H: 2.76
%, N: 2.25%, Found C: 38.39%, H: 2.92%, N: 2.23
%

Example 6: Synthesis of compound 6 Compound IV-2 175 mg (0.30 mmol) was dissolved in THF 4 ml and DIBAL (1 M toluene solution) 0.91 m at 0 ° C.
l (0.91 mmol) was added slowly and stirred for 25 minutes. The reaction solution was poured into 2N hydrochloric acid and extracted with ether. The organic phase was washed with brine, dried over MgSO _4. Solvent is distilled off and compound V-1
158 mg (98%) of a crude product was obtained. Compound V-1: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.85 (s, 2 H), 6.92 (d, J
= 3.2 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 1 H), 6.38 (d
d, J = 8.8, 3.1 Hz, 1 H), 4.66 (s, 2 H), 3.79 (s,
3 H), 1.55 (br s, 1 H), 1.35 (s, 9 H)

Compound V-1 155 mg (0.29 mmol) was dissolved in methanol-free methylene chloride (6 ml), and PCC 463 m
g (2.15 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was subjected to silica gel column chromatography (ethyl acetate:
n-Hexane = 1: 4) to give compound V-2 148 mg
(96%). Compound V-2: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.87 (s, 1 H), 8.34 (s, 2
H), 6.91 (d, J = 3.2 Hz, 1 H), 6.72 (d, J = 8.8 H
z, 1 H), 6.39 (dd, J = 8.8, 3.1 Hz, 1 H), 3.80 (s,
3 H), 1.35 (s, 9 H)

152 mg (0.80 mmol) of TiCl _{4 was} added to carbon tetrachloride
The solution dissolved in 1 ml was cooled in ice-cooled THF under argon.
to the ml over 15 minutes. If a yellow precipitate forms, compound V-2 143 mg (0.27 mmol), thiazolidinedione 3
7 mg (0.32 mmol), anhydrous pyridine 0.3 ml (3.6 mmol)
Was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate, the solid was removed by filtration, and the filtrate was washed sequentially with water, 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain Compound 6 (96 mg, 58%). Compound 6: yellow needles (ethyl acetate); melting point 282 ° C .; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.71 (b, 1 H), 8.
122 (s, 1 H), 8.121 (s, 1 H), 7.75 (s, 1 H), 6.88
(d, J = 9.0 Hz, 1H), 6.80 (d, J = 3.2 Hz, 1H), 6.
38 (dd, J = 8.8, 3.0 Hz, 1 H), 3.76 (s, 3 H), 1.31
(s, 9 H)

Example 7: Synthesis of compound 7 Compound I-1 2.00 g (4.78 mmol), compound VI-1 3.74 g
(5.74 mmol), copper powder 0.70 g, triethylamine 1 ml
20 ml of anhydrous methylene chloride was added to the mixture, and the mixture was stirred at room temperature for 6.5 hours. The copper was removed by filtration, and the filtrate was concentrated and then extracted with methylene chloride. The organic phase 1 N hydrochloric acid, the washed with brine, dried over MgSO _4. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane =
1:12) to give 1.03 g (34%) of compound VI-2. Compound VI-2: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.51 (s, 2 H), 6.65 (s, 2
H), 4.39 (q, J = 7.2 Hz, 2 H), 3.67 (s, 3 H), 1.40
(t, J = 6.7 Hz, 2 H), 1.36 (s, 18 H)

Compound VI-2 1.03 g (1.62 mmol) was added to TH
After dissolving in 10 ml of F, 4.86 ml (4.86 mmol) of DIBAL (1 M toluene solution) was gradually added at 0 ° C., followed by stirring for 30 minutes. The reaction solution was added to 2N hydrochloric acid, and extracted with ether. The organic phase was washed with brine, dried over MgSO _4. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give Compound VI-3 953
mg (99%). Compound VI-3: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.86 (s, 2 H), 6.66 (s, 2
H), 4.68 (s, 2 H), 3.66 (s, 3 H), 1.80 (br s, 1
H), 1.37 (s, 18 H)

Compound VI-3 950 mg (1.60 mmol) was dissolved in 6 ml of methanol-free methylene chloride, and PCC 689 was dissolved.
mg (3.20 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give Compound VI-4 74.
8 mg (79%) were obtained. Compound VI-4: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.88 (s, 1 H), 8.35 (s, 2
H), 6.65 (s, 2 H), 3.67 (s, 3 H), 1.37 (s, 18 H)

717 mg (3.78 mmol) of TiCl _{4 was} added to carbon tetrachloride
The solution dissolved in 3 ml was cooled in ice-cold THF 10 under argon.
ml over 15 minutes. When a yellow precipitate was formed, compound VI-4 745 mg (1.26 mmol), thiazolidinedione 177 mg (1.51 mmol), anhydrous pyridine 1.3 ml (1
(6.6 mmol) in THF at 0 ° C.
Stirred for hours. The reaction solution was extracted with ethyl acetate, the solid was removed by filtration, and the filtrate was washed successively with water, 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was subjected to silica gel column chromatography (ethyl acetate:
n-Hexane = 1: 1) to give compound 597 mg
(69%). Compound 7: colorless columnar crystals (ethyl acetate / n-hexane); melting point 245 ° C; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.69 (b, 1 H), 8.
13 (s, 2 H), 7.75 (s, 1 H), 6.62 (s, 2 H), 3.63 (s,
3 H), 1.37 (s, 18 H); Anal.Calcd for C ₂₅ H ₂₇ NO ₄ SI ₂ C: 43.43%, H: 3.94
%, N: 2.03%, Found C: 43.33%, H: 3.82%, N: 1.82
%

Example 8: Synthesis of compound 8 3.67 g (7.18 mmol) of compound VII-1 was added to anhydrous methylene chloride.
The suspension was suspended in 30 ml, and 500 mg of copper powder was added. Under ice-cooling, compound I-1 2.00 g (4.78 mmol), triethylamine 0.6 ml
Was added, and the mixture was stirred at room temperature for 20 hours. The reaction was filtered and the filtrate was extracted with methylene chloride. The organic phase was washed 2 N hydrochloric acid, brine and dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give compound VII-2.
1.78 g (66%) were obtained. Compound VII-2: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.50 (s, 2 H), 6.78 (d, J
= 8.8 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 1 H), 6.40 (d
d, J = 8.8, 3.1 Hz, 1 H), 4.39 (q, J = 6.9 Hz, 2
H), 3.79 (s, 3 H), 3.29 (h, J = 7.1 Hz, 1 H), 1.41
(t, J = 7.0 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 6 H)

Compound VII-2 1.78 g (3.14 mmol) was added to TH
F 10mL and dissolved at 0 ° C in DIBAL (1M toluene
Solution) 9.43 ml (9.43 mmol) was gradually added and stirred for 30 minutes.
Stirred. The reaction solution was poured into 2N hydrochloric acid, extracted with ether.
Was. The organic phase is washed with brine, MgSO _FourAnd dehydrated. solvent
Distillation gave 1.65 g (quantitative) of crude product of compound VII-3.
Obtained. Compound VII-3:¹ H-NMR (400 MHz, CDCl_Three) 7.85 (s, 2 H), 6.80 (d, J
= 3.1 Hz, 1 H), 6.69 (d, J = 9.0 Hz, 1 H), 6.40 (d
d, J = 9.0, 3.1 Hz, 1 H), 4.66 (d, J = 5.9 Hz, 2
H), 3.78 (s, 3 H), 3.28 (h, J = 7.0 Hz, 1 H), 1.78
 (t, J = 6.0 Hz, 1 H), 1.18 (d, J = 7.0 Hz, 6 H)

Compound VII-3 1.65 g (3.15 mmol) was dissolved in methanol-free methylene chloride (8 ml), and PCC 1.3
7 g (6.34 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours.
The reaction solution was purified by silica gel column chromatography (ethyl acetate; n-hexane = 1: 4) to give compound VII-4.
1.46 g (85%) were obtained. Compound VII-4: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.88 (s, 1 H), 8.35 (s, 2
H), 6.79 (d, J = 3.1 Hz, 1 H), 6.71 (d, J = 9.0 H
z, 1 H), 6.40 (dd, J = 8.9, 3.1 Hz, 1 H), 3.79 (s,
3 H), 3.29 (h, J = 7.0 Hz, 1 H), 1.18 (d, J = 7.0
(Hz, 6 H)

1.54 g (8.05 mmol) of TiCl _{4 was} added to carbon tetrachloride
The mixture was dissolved in 8 ml of ice-cold THF 20 under argon.
ml over 15 minutes. When a yellow precipitate formed, compound VII-4 1.40 g (2.68 mmol), thiazolidinedione 376 mg (3.22 mmol), anhydrous pyridine 2.8 ml
(35 mmol) in THF (5 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with ethyl acetate, the solid was removed by filtration, and the filtrate was washed successively with water, 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give compound VII.
-5 1.41 g (84%) were obtained. Compound VII-5: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.70 (b, 1 H), 8.
11 (s, 2 H), 7.74 (s, 1 H), 6.84 (d, J = 8.8 Hz, 1
H), 6.74 (d, J = 2.9 Hz, 1 H), 6.35 (dd, J = 8.8,
2.9 Hz, 1 H), 4.02 (h, J = 7.1 Hz, 1 H), 3.28 (s,
3 H), 1.12 (d, J = 6.9 Hz, 6 H)

1.45 g (2.25 mmol) of compound VII-5 was suspended in 8 ml of anhydrous methylene chloride, and 4.51 ml (4.51 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C., followed by stirring for 6 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain 8842 mg (62%) of a compound. Compound 8: colorless powder (THF / ethyl acetate / n-hexane); melting point 222 ° C .; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.69 (b, 1 H), 9.
00 (s, 1 H), 8.10 (s, 2 H), 7.73 (s, 1 H), 6.66 (d,
J = 8.8 Hz, 1 H), 6.64 (d, J = 2.9 Hz, 1 H), 6.23
(dd, J = 8.8, 2.9 Hz, 1 H), 3.15 (h, J = 6.8 Hz,
1 H), 1.11 (d, J = 6.8 Hz, 6 H); Anal.Calcd for C ₁₉ H ₁₅ NO ₄ SI ₂ C: 37.58%, H: 2.49
%, N: 2.31%, Found C: 37.43%, H: 2.52%, N: 2.13
%

Example 9: Synthesis of Compound 9 2.66 g (5.20 mmol) of Compound VII-1 was added to anhydrous methylene chloride.
The suspension was suspended in 17 ml, and 413 mg of copper powder was added. Under ice cooling, 488 mg (6.00 mmol) of p-hydroxybenzaldehyde and 0.5 ml of triethylamine were added, and the mixture was stirred at room temperature for 6 hours. The reaction was filtered and extracted with methylene chloride. The organic phase, 2 N hydrochloric acid and dried over wash ,, MgSO ₄ brine. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 8) to obtain 796 mg (74%) of compound VIII-1. Compound VIII-1: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.90 (s, 1 H), 7.81 (d. J
= 8.4 Hz, 2 H), 7.00 (d, J = 8.6 Hz, 2 H), 6.95
(d, J = 2.6 Hz, 1 H), 6.83-6.89 (m, 2 H), 3.85 (s,
3 H), 3.32 (h, J = 7.0 Hz, 1 H), 1.19 (d, J = 7.0
(Hz, 6 H)

1.67 g (8.78 mmol) of TiCl _{4 was} added to carbon tetrachloride
The mixture was dissolved in 8 ml of ice-cold THF 20 under argon.
ml over 15 minutes. When a yellow precipitate was formed, compound VIII-1 (790 mg, 2.93 mmol), thiazolidinedione (411 mg, 3.52 mmol), and anhydrous pyridine (3 ml, 39 ml)
(mmol) was added at 0 ° C and stirred at room temperature for 6 hours. The reaction solution was extracted with ethyl acetate, the solid was removed by filtration, and the filtrate was washed with water, 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain 831 mg of compound VIII-2 (7
7%). Compound VIII-2: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.51 (br s, 1 H),
7.74 (s, 1 H), 7.58 (d, J = 9.1 Hz, 2 H), 7.01
(d, J = 9.1 Hz, 2 H), 6.99 (d, J = 8.8 Hz, 1 H),
6.96 (d, J = 2.9 Hz, 1 H), 6.91 (dd, J = 8.8, 2.9
Hz, 1 H), 3.80 (s, 3 H), 1.13 (s, 6 H)

100 mg (0.27 mmol) of compound VIII-2 was suspended in 2 ml of anhydrous methylene chloride, and 0.81 ml (0.81 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C., followed by stirring for 3 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was dried over wash ,, MgSO ₄ brine.
After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 → ethyl acetate) to obtain 89.5 mg (93%) of compound 98. Compound 9: yellow plate-like crystal (ethyl acetate); melting point 206 ° C; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.50 (br s, 1 H),
9.32 (s, 1 H), 7.73 (s, 1 H), 7.56 (d, J = 8.8 H
z, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 2.
7 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.75 (dd, J
= 8.5, 2.9 Hz, 1 H), 3.21 (h, J = 7.0 Hz, 1 H), 1.
13 (d, J = 6.8 Hz, 6 H)

Example 10: Synthesis of Compound 10 Compound VII-1 (2.66 g, 5.20 mmol) was treated with anhydrous methylene chloride.
The suspension was suspended in 17 ml, and 413 mg of copper powder was added. 3,5-dimethyl-4-hydroxybenzaldehyde 600 mg (4.00
mmol) and 0.5 ml of triethylamine.
Stirred for hours. The reaction solution was filtered, and the filtrate was extracted with methylene chloride. The organic phase was washed 2 N hydrochloric acid, brine and dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain 886 mg (74%) of compound VIII-1. Compound VIII-1: ¹ H-NMR (400 MHz, CDCl ₃ ) 9.94 (s, 1 H), 7.63 (s, 2
H), 6.75 (d, J = 3.1 Hz, 1 H), 6.67 (d, J = 8.8 H
z, 1 H), 6.35 (dd, J = 8.8, 3.1 Hz, 1 H), 3.77 (s,
3 H), 3.27 (h, J = 7.0 Hz, 1 H), 2.197 (s, 3 H),
2.195 (s, 3 H), 1.16 (d, J = 7.0 Hz, 6 H)

1.69 g (8.86 mmol) of TiCl _{4 was} added to carbon tetrachloride
The mixture was dissolved in 8 ml of ice-cold THF22 under argon.
to the ml over 15 minutes. When a yellow precipitate formed, compound VIII-1 880 mg (2.95 mmol), thiazolidinedione 415 mg (3.54 mmol), anhydrous pyridine 3.1 ml
(39 mmol) in 22 ml of THF at 0 ° C.
Stir for 4.5 hours. The reaction solution was extracted with ethyl acetate, the solid was removed by filtration, and the filtrate was washed successively with water, 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain Compound VII.
934 mg (80%) of I-2 was obtained. Compound VIII-2: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.56 (br s, 1 H),
7.71 (s, 2 H), 7.38 (s, 2 H), 6.81 (d, J = 9.0 H
z, 1 H), 6.75 (d, J = 3.1 Hz, 1 H), 6.34 (dd, J =
9.0, 3.1 Hz, 1 H), 3.72 (s, 3 H), 3.19 (h, J = 6.8
Hz, 1 H), 2.10 (s, 6 H), 1.10 (d, J = 6.8 Hz, 6
H)

100 mg (0.25 mmol) of compound VIII-2 was suspended in 2 ml of anhydrous methylene chloride, and 0.76 ml (0.76 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C., followed by stirring for 2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain 96 mg (99%) of compound 10. Compound 10: colorless plate crystal (ethyl acetate); melting point 210
° C; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C) 12.56 (br s, 1 H),
8.92 (s, 1 H), 7.70 (s, 1 H), 7.37 (s, 2 H), 6.64
(d, J = 8.6 Hz, 1 H), 6.63 (d, J = 3.0 Hz, 1 H),
6.23 (dd, J = 8.6, 3.0 Hz, 1 H), 3.16 (h, J = 7.0
Hz, 1 H), 2.09 (s, 6 H), 1.09 (d, J = 7.1 Hz, 6 H)

Example 11: Synthesis of Compound 11 3.94 g (9.20 mmol) of Compound I-2 was added to anhydrous methylene chloride 3
The suspension was suspended in 0 ml, and 793 mg of copper powder was added. Compound under ice cooling
After adding 3.00 g (7.67 mmol) of IX-1 and 1 ml of triethylamine, the mixture was stirred at room temperature for 20 hours. Filter the reaction,
The filtrate was extracted with methylene chloride. The organic phase was washed 2 N hydrochloric acid, brine and dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 12) to give compound IX-2
1.10 g (40%) were obtained. Compound IX-2: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.72 (s, 2 H), 6.85 (d, J
= 9.2 Hz, 2 H), 6.71 (d, J = 9.0 Hz, 2 H), 3.79
(s, 3 H)

1.09 g (2.24 mmol) of compound IX-2 was dissolved in 18 ml of ethyl acetate, and 300 mg of Pt-C was added, followed by catalytic hydrogen reduction at room temperature. One hour later, 200 mg of 5% Pt-C and 3 ml of ethyl acetate were added. After 2 hours, the residue was purified by flash silica gel column chromatography (methylene chloride: n-hexane = 1: 2) after filtering through Celite and evaporating the solvent to obtain 748 mg (73%) of compound IX-3. . Compound IX-3: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.14 (s, 2 H), 6.80 (d, J
= 9.2 Hz, 2 H), 6.70 (d, J = 9.2 Hz, 2 H), 3.75
(s, 3 H), 3.62 (br s, 2 H)

Dissolve 1.47 g (3.32 mmol) of compound IX-3 in 16 ml of acetone and 4 ml of water, add 1.1 ml of concentrated hydrochloric acid and place at -15 ° C. 346 mg of sodium nitrite (5.02 mm
ol) was dissolved in 6.5 ml of water and gradually added, followed by stirring for 15 minutes.
4.12 ml (38.6 mmol) of ethyl acrylate was added dropwise, and 164 mg (1.16 mmol) of copper (I) oxide was gradually added at 40 ° C. After 20 minutes, the reaction was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) and then by flash silica gel column chromatography (ethyl acetate: n-hexane = 1: 20) to give compound IX- 4 318 mg (18%)
I got Compound IX-4: ₁ H-NMR (400 MHz, CDCl ₃ ) 7.72 (s, 2 H), 6.82 (d, J =
9.3 Hz, 2 H), 6.69 (d, J = 9.2 Hz, 2 H), 4.41 (d
d, J = 7.7, 6.8 Hz, 1 H), 4.24 (q, J = 7.2 Hz, 2
H), 3.77 (s, 3 H), 3.29 (dd, J = 14.3, 6.8 Hz, 1
H), 3.11 (dd, J = 14.1, 7.7 Hz, 1 H), 1.29 (t, J =
(7.2 Hz, 3 H)

314 mg (0.56 mmol) of compound IX-4 and 54 mg (0.71 mmol) of thiourea were dissolved in 10 ml of sulfolane, and the mixture was stirred at 120 ° C. for 90 minutes. Acetic acid 14 ml, concentrated hydrochloric acid
After adding a mixed solution of 3 ml and 1.5 ml of water to the reaction solution at room temperature, the mixture was stirred at 90 ° C for 18 hours. Baking soda was added to the reaction solution, and after carbon dioxide was completely removed, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporation of the solvent, the residue was subjected to flash silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 → 1:
Purification in 3) gave 53 mg (17%) of compound IX-5. Compound IX-5: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.73 (s, 2 H), 6.83 (d, J
= 9.0 Hz, 2 H), 6.69 (d, J = 9.1 Hz, 2 H), 4.53 (d
d, J = 9.5, 4.0 Hz, 1 H), 3.78 (s, 3 H), 3.47 (dd,
J = 14.3, 4.0 Hz, 1 H), 3.10 (dd, J = 14.1, 9.4 H
z, 1 H)

53 mg (0.094 mmol) of compound IX-5 was dissolved in 2 ml of anhydrous methylene chloride, and 0.28 ml (0.28 mmol) of BBr ₃ (1 M methylene chloride solution) was added at 0 ° C., followed by stirring for 3 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. The solvent was distilled off to obtain 46 mg (90%) of a crude product of compound IX-6. Compound IX-6: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.06 (br s, 1 H), 7.73 (s,
2 H), 6.77 (d, J = 9.0 Hz, 2 H), 6.64 (d, J = 9.0
Hz, 2 H), 4.70 (s, 1 H), 4.52 (dd, J = 9.5,4.0 H
z, 1 H), 3.46 (dd, J = 14.3, 4.0 Hz, 1 H), 3.09 (d
d, J = 14.3, 9.5Hz, 1H)

Compound IX-5 45 mg (0.082 mmol) was dissolved in aqueous ammonia 2 ml, and potassium iodide 84 mg (0.51
mmol) and 25 mg (0.098 mmol) of iodine dissolved in 1 ml of water, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydrogen sulfite, brine and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by flash silica gel column chromatography (twice; methylene chloride: ethyl acetate = 4: 1, and 10: 1) to give compound 1
126 mg (48%) were obtained. Compound 11: colorless oil; ¹ H-NMR (400 MHz, CDCl ₃ ) 8.10 (br s, 1 H), 7.73
(s, 2 H), 7.07 (d, J = 2.9 Hz, 1 H), 6.91 (d, J =
8.7 Hz, 1 H), 6.65 (dd, J = 9.0, 2.9 Hz, 1 H), 5.07
(s, 1 H), 4.53 (dd, J = 9.5, 4.1 Hz, 1 H), 3.47
(dd, J = 14.1, 4.0Hz, 1 H), 3.10 (dd, J = 14.3, 9.
(5 Hz, 1 H)

Example 12: Synthesis of compound 12 3.34 g (6.14 mmol) of compound IV-1 was added to anhydrous methylene chloride.
The suspension was suspended in 30 ml, and 529 mg (8.33 mmol) of copper powder was added.
After adding 2.00 g (5.11 mmol) of compound IX-1 and 0.7 ml (5.11 mmol) of triethylamine under ice-cooling, the mixture was added at room temperature for 40 minutes.
Stirred for hours. After filtering the reaction solution, the filtrate was concentrated,
Extracted with ethyl acetate. The organic phase was washed 2 N hydrochloric acid, brine and dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 20) to obtain 1.47 g of compound IX-7 (52
%). Compound IX-7: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.37 (s, 2 H), 6.88 (d, J
= 8.8 Hz, 1 H), 6.81 (d, J = 3.1 Hz, 1 H), 6.40 (d
d, J = 8.8, 3.1 Hz, 1 H), 3.28 (s, 3 H), 1.30 (s,
9 H)

Compound IX-7 (920 mg, 1.66 mmol) was dissolved in ethyl acetate (25 ml) and ethanol (5 ml) to give 5% Pt-C200.
mg was added and the mixture was subjected to catalytic hydrogen reduction at room temperature. 5 hours later, Pt-C
100 mg was added, and the mixture was further stirred for 8 hours. The reaction mixture was filtered through celite, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform) to give compound IX-
8 648 mg (75%) were obtained. Compound IX-8: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.16 (s, 2 H), 6.90 (d, J
= 3.1 Hz, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 6.42 (d
d, J = 8.8, 3.1 Hz, 1 H), 3.78 (s, 3 H), 3.62 (br
s, 2 H), 1.35 (s, 9 H)

Dissolve 220 mg (0.42 mmol) of compound IX-8 in 3 ml of acetone and 0.7 ml of water, add 0.15 ml of concentrated hydrochloric acid, and place at -15 ° C. Sodium nitrite 38 mg (0.55 mmo
l) was dissolved in 1 ml of water and added slowly, followed by stirring for 15 minutes. 0.46 ml (4.20 mmol) of ethyl acrylate was added dropwise,
, 18 mg (0.13 mmol) of copper oxide was gradually added. After 20 minutes, the reaction was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain 81 mg (30%) of compound IX-9
I got Compound IX-9: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.72 (s, 2 H), 6.89 (d, J
= 3.1 Hz, 1 H), 6.70 (d, J = 8.9 Hz, 1 H), 6.36 (d
d, J = 8.8, 3.1 Hz, 1 H), 4.41 (t, J = 7.0 Hz, 1
H), 4.24 (q, J = 7.1 Hz, 2 H), 3.79 (s, 3 H), 3.29
(dd, J = 14.0, 7.0 Hz, 1 H), 3.10 (dd, J = 14.0,
7.5 Hz, 1 H), 1.34 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3
H)

147 mg (0.23 mmol) of compound IX-9 and 22 mg (0.29 mmol) of thiourea were dissolved in 3 ml of sulfolane, and the mixture was stirred at 120 ° C. for 90 minutes. Acetic acid 6 ml, concentrated hydrochloric acid
After adding a mixed solution of 2 ml and water 1 ml to the reaction solution at room temperature,
Stirred at 90 ° C. for 20 hours. Baking soda was added to the reaction solution, and after carbon dioxide was completely removed, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . The solvent was distilled off to obtain 33 mg (22%) of a crude product of compound IX-10. Compound IX-10: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.16 (br, 1 H), 7.73 (s, 2
H), 6.88 (d, J = 3.1 Hz, 1 H), 6.71 (d, J = 9.0 H
z, 1 H), 6.37 (dd, J = 8.8, 3.1 Hz, 1 H), 4.53 (d
d, J = 9.5, 4.2 Hz, 1 H), 3.79 (s, 3 H), 3.46 (dd,
J = 14.1, 4.0 Hz, 1 H), 3.09 (dd, J = 14.3, 9.5 H
z, 1 H), 1.34 (s, 9 H)

45 mg (0.070 mmol) of Compound IX-10 was suspended in 2 ml of anhydrous methylene chloride, and 0.21 ml (0.21 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C., followed by stirring for 1 hour. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) and flash silica gel column chromatography (methylene chloride: ethyl acetate = 100: 1) to obtain 32 mg of compound 12 ( 7
5%). Compound 12: colorless oil; ¹ H-NMR (400 MHz, CDCl ₃ ) 7.97 (b, 1 H), 7.73 (s, 2)
H), 6.86 (d, J = 2.9 Hz, 1 H), 6.86 (d, J = 2.9 H
z, 1 H), 6.54 (d, J = 8.6 Hz, 1 H), 6.30 (dd, J =
8.5, 3.2 Hz, 1 H), 4.58 (s, 1 H), 4.53 (dd, J = 9.
3, 4.2 Hz, 1 H), 3.46 (dd, J = 14.2, 4.1 Hz, 1 H),
3.10 (dd, J = 14.4, 9.5 Hz, 1 H), 1.38 (s, 9 H)

Example 13: Synthesis of Compound 13 4.40 g (8.59 mmol) of Compound VII-1 was added to anhydrous methylene chloride.
The suspension was suspended in 30 ml, and 740 mg of copper powder was added. Compound IX-1 2.80 g (7.16 mmol) under ice cooling, triethylamine 0.9 m
and stirred at room temperature for 24 hours. Filter the reaction,
The filtrate was extracted with methylene chloride. The organic phase was washed 2 N hydrochloric acid, brine and dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain 3.50 g of compound IX-11
(91%). Compound IX-11: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.73 (s, 2 H), 6.79 (d, J
= 3.1 Hz, 1 H), 6.71 (d, J = 9.0 Hz, 1 H), 6.39 (d
d, J = 8.8, 3.1 Hz, 1 H), 3.80 (s, 3 H), 3.29 (h,
J = 6.8 Hz, 1 H), 1.18 (d, J = 7.0 Hz, 6 H).

3.50 g (6.49 mmol) of compound IX-11 was dissolved in 30 ml of ethyl acetate, and 1.0 g of 5% Pt-C was added, followed by catalytic hydrogen reduction at room temperature. After 4 hours, the mixture was filtered through celite, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform) to obtain 3.35 g (quantitative) of compound IX-12. Compound IX-12: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.16 (s, 2 H), 6.78 (d, J
= 2.9 Hz, 1 H), 6.69 (d, J = 8.8 Hz, 1 H), 6.43 (d
d, J = 8.8, 3.1 Hz, 1 H), 3.78 (s, 3 H), 3.63 (s,
2 H), 3.28 (h, J = 7.0 Hz, 1 H), 1.18 (d, J = 7.0
(Hz, 6 H)

Dissolve 3.30 g (6.48 mmol) of compound IX-12 in 32 ml of acetone and 8 ml of water, add 2.1 ml of concentrated hydrochloric acid and place at -15 ° C. Sodium nitrite 582 mg (8.43 mm
ol) was dissolved in 12 ml of water and gradually added, followed by stirring for 15 minutes.
7.01 ml (64.8 mmol) of ethyl acrylate was added dropwise, and then 276 mg (1.94 mmol) of copper oxide was gradually added at 40 ° C. After 30 minutes, the reaction was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by flash silica gel column chromatography (ethyl acetate: n-hexane = 1: 20) to give Compound I.
X-13 788 mg (19%) was obtained. Compound IX-13: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.72 (s, 2 H), 6.78 (d, J
= 2.9 Hz, 1 H), 6.69 (d, J = 8.8 Hz, 1 H), 6.37 (d
d, J = 9.0, 3.0 Hz, 1 H), 4.42 (t, J = 7.5 Hz, 1
H), 4.24 (q, J = 7.1 Hz, 2 H), 3.78 (s, 3 H), 3.28
(m, 2 H), 3.11 (dd, J = 13.0, 7.5 Hz, 1 H), 1.26
(t, J = 7.1 Hz, 3 H), 1.18 (d, J = 7.0 Hz, 6 H)

Compound IX-13 783 mg (1.25 mmol) and thiourea 121 mg (1.58 mmol) were dissolved in 6 ml of sulfolane and stirred at 120 ° C. for 90 minutes. Acetic acid 9 ml, concentrated hydrochloric acid
After adding a mixed solution of 6.7 ml and water 3.3 ml to the reaction solution at room temperature, the mixture was stirred at 90 ° C. for 17 hours. Baking soda was added to the reaction solution, and after the carbon dioxide had come out, the mixture was extracted with ether. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by flash silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain 318 mg (40%) of compound IX-14. Compound IX-14: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.07 (br s, 1 H), 7.73 (s,
2H), 6.78 (d, J = 3.1 Hz, 1 H), 6.70 (d, J = 8.8
Hz, 1 H), 6.36 (dd, J = 9.0, 3.1 Hz, 1 H), 4.53 (d
d, J = 9.5, 4.2 Hz, 1 H), 3.78 (s, 3 H), 3.47 (dd,
J = 14.3, 4.2Hz, 1 H), 3.28 (h, J = 7.0 hz, 1 H),
3.10 (dd, J = 14.1, 9.6 Hz, 1 H), 1.18 (d, J = 6.
(8 Hz, 6 H)

312 mg (0.49 mmol) of Compound IX-14 was suspended in 5 ml of anhydrous methylene chloride, and 1.48 ml (1.48 mmol) of BBr ₃ (1 M methylene chloride solution) was added at 0 ° C., followed by stirring for 1.2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 5) to obtain 302 mg (99%) of compound 13. Compound 13: colorless oil; ¹ H-NMR (400 MHz, CDCl ₃ ) 8.03 (br s, 1 H), 7.73 (s,
2 H), 6.75 (d, J = 3.1 Hz, 1 H), 6.63 (d, J = 8.6
Hz, 1 H), 6.31 (dd, J = 8.6, 3.1 Hz, 1 H), 4.53 (d
d, J = 9.3, 4.0 Hz, 1 H), 4.51 (s, 1 H), 3.47 (dd,
J = 14.3, 4.0Hz, 1 H), 3.17 (h, J = 7.0 Hz, 1 H),
3.10 (dd, J = 9.5 Hz, 1 H), 1.22 (d, J = 6.8 Hz,
6 H)

Example 14: Synthesis of compound 14 703 mg (1.91 mmol) of compound VIII-2 was dissolved in 10 ml of DMF, 500 mg of 10% Pd-C was added, and the mixture was subjected to catalytic hydrogen reduction at 50 ° C. One hour later, 500 mg of 10% Pd-C and 2 ml of DMF were added. After 2 hours, 10% Pd-C 500 mg, DMF 4
ml was added. After 6 hours, the reaction solution was filtered through celite,
Concentrated. The residue was subjected to flash silica gel column chromatography (ethyl acetate: n-hexane = 1: 4,
Twice) to obtain 440 mg (62%; raw material recovery 77 mg) of compound VIII-3. Compound VIII-3: ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 11.99 (br s, 1 H),
7.19 (d, J = 8.5 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 1
H), 6.88 (d, J = 2.9 Hz, 1 H), 6.84 (d, J = 8.5 Hz,
2 H), 6.79 (dd, J = 8.8, 2.9 Hz, 1 H), 4.86 (dd,
J = 9.3, 4.4 Hz, 1 H), 3.77 (s, 3 H), 3.33 (dd, J
= 13.9, 4.4 Hz, 1 H), 3.22 (h, J = 7.0 Hz, 1 H),
3.07 (dd, J = 14.1, 9.0 Hz, 1 H) 1.11 (d, J = 7.0
(Hz, 6 H)

340 mg (0.92 mmol) of compound VIII-3 was suspended in 6 ml of anhydrous methylene chloride, and 2.75 ml (2.75 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C., followed by stirring for 3 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO _4.
After evaporating the solvent, the residue was purified by flash silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain 328 mg (quantitative) of compound 14. Compound 14: colorless oil; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 11.99 (br s, 1 H),
9.18 (s, 1 H), 7.17 (d, J = 8.8 Hz, 2 H), 6.81
(d, J = 8.6 Hz, 2 H), 6.79 (d, J = 2.9 Hz, 1 H),
6.76 (d, J = 8.8 Hz, 1 H), 6.65 (dd, J = 8.8, 2.9
Hz, 1 H), 4.85 (dd, J = 9.3, 4.4 Hz, 1 H), 3.32 (d
d, J = 14.1, 4.4 Hz, 1 H), 3.19 (h, J = 6.8 Hz, 1
H), 3.06 (dd, J = 14.3, 9.5 Hz, 1 H), 1.11 (d, J =
(7.1 Hz, 6 H)

Example 15: Synthesis of compound 15 Compound VIII-5 (828 mg, 20.9 mmol) was dissolved in DMF (15 ml), 10% Pd-C (600 mg) was added, and the mixture was subjected to catalytic hydrogen reduction at 50 ° C. Two hours later, 300 mg of 10% Pd-C and 2 ml of DMF were added. After 5 hours, the mixture was filtered through Celite and the solvent was distilled off. The residue was purified by flash silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give Compound VII.
674 mg (81%; raw material recovery 144 mg) of I-6 was obtained. Compound VIII-6: ¹ H-NMR (400 MHz, CDCl ₃ ) 8.15 (br s, 1 H), 6.94 (s,
2 H), 6.75 (d, J = 11.4, 3.1 Hz, 1 H), 6.66 (d, J
= 13.9, 2.8 Hz, 1 H), 6.31 (dd, J = 8.8, 2.9 Hz,
1 H), 4.54 (dd, J = 10.1, 2.8 Hz, 1 H), 3.76 (s, 3
H), 3.52 (dd, J = 13.9, 2.8 Hz, 1 H), 3.05 (dd, J
= 14.1, 10.3 Hz, 1 H), 2.11 (s, 6 H), 1.16 (d, J =
(6.8 Hz, 6 H)

Compound VIII-6 670 mg (1.68 mmol) was suspended in 5 ml of anhydrous methylene chloride, and 5.04 ml (5.04 mmol) of BBr ₃ (1 M solution in methylene chloride) was added at 0 ° C., followed by stirring for 2.5 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO _4.
After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 3) to obtain 542 mg (84%) of compound 15. Compound 10: colorless oil; ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C.) 12.02 (br s, 1 H),
8.84 (s, 1 H), 7.00 (s, 2 H), 6.62 (d, J = 8.5 H
z, 1 H), 6.55 (d, J = 3.1 Hz, 1 H), 6.19 (dd, J = 1
2.9, 8.5 Hz, 1 H), 4.89 (dd, J = 9.5, 3.4 Hz, 1
H), 3.34 (dd, J = 14.2, 4.4 Hz, 1 H), 3.13 (h, J =
6.8 Hz, 1 H), 3.03 (dd, J = 13.9, 9.5 Hz, 1 H), 2.
01 (s, 6 H), 1.07 (d, J = 6.8 Hz, 6 H)

Test Example 1: Test for transcriptional activation of nuclear receptor for thyroid hormone in COS-1 cells COS-1 cells transfected with a human thyroid hormone nuclear receptor α (hTRα) expression vector and a reporter plasmid (TREpalx3-TKLUC) Was used to assay its ligand-dependent transcriptional activation ability using Promega's luciferase assay system. The concentration-dependent thyroid hormone receptor activating ability of each compound was measured. The values in Tables 2 and 3 show relative values when the transcriptional activation when only a solvent as a negative control was added was set to 1, and the concentration was shown as a logarithmic value. T3 represents 3,5,3'-triiodothyronine.

[0089]

[Table 2]

[0090]

[Table 3]

[0091]

The compound of the present invention has a thyroid hormone-like action, and is useful as a medicament for treating and / or preventing diseases such as obesity, hypercholesterolemia and atherosclerosis. Useful as an ingredient.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/425 601 A61K 31/425 601

Claims (4)

[Claims] 1. The following general formula (I): Wherein, R ¹ represents a hydrogen atom or a C _1-6 alkyl group; R ^2,
R ³ , R ⁴ , and R ⁵ each independently represent a hydrogen atom, a halogen atom, or a C _1-6 alkyl group; X represents —O—, —S—, —NR ⁶ —,
-C (R ⁷ ) (R ⁸ )-, -CH (OR ⁹ )-, or -CO- (wherein, R ⁶ , R ⁷ ,
R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-6 alkyl group), and ---- represents a single bond or a double bond.
Or a salt thereof. 2. The compound according to claim 1, wherein X is —O—, or a salt thereof. 3. A medicament comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient. 4. A thyroid hormone-like agent comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.